Chronic Kidney Disease

Med Clin N Am 89 (2005) xvxvi
Preface
Chronic Kidney Disease
Ajay K. Singh, MB, MRCP(UK)

Guest Editor
Much has changed in the collective view of chronic kidney disease. The
terms chronic renal insuciency, chronic renal failure, and chronic renal disease have all been replaced by the now almost ubiquitously used umbrella
term chronic kidney disease (CKD). CKD is increasingly recognized in the
United States and Europe as a problem aecting as many as 5% to 10% of
the population. Over the past few years, a new classication of CKD
encompassing ve stages of CKD from the earliest (stage 1) to the most
severe (stage 5) has been adopted. Furthermore, there is now consensus that
because the serum creatinine has major limitations as a measure of kidney
function, actual or calculated glomerular ltration should be used. Through
sterling work by the National Kidney Foundation, the Renal Physicians
Association, and the National Kidney Disease Education Program several
CKD clinical guidelines are now available. These address bone disease,
hypertension, nutrition, and cardiovascular disease; importantly, still more
guidelines from the National Kidney Foundation are being developed. Most
recently, two palpable shifts in perspective have occurred. First, there is
a big push to make guidelines in CKD global in reach and perspective.
Second, there is tremendous enthusiasm to raise the awareness of CKD as
a public health problem, both in the developed world and in the developing
world.
Despite all of this progress, much remains to be done. Although strategies
to slow progression are available, such as angiotensin blockade and a more
aggressive target for blood pressure reduction, many patients still progress
to end-stage renal disease. Understanding the role of genetic factors in
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xvi
PREFACE
disease progression and in disease treatment (pharmacogenomics) remains

an embryonic eld as it pertains to CKD care. The role of much investigated
treatments, such as dietary protein restriction, remains unresolved. Although
the toll that cardiovascular disease (CVD) has taken and continues to take in
terms of morbidity and mortality in CKD patients is obvious and staggering,
the precise role of factors that account for this heightened risk of CVD
remains unclear. Preventing CVD in CKD patients continues to be an important challenge. The mechanistic aspects of the complications of CKD (eg,
abnormalities in mineral metabolism and anemia) have not been completely
resolved; nor for that matter have all aspects of treatment. For example, the
optimal hemoglobin target in a CKD patient remains a conjecture. The
management of bone and mineral metabolism continues to be challenging.
To try and improve CKD management and implement guidelines in CKD
patients, the concept of the CKD clinic has emerged. The CKD clinic is
a multidisciplinary clinic led by a physician or a nurse that focuses on all
aspects of CKD care, running the gamut from renal progression management to the treatment of complications. Although many centers are now
setting up CKD clinics, the precise structure of these clinics, the target
population, and the relationship between the CKD clinic and referring
doctors has not been worked out.
With the advances in CKD and awareness of the vexing issues as
a backdrop, what follows in this issue of the Medical Clinics of North
America is a series of articles by true experts in the CKD eld on various
aspects of CKD care. They place in perspective the scope of the various
problems in CKD care. It is hoped that the next decade will herald new data
and better evidence so that CKD management improves dramatically.
Moreover, it is hoped that the next several years will allow us to tackle CKD
care as a global issue.
Ajay K. Singh, MB, MRCP(UK)
Clinical Chief
Renal Division
Brigham and Womens Hospital
Medicine/Building MRB
Room 404B
75 Francis Street
Boston, MA 02115, USA
E-mail address: asingh@partners.org
Med Clin N Am 89 (2005) 419445
Epidemiology and Risk Factors for

William M. McClellan, MD, MPHa,b,*
a
Department of Epidemiology, Rollins School of Public Health,

Emory University, Atlanta, GA 30322, USA
b
Health Services Research, Georgia Medical Care Foundation, 57 Executive Park South,
NE, Suite 200, Atlanta, GA 30329, USA
End-stage renal disease (ESRD) occurs when kidney function is

insucient to sustain life and hemodialysis, peritoneal dialysis, or kidney
transplantation is substituted for native kidney function. There are multiple
causes of kidney injury that lead to the nal common pathway of ESRD,
and this syndrome is characterized by hypertension, anemia, renal bone
disease, nutritional impairment, neuropathy, impaired quality of life, and
reduced life expectancy. The description and study of the epidemiology of
ESRD in the United States population has been greatly enriched by the
United States Renal Data System (USRDS), a surveillance system that
collects information about the occurrence and outcomes of care on all
incident patients receiving treatment for ESRD in the United States [1].
During the last two decades the USRDS has documented an epidemic of
ESRD in the United States and similar increases in ESRD incidence have
been reported for other industrialized and developing countries [28]. The
epidemic is illustrated by the increase in age-, race-, and gender-adjusted
incidence rates for all-cause ESRD in the United States population from 219
per million in 1991 to 334 per million persons in 2000, an increase of 51%
during the decade [1]. Individuals aged 75 years and older have experienced
the greatest increase in incidence (98% over the last decade), attributable in
part to improved survival of individuals with cardiovascular disease and
diabetes mellitus and expanded access to renal replacement therapy for
older patients [911]. ESRD incidence rates during the same period also
increased among younger Americans by 1% for those aged less than 20
* Georgia Medical Care Foundation, 57 Executive Park South, NE, Suite 200, Atlanta,
GA 30329.
E-mail address: bmcclell@gmcf.org
doi:10.1016/j.mcna.2004.11.006
420
MCCLELLAN
years, 27% for individuals 20 to 44 years, 47% for those 45 to 64 years, and
48% for those aged 65 to 74 years [1].
New ESRD patients in 2000 had a median age 65 years, and 53.5% were
male. Substantial racial disparities exist in age- and gender-adjusted, racespecic ESRD incident rates for the period 1998 to 2000: for white men, 304
per million persons; for black men, 1083 per million persons; for white
women, 197 per million persons; and for black women, 902 per million
persons [1]. Comparable rates for Native American and Asian men were 765
and 467 per million persons, respectively, and for Native American and
Asian women were 584 and 266 per million persons, respectively. Despite
these racial disparities, whites accounted for 64% of all incident ESRD
patients, with blacks accounting for 29%, Native Americans 1.3%, and
Asian Americans 3.4%, and the residual had either an unknown or other
ethnic-racial designation [1]. Two causes of ESRD account for over 70% of
all new patients during 2001: diabetes mellitus (43.4%) and hypertension
(25.5%) [1].
The public health impact of this epidemic is substantial. It was estimated
that in 1993 to 1995 2% of white men, 1.7% of white women, 5.5% of black
men, and 6.3% of black women would develop ESRD during their lifetime
[12]. Because of the increasing rate of ESRD, 5 years later these estimated
lifetime risks had increased for white men to 2.5%, for white women to
1.8%, for black men to 7.3%, and for black women to 7.8% [13]. This
increase in lifetime risk of ESRD can be expected to continue until ESRD
incidence rates are no longer increasing, which despite a recent deceleration in increasing incidence rates has not yet been observed in the USRDS
data [1].
The economic costs of the epidemic are substantial. In excess of 90% of
all ESRD patients are entitled to receive treatment within the Medicare
system regardless of their age. Over 93,000 new patients started renal
replacement therapy and there were nearly 400,000 prevalent ESRD at the
end of 2001, approximately 1% of the Medicare beneciary population [1].
The per-patient cost of care for these new and prevalent patients exceeded
by sixfold the cost incurred by non-ESRD Medicare beneciaries during the
same time period [14]. These costs only partially capture the full economic
burden of ESRD, which includes the costs of chronic disability, premature
mortality, and diminished quality of life.
Chronic kidney disease
Chronic kidney disease (CKD) is dened by the presence of sustained
abnormalities of renal function and results from dierent causes of renal
injury. CKD can lead to progressive loss of renal function, and may
terminate in ESRD after a variable period of time following the initiating
injury [15]. The public health impact of ESRD has led to increased interest
in clinical and public health interventions that can delay or prevent the
CKD: EPIDEMIOLOGY & RISK FACTORS
421
occurrence of ESRD in individual patients and in high-risk populations with

CKD. The National Kidney Foundation has begun this initiative for clinical
populations by the publication of the Kidney Disease Outcomes Quality
Initiative guidelines, a series of evidence-based clinical practice guidelines
that summarize recommendations for optimal care of CKD [1517]. This
project builds on and amplies the successful implementation of clinical
practice guidelines by the National Kidney Foundation for treatment of
patients with ESRD [1820].
Population-based interventions to control the ESRD epidemic are being
promoted through the Healthy People initiative developed by the Centers
for Disease Control and Prevention. Healthy People 2000: National Health
Promotion and Disease Prevention Objectives, initially published 1991 by the
Centers for Disease Control and Prevention, dened the public health
prevention goals for the United States during the last decade of the twenty
century [21,22]. It is of note that Healthy People 2000 did not include CKD
as a public health problem, whereas in contrast the second iteration, Healthy
People 2010, includes the following goals:
1. Reduce the rate of ESRD to 217 new cases per million population
2. Reduce ESRD rates caused by diabetes
3. Increase the proportion of CKD patients who receive nutritional
counseling, education about treatment choices, and cardiovascular care
12 months before ESRD
4. Reduce deaths from cardiovascular disease in persons with CKD by
26%
5. Increase the proportion of new hemodialysis patients with an
arteriovenous stula as rst vascular access
6. Increase the proportion of dialysis patients registered for transplantation
7. Increase the proportion of ESRD patients transplanted within 3 years of
registration
Dening chronic kidney disease
The National Kidney Foundation Kidney Disease Outcomes Quality
Initiative Clinical Practice Guidelines for Chronic Kidney Disease recommend that CKD be adopted to dene the presence of kidney injury and
impaired kidney function [15]. The National Kidney Foundation denition
includes the presence for 3 or more months of impaired renal function across
a continuum of renal injury from isolated anatomic, radiographic, biomarker, and urinary abnormalities to decreased glomerular ltration rate
(GFR), irrespective of the primary cause of the renal injury. Classication of
CKD requires that the clinician establish the presence or absence of renal
injury, estimate the GFR, and then determine that kidney disease has
persisted for 3 or more months. Equations that convert the serum creatinine
into an estimated GFR or creatinine clearance are available and should be
422
MCCLELLAN
used to avoid misinterpretation of serum creatinine values. An estimated

GFR above 60 mL/min/1.73 m2, in the absence of other anatomic,
radiographic, or urinary abnormalities, is not classied as CKD.
The National Kidney Foundation classication denes ve stages of
CKD by increasing degree of impaired kidney function (Table 1). As kidney
damage progresses the remaining nephrons compensate for the reduction in
nephron mass by increasing the single nephron ltration rate, and this
hyperltration promotes further injury [2325]. At each stage patients can
benet from measures that delay or prevent the progressive loss of renal
function, modication of medications with renal clearance, avoidance of
nephrotoxins, and reduction of cardiovascular risk factors [26]. Patients
with CKD need to be monitored for progression of kidney failure, and
patients who advance to CKD stage 3 require increased attention to control
of hypertension, anemia, renal bone disease, and nutrition. Recognition and
early referral of patients who advance to stage 4 and 5 CKD is important if
the transition to ESRD treatment is to be successful. There is evidence that
patients in these stages of CKD may not be recognized and appropriately
manage stage 4 and 5 CKD before the onset of ESRD. For example,
delayed referral for ESRD treatment has been associated with less than
optimal vascular access placement; failure to manage renal bone disease and
nutrition; poor anemia control; impaired quality of life; and increased risk
of severe hypertension, uremic symptoms, pulmonary edema, and emergent
dialysis [2736].
Epidemiology of chronic kidney disease within the United States population
The epidemiology of CKD is not as well understood as that of ESRD.
Recent studies of CKD epidemiology in the United States population have
Table 1
Stages of chronic kidney disease
Stage
Description
GFR mL/min/1.73 m2
Kidney damage with normal or

increased GFR
Kidney damage with normal with
mild decrease GFR
Moderate decrease GFR
Severe decrease GFR
Kidney failure/ESRD
90
5900
3.3
6089
5300
3.0
3059
1529
\ 15
7600
400
300
4.3
0.2
0.2
19,500
11.0
2
3
4
5
Total
a
N (1000)a
Prevalence estimates for stage 1 and 2 CKD are based on the lower estimates published by
the NKF where kidney damage is dened as two, rather than one, elevated spot urine albumin
to creatinine ratios.
Data from National Kidney Foundation K/DOQI Clinical Practice Guidelines for Chronic
Kidney Disease: Evaluation, Classication, and Stratication. Am J Kidney Dis 2002;39:
S1266.
423
extensively used the National Health and Nutrition Survey (NHANES), an

ongoing series of surveys of a representative sample of the United States
population conducted by the National Center for Health Statistics of the
Centers for Disease Control and Prevention. The NHANES surveys are
cross-sectional and provide estimates of the prevalence of CKD within the
United States population, but are not designed to estimate CKD incidence.
Recently, NHANES data have been linked to the ESRD surveillance system
data to allow studies of risk factors associated with progression of CKD.
These studies, although limited by the relatively small numbers of
individuals with stages 3 to 5 CKD sampled by NHANES, have clearly
established that simple extrapolation of patterns of ESRD incidence may
not be an entirely accurate guide to the epidemiology of CKD.
A major issue identied in these analyses of NHANES data has been the
discrepancy between the risk of ESRD and the prevalence of CKD among
dierent race groups within the United States population. When NHANES
III serum creatinine levels above 1.5 mg/dL are used to dene the presence
of kidney disease in the United States population, 9% of non-Hispanic
white men, 1.9% of non-Hispanic white women, 21.9% of non-Hispanic
black men, and 2.9% of non-Hispanic black women have evidence of
impaired kidney function, estimates consistent with the increased risk of
ESRD among black men relative to whites reported by the USRDS but
inconsistent with that observed for black women relative to white women
[37]. When estimated GFR of less than 60 mL/min/1.73 m2 was used to
dene the presence of CKD among nondiabetic NHANES III participants,
9.2% of white men, 17.8% of white women, 4.2% of black men, and 6.2%
of black women were found to have prevalent CKD [38]. When the
Cockcroft-Gault creatinine clearance was used the prevalence of CKD was
8.2% of white men, 20.7% of white women, 9.3% of black men, and 12.3%
of black women.
Analyses of the NHANES III data that adjusted for systematic bias
serum creatinine values between the NHANES III and Modication of Diet
in Renal Disease (MDRD) reference laboratories that included both
diabetic and nondiabetic subjects found that a GFR less than 60 mL/min/
1.73 m2 was observed in 5% of non-Hispanic whites, 3.4% of non-Hispanic
blacks, 1% of Mexican Americans, and 2.2% of other racial and ethnic
groups. The prevalence of impaired kidney function was higher among
women (5.3% compared with 3.6% for men); increased substantially over
time; and was more prevalent among NHANES III participants with either
diabetes mellitus or hypertension [39]. Cockcroft-Gault creatinine clearance
estimates using the adjusted serum creatinine value found that 7.5% of nonHispanic whites, 7.8% of non-Hispanic blacks, 1.8% of Mexican
Americans, and 4.1% of other racial and ethnic groups had a creatinine
clearance of less than 60 mL/min.
NHANES data have been used to examine the prevalence of causespecic CKD in the United States population. Garg et al [40] used the
424
MCCLELLAN
NHANES III data to examine the joint prevalence of a GFR less than
60 mL/min/1.73 m2 or the presence of any microalbuminuria or macroalbuminuria determined by a single albumin-to-creatinine ratio. As age
increased the prevalence of albuminuria increased from 5.7% of the
population for individuals aged 20 to 29 years to 32.7% among those aged
80 years and older. Within each 10-year age group the prevalence of
albuminuria was highest among NHANES III participants with diabetes
mellitus, followed by nondiabetic hypertensive participants, and was lowest
among individuals with neither condition [40]. Finally, within any 10-year
age group and for each comorbid state (diabetes mellitus, hypertension, and
neither), the prevalence of albuminuria increased with decreasing GFR. For
example, among nonhypertensive, nondiabetic individuals with a GFR
between 30 and 60 mL/min/1.73 m2 and age 60 to 79 years, the prevalence of
albuminuria was 20.6% compared with 14.1% among individuals with
a GFR greater than 60 mL/min/1.73 m2.
An analysis of NHANES data by Muntner et al [41] draws attention to
the increased risk of ESRD among individuals with cardiovascular disease.
They estimated the prevalent population of individuals with diabetes and
cardiovascular disease (myocardial infarction and stroke survivors) and
computed cause-specic ESRD rates based on these denominator populations and incidence counts derived from the USRDS data for individuals
with diabetes mellitus as the cause of ESRD, those with cardiovascular
disease with and without diabetes mellitus, and incident patients without
either condition. Based on this report Muntner estimated that the incidence
of ESRD caused by diabetes mellitus was 2307 per million persons with
diabetes, 781 per million for those with cardiovascular disease alone, 3294
per million among individuals with both diabetes and cardiovascular
disease, and 156 per million for those without either condition (Paul
Muntner, PhD, personal communication). This report compliments the
extensive literature on the role of CKD as a risk factor for the development
and outcomes of cardiovascular disease [42].
At present the prevalence of CKD in the United States population based
on analyses of NHANES III data is best summarized by the National
Kidney Foundation Kidney Disease Outcomes Quality Initiative Clinical
Practice Guidelines for Chronic Kidney Disease (see Table 1) [15]. These
analyses estimate that 3.3% of the United States population (5.9 million
individuals) has stage 1 CKD, based on the presence of two elevated spot
albumin-to-creatinine measurements greater than 17 mg/g for men and 25
mg/g for women [15]. The prevalence of stage 2 CKD is estimated as 3% or
5.3 million individuals, that of stage 3 as 4.3% or 7.6 million individuals,
and stage 4 as 0.2% or 4000,000 persons in the United States population
[15]. The prevalence of CKD increases with age and is higher among
individuals with hypertension and diabetes and may be associated with the
presence of cardiovascular disease. The details of gender- and race-specic
patterns of CKD are complex and, based on current analyses, suggest
425
comparable prevalence among whites and blacks and higher rates among
women compared with men.
High-risk populations for progression of chronic kidney disease to end-stage

renal disease
There are a number of populations that are considered to be at high risk of
developing ESRD [15]. Clinicians should be particularly aware of four groups
of high-risk individuals likely to be encountered on a frequent basis: (1)
patients with hypertension, (2) patients with diabetes mellitus, (3) patients
with cardiovascular disease, and (4) family members of incident ESRD
patients. Members of these high-risk groups benet from early detection and
treatment of CKD and clinicians caring for them should be particularly
attentive to opportunities to screen for kidney disease when caring for them.
Patients with hypertension and the renin-angiotensin system
Hypertension is the second most common cause of ESRD in the United
States, accounting for 23% of incident ESRD patients between 1996 and
2000 [1]. Elevated blood pressure is also an important modiable risk factor
for progressive CKD regardless of the initial cause of kidney injury.
Observational studies have established that patients with nonmalignant,
nonaccelerated levels of hypertension are at high risk of progressive renal
insuciency [4346]. Evidence from clinical trials shows that blood pressure
reduction reduces the rate of loss of renal function and progression to renal
failure and this information has been incorporated into widely disseminated
clinical practice guidelines [4750]. These studies have demonstrated a strong
and graded association between blood pressure reduction and reduction in
rate of decline in GFR that persists to blood pressure levels of 130/80 mm
Hg, and this threshold has been adopted for management of hypertensive
patients with CKD [5162].
Evidence from both animal models of renal injury and clinical trials
shows that blockade of the renin-angiotensin system with angiotensinconverting enzyme inhibitors and angiotensin type 1 receptor blockers
reduces the risk of progressive renal injury. Further, renin-angiotensin
system blockade confers renoprotection beyond that which can be
attributed to reduction in blood pressure. A patient-level meta-analysis of
11 randomized, controlled trials, reported between 1992 and 1999 found
that nondiabetic patients treated with renin-angiotensin system blockers had
a 30% reduction in the risk of ESRD [63]. A meta-analysis of 100 controlled
and uncontrolled studies of patients with diabetes found that therapy with
angiotensin-converting enzyme inhibitors was independently associated with
a 3.41 mL/min lower rate of decline in GFR compared with other
antihypertensive agents [64]. A pooled analysis of 22 clinical trials of
angiotensin-converting enzyme inhibitors of both diabetic and nondiabetic
426
MCCLELLAN
patients reported that the risk for developing macroalbuminuria was

reduced by 65% for patients treated with angiotensin-converting enzyme
inhibitors and, among subjects with overt proteinuria, the risk for doubling
of serum creatinine or developing ESRD was reduced by 40%, suggesting
a stronger benet for individuals treated with renin-angiotensin system
blockade earlier in the course of their CKD [65]. Blockade of the reninangiotensin system is eective in blacks and whites. The African American
Study of Kidney Disease and Hypertension trial found that angiotensinconverting enzyme inhibitor treatment reduced the risk of doubling of GFR,
ESRD, or death 22% compared with b-blocker therapy and 38% compared
with calcium channel blocker therapy [62].
The crucial role of blood control and rabbit serum albumin blockade
have been incorporated into the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure VII
guidelines published in 2003 [50]. These guidelines recommend that the
presence of CKD, dened by either an estimated GFR below 60 mL/min/
1.73 m2 or an albumin-to-creatinine ratio of 200 mg albumin/g creatinine or
greater, be considered a compelling indication to adopt therapeutic goals to
slow deterioration of renal function. The guidelines recommend that these
CKD patients have a more aggressive blood pressure management goal of
less than 130/80 mm Hg and agents that block the renin-angiotensin system
should be rst-line drugs for the management of hypertension.
Patients with diabetes mellitus and control of blood glucose
The most common cause of ESRD reported by the USRDS for the
United States population is diabetes mellitus, accounting for nearly 45% of
all new cases of ESRD starting renal replacement therapy between 1996 and
2000 [1]. The incidence of renal failure caused by diabetes is increasing at
a 10% per year rate and if sustained the new patients being treated for
diabetic renal failure within 8 years will double [1]. Elevated blood glucose
level is the common factor in the initiation and progression of renal injury
among diabetic patients. Strict control of hyperglycemia reduces the rate of
loss of renal function and progression to renal failure among patients with
both type 1 and type 2 diabetes mellitus [6671]. Further, blood pressure
control and use of renin-angiotensin system blockers are also are essential
steps in the management of diabetes mellitus that can delay or prevent the
occurrence of ESRD. This information has been incorporated into clinical
practice guidelines disseminated by the American Diabetes Association [72].
Cardiovascular disease as a risk factor for progressive chronic kidney
disease
Patients undergoing coronary angiography, patients treated with
percutaneous coronary interventions and coronary artery bypass surgery,
427
and participants in clinical trials of atherosclerotic disease are at increased

risk of CKD [7396]. This is illustrated by the reported prevalence of CKD
among 28 dierent study populations included in Table 2, which varies from
less than 10% to over 60% of participants, with an average prevalence of
29.9%. The variability in prevalence of CKD among these studies is caused,
in part, by the dierences in study source populations and inclusion and
exclusion criteria. They provide substantial evidence, however, that persons
with cardiovascular disease are at high risk of having CKD.
Patients with cardiovascular disease and CKD are at increased risk of
developing ESRD. For example, a study of 12,000 hypertensive male
veterans found that the risk of developing ESRD was increased twofold
among individuals who experienced a new myocardial infarction and
vefold among those who developed heart failure during follow-up [97].
Bleyer et al [98] noted that the prevalence of atherosclerotic cardiovascular
disease is higher among incident patients with ESRD attributed to
hypertension. The disproportionate prevalence of atherosclerotic cardiovascular disease among hypertensive ESRD was observed among white, but
not black, patients, which led them to suggest that atherosclerosis was a risk
factor for progressive chronic renal failure and that the association between
hypertension and ESRD may be confounded by the presence of
atherosclerotic cardiovascular disease [98]. The author has recently reported
that 60% of Medicare beneciaries discharged following an admission for
hospital heart failure and 52% of those discharged following an admission
for acute myocardial infarction had an estimated MDRD GFR of less than
60 mL/min/m2 [99]. Medicare patients with both cardiovascular diseases and
CKD were at substantially greater risk of ESRD then were patients without
CKD.
Finally, autopsy studies have found a correlation between extent of
atherosclerosis and degree of glomerular scarring [100103]. For example,
Kasiske [100] observed that the prevalence of glomerulosclerosis was
substantially greater among individuals with moderate to severe atherosclerosis (15%) compared with individuals with mild disease (8%). Further,
comparison of the mean glomerular area of nonsclerotic glomeruli suggested
that there were compensatory increases in glomerular size in individuals
with moderate to severe atherosclerotic disease and glomerular area was
independently associated with increasing coronary artery atherosclerosis.
Based on these observations clinicians should carefully screen patients with
cardiovascular disease for the presence of kidney disease and include
interventions to preserve kidney function in their management plans.
Family members of patients with end-stage renal disease
ESRD aggregates within families [104111]. An association between
family history of ESRD and an increased risk of ESRD was rst reported
by Ferguson et al [104] who noted that a family history of a rst- or
428
MCCLELLAN
Table 2
Prevalence estimates of chronic kidney disease among populations with cardiovascular disease
Authors [Ref.]
Study
Atherosclerotic heart disease

Matts et al [73]
POSCH
Anderson et al [74]
Rubenstein et al [75]
Szczech et al [76]
Szczech et al [77]
BARI
Mann et al [78]
HOPE
McCullough et al [79]
Wright et al [80]
Shilpak et al [81]
CCP
Reis et al [82]
Best et al [83]
Shilpak et al [84]
CHS
Muntner [40]
Walsh et al [85]
Al Suwaidi et al [86]
Januzzi et al [87]
Wison et al [88]
Tonelli et al [89]
Freeman et al [90]
Gruberg et al [91]
Reinecke et al [92]
Heart failure
Dries et al [93]
Hillege et al [94]
Mahon et al [95]
Year
Denition of CKD
% CKD
1993
1999
2000
2001
2001
2001
2001
2002
2002
2002
2002
2002
417
3954
3307
58,576
3608
9287
9017a
3062a
130,099
130c
5277a
2449d
Scr > 1.4 mg/dL

Scr 1.5 mg/dL
Scr 1.5 mg/dL
Scr 2.5 mg/dL
Scr > 1.5 mg/dL
Scr 1.4 mg/dL
Crcr \ 63.1 mL/minb
Crcr 75 mL/min
Scr 1.5 mg/dL
Scr = 1.21.9 mg/dL
Crcr 70 mL/min
Men: Scr 1.5 mg/dL
Women: Scr 1.3 mg/dL
GFR \ 70 mL/min
Scr > 1.5 mg/dL
GFR \ 70 mL/min
GFR \ 60 mL/min
3.2
17.3
10.1
1.4
2.1
10.6
50.0
43.2
36.7
56.1
49.1
15.1
NHANES
PRISMPLUS
CARE
2002
2002
2002
2002
351e
483
37,925
1537
2003
2003
2003
2003
2003
2503
4156
889
1265
1049
GFR \ 63.8 mL/min

Crcr 75 mL/min
GFR \ 60 mL/min
GFR 70 mL/min
Scr 1.5 mg/dL
50.0
41.1
35.1
49.5
8.9
SOLVD-T
SOLVD-P
PRIME-II
DIG Trial
2000
2000
2000
2002
2161
3673
1906
584
Crcr \ 60 mL/minb
Crcr \ 60 mL/min
Crcr \ 58 mL/minb
Crcr \ 63.9 mL/minb
35.6
20.6
50.0
50.0
63.5
21.5
42.0
39.7
Abbreviations: BARI, Bypass Angioplasty Revascularization Investigation; CARE, Cholesterol and Recurrent Events; CCP, Cooperative Cardiovascular Project; CHS, Cardiovascular
Heart Study; DIG Trial, Digitalis Investigation Group; HOPE, Heart Outcomes Prevention
Evaluation; POSCH, Program on the Surgical Control of the Hyperlipidemias; PRIME-II,
Prospective Randomised Study of Ibopamine on Mortality and EcacyII; PRISM-PLUS,
Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by
Unstable Angina Signs and Symptoms; SOLVD-P, Studies of Left Ventricular Dysfunction
Prevention; SOLVD-T, Studies of Left Ventricular Dysfunction Treatment.
a
Excludes patients with ESRD.
b
Estimated from quartiles.
c
Reported to angiographically mild and severe coronary artery disease.
d
Estimated from data in Table 2 in [84].
e
Estimated from data in Table 1 in [40].
second-degree relative with CKD was reported by 26% of prevalent ESRD

patients and 11% of community controls. Freedman et al [105] has
reported that a family history of ESRD among rst- or second-degree
relatives is reported by 20% of incident ESRD patients in North Carolina,
429
South Carolina, and Georgia during a single year. There was substantial
racial disparity in the frequency of a positive family history of ESRD
among race-sex groups, with 14.1% of white men, 14.6% of white women,
22.9% of black men, and 23.9% of black women reporting a rst- or
second-degree relative with ESRD. A positive family history was reported
more frequently among individuals with ESRD attributed to diabetes
mellitus (22.2%) and hypertension (18.9%) compared with those without
either diagnosis (13%). Patients reporting a positive family history were
more likely to be black, to be younger, and to be better educated.
Several studies have now examined the prevalence of CKD among family
members of ESRD patients. Bergman et al [112] screened the rst-degree
relatives of patients with hypertensive ESRD and found evidence for renal
disease in 65% of participating families. Among these family members,
nearly 5% had a serum creatinine of 1.4 mg/dL or greater and 9.7% had
proteinuria. Family members of ESRD patients who participated in
a voluntary high-risk screening program found that 13.9% had a creatinine
clearance less than 60 mL/min and that 9.9% had proteinuria [113]. A study
of a large multiracial Asian population who participated in an early
detection of renal disease screening program found that 3.7% of individuals
reported a family history of kidney disease [114]. The prevalence of
proteinuria was three times as great among those individuals with a selfreported family history of kidney disease and the increased prevalence
persisted after controlling for age, gender, race and ethnicity, hypertension,
diabetes mellitus, prior history of kidney disease, body mass index, blood
pressure, and other urinary abnormalities [114]. Thompson et al [115] found
that a family history of ESRD among both diabetic and nondiabetic
subjects was associated with an increased mean albumin-creatinine ratio
compared with diabetic and nondiabetic subjects without a family history of
ESRD. An increased albumin-creatinine ratio was independently associated
with systolic blood pressure, hyperglycemia, a family history of renal failure,
female gender, and total cholesterol, but not with a family history of
diabetes.
There is also familial clustering of diabetic nephropathy [116125].
Seaquist et al [116] reported that 83% of siblings of patients with diabetic
nephropathy and 17% of those with a diabetic sibling who did not have
kidney disease were found to have proteinuria. Similar familial aggregation
of diabetic nephropathy has been reported for Pima Indians in the
Southwest United States [117]. Among the Pima, parental diabetic
nephropathy was a risk factor for diabetes in the ospring, after controlling
for age of onset of parental diabetes. Faronato et al [118] reported that the
diabetic siblings of patients with type II diabetes mellitus and nephropathy
were themselves at increased risk of albuminuria and this increased risk
persisted after adjusting for age, gender, hypertension, duration of hypertension, body mass index, smoking, alcohol intake, hemoglobin A1c percent,
and duration of noninsulin-dependant diabetes mellitus. Freedman et al
430
MCCLELLAN
[119] has reported that a family history of ESRD is more prevalent among
black ESRD patients than among comparison groups.
Clinicians should also obtain a careful family history of ESRD among
rst-degree relatives from all patients, including minority patients, with
CKD. Although not fully established by prospective studies, it is reasonable
to suggest that a positive family history of ESRD identies individuals with
CKD who are at increased risk of progression to ESRD. Periodic screening
for undetected hypertension, diabetes, and kidney disease should be
recommended and education about the familial aggregation of ESRD
should be oered to these families.
Risk factors associated with progression of chronic kidney disease

There is considerable variation in the rate of loss of renal function among
individuals with comparable degrees of impaired renal function regardless of
the cause of the initial renal injury [126]. For example, the MDRD study
reported a mean rate of decline (95% condence interval) in GFR that
varied between 3.8 (12.24.4) for individuals with stage 3 to 4 CKD and
4 (10.22.2) mL/min/y among individuals with stage 4 to 5 CKD. Further,
over 10% of MDRD participants experienced no loss of renal function over
time [126].
Variability in the rate of progression of CKD among individuals with
similar primary causes of renal injury suggests that risk factors exist that
may inuence the course of the renal disease. Risk factors may be casual,
where modication of the factor results in changes in the occurrence or
progression of CKD, or they may be associated with some other, perhaps
unidentied, causal factor. Risk factors can be used to identify individuals
with high risk for the occurrence and progression of CKD. For example,
hypertension and diabetes are modiable risk factors that dene high-risk
populations. Clinicians caring for patients CKD should also be aware of
evidence that modication of hyperlipidemia, smoking, dietary protein consumption, and obesity may delay or prevent progressive CKD. Recommendations for management of these risk factors have been incorporated
into recent reviews and clinical practice guidelines.
Hyperlipidemia
Hyperlipidemia was initially proposed as a risk factor for progressive
CKD by Moorhead et al [127] and evidence in support of a role of lipids in
CKD has steadily accumulated [128,129]. A meta-analysis by Fried et al
[129] of 13 small clinical trials of the eects of lipid lowering therapy found
that treated patients had a lower decline in GFR of 0.156 mL/min/mo (95%
condence interval, 0.0260.285 mL/min/mo) when compared with controls.
431
Comparable dierences among treated subjects on protein or albumin

excretion were noted but were not statistically signicant. At present
hyperlipidemia must be considered a risk factor for both cardiovascular
disease and progressive renal insuciency and lipid lowering therapy may
be renoprotective and cardioprotective.
Smoking
Smoking is a well recognized risk factor for cardiovascular disease,
malignancy, and pulmonary disease. It is also a pleiotropic risk factor for
genitourinary disease, including cancer, proteinuria, and CKD [130,131].
Recently, several small observational studies have reported that smoking
cessation is associated with reduced risk of progressive renal injury,
suggesting that smoking should be considered a risk factor for progressive
renal insuciency and cessation may be renoprotective and benecial to
general and cardiovascular health [131133].
Dietary protein consumption

It is now well established that restricting the amount of protein consumed
in the diet delays the progression of CKD to ESRD. For example, Fouque
et al [134] conducted a meta-analysis of six early randomized trials of dietary
protein restriction among patients with mild to moderate CKD. A dierence
in 0.2 g/kg/d of protein consumption between intervention and comparison
groups was associated with 44% reduction in end point of either death or
dialysis. A later extension of this analysis by the same group of 40 studies
found that a low-protein diet, compared with control, was associated with
an odds ratio of 0.61, 0.46 to 0.83 for renal outcomes [135]. Kasiske et al
[136] used a meta-analytic approach of 13 randomized trials of diabetic and
nondiabetic subjects to determine the eect of restriction of dietary protein
on the change in GFR. They reported that dietary protein restriction
reduced the rate of estimated GFR decline by 0.53 mL/min/y. Pedrini et al
[137] examined the eect of low-protein diet separately among nondiabetic
and diabetic individuals with CKD participating in randomized trials of
protein restriction. Among individuals with nondiabetic CKD, the relative
risk for death or dialysis was 33% lower for those randomized to a lowprotein diet. A comparable reduction of 44% was noted for protein
restriction in studies of diabetic subjects with CKD. Taken together, there is
strong evidence for dietary protein restriction in the management of
progressive CKD among both diabetic and nondiabetic patients.
Evidence from observational studies supports the generalizability of these
clinical trials to the general population. Wrone et al [138] examined the
association between dietary protein intake as assessed from 24-hour dietary
recall and the prevalence of albuminuria among NHANES III participants.
432
MCCLELLAN
They reported that persons with both hypertension and diabetes and in the
highest quintile of dietary protein consumption had over threefold increased
risk for albuminuria compared with those in the lowest quintile of protein
intake. Protein intake among participants in the Nurses Health Study
measured using a semiquantitative food-frequency questionnaire was associated with the rate of decline in estimated GFR among women with
impaired kidney function at baseline [139]. The rate of GFR change over
11 years of follow-up among women with normal renal function and a
high protein intake was 0.25 mL/min/1.73 m2 compared with 1.69 mL/min/
1.73 m2 per 10-g increase in protein intake among women with an estimated
GFR between 55 and 79 mL/min/1.73 m2. Interestingly, the source of dietary
protein consumption was related to the rate of decline in GFR among
women with impaired kidney function with nondairy animal protein
associated with a signicantly greater change in estimated GFR [139].
Obesity
There is growing evidence that obesity may be a risk factor for
progressive renal injury [140145]. Among NHANES III participants the
risk of either incident ESRD or kidney diseaserelated death was
independently associated with physical inactivity, smoking, and a body
mass index greater than or equal to 35 kg/m2 with a relative risk of 2.3
among those morbidly obese individuals [140]. Similar observations have
been reported by Vupputuri and Sandler [141] in a case-control study of
newly diagnosed patients with CKD.
Obesity has also been associated with changes in renal function. Obese
participants in the Framingham study who were initially free of kidney
disease at baseline were more likely to have a decrease in estimated GFR
[142]. In multivariable models, increased body mass index at baseline was
independently associated with progression to CKD, with an odds ratio of
1.23 for each increase of one standard deviation [142]. Similar increased risk
of more rapid loss of kidney function has been noted among pediatric
transplant recipients [143].
There is some evidence that weight loss preserves renal function. For
example, a study of weight reduction among 24 type 1 and type 2 diabetic
patients with nephropathy found that a reduction of body mass index from
33 to 26 kg/m2 was associated with a decrease of proteinuria from 1.3 to
0.623 g per 24 hours and an improvement of GFR from 66 to 81 mL/min/
1.73 m2 [144]. Chagnac et al [145] compared renal function among eight
subjects with a mean body mass index of 48 and normal renal function
before and after weight loss with that of normal subjects. The subjects in the
comparison group had somewhat higher blood pressures. They observed
that both GFR and renal plasma ow in the obese subjects were greater
than in nonobese subjects and with a decrease in body mass index GFR and
433
renal plasma ow moved toward the values observed in the nonobese

subjects [145].
Urine protein excretion

The presence and degree of proteinuria are strong risk factors for
progressive kidney disease in both diabetic and nondiabetic kidney disease
[146150]. Although there have been no studies that have used reduction in
levels of proteinuria as a therapeutic target, recent meta-analyses of clinical
trials have suggested that the degree of proteinuria at the start of treatment
is an independent predictor of progressive kidney disease [147]. A metaanalysis of patient-level data from 11 randomized, controlled trials found
that the risk of doubling of baseline serum creatinine level or onset of kidney
failure was independently associated with both blood pressure reduction
and urine protein excretion less than 2 g/d and was associated with the
lowest risk for kidney disease progression. Further, a higher level of urine
protein excretion during follow-up, determined by the dierence between
baseline and nal levels of proteinuria, was found to increase the risk of
progressive kidney disease by nearly sixfold for each 1 g/d higher protein
excretion [147].
Race and poverty

Blacks have a disproportionate risk of ESRD. In contrast to ESRD, an
unequivocally disproportionate risk of CKD among blacks compared with
whites has not been demonstrated [151]. Fig. 1 derived from the analysis of
the prevalence CKD in the NHANES III study illustrates this point [39]. For
each age group the prevalence of stage 3 CKD in the United States
population is greater among whites and, within race groups, higher in women
compared with men. The reasons for the discrepant patterns of risk for
prevalent CKD and incident ESRD are not clear. It has been suggested that
higher ESRD incidence rates among blacks could reect a faster progression
of CKD, and racial dierences in the progression of CKD to ESRD have
been reported in an ecologic study using NHANES III data [151]. Among
black and white NHANES III participants with a GFR between 15 and 59
mL/min/1.73 m2 it was estimated that, despite comparable prevalence of
CKD, the subsequent risk of ESRD for blacks during follow-up was vefold
(relative risk, 4.8; 95% condence interval, 2.98.4). The increased black risk
persisted after controlling for age, gender, and diabetes and was associated
with higher blood pressure and prevalence of albuminuria.
Circumspection must be used when racial dierences are used to describe
variations in ESRD because racial categories are poorly representative of
genotypic dierences and are more appropriately thought of as related to
social, economic, and political circumstances [152154]. There is growing
434
MCCLELLAN
80
70
% Stage 4 CKD
60
50
White males
White females
Black males
Black females
40
30
20
10
0
20-29
30-39
40-49
50-59
60-69
70-79
80+
Age
Fig. 1. Prevalence of nondiabetic stage 4 CKD by age and gender-race group. (Adapted from
Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular ltration rate in nondiabetic
Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am
Soc Nephrol 2002;13:133849; with permission.)
evidence that racial disparities in the risk of progressive CKD may reect
socioeconomic, environmental, and behavioral factors. Black participants in
the NHANES II survey had an 8.9-fold increase in risk of treated ESRD
[155]. After adjusting for age and gender 43.8% of the excess risk among
blacks was explained by lifestyle and clinical risk factors that were
potentially modiable. Rostand et al [156] reported that among treated
hypertensive patients blacks were two times more likely than whites to have
a signicant elevation increase in serum creatinine and that factors
independently associated with a signicant increase in serum creatinine
included older age, a higher number of missed oce visits, and employment
as a laborer. Progressive renal disease was observed two times more
frequently among black women and nine times more frequently among
black men compared with whites among participants of the Coronary
Artery Risk Development in Young Adults studies [157]. After adjusting for
weight, systolic blood pressure, uric acid, glucose, and socioeconomic status
the increased odds of CKD for black women was no longer signicant,
whereas that for black men had increased to 11.4.
Whelton and his associates have brought attention to the mediating role
of poverty and access to health care in racial dierences in ESRD risk [158
161]. They found that racial disparities in the incidence of hypertensive
ESRD were independently associated with community characteristics where
a person resided at the initiation of renal replacement therapy including the
community-specic prevalence of hypertension, lower educational levels,
lower household income, and higher mean age [158]. These observations
were extended to incident diabetic patients, where community-specic
435
characteristics associated risk of incident ESRD caused by diabetes mellitus

included lower educational levels [158]. A case-control study by this group
of the association between incident ESRD and socioeconomic status and
health care disparities found that respondent income level, being a Medicaid
recipient, and the number of teeth missing was independently associated
with increased risk of incident ESRD [160]. The eightfold disparity in risk of
ESRD among blacks compared with whites noted before accounting for
these factors was reduced to 5.5-fold after controlling for measures of
socioeconomic and health care status, suggesting that part of the racial
disparity in risk was attributable to community-associated characteristics.
There may also be racial dierences in the response to protective benets
of antihypertensive therapy. The mean change in serum creatinine levels
among participants in the Hypertension Detection and Follow-up Program
clinical trial during follow-up was 0.67 mg/dL for black men, 0.025 mg/dL
for black women, 0.14 mg/dL for white men, and 0.08 mg/dL for white
women [162]. Although treatment status (referred versus stepped care) was
not signicantly associated with dierences in the rate of change in serum
creatinine among any of the four race-gender groups, the rates of change in
serum creatinine in the stepped care group, despite comparable blood
pressure control, were lower for whites and black women, whereas they were
higher in black men randomized to the stepped care. Walker et al [163]
evaluated the rate of loss of renal function among white and black
participants in the Multiple Risk Factor Intervention Trial. During followup the mean rate of change in renal function as measured by serum
creatinine for black subjects was 0.0090 0.0013 mg/dL/y compared with
0.0018 0.0004 mg/dL/y for whites. Blood pressure control was similar for
both blacks and whites. Factors associated with increased rate of change in
serum creatinine included age and degree of blood pressure control. When
the Multiple Risk Factor Intervention Trial participants were stratied by
race, better blood pressure control was associated with slower loss of renal
function in whites, but not in blacks.
The Kidney Disease Outcomes Quality Initiative guidelines recommend
that blacks and other minority groups be regarded as high-risk CKD
groups. Clinicians caring for CKD among members of minority populations
should pay particular attention to managing medication cost, reducing
barriers to appointment keeping, ensuring patients have access to culturally
appropriate CKD educational materials and dietary counseling, and closely
monitoring the progression of renal function.
Geographic areas and poverty dening populations for high risk of chronic
kidney disease
There is considerable regional variation with respect to the occurrence of
ESRD between and within dierent countries [164167]. Of particular
interest in the United States is the change in the regional variation in risk of
436
MCCLELLAN
ESRD that has occurred since the inception of the Medicare ESRD
program. During the rst part of the 1980s age- and sex-adjusted all-cause
and race-specic ESRD rates were lower in south-central states in the
United States and higher in southwestern states [166]. By mid-decade high
rates of ESRD persisted in counties in the southwest, whereas the
southeastern United States had emerged as a high ESRD incidence area
[167]. The USRDS annual report for 2002 traces the subsequent regional
change from 1990 and 2000, showing the persistence of high ESRD rates in
the southwest and emergence of the southeastern United States as
a conuent ESRD belt stretching from the mid-Atlantic states through
Texas [1]. These rapid changes suggest that factors other than biologic
characteristics of the regional populations may be associated with the
varying patterns of increased risk of ESRD. Among the possible
explanations that have been advanced for observed regional variation in
ESRD rates are that access to medical care and poverty may mediate some
of the variation in risk. It is as yet unclear to what extent similar geographic
variations in the prevalence of CKD exist.
Geographic variations in risk of ESRD seem to reect socioeconomic
factors. A comparison of county-specic rates of per-capita income and
racial disparities in incident ESRD found that ESRD rates were higher in
low-income populations and higher in more rural communities for whites,
but not for blacks [168]. An association between decreasing communityspecic median family income and increased risk of ESRD was found for
whites in a mid-Atlantic state [169]. The income eect for whites was noted
for ESRD caused by diabetes mellitus and hypertension, but not for
glomerulonephritis. In contrast to these studies, Powe et al [170] conducted
a nested case-control study of participants who enrolled in NAHES II
between 1976 and 1980. They used educational attainment, family income,
and place of residence to characterize the socioeconomic status of their
subjects. The NHANES II participants were then linked to the USRDS to
identify cases of ESRD and a random sample of noncases drawn from the
cohort for comparison. Blacks had a fourfold increased risk of incident
ESRD compared with whites, which after adjusting for age, sex, education,
poverty, community of residence, and presence of other comorbid
conditions was reduced to 1.8-fold with a nonsignicant condence interval
of 0.51 to 6.40. Unexpectedly, the association between income, community
of residence, and education were in the opposite direction from previous
reports, with individuals of higher income, more populous areas, and more
education having increased risk of ESRD. After controlling for all other
factors the associations for income and education were no longer signicant.
Summary
Kidney disease is highly prevalent in the United States population and
groups at high risk for increased prevalence of CKD include individuals
437
with a family history of ESRD, diabetes, hypertension, and cardiovascular

disease. Despite the increased risk of ESRD observed for blacks compared
with whites, racial disparities in the prevalence of kidney disease have not
been consistently demonstrated in the United States population. Although
the reasons for this discrepancy in risk of ESRD and CKD have not been
established, clinicians should be aware that more rapid progression of CKD
among blacks is a possible explanation for this observation and that closer
monitoring and intensive care of risk factors associated with progressive
renal injury is warranted for blacks with CKD and in other high-risk
groups. Therapeutic interventions that delay or prevent progressive kidney
disease are well established and incorporated into widely disseminated
clinical practice guidelines. These interventions include aggressive blood
pressure control with agents that block the renin-angiotensin system,
reduction of dietary protein to recommended levels for the American diet,
weight loss, smoking cessation, and control of hyperlipidemia. These
interventions also reduce the risk of cardiovascular disease and should be
regarded as essential components of care of CKD. Achieving high levels of
medically appropriate care of CKD patients and reduction in risk of
progression to ESRD may be delayed by barriers created by individual and
regional poverty.
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Med Clin N Am 89 (2005) 447456
The Familial Clustering of Renal Disease

and Related Phenotypes
Scott G. Satko, MD*, Barry I. Freedman, MD
Section on Nephrology, Wake Forest University School of Medicine,
Winston-Salem, NC 271571053, USA
This article reviews the familial aggregation of chronic kidney diseases

including end-stage renal disease (ESRD) and albuminuria, along with
variation in glomerular ltration rate. In addition to environmental
inuences on the progression of nephropathy, epidemiologic evidence in
support of the existence of renal failure susceptibility genes is presented.
Nephropathy in systemic disease

It is dicult to predict accurately whether kidney disease will develop in
an individual having a common, complex systemic disease that can involve
small intrarenal blood vessels or glomeruli. A minority, approximately 35%,
of diabetic individuals ultimately develop overt nephropathy after prolonged follow-up [1]. A smaller percentage of subjects with essential
hypertension develop arteriolar nephrosclerosis [2]. Ones family history of
nephropathy or ESRD, however, is strongly predictive of risk for
subsequently developing nephropathy.
Consistent familial aggregation of the common, complex etiologies of
kidney disease has been reported. Clustering has been observed in multiple
racial and ethnic groups, including African Americans with hypertensive
and diabetic ESRD [37], white individuals of European and American
descent with nephropathy caused by types 1 and 2 diabetes mellitus [812],
Asian [13], Australian [14], South American [15], and Native American
populations [16]. The familial aggregation of ESRD in African Americans
has been widely reported throughout the United States. The similar familial
risk in a broad geographic distribution lessens the likelihood that environmental factors are the sole etiology of the familial clustering.
* Corresponding author.
E-mail address: ssatko@wfubmc.edu (S.G. Satko).
doi:10.1016/j.mcna.2004.11.011
448
SATKO & FREEDMAN
Among African Americans residing in the southeastern United States,

those having a rst-degree relative with diabetic or hypertensive ESRD are at
ninefold greater risk for ultimately developing ESRD, compared with African
Americans lacking family members with nephropathy [4]. Those having either
a rst- or second-degree relative with ESRD were found to be at vefold
greater risk, similar to a report from Los Angeles [3]. These results are in
contrast to European Americans in the southeastern United States, in whom
weaker familial aggregation of ESRD has been observed [17].
A report in 4289 incident dialysis patients in ESRD Network 6 (serving
North Carolina, South Carolina, and Georgia) revealed that 20% of
patients reported a family history of ESRD in rst- or second-degree
relatives [18]. The prevalence of a positive family history of ESRD was
14.1% in white men, 14.6% in white women, 22.9% in African American
men, and 23.9% in African American women. Younger age at ESRD onset,
higher level of education (high school or beyond), African American race,
and etiology of ESRD (hypertension, glomerulonephritis, or diabetes versus
other causes) were all independently associated with an increased likelihood
of having a positive family history.
The nding that individuals with earlier onset of kidney disease
demonstrate stronger familial clustering has repeatedly been observed.
The ks, or sibling recurrence risk (risk in a sibling compared with the risk in
the general population), is signicantly higher in younger patients with HIVassociated nephropathy [19]. Polish investigators reported a family history
of ESRD in 15.5% of the rst-degree relatives of 4808 dialysis patients [20].
Cases developing ESRD before the age of 45 years reported having
a positive family history twice as often as did those over 65 years old.
Clustering of cases with earlier age at disease onset supports a genetic
contribution to the familial aggregation.
A familial clustering of disparate etiologies of ESRD within African
American families has been repeatedly reported, including kidney failure
caused by type 1 and type 2 diabetes mellitus, hypertension, systemic lupus
erythematosus, and HIV infection [4,2123]. This nding supports the
presence of inherited factors producing susceptibility to nephropathy (ie,
renal failure susceptibility genes). A population-based case control study
supports this concept [5]. This report revealed that the familial aggregation
of ESRD in African American families was not solely caused by excessive
prevalence or severity of diabetes and hypertension within multiply aected
families.
Renal failure susceptibility genes may occur independently from the
systemic diseases of diabetes, high blood pressure, systemic lupus
erythematosus, or HIV infection. The lack of a familial aggregation of
nephropathy among patients with long-standing diabetes, hypertension,
lupus, or HIV infection and normal kidney function supports the concept
that additional factors beyond a permissive environment (ie, hyperglycemia
or hypertension) are required to initiate renal disease.
CKD & RELATED PHENOTYPES: FAMILIAL CLUSTERING
449
Familial clustering of surrogate markers of renal disease

In addition to the familial aggregation of ESRD, other markers of renal
disease have been evaluated to determine whether they cluster in families.
The heritability of urine albumin excretion (particularly the albumin:creatinine ratio [ACR]) and several measures of kidney function (estimated
glomerular ltration rate [GFR] and measured creatinine clearance) have
been evaluated in reports from families with various underlying risk factors
for kidney disease.
It is important to note that there are limitations to assessing the heritability
of urine ACR. Albuminuria varies by as much as 40% on repeat measures in
individual subjects [24]; spontaneous resolution of microalbuminuria is
observed [25]; medications, such as angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers, clearly impact ACR [26,27]; and elevations
in ACR seem to predict cardiovascular death more strongly than progression
of renal disease in hypertensive and type 2 diabetic individuals [2830].
Nonetheless, albuminuria is a marker of renal vascular involvement in
diabetes mellitus and a large proportion of albuminuric patients progress to
require renal replacement therapy. Based on the variability in measurement of
ACR, medication eects, and spontaneous regression of proteinuria
complicating the analysis of familial clustering, one might not expect to see
strong evidence for familiality. In fact, this has not been the case.
In a segregation analysis of ACR in multiply aected European American
type 2 diabetic families (630 diabetic individuals and 1269 total relatives) from
the Joslin Diabetes Center, a major gene eect regulating ACR was suggested
[31,32]. When limited to only diabetic family members, a single major locus
with multifactorial eects was most strongly supported, although evidence for
mendelian inheritance was also observed. The heritability of ACR was 0.27 in
the overall Joslin family sample, increasing to 0.31 when restricted to diabetic
family members. Similar results were seen in diabetic Pima Indians. In
a segregation analysis evaluating 715 Pima families, support was found for the
existence of a major gene eect on ACR with mendelian inheritance [33]. The
heritability of ACR was 0.21 in Pima families.
The authors have performed heritability analyses in sibling pairs
concordant for type 2 diabetes mellitus from the Diabetes Heart Study
and also in multiply aected hypertensive families from the Hypertension
Genetic Epidemiology Network (HyperGEN). In Diabetes Heart Study
families, the heritability of ACR was 0.46 (P \ .0001) in 662 European
American diabetic individuals comprising 422 diabetes-concordant sibling
pairs from 310 families [34]. These analyses controlled for age, gender, use of
medicines aecting ACR, and blood pressure. Only 8.7% of the variation in
ACR was attributable to these covariates. Similar heritability estimates were
observed in 1164 hypertensive sibling pairs from HyperGEN families.
Heritability of urine ACR was 0.49 (P \ 1 107) after controlling for the
signicant and interactive eects of age, gender, race, body mass index,
450
SATKO & FREEDMAN
blood pressure, and medication use [35]. A genome-wide scan for loci
contributing to ACR in HyperGEN families revealed a maximum log of the
odds (LOD) score of 2.73 on chromosome 19 at 9 cM, with a lesser peak on
chromosome 12 at 112 cM (LOD 2, P \ .002). The authors detected strikingly similar heritabilities for ACR in Diabetes Heart Study diabetic and
HyperGEN hypertensive families (0.46 and 0.50, respectively). These reports
strongly support the presence of genes inuencing urine ACR in type 2
diabetic and hypertensive families. Whether these loci underlie generalized
endothelial dysfunction with microalbuminuria and resultant risk for
cardiovascular events, or risk for progressive renal disease is less clear.
The heritability of kidney function (estimated GFR or creatinine
clearance) has been evaluated in four published reports. In a study
evaluating monozygotic and dizygotic twins, the heritability of calculated
creatinine clearance was 0.63 [36]. In HyperGEN families, heritabilities for
creatinine clearance on 24-hour urine collections were 0.17 and 0.18,
respectively, in African American and white families [37]. Loci on dierent
regions of chromosome 3 were linked to creatinine clearance in hypertensive
participants of each race. This report supports the concept that dierent loci
are associated with ACR and GFR susceptibility in HyperGEN hypertensive families, because the chromosome 3 linkages were not detected in the
genome scan for ACR in these families [35]. Hunt et al [38] evaluated the
heritability of measured creatinine clearance in European American families
containing members at high risk for cardiovascular disease. Participants
performed 12-hour overnight urine collections three times over a 10-year
period. The heritability of creatinine clearance ranged from 0.17 to 0.53 in
these urine collections. Linkage of creatinine clearance to markers on
chromosome 10, in a region previously identied as linked to ESRD
susceptibility in African Americans and near the human homologue of the
rodent renal failure-1 (Rf-1) gene, was observed [39,40]. Only one report of
the heritability of estimated GFR has been reported in diabetic families. In
Diabetes Heart Study families, a heritability of 0.75 was calculated using the
modied Modication of Diet in Renal Disease calculated GFR in diabetic
sibling pairs [34]. The proportion of the variance in GFR attributed to mean
arterial blood pressure, medications, and hemoglobin A1c was only 2%.
These reports support the concept that genetic factors inuence renal
function in both diabetic and hypertensive families. The familial aggregation
of various measures of kidney function is likely less subject to variation than
is urine ACR. Although reduced kidney function is also a risk factor for
cardiovascular disease, it may prove to be a better predictor of the risk for
developing progressive renal disease than microalbuminuria.
Genes underlying susceptibility to renal disease
The familial aggregation of disparate etiologies of ESRD in families
suggests that renal failure genes, independent from the genetic and
451
environmental causes of high blood pressure or diabetes mellitus, may exist.

In the presence of a suitable environment (hyperglycemia or high blood
pressure) these genes could promote renal scarring.
Recent genetic analyses seem to lend some support to this hypothesis.
Moczulski et al [41] evaluated several genomic regions suspected of
involvement in type 1 diabetic nephropathy using discordant sibling pairs
(type 1 diabetic siblings, one sibling with nephropathy and one without).
They detected evidence for linkage to nephropathy on the long arm of
chromosome 3 in the region of the angiotensin II type 1 receptor (AGTR1)
gene. The AGTR1 gene itself, however, was not linked to diabetic
nephropathy. This region on chromosome 3 was again linked to type 1
diabetic nephropathy in a discordant sibling pair analysis in Europe (Karl
Tryggvason, MD, PhD, personal communication, 2003). Replication was
again reported in a genome-wide scan for type 2 diabetic nephropathy
susceptibility loci in 206 African American sibling pairs [42]. Data were
analyzed using nonparametric linkage regression and ordered subsets
analysis. Signicant evidence for linkage of markers on chromosome 3q at
135 cM was detected in families with the earliest age at onset of ESRD (29%
of families, maximum LOD score 4.55). This nding was replicated by
nonparametric linkage regression interaction analyses. Types 1 and 2
diabetic nephropathy seemed to be linked to the same region on
chromosome 3q, raising the possibility that a common predisposing gene
may be implicated in these diseases.
Vardarli et al [43] detected strong evidence for linkage to type 2 diabetic
nephropathy in multigenerational Turkish families on chromosome 18q. In
this report, a LOD score of 6.1 was detected on chromosome 18q22.2q23.
A maximum LOD score of 3.72 was also detected on chromosome 18q
(100.5 cM) in African American type 2 diabetic sibling pairs when subsetting
by age at diabetes onset using ordered subsets analysis in 64% of families
[42]. Replication of linkage results in dierent ethnic groups and family
structures strengthens these ndings.
Linkage to kidney disease or kidney function has also been repeatedly
demonstrated in the chromosome 10q region in type 2 diabetic nephropathy
[39,40,42], and to creatinine clearance in multiply aected white families
with hypertension [38]. This region is interesting because it contains the
human homologue of the rodent Rf-1 gene [44].
Other reports reveal linkage between nondiabetic renal disease in African
Americans on chromosome 9q31q32 [45] and type 2 diabetic nephropathy
in the Pima on chromosomes 7q, 3q, 9q, and 20p [46].
Genes associated with progression of kidney disease
Because hypertension is a signicant risk factor determining the rapidity
of progression of renal failure, it has been proposed that genes associated
with hypertension susceptibility may also play a role in the development of
452
SATKO & FREEDMAN
chronic kidney disease. In 32 white European subjects with type 2 diabetes

mellitus, the AGT-MM genotype occurred at a reduced frequency (28.1%
versus 52.8%, P \ .01), and the AGT-TT genotype occurred at an increased
frequency (15.6% versus 2.7%, P \ .05) in those with nephropathy compared with those without [47]. These investigators also reported that the
AGT-TT genotype was associated with more rapid progression of chronic
kidney disease in 76 white Europeans with glomerulonephritis, with a mean
time from diagnosis to onset of ESRD approximately 11.5 years for those
with the AGT-MM genotype, 10 years with the AGT-TM genotype, and
9 years with the AGT-TT genotype.
The angiotensin-converting enzyme insertion-deletion polymorphism has
been associated with the rate of progression of chronic kidney disease. The
D allele has been shown to be a poor prognostic factor, associated with
more rapid progression of IgA nephropathy in children [48] and type 1
diabetic nephropathy in French subjects [49]. The angiotensin-converting
enzyme DD genotype has been associated with more rapid progression of
chronic kidney disease in white Europeans with varied etiologies of renal
disease [47], higher likelihood of steroid-unresponsiveness and development
of chronic renal failure in minimal change disease and focal segmental
glomerulosclerosis [50], and higher likelihood of progression of type 1
diabetic nephropathy to ESRD [51]. Children with congenital renal
malformations and the angiotensin-converting enzyme DD genotype have
a higher likelihood of developing progressive renal failure [52]. Other
investigators identied no inuence of the angiotensin-converting enzyme
insertion-deletion polymorphism on the progression of or susceptibility to
type 2 diabetic nephropathy [53], autosomal-dominant polycystic kidney
disease [54], or development of IgA nephropathy [55].
Renal disease screening programs
Family history of kidney disease has a higher predictive value for
determining risk of subsequent nephropathy than does an individuals
personal history of hypertension or diabetes. It has been proposed that close
relatives of those with ESRD should be regularly screened for the presence
of chronic kidney disease, proteinuria, and potentially modiable risk
factors for nephropathy (high blood pressure, diabetes, and hyperlipidemia).
Two studies have screened high-risk American populations: the National
Kidney Foundation-sponsored Kidney Early Evaluation Program (KEEP)
[56] and the Southeastern Kidney Council/ESRD Network 6sponsored
Family History of ESRD Prevention Project [57]. A large population-based
screening program is also underway in Singapore, where IgA nephropathy
and diabetic kidney disease are common etiologies of ESRD [58].
The KEEP evaluated high-risk subjects for the presence of silent
nephropathy. Those screened included hypertensives; diabetics; or those
having a rst-degree relative with hypertension, diabetes, or kidney disease.
453
During this programs rst year (1997), 889 individuals were screened. One
hundred fourteen (12.8%) had an elevated serum creatinine concentration
(> 1.2 mg/dL in women, > 1.4 mg/dL in men); 25% of these had serum
creatinine concentrations above 2 mg/dL. One hundred and seventy-one
subjects (19.2%) had microalbuminuria. It is not clear what the prevalence
of asymptomatic renal disease was in relatives of dialysis patients from the
KEEP, although the authors did note that 25% of the subjects reported
a positive family history of kidney disease. Jurkovitz et al [59] screened
a southeastern United States population similar to KEEP. They found that
13.9% of 769 subjects had diminished renal function (dened as
a Cockcroft-Gault estimated creatinine clearance less than 60 mL/min)
and 9.9% had dipstick albuminuria greater than or equal to 1. Twenty-one
percent of subjects were aware of having a family member with ESRD.
The ESRD Network 6 Family History of ESRD Prevention Project
screened individuals who had a known rst-degree relative with ESRD [60].
Of 88 relatives, 26.2% had trace or greater albuminuria (none were found to
have elevated serum creatinine concentrations). The goal of this Network
6 project was to educate family members of ESRD index cases about their
own risk for having early, silent nephropathy. For this reason, potential
subjects who were previously aware of a personal history of kidney disease
or who were receiving treatment from a nephrologist were excluded. These
eorts demonstrate the potential usefulness of large-scale screening eorts
among high-risk populations. Unfortunately, the high costs of screening and
the diculty in identifying close relatives of kidney disease patients limit the
widespread application of these programs.
Future directions
Two large consortia are collecting families with members having severe
diabetic kidney disease to identify the genes producing susceptibility to type
1 and type 2 diabetic nephropathy. The National Institute of Diabetic and
Digestive and Kidney Diseases (NIDDK)-supported Family Investigation
of Nephropathy and Diabetes is recruiting diabetic siblings concordant or
discordant for nephropathy, and other relatives, for a family-based linkage
analysis. Recruiting is being performed in European American, African
American, Hispanic American, and Native American families for the
Family Investigation of Nephropathy and Diabetes family study. In
addition, Family Investigation of Nephropathy and Diabetes is recruiting
unrelated African American and Hispanic American diabetic nephropathy
cases and diabetic nonnephropathy controls to perform mapping by
admixture linkage disequilibrium association analyses [61]. The Genetics
of Kidney Disease in Diabetes is recruiting trios consisting of type 1 diabetic
nephropathy index cases and their parents [62]. Transmission disequilibrium
testing will be performed to identify diabetic nephropathy susceptibility loci.
It is hoped that these large collaborative genetic analyses will identify the
454
SATKO & FREEDMAN
genes underlying diabetic nephropathy and determine if the loci identied in

prior smaller studies can be replicated.
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Med Clin N Am 89 (2005) 457473
Measurement of Kidney Function

Lesley A. Stevens, MD, FRCPC*,
Andrew S. Levey, MD
Division of Nephrology, Tufts University School of Medicine,
TuftsNew England Medical Center, 750 Washington Street,
Box 391, Boston, MA 02111, USA
Accurate estimation of kidney function is central to the detection,

evaluation, and treatment of chronic kidney disease (CKD). Glomerular ltration rate (GFR) is widely accepted as the best overall measure of kidney
function. For this reason, CKD is dened based on the level of GFR
(Box 1), and clinical recommendations for individuals at increased risk of
CKD and for patients at each stage of CKD include assessment of GFR
(Table 1). This article reviews the physiologic basis of GFR, the methods for
measurement of GFR, and new recommendations for GFR estimation in
clinical practice. In particular, it emphasizes the strengths and limitations of
dierent methods and describes the current recommendations based on
this discussion.
Determinants and measurement of glomerular ltration rate

Determinants of glomerular ltration rate
The GFR is the product of the ltration rate in single nephrons and the
number of nephrons in both kidneys. Reductions in GFR can be caused by
either a decline in nephron number (as in CKD) or by a decline in single
nephron GFR, which can be caused by physiologic or pharmacologic
factors causing hemodynamic alterations in glomerular ltration (Box 2).
An increase in single nephron GFR caused by increased glomerular
capillary pressure or glomerular hypertrophy can compensate for a decrease
in nephron number, and the level of GFR may not reect the loss of
nephrons. There may be substantial kidney damage before GFR declines.
* Corresponding author. 35 Kneeland Street, 6th Floor, Boston, MA 02111.

E-mail address: Lstevens1@tufts-nemc.org (L.A. Stevens).
doi:10.1016/j.mcna.2004.11.009
458
STEVENS & LEVEY
Box 1. National Kidney Foundation Kidney Disease Outcomes

Quality Initiative definition of/criteria for chronic kidney
disease
Kidney damage for 3 months or more, as defined by
structural or function abnormalities of the kidney, with or
without decreased GFR, manifest by either
pathologic abnormalities; or
markers of kidney damage, including abnormalities in the
composition of the blood or urine, or abnormalities in
imaging tests.
GFR < 60 mL/min/1.73 m2 for 3 months or more, with or
without kidney damage.
Data from Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice
guidelines for chronic kidney disease: evaluation, classification, and stratification.
Am J Kidney Dis 2002;39(2 Suppl 2):S1246.
Given this, detection of early stages of CKD requires testing for markers of
kidney damage in addition to estimation of GFR.
Normal range for glomerular ltration rate
The normal level of GFR varies according to age, sex, and body size, and
is aected by normal physiologic states that aect single nephron GFR,
such as pregnancy or protein intake. Within an individual, GFR is
remarkably constant over time [1], but varies considerably among people,
even after adjustment for the known variables of age, sex, and body size [2].
Normal GFR in young adults is approximately 120 to 130 mL/min/1.73 m2
and declines with age [3,4]. More than 25% of individuals of age greater
than or equal to 70 years have GFR less than 60 mL/min/1.73 m2, which
may be caused by normal aging or the high prevalence of systemic diseases
that cause kidney disease [5]. Regardless as to whether the cause of the
reduced GFR is from normal aging or from pathologic processes, the level
of GFR for the denition of CKD does not vary by age. GFR less than
60 mL/min/1.73 m2 in the elderly is an independent predictor of adverse
outcomes, such as death and cardiovascular disease [6], and also requires
adjustment in drug dosages, as in younger patients with CKD.
Urinary clearance
The GFR cannot be measured directly. Instead, it is estimated from the
urinary clearance of a ltration marker. The clearance of a substance is
dened as the rate at which it is cleared from the plasma per unit
459
KIDNEY FUNCTION MEASUREMENT
Table 1
Uses of glomerular ltration rate according to stage of chronic kidney disease
CKD
stage
Description
GFR
(mL/min/1.73 m2)
At high, increased risk
> 90
Kidney damage with

normal or high GFR
Kidney damage with mild,
low GFR
Moderate, low GFR
3059
4
5
Severe, low GFR

Kidney failure
1529
\ 15
6089
Importance of GFRa
Detection of CKD
GFR \ 60 mL/min/1.73 m2
for 3 mo denes CKD
Initiate treatment and monitor
response to treatment
Quantify progression
Selection of appropriate
treatment strategies
Measure response to treatment
Association of comorbid
conditions
Drug dosing
Referral to nephrologist
Interpretation of symptoms
Initiate kidney replacement
therapy
The importance of GFR is cumulative in that recommended care at each stage of disease
includes care for less severe stages.
CKD denition and stages from Kidney Disease Outcome Quality Initiative. K/DOQI
clinical practice guidelines for chronic kidney disease: evaluation, classication, and
stratication. Am J Kidney Dis 2002;39(2 Suppl 2):S1246.
concentration. For substances that are cleared from the plasma by excretion
in the urine,
Cx Ux V=Px
where Cx is the clearance of the marker X, Ux is the urinary concentration of

X, V is the urine ow rate, and Px is the average plasma concentration of X
Box 2. Factors affecting glomerular filtration rate

Kidney disease
Pregnancy
Reduced kidney perfusion
Marked increase or deficit of extracellular fluid volume
Nonsteroidal anti-inflammatory drug use
Acute protein load and habitual protein intake
Blood glucose control (in patients with diabetes)
Level of arterial blood pressure and class of antihypertensive
agents used
460
STEVENS & LEVEY
during the time interval of urine collection. If substance X is freely ltered

across the capillary wall, unhindered by its size, charge, or binding to
plasma proteins, and neither secreted nor reabsorbed then
GFR Px Ux V
GFR Cx
A substance that meets these requirements is dened as an ideal ltration

marker because its clearance can be used to estimate GFR. For markers that
exhibit tubular secretion (TSx) in addition to glomerular ltration, clearance
exceeds GFR, and for markers that exhibit tubular reabsorption (TRx) in
addition to glomerular ltration, clearance is less than GFR.
GFR Ux V TSx TRx =Px
GFR Cx TSx =Px TRx =Px
Estimation of glomerular ltration rate using exogenous ltration markers

In addition to the properties of an ideal marker described previously, an
exogenous marker used for the estimation of GFR must be physiologically
inert, not alter kidney function or be altered during its passage through the
nephron, and be accurately and reproducibly measured. Inulin, a 5200-d
uncharged polymer of fructose, is freely ltered, is inert, does not alter
kidney function, is neither secreted nor reabsorbed, and is the gold standard
ltration marker. The clearance method originally described includes
a continuous intravenous infusion; bladder catheterization; and performance under standard conditions (water loading, morning measurement,
fasting [7]). Inulin is not readily available, however, and is dicult to assay.
Recently, a number of alternative ltration markers have been validated,
including iohexol, chromium-51ethylenediaminetetraacetic acid, technetium-99mdiethylenetriamine pentaacetic acid, and iodine-125iothalamate.
Alternative clearance methods, including bolus subcutaneous infusion,
spontaneous bladder emptying, and plasma disappearance (rather than
urinary clearance), have also been validated. These measurement protocols
are still too complicated, however, for routine clinical practice in most
centers.
Estimation of glomerular ltration rate using endogenous ltration markers

Because of the complexities of the measurement of the clearance of
exogenous markers for routine clinical practice, the discovery and
461
evaluation of endogenous ltration markers has been an area of continuous

investigation. GFR can be estimated either from urinary clearance or
plasma (serum) levels during the steady state. Examples of endogenous
markers are urea, creatinine, and cystatin C. All have some use as markers
for GFR, but none meets all criteria required of an ideal ltration marker.
Before considering individual endogenous markers, it is important to review
some general considerations.
Estimation of glomerular ltration rate from urinary clearance

For substances that are excreted in the urine, clearance measurements are
usually obtained from a 24-hour urine collection to measure excretion rate
and a single measurement of serum concentration (usually equivalent to
plasma). Twenty-fourhour urine collections are inconvenient, however,
and their accuracy and reliability are limited because of frequent errors in
timing and collection. Current guidelines recommend 24-hour urine
collections only in special circumstances (discussed later). More importantly,
all of the endogenous markers are either reabsorbed or secreted in the
tubules, and the measurement of their urinary clearance induces a systemic
bias in the estimation of GFR.
Estimation of glomerular ltration rate from serum levels

If a substance X is in steady state, its plasma level can be used to estimate
GFR. A steady state is achieved when the rate of generation and release into
body uids of X is constant and is equal to the rate of elimination of X from
body uids (either from excretion or metabolism). In the steady sate, the
plasma concentration of substance X is stable. In addition, if substance X is
excreted solely in the urine, the rate of generation can be assessed by the
urinary excretion rate.
Ux V Gx
And substituting back into equation 4,

GFR Gx TSx TRx =Px
If extrarenal elimination (Ex) is present, then

Ux V Gx Ex
GFR Gx Ex TSx TRx =Px
462
STEVENS & LEVEY
By rearranging equation 9, the plasma level can be related to generation,

extrarenal elimination, tubular secretion, and tubular reabsorption, and to
the level of GFR.
Px Gx Ex TSx TRx =GFR
10
Although values for G, E, TS, TR, and GFR may dier among individuals
and within individuals over time, this physiologic relationship is invariant
across settings and over time. Understanding equation 10 allows for explicit
articulation of the physiologic factors that inuence the plasma level of any
substance excreted by the kidney. All of these factors should be considered
when interpreting a plasma level for estimation of GFR. Unfortunately,
other than the level of GFR, whose reciprocal relationship with the serum
level has been well-described, these factors are rarely considered and often
not known.
Estimation of glomerular ltration rate from equations based on serum
levels of endogenous markers
The physiologic factors inuencing the plasma level of a substance, as
described in equation 10, are usually not measured. Many of these factors,
however, especially those related to the generation of the endogenous serum
marker, are related to demographic or clinical variables (eg, age, sex, and
race) that are easily observed. Estimating equations for GFR using the
serum marker in combination with observed surrogates for these unmeasured physiologic factors can provide more accurate estimates of GFR
than plasma levels alone.
The relationships between the observed surrogates and the unmeasured
physiologic factors are likely to vary among dierent populations and
clinical settings, and an estimating equation developed in one setting may
perform poorly in a dierent setting. In addition, the relationship between
the observed surrogates and the unmeasured physiologic determinants may
dier over time. An estimating equation developed based on a crosssectional analysis may be suboptimal for estimation of longitudinal changes
in GFR, even in the same data set or same population [8]. For these reasons,
the value of any estimating equation lies in the rigor of its development and
the variety of settings and validation in populations other than the study
population in which it was developed [9].
Urea as a ltration marker

The excretion of urea was recognized as an estimate of kidney function
even before the elaboration of the concept of the GFR. The factors
inuencing both the excretion of urea by the kidney and its generation are
complex and vary widely among individuals and over time. As a result,
463
neither the urea clearance nor the serum urea level (for historical reasons,
usually referred to as the blood urea nitrogen) are used today as an index of
kidney function.
Urea is a 60-d end product of protein catabolism. It is freely ltered by
the glomerulus, passively reabsorbed in both the proximal and distal
nephron [10], and excreted in high concentration in the urine. Because of
tubular reabsorption, urea clearance underestimates GFR. Extracellular
uid volume depletion and states of antidiuresis are associated with
increased urea reabsorption, leading to a greater decrease in urea clearance
than the concomitant decrease in GFR. Under these conditions, the ratio of
blood urea nitrogen in milligrams per deciliter to serum creatinine
concentration in milligrams per deciliter exceeds the usual value of 10:1.
Conversely, extracellular volume expansion and states of diuresis increase
urea clearance more than GFR and can be associated with a blood urea
nitrogentocreatinine ratio less than 10:1.
Urea is synthesized primarily by the liver, with dietary protein intake as
the principal determinant of urea generation. Variation in urea generation
can cause alterations in the blood urea nitrogen in addition to those caused
by variation in urea clearance. Causes of increased urea generation include
administration of corticosteroids, diuretics, or tetracyclines; absorption of
blood from the gut; infection; acute kidney failure; trauma; congestive heart
failure; and sodium depletion. Decreases in urea generation may occur in
severe malnutrition and liver disease.
Creatinine as a ltration marker

Creatinine is a 113-d end product of muscle catabolism and the serum
creatinine concentration is the most commonly used index of kidney
function. Advantages for the use of serum creatinine concentration are that
it is easy to measure, inexpensive, and widely available. There is a wide body
of literature that supports the reciprocal relationship between the steady
state plasma level of creatinine with GFR [11]. There are important
limitations, however, to its use. Understanding these limitations is essential
to interpretation of GFR estimates using serum creatinine.
Urinary clearance
Creatinine is freely ltered at the glomerulus, actively secreted by cation
transporters in the proximal nephron, and excreted in the urine.
Approximately 5% to 10% of urinary creatinine excretion is caused by
creatinine secretion at normal levels of GFR, and creatinine clearance
overestimates GFR by approximately 10 to 20 mL/min/1.73 m2. The rate of
creatinine secretion varies among individuals and over time and the GFR
cannot be precisely predicted from level of creatinine clearance. As GFR
declines, the relative proportion of creatinine secretion versus ltration rises.
464
STEVENS & LEVEY
Consequently, creatinine secretion has a greater eect on the serum

creatinine concentration at lower levels of GFR. Polycystic kidney disease
and tubulointerstitial disease seem to be associated with lower mean levels
of creatinine secretion than other diseases [12]. Higher protein intake can
cause increased creatinine secretion. Several medications, such as cimetidine,
trimethoprim, and fenobrate, can inhibit tubular secretion of creatinine.
Some have advocated administration of cimetidine to block creatinine
secretion during 24-hour urine collections for creatinine clearance, thereby
allowing for a more accurate measurement of GFR, especially in patients
with moderate to severe reductions in GFR. Cimetidine causes only a partial
blockade of tubular secretion, however, and does so variably, making it
dicult to compare across individuals or even within the same individual
over time.
Creatinine metabolism
Creatinine generation is related to the muscle metabolism and dietary
meat intake. Creatinine is generated in muscle from the nonenzymatic
conversion of creatinine and phosphocreatine [13]. Approximately 98% of
the creatinine pool is maintained in muscle [14], and approximately 1.6% to
1.7% per day is converted to creatinine [15], which is rapidly excreted by the
kidney. Creatinine generation is directly proportional to muscle mass, which
in turn varies according to age, sex, and race and is aected by conditions
causing muscle wasting. Creatinine generation is also aected by dietary
meat intake, because meat includes creatine, which can be converted to
creatinine by cooking [16,17]. Increased meat intake can cause a long-term
increase in serum creatinine because of an increase in the creatinine pool,
and a transient increase in serum creatinine caused by gastrointestinal
absorption of creatinine.
Extrarenal elimination of creatinine can occur in the gastrointestinal tract
by bacterial degradation of creatinine contained in intestinal secretions.
Extrarenal elimination is not detectable in normal individuals, but may
account for up to 68% of daily creatinine generation in patients with
severely reduced GFR [18,19] because of increased concentration of
creatinine in gastrointestinal secretions and bacterial overgrowth of the
upper gastrointestinal tract. In principle, antibiotics could cause an increase
in serum creatinine in patients with CKD because of eradication of bacterial
overgrowth and decrease in extrarenal elimination of creatinine. This may
be a relevant consideration in patients with CKD who develop superimposed acute renal failure.
Table 2 summarizes the impact of these and others factors on serum
creatinine levels. The implications of variation in these physiologic
determinants among individuals and within individuals over time are that
for the same level of GFR, dierent people or even the same person at two
points in time can have dierent levels of serum creatinine. Fig. 1A shows
465
Table 2
Factors aecting serum creatinine concentration
Factor
Aect on serum
creatinine
Age
Decrease
Reduction in creatinine generation

because of age-related decline
in muscle mass
Sex
Female
Decrease
Reduced creatinine generation

because of reduced muscle mass
Race
African American
Increase
Higher creatinine generation rate

because of higher average
muscle mass in African Americans;
not known how muscle mass in
other races compares to that of
African Americans or whites
Diet
Vegetarian diet
Ingestion of cooked meats
Decrease
Increase
Decrease in creatinine generation

Transient increase in creatinine
generation; however this may
be blunted by transient increase
in GFR
Body habitus
Muscular
Increase
Increased muscle generation

because of increased muscle
mass increased protein intake
Reduced creatinine generation
because of reduced muscle
mass reduced protein intake
Excess mass is fat, not muscle
mass and does not contribute
to increased creatinine generation
Malnutrition, muscle wasting,

amputation
Decrease
Obesity
No change
Medications
Trimethoprim, cimetidine,
bric acid derivatives other
than gembrozol
Keto acids, some cephalosporins
Mechanism and comment
Increase
Reduced tubular secretion of

creatinine
Increase
Interference with alkaline picrate

assay for creatinine
Data from Levey AS. Assessing the eectiveness of therapy to prevent the progression of
renal disease. Am J Kidney Dis 1993;22:20714.
the variability in serum creatinine (shown as the inverse) for the same level
of GFR. The lines indicate that for a GFR of 60 mL/min/1.73 m2, the serum
creatinine concentration can vary between 0.8 and 1.7 mg/dL.
Creatinine assay
Accurate measurement of serum creatinine is critical to accurate and
consistent estimates of GFR. The most commonly used assay for serum
466
STEVENS & LEVEY
Fig. 1. GFR measured as urinary clearance of iodine-125iothalamate and adjusted for body surface area in 1628 patients. Estimates include (A) reciprocal
serum creatinine (100/Pcr) (R2 = 80.4%), (B) Cockcroft-Gault equation standardized for body surface area (R2 = 84.2%), and (C) MDRD Study equation 7
(R2 = 90.3%).
467
creatinine, the alkaline picrate (Jae) assay, detects a color change when
creatinine interacts with picrate under alkaline conditions. This reaction is
subject to interference from substances other than creatinine (noncreatinine
chromogens), which in normal serum can account for up to 20% of the
color reaction. Calibration of assays to adjust for this interference is not
standardized across laboratories. In one study, there was a 13% average
overestimation of serum creatinine compared with the reference standard
[20]. In contrast, the average coecient of variation (reproducibility) of
serum creatinine measures within laboratories was 8%, which is much better
than for many other analytes [20]. In this same study, dierences in
calibration of serum creatinine assays to the reference standard accounted
for 85% of the dierence between laboratories. The wide range of normal
values for serum creatinine among clinical laboratories seems to be caused
by lack of standardization of calibration, rather than imprecision of
measurement.
Dierences can also occur within laboratories over time. For example,
Fig. 2 shows results over time in serum creatinine results in quality control
procedures conducted by the College of American Pathology at the central
laboratories for the Modication of Diet in Renal Disease (MDRD) Study
(Cleveland Clinic Laboratory) and NHANES III (White Sands clinical
Laboratory) [21]. Current eorts are underway to standardize serum
Fig. 2. Serum creatinine values in MDRD Study and NHANES III clinical laboratories over
time. Serum creatinine values in the Cleveland Clinic (MDRD Study) and White Sands
(NHANES III) laboratories minus the mean serum creatinine level in all laboratories
participating in the College of American Pathology survey for that quarter. The same ve
samples are analyzed in all participating laboratories in each quarter. Lines indicate the average
of the dierence for each quarter at Cleveland Clinic and White Sands during 1992 to 2000.
468
STEVENS & LEVEY
creatinine testing among clinical laboratories and to trace results to a gold

standard at the National Institute for Standards and Technology.
The concentration of noncreatinine chromogens does not increase as
GFR declines; therefore, the overestimation of serum creatinine is
proportionately greater at low serum creatinine values (higher GFR). Other
substances can interfere with the alkaline picrate assay, such as keto acids
and some cephalosporins (see Table 2). Of note, noncreatinine chromogens
do not interfere with measurements of urine creatinine.
Estimating equations for glomerular ltration rate using serum creatinine

Estimating equations overcome some of the limitations of using serum
measurements alone and avoid the inconvenience of 24-hour urine
collections. The most often used one is the Cockcroft-Gault equation [22],
which estimates creatinine clearance (Ccr based on serum creatinine, age,
sex, and body weight).
Ccr 140 age weight 0:85 if female=72 Px
11
Where Ccr is expressed in mL/min, age in years, weight in kg, and Px in

mg/dL.
The equation was developed in 249 men with creatinine in steady state,
with the adjustment factor for women based on a theoretical 15% lower
muscle mass. Because of the inclusion of weight in the numerator, as
a measure of muscle mass, the equation overestimates creatinine clearance in
patients who are edematous, overweight, or obese. Comparison with normal
values for creatinine clearance requires measurement of height, computation
of body surface area, and adjustment to 1.73 m2. As expected, the
Cockcroft-Gault equation systematically overestimates GFR because it was
developed to estimate creatinine clearance, not GFR (Fig. 1B).
A more recent equation for the estimation of GFR adjusted for 1.73 m2
has been rigorously developed using data from 1628 patients enrolled in the
baseline period of the MDRD Study (Fig. 1C) [23,24]. The MDRD Study
equation is more accurate than the Cockcroft-Gault equation and measured
creatinine clearance, with 91% of the estimated values falling within 30% of
the measured values. The four-variable equation is as follows:
GFR 186 Pcr
1:154
age
0:203
0:742 if female
1:210 if African American
(12)
GFR is expressed in mL/min/1.73 m2, Pcr in mg/dL, age in years, and race
as African American or not.
469
The MDRD Study equation was developed in patients with CKD (mean
GFR 40 = mL/min/1.73 m2) who were predominantly white and did not
have diabetic kidney disease or kidney transplants. The equation has now
been validated in African Americans with nondiabetic kidney disease, in
diabetic kidney disease, and in kidney transplant recipients [25], but not in
individuals at the extremes of body size; with high levels of dietary meat
intake; overweight or obesity; amputation; conditions associated with
muscle-wasting; children; pregnant women; the elderly (age>70 years);
other racial or ethnic subgroups; in individuals at increased risk for CKD;
or in normal individuals.
The Cockcroft-Gault and MDRD Study equations improve on the use of
serum creatinine alone by incorporating known demographic and clinical
variables as observed surrogates for the unmeasured physiologic factors
other than GFR that aect serum creatinine concentration (see equation
10). For example, terms for age, sex, and race reect dierences in the
creatinine generation related to changes in muscle mass with aging and
between sexes and races. It is likely, however, that neither equation is
accurate in individuals who were not included in the study population in
which the equation was developed. In these populations, the most
appropriate estimate of kidney function is creatinine clearance measured
in a 24-hour urine collection. Box 3 lists indications for collecting a 24-hour
urine specimen for the measurement of creatinine clearance to estimate
GFR.
Estimating equations based on serum creatinine also requires attention to
calibration of the serum creatinine assay [21]. The use of the MDRD Study
equation, or any other equation, without recalibration of serum creatinine
assay to the assay used in the laboratory in which the equation was
developed can introduce a systematic error into GFR estimates because of
variability in measurement of serum creatinine between the two laboratories
Box 3. A 24-hour urine collection may be required to estimate

glomerular filtration rate in the following conditions

Extremes of age and body size

Severe malnutrition or obesity
Disease of skeletal muscle
Paraplegia or quadriplegia
Vegetarian diet
Rapidly changing kidney function
Pregnancy
Before dosing drugs with significant toxicity that are
excreted by the kidneys
470
STEVENS & LEVEY
[21]. This error is signicantly reduced at lower levels of GFR because of

relative decrease in noncreatinine chromogens relative to the level of
creatinine. The eect of calibration on Cockcroft-Gault cannot be similarly
tested because the methods in the laboratory where this equation was
developed have not been maintained.
Despite the limitations of the MDRD Study equation, it represents
a signicant advance over using serum creatinine alone or measured
creatinine clearance to estimate GFR. Advantages include that it is more
accurate than other equations previously developed; it can be easily
implemented with measurement of creatinine and knowledge of age, sex,
and race; it does not require urine collection or measurement of height and
weight; and it predicts GFR rather than creatinine clearance. The MDRD
Study equation has now been recommended for routine clinical use by the
National Kidney Foundation, American Society of Nephrology, and the
National Kidney Disease Education Program of the National Institutes of
Health. Appreciation of the limitations of the equation and of serum
creatinine helps interpretation of the value for an individual patient.
Cystatin C as a ltration marker

At this time, cystatin C is the only endogenous ltration marker being
considered as a potential replacement for serum creatinine [2630].
Cystatin is a 13-kd nonglycosylated basic protein. Indirect evidence
suggests that cystatin C is produced at a constant rate by all tissues; its
generation may be invariant across populations and over time. Its small
size and limited direct measurements in the rat suggest that cystatin C is
freely ltered by the glomerulus. After ltration, cystatin C is reabsorbed
and catabolized by the tubular epithelial cells, with only small amounts
excreted in the urine [27,30]. Consequently, urinary clearance of cystatin C
cannot be measured. Advantages of using cystatin C as a ltration marker
are the laboratory assay is becoming standardized across the industry, and
its generation is thought to be constant over time and not related to muscle
mass. There is some preliminary evidence, however, that serum levels of
cystatin C may be associated with age, gender, weight and height, smoking
status, and level of C-reactive protein even after adjustment for creatinine
clearance [31]. The major disadvantage of cystatin C as a ltration marker
is the absence of excretion in the urine, which precludes simple
investigations to understand better factors that may aect its generation
and extrarenal elimination.
Several studies have compared creatinine with cystatin C with conicting
results [26]. Most studies are small, however, and the populations included
are limited in range of age and level of GFR. In general, it seems that
cystatin C may have an advantage in detecting mildly decreased GFR,
whereas serum creatinine may be better at lower levels of GFR.
471
Clinical applications
Accurate estimation of GFR is critical to care of patients with CKD.
The current staging system for CKD is built primarily on the level of GFR
in that as GFR declines, the stage increases (see Table 1). Decreasing
levels of GFR (or higher CKD stage) are associated with a higher
prevalence of a wide range of symptoms and complications including
hypertension, anemia, malnutrition, bone disease, and neuropathy. At
each stage, accurate assessment of GFR is required for evaluation and
treatment. Recommendations for evaluation or care of CKD at each stage
are cumulative, with care at each stage of disease including care for less
severe stages (see Table 1). Although the type of kidney disease
(diagnosis), level of proteinuria, and other factors are important in
determining rate of progression, CKD progression is often dened as the
decline in GFR.
Current guidelines recommend using estimated GFR from serum
creatinine as the primary method of reporting kidney function, because of
inadequacies in serum creatinine alone. Currently, the most accurate
method for estimation of GFR seems to be the MDRD Study equation.
The MDRD Study equation is mathematically more complex than
the Cockcroft-Gault equation, and cannot be used at the bedside. The
MDRD Study equation has been programmed into medical decision
support software for PDAs and is available on websites, such as http://
www.kidney.org/kls/professionals/gfr_calculator.cfm. With the increasing
use of technology for physician education support, the complexity of an
equation should not be a barrier to its use.
Current guidelines also recommend that clinical laboratories automatically report estimated GFR whenever a serum creatinine is ordered. Until
there is a national program for standardization of the creatinine assay,
clinical laboratories that wish to report estimated GFR using the MDRD
Study equation could calibrate the serum creatinine assay to the Central
Laboratory of the MDRD Study. If the assay cannot be calibrated,
laboratory reports could provide a specic number for patients with
estimated GFR less than 60 mL/min/1.73 m2, and greater than 60 mL/min/
1.73 m2 for other patients.
Recognition of the limitations in all estimating equations and in all
ltration markers discussed in this article should assist in clinical interpretation of GFR estimates. Estimation of GFR from the MDRD Study
equation is not appropriate for all patients (see Table 2 and Box 3). In these
patients, a clearance measurement (either a 24-hour urine collection for
creatinine clearance or an exogenous ltration) can be used. In assessing
a change in GFR over time for an individual patient, recognition of the
potential role of changes in creatinine generation (ie, muscle loss or gain,
meat intake) is important to proper interpretation in dierences between the
two estimates of GFR. As with all diagnostic tests used in medical practice,
472
STEVENS & LEVEY
understanding of the strengths and limitations is a prerequisite for excellent

medical care.
In the future, if equations are improved or new ltration markers, such as
cystatin C, ultimately replace creatinine as a ltration marker, then clinical
laboratories can easily adjust the formulas or change analytes without
signicant interruption in the workow or ability to report GFR estimates.
Some laboratories have begun automatic GFR reporting. It is expected that
this will increase in frequency with the recognition of the importance of GFR
estimates to the proper evaluation and treatment of patients with CKD.
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measurements in African-Americans with hypertensive nephrosclerosis and of primary
formulas to estimate glomerular ltration rate. Am J Kidney Dis 2001;38:74453.
Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as
a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002;40:2216.
Laterza OF, Price CP, Scott MG. Cystatin C: an improved estimator of glomerular ltration
rate? Clin Chem 2002;48:699707.
Newman DJ, Thakkar H, Edwards RG, et al. Serum cystatin C: a replacement for creatinine
as a biochemical marker of GFR. Kidney Int Suppl 1994;47:S201.
Randers E, Erlandsen EJ. Serum cystatin C as an endogenous marker of the renal function:
a review. Clin Chem Lab Med 1999;37:38995.
Grubb AO. Cystatin C: properties and use as diagnostic marker. Adv Clin Chem 2000;35:
6399.
Knight E, Verhave J, Spiegelman D, et al. Factors inuencing serum cystatin C levels other
than renal function and the impact on renal function measurement. Kidney Int 2004;65:
141621.
Med Clin N Am 89 (2005) 475488
Racial Disparities in the Optimal

Delivery of Chronic Kidney Disease Care
Neil R. Powe, MD, MPH, MBAa,b,c,*,
Michal L. Melamed, MDa,c
a
Department of Medicine, Johns Hopkins School of Medicine,

2024 East Monument Street, Suite 2-600, Baltimore, MD 21205, USA
b
Departments of Epidemiology and Health Policy and Management,
Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street,
Suite 2-600, Baltimore, MD 21205, USA
c
Welch Center for Prevention, Epidemiology, and Clinical Research,
Johns Hopkins Medical Institutions, 2024 East Monument Street, Suite 2-600,
Baltimore, MD 21205, USA
Ethnic minorities make up a disproportionate share of the end-stage

renal disease (ESRD) population in the United States. The reasons for this
are multifactorial including a concentration of biologic-clinical, sociodemographic, and behavioral risk factors for chronic kidney disease (CKD)
among certain racial and ethnic minorities. Behavioral factors including
patient and provider interactions are not yet fully explored and may be
central to the delivery of optimal care and prevention of ESRD in racial and
ethnic minorities. More attention to understanding the clustering and
reduction of these risk factors may help to arrest the continuing epidemic of
ESRD in racial and ethnic minorities in the United States.
Epidemiology of chronic kidney disease in racial groups
Racial minorities including African, Native, and Hispanic Americans
have a high risk of CKD and ESRD (Table 1). Currently, ethnic minorities
make up 38.5% of the ESRD population in the United States [1]. The
United States Renal Data System estimates that by 2030 approximately
50% of the ESRD population will be composed of ethnic minorities [1].
Dr. Powe is supported by grant number K24 DK59616 and Dr. Melamed is supported by
grant numbers T32 DK007732 and F32 DK069017 from the National Institute of Diabetes,
Digestive and Kidney Disease, Bethesda, Maryland.
E-mail address: npowe@jhmi.edu (N.R. Powe).
doi:10.1016/j.mcna.2004.11.004
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POWE & MELAMED
Table 1
Prevalence of incident end-stage renal disease and chronic kidney disease risk factors in dierent
populations
Disease and
condition [Ref.]
Denominator
(persons)
White
African
American
Mexican
American
Incident ESRD [1]

CKD risk factors
HTN [2]
DM [77]a
Obesity [10]
Per million
254
988
N/A
Per 100
Per 100
Per 100
28.9 (2.3)
7.4 (5.79.1)
28.7
33.5 (3.2)
14.9 (12.717.1)
39.9
20.7 (2.7)
12.0 (10.313.7)
34.4
Abbreviations: DM, diabetes mellitus; HTN, hypertension; N/A, not available.

a
Adjusted for age and sex.
Before the 1990s, interest and attention on prevention of CKD was

nonexistent. Knowledge about the substantial burden of ESRD in
minorities and its human and economic cost to society has in part resulted
in prevention-oriented research performed in the last decade to understand
the reasons for the excess burden of CKD among racial and ethnic
minorities in the United States. Much of this research has focused on
African Americans, but Native Americans and Hispanics who also have an
increased risk of CKD present other signicant challenges in the understanding of disparities. The work is beginning to point to many
responsible factors that cause kidney dysfunction or progression of preexisting kidney dysfunction. They include biologic and clinical factors (eg,
hypertension and diabetes) and sociodemographic factors (eg, health
insurance) (Fig. 1). New research is beginning to identify behavioral factors
that may inuence the development and progression of CKD. This article
summarizes work that has been done to understand the reasons for a higher
burden of CKD in racial and ethnic minorities and indicates where more
focus needs to be placed, thereby providing a framework for the goal of
prevention of CKD and its progression in these high-risk groups.
Clinical and biologic risk factors

Among the most important clinical and biologic risk factors for CKD are
hypertension and diabetes. These risk factors for CKD are more prevalent
in many minority populations, possibly explaining some of the disparities in
ESRD risk (see Table 1).
According to the National Health and Nutrition Examination Survey
(NHANES) data, African Americans have a higher prevalence of
hypertension, 33.5% compared with 28.9% in non-Hispanic whites [2].
Klag et al [3] showed that African Americans who underwent screening for
the Multiple Risk Factor Intervention Trial had a relative risk of 1.87 (95%
condence interval 1.472.39) of ESRD compared with whites with the same
blood pressure levels. They also used median income from zip code data as
477
RACIAL DISPARITIES IN CKD CARE
Clinical/biologic factors
BP, HbA1c, family hx, obesity, urine
protein (micro and macro albuminuria)
inflammation, genotype, nephron mass
HIV, systemic lupus erythematosis
medication use
Normal Kidney
Function
Sociodemographic factors
age, sex, education, income,
occupation, health insurance
Impaired
GFR
Stages 1-4
Behavioral factors
health beliefs/knowledge/attitudes
health habits (e.g. smoking)
problem solving ability
patient-MD communication
-participatory decision making
-patient centeredness of visits
-respectful treatment
adherence to visits and therapy
locus of control
trust in providers & system
death
ESRD
Stage 5
transplant
dialysis
Fig. 1. Interaction of factors that may be responsible for disparities in CKD at dierent
transitions in health and treatment. BP, blood pressure.
a surrogate for socioeconomic class and showed that the elevated risk for
African Americans was higher in this population independent of socioeconomic class. Also using the Multiple Risk Factor Intervention Trial data,
Walker et al [4] showed that African Americans have a faster decline in their
renal function, based on serum creatinine measurements, than whites.
Diabetes mellitus, both type 1 and 2, leads to diabetic nephropathy, the
most common cause of ESRD in the United States. African Americans and
other racial minorities have been shown to be more prone to development of
type 2 diabetes mellitus. Brancati et al [5] showed that African American
women had 2.4 times the risk of white women and the risk in African
American men was 1.5 times higher than their white counterparts in the
Atherosclerosis Risk in Communities (ARIC) study. Data from the 2001
Behavioral Risk Factor Surveillance System, based on 163,584 patients,
evaluated associations between race, ethnicity, and prevalence of diabetes.
Adjusted for age, sex, body mass index, and health insurance status, in
comparison with white Americans, Asians Americans had an odds ratio for
diabetes of 1.6 (1.12.2); Native Americans of 1.8 (1.32.5); African
Americans of 1.9 (1.72.1); Hispanics of 1.9 (1.62.1); and Pacic Islanders
of 3 (1.46.7) [6].
African Americans with type 2 diabetes mellitus have a higher risk of
developing ESRD compared with whites with type 2 diabetes mellitus. In
a study comparing incidence of ESRD in Maryland, African Americans
were found to have a relative risk of 4.80 (3.097.46) compared with whites
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POWE & MELAMED
after adjustment for age, prevalence of diabetes, prevalence of poorly

controlled hypertension, no college education, and lack of a regular source
of health care [7]. Comparing ESRD rates in the Michigan Kidney Registry
with national data on the prevalence of diabetes showed that the incidence
of ESRD was 2.6-fold higher in African Americans than whites, adjusting
for the prevalence of diabetes [8]. More recently, in a large population of
patients using the Kaiser Permanente health system, African Americans,
Latinos, and Asians had higher hazards of developing ESRD than their
white counterparts but had similar risks of myocardial infarction, stroke,
congestive heart failure, and lower extremity amputation [9].
CKD has been associated with obesity both through predisposition to
type 2 diabetes mellitus and through other renal pathologies. Obesity is
a health epidemic in the United States. It is particularly prevalent in the
African American population, especially among women. NHANES 1999 to
2000 data show that approximately 50% of African American women are
obese (dened as body mass index 30) compared with 30% of nonHispanic white women [10]. A recent look at Framingham data revealed that
a higher body mass index was an independent predictor of developing kidney
disease controlling for diabetes at baseline [11]. In a nationally representative
sample from NHANES, Stengel et al [12] found an association between
morbid obesity and CKD, which was explained by diabetes and hypertension. They also found a relative risk of 2.2 (1.33.8) for CKD among those
with low levels of physical activity compared with their counterparts with
higher levels of physical activity. Obesity-related focal segmental glomerulosclerosis has been increasing in prevalence according to one biopsy series [13].
Other authors have noted modication of markers of kidney damage
(decreased proteinuria) in obese patients who lose weight [14,15], suggesting
that obesity plays a role in the pathogenesis of chronic kidney damage.
Familial clustering of ESRD among African Americans, including those
with type 2 diabetes, systemic lupus erythematosis, and HIV, has raised the
possibility of genetics playing a role in disparities in CKD occurrence or
progression [16]. A great deal of work in gene identication has focused on
the renin-angiotensin-aldosterone system because of its importance in renal
physiology. Although genes that can account for a large number of ESRD
cases in African Americans have not yet been identied, more ecient
techniques for scanning of the human genome for candidate genes should
add to the knowledge in future years about the genetic control of CKD.
Another intriguing hypothesis is that lower nephron mass at birth resulting
from abnormalities in intrauterine growth is associated with chronic disease
including hypertension and chronic renal disease later in life [17,18]. Very
low birth weights (dened as \ 1500 g) and low birth weights (dened
as \ 2500 g) are more common among African Americans than whites and
are associated with lower nephron number and albuminuria, rendering
plausibility of this hypothesis as a contributor to the excess burden of CKD
in African Americans.
479
Systemic lupus erythematosus and HIV infection are diseases responsible

for fewer cases of CKD than diabetes and hypertension, yet these diseases
when they aect the kidney also show racial dierences, possibly because of
genetics. Proliferative lupus nephritis has been shown to have a worse
prognosis in patients who are of African American race [19]. A more recent
report suggests that some of the racial dierences can be explained by lower
socioeconomic status rather than genetic factors [20]. HIV infection is
associated with several renal manifestations, the most common being HIVassociated nephropathy. In a cohort of 2059 women with HIV followed
prospectively, African American race was associated with presence of
proteinuria [21]. In a cohort of 3976 patients followed prospectively in an
inner city hospital, Lucas et al [22] showed that African American patients
had a relative risk of 9 for developing HIV-associated nephropathy
compared with their white counterparts.
There are other biologic risk factors that have been associated with CKD;
however, these do not seem to be more prevalent in racial and ethnic groups.
These include the metabolic syndrome, high serum triglycerides, and low
high-density lipoprotein [11,2325]. Biologic and clinical factors among
other factors probably contribute substantially to the excess burden of CKD
in racial minorities; however, they are unlikely to explain all of it.
Sociodemographic risk factors

Demographic and socioeconomic factors contributing to early progression may include age, sex, lower education, income, or health insurance
leading to poor access to appropriate therapies for patients with CKD.
Studies have shown the importance of sociodemographic characteristics,
such as income, in renal disease progression. Klag et al [3] showed that lower
income was associated with a higher risk of ESRD in African Americans.
This was true also among whites. Dierent authors have tried to explain the
mechanisms behind these disparities evaluating dierent steps in the
continuum of health care, including availability of insurance. In diabetic
participants of NHANES III there was a dierence in insurance coverage
with non-Hispanic whites and non-Hispanic blacks having approximately
90% insurance coverage, whereas only 66% of Mexican Americans
had health insurance. More non-Hispanic whites had private health
insurance (81%) than non-Hispanic blacks (56%) and Mexican Americans
(45%) [26].
National, population-based cohort studies from NHANES II and the
ARIC study suggest that 10% to 12% of the excess risk of CKD in African
Americans compared with whites is explained by socioeconomic factors,
such as education, household income, and insurance status [27,28]. Kinchen
et al [29] show that lack of health insurance is an important predictor of the
timing of referral for CKD to a nephrologist.
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POWE & MELAMED
Behavioral risk factors

It is increasingly recognized that there is interplay of biologic, clinical,
sociodemographic, and behavioral factors in chronic disease progression
and that fundamental research is needed to understand what behaviors can
prevent complications and maintain health. With the excess prevalence of
biologic, clinical, and sociodemographic risk factors, racial and ethnic
minorities should be targeted for prevention and treatment of risk factors
but studies show that risk factors may actually be undermanaged compared
with their white counterparts. The reasons for undermanagement are
complex, involving behaviors of patients, behaviors of providers, and
interactions between patients and health care providers. Chronic disease
care can be viewed on the continuum of awareness of the disease, treatment
of the condition, and control of the condition. This paradigm has been used
to assess hypertension treatment and can be applied to other chronic
diseases. Having a regular health care provider could promote awareness of
an asymptomatic disease, taking appropriate medications, and nally
control of disease.
The full scope of behavioral factors that could impact on chronic disease
is health knowledge and awareness of disease, beliefs, and attitudes
including locus of control [30]; dietary or lifestyle habits; language and
health literacy; patient-physician communication [31]; participatory decision
making by providers [32,33]; trust in physicians and the health care system
[34,35]; patient perceptions of respectful treatment by health care providers [36]; and patient adherence to recommended therapies [37,38]. Few of
these factors have been explored for their contribution to disparities in
CKD.
In addition, progression of disease can be inuenced by a patients healthrelated problem-solving ability, especially managing the sometimes complex
regimens needed to control hypertension and diabetes [3941]. Patients with
CKD must monitor their disease (eg, blood pressure, glucose, cholesterol);
make decisions about diet and physical activity; adjust their medication;
engage their physicians; and prioritize activities in their life to achieve
control of their disease. Eective problem solving to do this requires
knowledge, the ability to apply it, eective transfer of past learning to new
problem situations, positive problem-solving orientation and self-ecacy,
and rational systematic problem-solving skills and processes. Research in
patients with diabetes mellitus suggests that problem-solving ability and
patient-physician communication impact on complications of the disease
[42,43].
Locus of control refers to an individuals perception of what causes
a health event [30]. An internal control orientation includes beliefs about
whether the health outcomes of a persons actions are contingent on what
they do, whereas an external control orientation includes beliefs about
whether the health outcomes of a persons actions are contingent on events
481
outside their personal control. Such learned orientations could impact on

whether patients adhere to providers advice and treatment regimens.
Persons from minority groups have been shown to have less trust in
providers [44]. Many believe this stems from experiences of discrimination
in health care and history of inappropriate research experimentation in
minority groups. In addition, participatory decision making, whereby
physicians encourage patients to be more involved in treatment decisions
and to take greater responsibility for their care, has been shown to be
lacking in some patient-physician relationships among racial and ethnic
minorities [45]. Studies indicate that increased patient involvement and
greater patient control have a favorable impact on health status, patient
satisfaction, and remaining under the care of a specic health care provider
[4648]. This could contribute to the early progression of CKD in
underserved patients, but it is relatively understudied.
The content and quality of patient-physician discussions regarding CKD
(eg, measured using techniques that group observed communication behaviors into categories of content, aect, and process) may be important in
eecting behaviors [31,49]. One study of patient-physician communication,
however, could not demonstrate that dierences in patient-reported outcomes among minority groups were explained by patient-physician communication [50]. Health literacy of patients could have important impacts on
patient-provider communication, but is understudied in CKD.
A few studies have begun to address behavioral factors in development
and progression of CKD. These are worthy of comment. Awareness of
having risk factors for CKD is still lacking in many populations. NHANES
1999 to 2000, using a representative national sample of noninstitutionalized
adults, asked participants if they have ever been told by a doctor or health
care professional of weak or failing kidneys. Using results from this
question and estimated glomerular ltration rate (GFR) and albuminuria
collected as part of NHANES, Nickolas et al [51] showed that only 39.5%
of participants with stage 1 and 2 CKD were aware of their kidney
problems, whereas only 23.1% of participants with stage 3 and 4 CKD had
similar awareness. In multivariate regression, factors associated with lack of
awareness about the diagnosis of kidney disease for early CKD were male
sex, non-Hispanic black race-ethnicity, and a history of hypertension. This
study did not nd any dierence in health care access between participants
who were aware or unaware of their kidney disease. Among patients with
diabetes, hemoglobin A1c levels were signicantly higher in the unaware
group (8.3% versus 7.4%). This study suggests that there are racial
disparities in awareness of kidney disease and that unawareness of kidney
disease is associated with less adequate control of comorbidities, such as
diabetes.
To promote awareness of kidney disease the National Kidney Foundation initiated the Kidney Early Evaluation Program. This program
screened 6071 high-risk participants in 33 states for CKD and its risk
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POWE & MELAMED
factors. Screening in this population with rst-degree relatives having

diabetes, hypertension, CKD, or a personal history of diabetes or hypertension revealed 82 participants with elevated blood sugars, 1014
participants with undiagnosed high blood pressure, and 839 participants
with reduced kidney function based on estimated GFR. Eighty-six percent
of these participants had health insurance coverage suggesting that they
had the ability to seek medical care and yet were not previously diagnosed.
In this volunteer population with health insurance there was a high
prevalence of undiagnosed risk factors. This raises extreme concern about
the other population that does not come for screening and does not have
health insurance in which risk factors for kidney disease are not being
treated [52].
The amount of attribution of behavioral factors to racial and ethnic
disparities in CKD compared with biologic and demographic factors is
largely understudied. Data from a national population cohort study of 9082
adults in NHANES II suggest that 12% of the excess risk of progression of
CKD among African Americans may be attributable to lifestyle factors,
such as physical activity, body mass index, alcohol use, and cigarette
smoking [27]. Among 1434 persons with diabetes enrolled in the ARIC
study, 15% of the excess risk among African Americans in CKD
progression could be attributed to health behaviors [28].
Data about racial disparities in the process and outcomes care of patients
with diabetes mellitus exist but are inconsistent. Although diabetes mellitus
is an important risk factor for CKD, there is evidence to suggest that it is
not being adequately controlled to prevent diabetic complications. In
nationally representative data from NHANES III, the mean hemoglobin
A1c for all patients with type 2 diabetes mellitus was 7.6%, above the
recommended 7%. Non-Hispanic black women and Mexican American
men had signicantly higher mean hemoglobin A1c levels (8.3% and 8.2%,
respectively) [53].
There are data that reveal less routine screenings for minority patients
with diabetes for low-density lipoprotein and dilated eye examinations [54]
and hemoglobin A1c [55]. Some of these eects disappeared after adjustment
for age, sex, and insurance type, suggesting that the type of insurance may
explain some of the dierences. Another study of diabetics revealed that
African Americans and Hispanics were equally as likely to receive treatment
for diabetes but they had higher hemoglobin A1c and blood pressures [56].
National data from NHANES III reveal that minority patients are less
likely to self-monitor their blood sugar, have higher hemoglobin A1c and
blood pressure, but that non-Hispanic whites were also not at the goals set
by national guidelines [57]. A precise understanding of the relative contribution of behavioral, clinical, biologic, and sociodemographic factors and
their interactions in progression of CKD could help identify targets for
future interventions aimed at slowing the early progression of CKD in
African Americans.
483
Optimal delivery of care for conditions associated with and treatment of

chronic kidney disease
Racial and ethnic disparities are also evident in the early care of
complications of CKD including anemia management and calciumphosphate metabolism management and the treatment for ESRD, such as
placement of vascular access, renal replacement therapy choice, and listing
for transplantation. This article is not complete without mention of some of
this work that has been also discussed elsewhere [58]. Early referral to
a nephrologist has been shown to be associated with lower mortality in
selected cohorts and population-based studies [29,5962] and diers by race.
A nephrologists role in the care of pre-ESRD patients includes preparing
patients for renal replacement therapy and treating complications of
decreased renal function. Because the number of cases of CKD vastly
exceeds the capacity of the nephrologist workforce, exemplary models of
integrative comanagement of CKD between specialists and primary care
physicians are needed.
Anemia is common in people with chronic kidney disease. NHANES III
data show a 44.1% prevalence of anemia in people with estimated GFR of
15 to 29 and 5.2% prevalence in those with an estimated GFR of 30 to 59
[63]. In addition, non-Hispanic blacks in the NHANES survey have
a signicantly higher prevalence of anemia at all levels of estimated GFR
compared with non-Hispanic whites. Erythropoietin use in chronic kidney
disease care correlates with an early referral to a nephrologist. In the
CHOICE cohort only 12.7% of patients with late evaluation by a nephrologist were on erythropoietin therapy compared with 25.3% of those
with an early referral [29]. Using Center for Medicare and Medicaid Studies
data, Obrador et al [64] found that non-Hispanic blacks had lower
hematocrits at the initiation of dialysis and were less likely to have received
erythropoietin as part of their chronic kidney disease care.
Disorders of bone metabolism are common in patients with ESRD, but
there has been little attention to disparities in this complication [65].
Measurement of metabolic bone disease parameters, including serum
calcium, phosphate, and parathyroid hormone level, should begin when
the GFR decreases below 60 mL/min/1.73 m2 [65]. Management of preESRD bone disease is not common. In one study only 3.4% of incident
ESRD patients in New Jersey had their parathyroid hormone assessed
before initiation of renal replacement therapy, whereas 12% were on
a vitamin D formulation and 16% were on calcium-containing phosphate
binders. This study compared the 1-year mortality of patients who had had
bone disease addressed in pre-ESRD care with those who had not and found
a 35% decreased likelihood of death in the rst year of renal replacement
therapy [66]. This study suggests both that metabolic bone disease is
undermanaged in CKD care and that perhaps it is an area where
intervention may increase patient survival.
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POWE & MELAMED
Recent evidence shows that ESRD patients treated with peritoneal

dialysis report a higher quality of life [67]. The choice of dialysis modality is
inuenced by racial factors. There are fewer non-Hispanic blacks who
choose peritoneal dialysis. The dierence persists after adjustment for age,
education, social support, home ownership, functional status, albumin level,
and comorbid diseases [68].
The type of vascular access for hemodialysis can inuence a patients
mortality on dialysis. Initiating dialysis with a vascular catheter is associated
with a higher mortality than dialysis with an arteriovenous stula [69]. In
a study of Medicare patients, initiating dialysis with a catheter was associated with a hazard ratio of death of 1.7 (95% condence interval 1.59
1.81) compared with initiation with an arteriovenous stula [69]. Predictors
of dialysis with a catheter in 7497 prevalent ESRD patients were African
American race, younger age, female sex, short duration since initiation of
dialysis, and impaired functional status [70]. In another study of 356 incident ESRD patients, late referral to a nephrologist was predictive of using
a dialysis catheter for a longer period of time [71]. These studies emphasize
the fact that obtaining an arteriovenous stula or graft is an important
predictor of survival and that ethnic disparities exist in vascular access
placement. More studies are needed to clarify mechanisms (ie, sociodemographic, biologic, behavioral) behind these disparities.
Kidney transplantation is the preferred renal replacement solution for
those who qualify to be placed on the waiting list because of improved
survival and decreased costs over time [72]. Several studies have shown that
African American patients are not activated on the renal transplant list at
the same rates as their white counterparts. Garg et al [73] showed that in
a nationally representative sample of over 7000 patients the most striking
disparity between African American and white patients activation was in
the youngest, healthiest group of patients. In this group that benets most
from renal transplantation, African Americans had 50% less chance of
being activated on the waiting list than whites.
Various barriers have been shown to contribute to disparities in kidney
transplantation. Using dialysis records Alexander and Sehgal [74] identied
four steps in the process to be listed for a kidney transplant: (1) being
medically suitable and possibly interested, (2) being denitely interested, (3)
completing the pretransplant evaluation, and (4) waiting on the waiting list
to receive a transplant. African Americans in their study were less likely to
nish the last three steps [74]. To explore reasons for dierences further,
Klassen et al [75] evaluated racial discrimination and attitudes by patients.
They found that 49 African Americans who had experienced racial discrimination were less likely to be on the transplant waiting list than those
who had not experienced discrimination. To explore physician barriers,
Ayanian et al [76] surveyed 278 nephrologists and 606 patients and found
that fewer physicians thought that kidney transplantation improved survival
in African Americans than in whites. More physicians thought patient
485
factors were responsible for disparities in transplantation than physician

factors, such as patient-physician communication and trust and physician
bias. The true reasons behind racial disparities in renal transplantation and
other CKD care are probably numerous and include patient, physician, and
system factors, including those mentioned previously.
Summary
This article provides evidence that the current and growing burden of
CKD in racial and ethnic minority populations is likely to be multifactorial
involving the interplay of biologic, clinical, social, and behavioral
determinants. To eliminate these disparities, crafting successful solutions
requires more attention to the constellation of contributing factors not only
by specialists, primary care physicians, and other health care providers
involved in CKD care, but also by clinical and behavioral scientists, payers
of health care, and patients.
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Med Clin N Am 89 (2005) 489509
Strategies to Retard the Progression

of Chronic Kidney Disease
Kambiz Zandi-Nejad, MDa,b,
Barry M. Brenner, MDa,b,*
a
Renal Division, Brigham and Womens Hospital,

75 Francis Street, Boston, MA 02115, USA
b
Harvard Medical School, Boston, MA, USA
Chronic kidney disease (CKD) is a common and, in advanced cases,

highly morbid disorder. An estimated 20 million people in the United States
suer from CKD [1] as dened by the new guidelines of the National Kidney
Foundation. The most severe form of CKD is end-stage renal disease
(ESRD), in which the patient requires some form of renal replacement
therapy (eg, dialysis or transplantation) to survive. The current prevalence
of ESRD in the United States is greater than 400,000 and is projected to
increase to 660,000 by the year 2010 [2,3]. The cost of this increase in the
number of patients with ESRD is enormous from both the human and the
economic perspective.
The annual cost of managing patients with ESRD in the United States is
predicted to be more than $35 billion (approximately $28.3 billion by
Medicare) by 2010. Despite the resources allocated to the management of
patients with ESRD (approximately 6% of the Medicare budget for
approximately 0.1% of the total United States population), these patients
continue to have signicant morbidity; mortality (approximately 10%20%
per year on dialysis); and a reduced quality of life. A recent study showed
that most patients with CKD are willing to go on a restricted diet, take six
extra medications per day, and make six extra oce visits per year to delay
the initiation of dialysis by only a few weeks. The same study estimated that
slowing the progression of CKD (by decreasing the rate of decline in
glomerular ltration rate [GFR]) by 10%, 20%, and 30% in patients with
Dr. Zandi-Nejad is a recipient of the American Heart Association Postdoctoral
Fellowship Award 0225706T.
* Corresponding author. Renal Division, Brigham and Womens Hospital, Harvard
Medical School, 75 Francis Street, Boston, MA 02115.
E-mail address: bbrenner@partners.org (B.M. Brenner).
doi:10.1016/j.mcna.2004.11.001
490
ZANDI-NEJAD & BRENNER
GFR of less than 60 mL/min from the year 2000 through the year 2010 and
preventing patients from reaching the ESRD level can potentially lead to
cumulative direct health care savings of $18.56, $39.02, and $60.61 billion,
respectively [3]. The increasing incidence, prevalence, and costs of ESRD are
major national health care concerns. Interventions that may prevent or slow
the progression of CKD toward ESRD are extremely important and the
focus of this article.
Mechanisms of progression of chronic kidney disease
After the GFR declines to below half of the normal value, a progressive
loss of function ensues, even in the absence of the original disease activity;
this deterioration is characterized by proteinuria, systemic hypertension, and
a progressive decline in GFR [4]. In addition to the acquired loss of
nephrons, inborn decits in the total number of nephrons associated with low
birth weight contribute to hypertension and progressive glomerular injury in
adult life [5,6], a hypothesis now conrmed in several recent reports [79].
In response to this reduction in renal mass and function and to meet
excretory demands, the remaining nephrons undergo structural and
functional adaptations that increase single-nephron GFR. The most
prominent of these maladaptive changes are glomerular hemodynamic
adaptations (glomerular capillary hypertension), which ultimately lead to
glomerular sclerosis and nephron death. The glomerular capillary hypertension is maintained primarily by angiotensin-dependent mechanisms
through both elevated systemic blood pressure and the vasoconstriction of
eerent arterioles [10]. In addition to the central role of angiotensin II in the
changes in glomerular hemodynamics associated with nephron loss,
angiotensin II has several nonhemodynamic eects (eg, stimulation of
transforming growth factor-b (TGF-b), mesangial cell proliferation,
plasminogen activator inhibitor-1, and macrophage activation and inltration) that are also important in the progression of CKD.
It is now widely believed that progression of CKD occurs by a common
pathway, with angiotensin II playing a central role in the process. This
article focuses on the strategies to retard the progression of CKD and to
achieve the maximal renoprotection irrespective of the etiology of nephron
loss. It should be noted that these strategies are complementary to the
treatment of the original cause of the renal disorder, which is of outmost
importance and needs to be pursued aggressively.
Reninangiotensin system inhibitors as renoprotective agents
Angiotensin-converting enzyme inhibitors
Diabetic nephropathy
The renoprotective role of angiotensin-converting enzyme inhibitors
(ACEIs) was rst demonstrated in an animal model of diabetes [11]. This
STRATEGIES TO RETARD CKD PROGRESSION
491
study was followed by several small studies (reviewed in [12]) aimed at

assessing the eects of antihypertensive therapy, particularly ACEIs, on the
progression of diabetic nephropathy. Although these studies showed some
benet of therapy, because of their small size and lack of statistical power,
they failed to demonstrate any conclusive benet. This issue was resolved
when the Captopril Collaborative Study Group published their data in 1993,
which clearly demonstrated the renoprotective eect of an ACEI (captopril)
beyond its antihypertensive eects in type 1 diabetics with nephropathy [13].
In this study, 409 type 1 diabetic patients with nephropathy (proteinuria
0.5 g/d and serum creatinine 2.5 mg/dL) were randomized to captopril
or placebo (plus conventional therapy in both groups) and were followed for
a median duration of 3 years. Treatment with captopril was associated with
a 48% reduction in the doubling of serum creatinine level and a 50%
reduction in the risk of the combined end point of death, transplantation, or
dialysis [13]. This study provided solid clinical proof that ACEIs are
eective in retarding the progression of CKD, in this case caused by type 1
diabetes, and led to the rst Food and Drug Administration (FDA)
approved treatment for slowing the progression of CKD.
With regard to patients with type 1 diabetes and microalbuminuria,
a meta-analysis of raw data from 12 such studies including 698 patients
found that, in normotensive patients with type 1 diabetes and microalbuminuria, ACEIs were associated with a signicant reduction (odds ratio
[OR] of 0.38) in the risk of progression to overt proteinuria and an increased
chance of regression to normoalbuminuria (OR of 3.07) [14]. These results
are further supported by a randomized controlled trial of 44 normotensive
patients with type 1 diabetes and microalbuminuria in which treatment with
an ACEI (captopril) was associated not only with a reduced risk of
progression to macroalbuminuria but also with preservation of GFR [15].
The role of ACEIs in primary prevention of microalbuminuria in patients
with type 1 diabetes has also been studied. The EUCLID study failed to
show any signicant benecial eect of an ACEI (lisinopril) in normoalbuminuric type 1 diabetic patients followed for 2 years [16]. A later prospective, double-blind, randomized study in type 1 diabetic patients with normal
blood pressure, normal kidney function, and normoalbuminuria followed
for 3 years showed, however, a signicantly lower albumin-creatinine ratio
in patients treated with an ACEI (perindopril) [17].
Compared with various other antihypertensive regimens, ACEIs have not
shown consistent renoprotective eects in patients with type 2 diabetes.
Three studies showed a reduction of proteinuria along with stabilization of
renal function [1820], whereas other studies found no association between
a reduction in proteinuria and stabilization of renal function [2123]. The
United Kingdom Prospective Diabetes Study (UKPDS) and The Appropriate Blood Pressure Control in Diabetes (ABCD) trial failed to show any
benecial eect on either reduction of proteinuria or stabilization of renal
function [24,25]. Of note, none but two of the studies evaluated the eect of
492
ACEIs on the prevention of or slowing the progression to ESRD. Of the two

studies (including the Microalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation [MICRO-HOPE] substudy)
that did, neither demonstrated that ACEIs prevented or slowed the
progression to ESRD [26,27]. Several studies, however, have shown the
benecial eects of ACEIs on reducing microalbuminuria or the risk of its
progression to macroalbuminuria [21,2731]. With respect to primary
prevention of microalbuminuria in patients with type 2 diabetes, one study
in normotensive, normoalbuminuric type 2 diabetic patients showed
a 12.5% reduction (versus placebo) in the risk for developing microalbuminuria in patients treated with an ACEI (ramipril) [32].
Based on the previously mentioned data, it is justiable to recommend the
use of ACEIs in all type 1 diabetic patients with microalbuminuria or
macroalbuminuria; data regarding ACEI therapy in normoalbuminuric
patients are not conclusive. Whereas it is justied to recommend ACEI
therapy for type 2 diabetic patients with microalbuminuria, data with respect
to such patients with overt nephropathy are not conclusive. Considering the
association between type 2 diabetes and cardiovascular diseases, however, it
is justiable to consider ACEI therapy in these patients to reduce cardiovascular risk.
Nondiabetic nephropathy
Several studies have investigated the potential role of ACEIs on the
progression of nondiabetic forms of CKD. The Angiotensin-Converting
Enzyme Inhibition in Progressive Renal Insuciency trial [33] randomly
assigned 583 patients with CKD of diverse etiology to treatment with an
ACEI (benzapril) or placebo (plus conventional therapy in both groups).
Patients were followed for 3 years with the composite primary end point of
doubling of the baseline serum creatinine or the need for dialysis. Although
the study found an overall 53% reduction in the composite primary end
point associated with benzapril treatment, a signicantly lower blood
pressure in the treatment group precluded the conclusion of attributing the
benecial eects solely to the unique renoprotective eects of ACEIs.
The Ramipril Ecacy in Nephropathy (REIN) study [34], which
randomly assigned 352 patients with nondiabetic CKD to either an ACEI
or placebo (plus conventional therapy in both groups) and achieved similar
blood pressure control in the two groups, helped to separate the unique
renoprotective eects of ACEIs from their blood pressurelowering eects.
In this study, patients with proteinuria of greater than or equal to 3 g per
day at baseline who were assigned to receive an ACEI (ramipril) experienced
a signicantly lower rate of decline in GFR than did the placebo group (0.53
versus 0.88 mL/min) and this led to the early termination of placebo
treatment. In the extension phase of the study, an amended protocol allowed
initially placebo-treated patients to receive ramipril, whereas the patients
493
initially randomized to ramipril continued this therapy [35]. The rate of

decline of GFR in patients switched to ramipril was reduced signicantly.
Patients in the initial ramipril group who continued ramipril therapy
showed a further reduction in the rate of decline of GFR, with the GFR
slope reaching values similar to those associated with the normal aging
process. Patients who received ramipril from the beginning of the study had
a signicantly lower risk of progression to ESRD compared with patients
who were switched to ramipril therapy after the initial phase of the study. Of
note, a small number of patients who continued ramipril therapy experienced an increase in GFR [36]. In those patients enrolled in the REIN study
with baseline proteinuria of 1 to 3 g per day, who were followed-up for
a median of 31 months, ACEI therapy was again associated with a
signicant reduction in the risk of progression to ESRD [37].
The AIPRD data study, a recent meta-analysis of 11 studies involving
1860 patients with nondiabetic proteinuric CKD, showed (after adjustment
for patient and study characteristics at baseline and changes in systolic
blood pressure and urinary protein excretion during follow-up) an inverse
association between ACEI therapy and the risk of progression of CKD
(relative risk of 0.69 and 0.70 for ESRD or for the combined end points of
doubling of the baseline serum creatinine or ESRD) [38]. The AASK trial in
hypertensive African Americans reached the same conclusion (ie, that the
ACEI ramipril was more renoprotective than amlodipine [a calcium channel
blocker] or metoprolol [a b-blocker]) [39].
Angiotensin-receptor blockers
Angiotensin-receptor blockers (ARBs) exert their eects by inhibiting the
type 1 angiotensin II receptor. In general they have a more desirable side
eect prole compared with ACEIs. Although data regarding the role of
ACEIs in slowing the progression of CKD in type 2 diabetic patients with
overt nephropathy are conicting, two large, prospective, randomized trials
recently demonstrated that interruption of the reninangiotensin system
with ARBs delays the progression of CKD in type 2 diabetic patients with
overt nephropathy [40,41]. The Irbesartan Diabetic Nephropathy Trial
(IDNT) evaluated the eect of an ARB (irbesartan) versus either
conventional therapy or a calcium channel blocker (amlodipine) in 1715
hypertensive patients with type 2 diabetic nephropathy [40]. The primary
composite end point of the study was the time to a rst event of doubling of
baseline serum creatinine, ESRD, or death. The median follow-up period
was 2.6 years. The adjusted relative risk of reaching the composite end point
for patients treated with irbesartan was 20% (P = .02) and 23% (P = .006)
less than the risk in the placebo- and amlodipine-treated groups,
respectively. The relative risk of doubling of serum creatinine in patients
treated with irbesartan was 29% (P = .009) and 39% (P \ .001) less than
the risk in the placebo- and amlodipine-treated groups, respectively. The
494
relative risk of ESRD in patients treated with irbesartan was 17% lower
than the risk in those who received placebo and 24% lower than those who
received amlodipine, but the dierence did not reach statistical signicance.
The Reduction of End Points in NIDDM with the Angiotensin II
Antagonist Losartan (RENAAL) study also compared the eect of an ARB
(losartan) with that of placebo in 1513 hypertensive type 2 diabetic patients
with overt nephropathy [41]. The primary composite end point of this study
was similar to that of the Irbesartan Diabetic Nephropathy Trial, but the
average follow-up period was longer: 3.4 years rather than 2.6 years. The
dosage of losartan was 50 or 100 mg once daily, with 71% of the patients
receiving 100 mg per day by the end of the study. More patients in the
placebo group than in the losartan group discontinued study treatment. The
trough systolic-diastolic blood pressure, which averaged 152/82 mm Hg in
the losartan group and 153/82 mm Hg in the placebo group at baseline, was
140/74 mm Hg in the losartan group and 142/74 mm Hg in the placebo
groups at the end of the study. Losartan treatment reduced the relative risk
of the primary composite end point by 16% (P = .024). The risks of
doubling of serum creatinine, of ESRD, and of the combined end point of
ESRD or death were decreased by 25% (P = .002), 28% (P = .006), and
20% (P = .010), respectively.
Two recent trials, the Ibresartan in Patients with Type 2 Diabetes and
Microalbuminuria (IRMA2) study and the Microalbuminuria Reduction
with Valsartan (MARVAL) trial, evaluated the role of ARBs in the
progression of proteinuria in type 2 diabetic patients with microalbuminuria [42,43]. In the IRMA2 study, 590 hypertensive type 2 diabetic
patients with microalbuminuria and a serum creatinine of less than or equal
to 1.5 mg/dL in men and less than or equal to 1.1 mg/dL in women were
randomized to receive irbesartan at one of two dierent doses (150 and 300
mg/d) or placebo and were followed for 2 years. Dose adjustments were
made to achieve a blood pressure goal of less than 135/less than 85 mm Hg.
Thirty patients in the placebo group developed overt nephropathy
compared with 10 in the irbesartan 300-mg group (P \ .001) and 19 in
the irbesartan 150-mg group (not statistically signicant). By the last visit,
34% of the irbesartan 300-mg group (P = .006 versus placebo), 24% of the
irbesartan 150-mg group, and 21% of the placebo group had achieved
normoalbuminuria. In the MARVAL trial, 332 type 2 diabetic patients
with microalbuminuria (with or without hypertension) were randomized to
valsartan or amlodipine for a period of 24 weeks. Valsartan reduced the
rate of albumin excretion more than did amlodipine (P \ .001), with more
patients in the valsartan group achieving normoalbuminuria (29.9%
versus 14.5% for amlodipine group). Although data from large clinical
studies evaluating the role of ARBs in retarding the progression of CKD
in patients with type 1 diabetes and nondiabetic patients are still
awaited, preliminary data suggest that ARBs are probably as eective as
ACEIs.
495
Combined angiotensin-converting enzyme inhibition and angiotensin

receptor antagonism
Whereas ACEIs interrupt the reninangiotensin system by reducing the
production of angiotensin II, with ARBs interruption of the renin
angiotensin system occurs through blocking of the type 1 angiotensin II
receptor. These dierent modes of action in addition to the capabilities of
other proteases (eg, chymase) to convert angiotensin I to angiotensin II and
the fact that ACE is also a kininase has prompted the combined use of
ACEIs and ARBs for maximal reninangiotensin system blockade. In fact,
in a group of studies ACEI-ARB combination led to further reductions in
surrogate markers of CKD progression, such as blood pressure [4446],
microalbuminuria [44], and proteinuria [4548]. Recently, the results from
the COOPERATE trial demonstrated the more robust renoprotective eect
of the combined ACEI-ARB treatment to either therapy alone [49]. In this
study, after screening and a run-in period of 18 weeks, 263 patients with
nondiabetic CKD were randomly assigned to either losartan (89 patients),
trandolapril (86 patients), or a combination of losartan and trandolapril (88
patients) and followed for 3 years. The frequency of side eects was similar
in trandolapril and combination groups. The composite primary end point
of the study was time to doubling of serum creatinine or ESRD. Whereas
only 10 patients (11%) on combination therapy reached the composite
primary end point, 20 (23%) from each of the trandolapril and losartan
groups reached the composite primary end point (P = .018 and P = .016
for combined therapy versus trandolapril and losartan groups, respectively).
The progression of CKD can be reduced further by the combination of
ACEIs and ARBs. In general this combination is well tolerated in patients
with moderate CKD [50]. Additional clinical-trial data are needed, however,
to support the use of this combination in dierent patient populations and
also to conrm its safety. In the interim, the combined ACEI and ARB
treatment should be recommended only in patients who cannot achieve the
goal (vide infra and Table 1) with maximum monotherapy dose with either
an ACEI or an ARB and with caution and close follow-up for potential side
eects, such as hyperkalemia and continuous rise in serum creatinine.
Practical points in relation to the use of angiotensin-converting enzyme
inhibitors and angiotensin-receptor blockers in chronic kidney disease
Despite the well-demonstrated and accepted role of both ACEIs and
ARBs in retarding the progression of CKD, they are signicantly
underused. The major reason for this underuse seems to be physicians
reluctance because of potential adverse eects, namely hyperkalemia and
rise in serum creatinine, particularly in patients with impaired renal function
at baseline. Both of these eects can occur following the initiation of therapy
with both ACEIs and ARBs and their incidence is higher in patients with
496
Table 1
A comprehensive strategy to achieve maximal renoprotection in patients with chronic kidney
disease
Intervention
Goal
Specic renoprotective
ACE inhibitor or ARB treatment. May consider
combination therapy if goals not achieved
with full-dose monotherapy
Proteinuria \ 0.5 g/d

GFR decline \ 2 mL/min/y
Adjunctive cardiorenal protective

Additional antihypertensive therapy as needed
Dietary protein restriction
Tight glycemic control in diabetics
Cholesterol-lowering therapy
Erythropoietin therapy
Dietary salt restriction
Smoking cessation
Weight control
Antiplatelet therapy
Reduce elevated calcium X phosphate product
Avoid nephrotoxic drugs including some herbal
remedies and dietary supplements
BP \ 130/80 if proteinuria \ 1 g/d

BP \ 125/75 if proteinuria [ 1 g/d
0.60.8 g/kg/d
HbA1c \ 6.5%
LDL \ 100 mg/dL
Hb 12 g/dL
35 g/d
Abstinence
Ideal body weight
Abbreviation: BP, blood pressure.
lower remnant renal function. It should be remembered, however, that these

are the patients who benet the most from these drugs to slow the
progression of CKD.
To minimize the risk of a rise in the serum creatinine, volume depletion
(eg, stopping diuretics temporarily) and nonsteroidal anti-inammatory
drugs should be avoided before initiation of therapy with ACEIs or ARBs;
decreased eective arterial volume is the most common cause of an acute
rise in serum creatinine following initiation of therapy with these agents.
Bilateral renal artery stenosis may also be a factor, although with a much
less frequency. ACEIs and ARBs should be initiated at low dose and titrated
up as necessary. Serum creatinine level should be monitored 3 to 5 days
following the initiation of therapy and after each dose increment, and if the
rise in serum creatinine is less than 30% the baseline, therapy should be
continued and serum creatinine rechecked in 2 to 3 days. If the creatinine
level continues to rise and reaches a level higher than 30% from baseline,
ACEI or ARB should be stopped. In fact, a strong association between early
rise in serum creatinine (\ 30% in the rst 2 months of therapy) and longterm benecial eect on renal function in patients with serum creatinine
level greater than 1.4 mg/dL has been noted [51].
Hyperkalemia is a well-known side eect of reninangiotensin system
interruption. In large trials elevation in serum potassium (K) of 0.3 to
0.6 mmol/L has been associated with ACEI; the average raise in serum K
497
level is smaller with ARBs [52]. In most studies, however, the risk of
hyperkalemia (K 6 mmol/L) requiring discontinuation of therapy is very
low with ACEIs (\ 2%) and even lower with ARBs [51,52]. To minimize the
risk of hyperkalemia the patient should stop K supplements and Ksparing diuretics, avoid nonsteroidal anti-inammatory drugs, and maximize her or his compliance with a low K-diet (eg, fruits, dry fruits, and salt
substitutes). Patients K levels should be checked 3 to 5 days following the
initiation and after each dose increment of ACEI or ARB. If K level is
greater than 5.6 mmol/L, ACEI or ARB should be stopped and
hyperkalemia treated accordingly. If K level is increased but is less than
5.6 mmol/L, predisposing factors should be reassessed and K level
rechecked in 1 to 2 days. If K level remains stable ACEI or ARB can be
continued; otherwise, they should be stopped and hyperkalemia treated
accordingly.
Treatment of hypertension
A role of hypertension in the progression of CKD has been postulated for
almost a century [53]. During the past 30 years or so, a variety of studies
have conrmed the importance of hypertension in the progression of CKD
[5458]. It is now widely accepted that high blood pressure is one of the most
important factors in the progression of CKD and that lowering the blood
pressure can slow or even prevent progression of CKD in both diabetic and
nondiabetic patients. In fact, treating hypertension was one of the rst
successful interventions used to slow the rate of progression of CKD and
remains the cornerstone of its successful management. The target to which
blood pressure should be reduced, however, remains less clear. The
Modication of Diet in Renal Disease (MDRD) study [59] attempted to
answer this question; it divided 840 mainly nondiabetic patients into two
groups on the basis of their GFR level and a mean follow-up of 2.2 years. In
study 1, 585 patients with a GFR of 25 to 55 mL/min per 1.73 m2 were
randomized into two groups according to the goal for their blood pressure
(mean arterial pressure of 107 versus 92 mm Hg) and to a usual- or lowprotein diet (vide infra). In study 2, 255 patients with GFR of 13 to 24 mL/min
per 1.73 m2 were again randomized into two groups according to the goal for
their blood pressure (mean arterial pressure of 107 mm Hg versus 92 mm Hg)
and to a usual- or low-protein diet (vide infra). The primary analysis of the
results failed to show any advantage for the low blood pressure group in
respect to GFR decline. Secondary analysis, however, demonstrated
signicant correlation between the blood pressure achieved and the rate of
GFR decline; this correlation was stronger in patients with greater
proteinuria at baseline [60]. As a result, authors recommended blood pressure goal of less than 130/80 mm Hg and less than 125/75 mm Hg for patients
with less than 1 g per day and greater than 1 g per day proteinuria,
498
respectively. Although other data with respect to blood pressure goal for
patients with CKD are far from perfect, general consensus is in accord with
the MDRD study results and a blood pressure goal of less than 130/80 mm Hg
is recommended by the Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
[61].
A blood pressure goal of less than 130/80 mm Hg and less than 125/75
mm Hg is recommended for patients with less than 1 g per day and greater
than 1 g per day proteinuria, respectively. It should be remembered,
however, that these goals should be achieved with caution in patients with
labile blood pressure, severe arteriosclerosis, and autonomic neuropathy,
who were not included in the MDRD study. The use of an ACEI or ARB
should be part of the therapeutic regimen (vide supra). With respect to
calcium channel blockers and dihydropyridine subclass in particular, data
from the REIN and AASK trials showed an association between their use
and a faster rate of GFR decline [62,63]. The authors recommend that their
use should be limited to CKD patients in whom they are necessary to
control the blood pressure and only in combination with an ACEI or an
ARB.
Proteinuria
The association between continued proteinuria and irreversible impairment of renal function has been known for some time [64], but not until the
past two decades has proteinuria been recognized as a possible contributor
to the progression of renal disease rather than only an ominous biomarker
of the degree of glomerular and tubulointerstitial damage. Glomerular
hypertension and damage to the glomerular barrier causes nonselective
proteinuria; this excess of protein is taken up by proximal tubule cells by
way of endocytosis. This in turn activates a host of inammatory and
cytokine responses, which ultimately result in the brosis and scarring of the
kidney and the progression of CKD [65].
In studies of diabetic and nondiabetic kidney disorders, early reduction in
proteinuria is associated with slower progression of CKD [6670]. In the
REIN study, the severity of initial proteinuria was associated with more
rapid decline in GFR [34,37]. A recent analysis of the REIN study data
showed that the level of residual proteinuria was also a predictor of CKD
progression irrespective of blood pressure control and treatment randomization [66]. Furthermore, both the MDRD study and a recent metaanalysis of 11 studies involving 1860 patients with nondiabetic proteinuric
renal disease demonstrated that a reduction in urine protein excretion was
independently associated with a lower risk of progression of CKD [60,71].
Data from the RENAAL study also showed that the baseline urine albumincreatinine ratio was the strongest independent predictor of reaching the
499
combined end point of doubling of baseline serum creatinine concentration

or ESRD among type 2 diabetic patients with nephropathy [72] and again
the level of residual proteinuria during therapy was as strong a marker of
disease progression as baseline proteinuria [70]. Finally, there is an increasing body of evidence suggesting that proteinuria is also a cardiovascular risk
marker [73,74].
There is a strong association between proteinuria and progression of
CKD and its reduction and retardation of the progression of CKD. It is
justied to state that as for hypertension, reducing the rate of proteinuria to
a predetermined target (\ 0.5 g/d) should be vigorously pursued as an
independent therapeutic goal [66].
Dietary protein restriction

The possibility of retarding the progression of CKD by restricting protein
intake was one of the earliest suggested clinical interventions [75] and was
supported by subsequent animal studies [76]. The results from recent clinical
trials, however, including the MDRD study, were controversial and inconclusive. The MDRD study is the largest clinical trial designed to address
this issue; it included 840 patients, who were divided into two study groups
on the basis of GFR. Study 1 included 585 patients (diabetics requiring
insulin were excluded) with CKD (GFR 2555 mL/min per 1.73 m2) who
were randomized to a usual-protein (1.3 g/kg) or a low-protein (0.58 g/kg)
diet. Study 2 included 255 patients with severe CKD (GFR 1324 mL/min
per 1.73 m2) who were randomized to a low-protein (0.58 g/kg) or a verylow-protein (0.28 g/kg) diet. The diet of the patients on the very-low-protein
diet was supplemented with ketoacid-amino acids. The mean duration of
follow-up was 2.2 years. Unlike the primary results of this study, which
failed to show a signicant benecial eect of the low-protein diet and were
not conclusive [59], the secondary analysis of the MDRD study data is
suggestive of a benecial eect of dietary protein restriction on CKD
progression [77]. In fact, there was an initial drop in the GFR in the group
receiving the low-protein diet during the rst 4 months; this might have been
caused by functional factors (eg, hemodynamic) other than nephron loss.
This decrease was followed by a slower rate of deterioration in renal
function in the low-protein group, which might have achieved signicance if
the follow-up period had been longer. Two relatively recent meta-analyses
of randomized studies showed an overall benecial eect of dietary protein
restriction on the progression of CKD in both diabetic and nondiabetic
patients [78,79].
The available data indicate that recommending dietary protein restriction
(0.60.8 g/kg/d) is justiable in patients with CKD as part of an integrated
approach to retard the progression of CKD. Although current evidence
suggests that this approach is safe, it should be approached with caution and
500
with continuous monitoring to prevent malnutrition and ensure dietary

compliance [80].
Treatment of dyslipidemia
Dyslipidemias commonly accompany CKD in the form of high very-lowdensity lipoprotein (VLDL; rich in triglycerides), high calculated lowdensity lipoprotein (LDL), and low high-density lipoprotein (HDL)
cholesterol levels [81]. Whereas the role of dyslipidemias in atherosclerotic
cardiovascular diseases is well known, their role in the initiation or
progression of CKD is less clear. A group of studies point toward their
possible role in the progression or even initiation of CKD, although no
specic dyslipidemia has yet been singled out as the most likely candidate.
Hypercholesterolemia, low levels of HDL, high levels of triglyceride, and
elevated levels of apolipoprotein Bcontaining lipoproteins have been
mentioned as possible candidates. An association between hypercholesterolemia and a faster rate of CKD progression has been shown in diabetic
patients [82]. Both the MDRD study and the Helsinki Health Study found
low HDL levels and an elevated LDL to HDL ratio ([ 4.4) to be a risk
factor for the deterioration of kidney function [83,84]. In a recent study of
12,728 subjects, a higher level of triglycerides and a lower level of HDL at
baseline were associated with an increased risk for an increase in serum
creatinine levels. These associations were signicant both in patients with
some renal function impairment and in subjects with normal baseline
creatinine levels (\ 1.4 mg/dL in men and \ 1.2 mg/dL in women), ndings
suggestive of a role for dyslipidemias in the initiation of CKD [85].
The mechanisms by which dyslipidemias may aect renal function are not
completely understood. Alteration in the proliferation of mesangial cells,
expression of cytokines and growth factors, formation of reactive oxygen
species, and inhibition of nitric oxide have been postulated [86].
A recent meta-analysis showed a signicant decrease in the rate of GFR
decline and a trend toward a reduction in albuminuria and proteinuria with
the use of lipid-lowering agents (statins or triglyceride-lowering agents) [87].
In addition, a recent randomized trial in 56 patients with CKD being treated
with atorvastatin (in addition to ACEIs or ARBs) showed signicant
additive benets on proteinuria and the rate of GFR decline [88]. It is
noteworthy that statins, apart from their lipid-lowering eect, exert other
functions (eg, down-regulation of transforming growth factor-b expression,
antioxidant eect), which may be benecial in retarding the progression of
CKD [86].
Although the role of lipid-lowering agents in retarding the progression of
CKD awaits further investigation and large randomized, prospective trials,
it seems prudent to recommend their use in patients with CKD not only for
their possible role in slowing CKD progression but also for their proved
501
benecial eects in the management of atherosclerotic cardiovascular

disease (which continues to be the main cause of mortality in CKD
patients).
Smoking cessation
Available data are suggestive of adverse eects of smoking on the kidney
and that smoking increases the risk of proteinuria and the rate of
progression of CKD. In the Heart Outcome Prevention Evaluation trial,
microalbuminuria was associated with several risk factors for cardiovascular
disease, including current smoking [89].
Association between smoking and progression of the CKD has been
shown in patients with diabetes [9093]. Smoking increases the risk of
development of microalbuminuria, the advancement of microalbuminuria to
overt proteinuria, and the rate of progression of CKD in patients with either
type 1 or type 2 diabetes [94]. In addition, the benecial renoprotective
eects of ACEIs may be attenuated in diabetic patients who smoke [92].
Earlier studies (in nondiabetic patients) have failed to show such an eect
[95], however, and further studies are required to clarify this issue.
In patients with essential hypertension, smoking almost doubles the risk
of microalbuminuria and macroalbuminuria [96]. In addition, smoking may
accelerate the rate of progression of CKD in hypertensive patients [97],
although an older (but larger) study failed to show a relation between
smoking and the risk of ESRD [98]. The association between smoking and
progression of CKD has been shown in patients with a variety of primary
renal disorders. In patients with CKD caused by adult polycystic kidney
disease and IgA nephropathy, smoking signicantly increased the risk of
progression to ESRD, particularly among men who were not receiving an
ACEI [95]. In patients with lupus nephritis, smoking was associated with
a faster rate of decline in kidney function and progression to ESRD [99].
Another study found a relation between smoking and increased risk for
microalbuminuria, high GFR, and eventually low GFR [100], suggesting
that smoking may cause hyperltration in the earlier stages, which in turn
predisposes patients to microalbuminuria and later to CKD.
Potential mechanisms for the adverse eects of smoking on the kidney
include increased blood pressure (eg, activating sympathetic nervous system,
inhibiting the nocturnal decline in blood pressure); increasing intraglomerular pressure and hyperltration; endothelial cell dysfunction (eg,
reducing nitric oxide level); atherosclerosis of renal arteries; and possibly
increasing angiotensin II production [94].
Present data are insucient to allow a denitive conclusion on the role
of smoking cessation on progression of CKD. A body of evidence, however,
points to possible benets of stopping smoking in retarding the progression
of CKD [91,100,101]. These data and the body of evidence pointing to the
deleterious eect of smoking on kidney function (particularly in patients
502
with CKD) justies the statement that smoking cessation may retard the
progression of CKD and that all patients with CKD should be counseled in
this regard, not to mention the proved benets of smoking cessation on
cardiovascular and lung cancer risks.
Anemia
It has been proposed that hypoxia of the renal tubule cells exerts a role in
the progression of CKD by stimulating extracellular matrix production, and
inducing production and release of probrotic cytokines. Decreasing
hypoxia by correcting anemia may be benecial in retarding the progression
of CKD. In fact, experimental data support the notion that erythropoietin
therapy and correction of anemia may slow the progression of CKD
(reviewed in [102]). At least three clinical trials have looked at the eect of
erythropoietin treatment and correction of anemia on the progression of
CKD. The rst of these included 83 patients with mean GFR of 10 mL/min
(measured by 125I-iothalamate) and mean hematocrit of 26.8% who (after a
2-month stabilization period) were randomly assigned to receive erythropoietin (43 patients, hematocrit goal of 35%) or no therapy (40 patients).
Although the overall results after 48 weeks of follow-up did not show any
benet of the treatment on slowing the progression of CKD, the GFR
decline in the treated group was signicantly (P = .05) lower after they
reached the target hematocrit (after week 16) [103]. In another study 73
CKD patients (mean serum creatinine of 2.9) with anemia (hematocrit
\ 30%) were randomly assigned either to receive (42 patients) or not receive
(31 patients) erythropoietin. This study also included a third group as
less-anemic controls (hematocrit > 30% and mean serum creatinine of
2.6 mg/dL). The primary end point of the study was doubling of the baseline
serum creatinine. After 36 weeks of follow-up, serum creatinine doubled in
84% of untreated patients, whereas doubling of the serum creatinine in
erythropoietin-treated and less-anemic control patients averaged 52% and
60%, respectively. The more favorable result in the treated group was seen
mainly in nondiabetic patients [104]. Recently, a small retrospective study
has also shown a slower rate of progression of CKD in patients treated with
erythropoietin [105].
Although the role of erythropoietin therapy in retarding the progression of CKD awaits larger randomized controlled trials, the role of
eective treatment of anemia in improving survival and quality of life
[106109], and in decreasing morbidity and mortality [110] in patients
with CKD, justies its use in the pre-ESRD management of patients with
CKD.
Obesity
Animal studies have shown an association between obesity and
glomerular hyperltration, the latter caused by glomerular aerent arteriole
503
vasodilation [111]. Human studies have also shown an increase in GFR and
ltration fraction in nondiabetic, normotensive, obese subjects, conrming
results from animal studies [112]. In a study of a group of patients with
obesity-related proteinuria, dieting led to a mean weight loss of 12% and
a reduction in proteinuria of greater than 80% [113,114]. In a group of
73 patients followed after unilateral nephrectomy, 20 showed slowly progressive proteinuria and GFR decline, almost all of whom had signicantly
higher body mass index in comparison with 53 others who remained
normoproteinuric with normal renal function [115]. In a recent study of
30 overweight patients (body mass index > 27) with various nephropathies
randomly assigned to either a low-calorie diet or their usual diet, a mean
weight loss of 4.1% in the diet group was associated with a 31.2% reduction
in proteinuria [116].
A comprehensive strategy to maximize renoprotection in chronic kidney

disease patients
The use of ACEIs and ARBs to slow the progression of CKD has revolutionized the management of these patients. Although reninangiotensin
system blockade can slow the progression of CKD, it is often not enough to
prevent the progression. To achieve a more eective renoprotection,
a comprehensive strategy using multiple therapies and directed at dierent
aspects of pathophysiology underlying the progression of CKD is required
(see Table 1). Furthermore, once treatment has been initiated, frequent
monitoring is necessary to ensure the achievement of set goals (eg, for blood
pressure, proteinuria, and rate of GFR decline) (see Table 1). This suggested
approach should be considered analogous to that applied in modern
chemotherapy for malignancies, in which multiple agents and approaches
are used until the patient is said to be in remission.
The recommendations outlined in Table 1 are based on currently
available interventions. Whereas it is likely that additional renoprotective
interventions are needed, it is also true that currently available therapies are
not yet applied optimally to all patients with CKD. It is hoped that if
implemented widely, the comprehensive renoprotective strategy might not
only delay the need for renal replacement therapy but might actually prevent
patients from ever reaching ESRD.
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Med Clin N Am 89 (2005) 511523
Multiple Risk Factor Intervention in

Chronic Kidney Disease: Management
of Cardiac Disease in Chronic Kidney
Disease Patients
Bryan M. Curtis, MD, FRCPCa,
Adeera Levin, MD, FRCPCb,c,
Patrick S. Parfrey, MD, FRCPCa,*
a
Division of Nephrology and Clinical Epidemiology Unit, Patient Research Centre,

Health Sciences Centre, Memorial University of Newfoundland,
300 Prince Philip Drive, St. Johns, NF A1B 3V6, Canada
b
Nephrology Education and Research, St. Pauls Hospital, 1081 Burrard Street,
Room 6010A, Vancouver, BC V6Z 1Y6, Canada
c
Division of Nephrology, Department of Medicine, University of British Columbia,
St. Pauls Hospital, Vancouver, BC, Canada
This article describes the prevalence of chronic kidney disease (CKD),

cardiovascular disease (CVD), and the relationship between CKD and
CVD, from both pathophysiologic and epidemiologic perspectives. Also
explored are the management of CVD in patients with CKD, and the
evidence base that supports the implementation of targeted multiple risk
factors for CVD in CKD patients.
Burden of illness
The burden of illness and costs associated with CKD is a large and
growing health care concern. A recent analysis of United States data
indicates that end-staged kidney disease (ESKD) leads to more lost lifeyears than prostate cancer in men, and almost as many as breast cancer in
black women [1]. The largest contributor to this mortality is cardiac disease
[2], and although the mortality rate in elderly patients with kidney disease is
Dr. Curtis is a Research Fellow supported by the Kidney Foundation of Canada.

E-mail address: pparfrey@mun.ca (P.S. Parfrey).
doi:10.1016/j.mcna.2004.12.002
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CURTIS et al
a little greater than in the normal population, the mortality in patients who
are 25 to 34 years old is several orders of magnitude higher than in normal
individuals of the same age [3]. Similarly, the nancial cost of ESKD far
exceeds that for prostate or colorectal cancer in men, and breast cancer in
black women [1], with the direct cost of caring for a patient on dialysis over
$50,000 annually [4,5]. As of 2001, the incidence and prevalence of the
ESKD population in the United States was greater than 90,000 and 290,000,
respectively, with over 15,000 patients receiving kidney transplants [6]. It
is estimated that by 2030 the number of patients with ESKD may reach
2.24 million [6].
Prevalence estimates of CKD are sensitive to the denitions and
methods used to identify the disease [79] and may be somewhat articially
increased by the impact of within-person measurement error resulting from
reliance on a single serum creatinine measurement [9]. Estimates of CKD
are also age dependant because CKD was present in about 8% of the
Framingham population, but increased to 20% in the elderly [10].
Population studies, such as the National Health and Nutrition Survey III
cross-sectional survey of 29,000 persons, revealed that 3% of people over
17 years of age had elevated serum creatinine above the 99th percentile
[11]. Furthermore, it is estimated that approximately 8 million people in
the United States have kidney disease of stage III or higher [12].
Hypertension, diabetes, and cardiac disease are associated with a higher
prevalence of CKD [7,10,11].
Although most patients reach ESKD secondary to chronic progressive
disease (in North America largely caused by diabetes and hypertension [6])
there are limited data on the natural history of CKD in unselected
populations. Most CKD patients do not progress to ESKD because either
the CKD is not progressive [13,14] or they die rst, the major contributor of
mortality being CVD [10]. CKD imparts cardiac risk through coexisting
diseases, such as hypertension, atherosclerosis, diabetes, or hyperlipidemia;
through factors associated with CKD including anemia, inammation,
divalent ion abnormalities, and hyperhomocysteinemia; and other putative
risk factors, including oxidative stress (Box 1). As CKD deteriorates it is
likely that the prevalence and severity of several risk factors change [15,16].
Fortunately, interventions that retard progression of CKD are similar to
measures that reduce CVD risk. Cardiac risk factor intervention in the early
phases of CKD should not only reduce rate of cardiac death but also slow
the progression of kidney disease. In fact, it is currently unknown how much
of the growth in ESKD is caused by growth in the prevalence of CKD [17]
as opposed to a reduction in mortality resulting from improved CVD
management [18].
Recent epidemiologic analyses dier in their conclusions about whether
CKD independently contributes to the risk of cardiovascular mortality
[19,20], but agree that CKD is a marker of high cardiovascular risk. It is
unclear how much of the association between kidney and vascular disease
CKD MANAGEMENT: CARDIAC DISEASE
513
Box 1. Risk factors associated with cardiac disease

Traditional
Age
Gender
Race
Smoking
Diabetes
Body mass index
Hypertension
Dyslipidemia
Left ventricular hypertrophy (LVH)
Fibrinogen
Therapy-related
Dialysis
Modality
Transplant
Acute rejection
Immunosuppressives
Uremia-related
Anemia
Calcium phosphate
Electrolyte abnormality
Malnutrition
Hypoalbuminemia
Inflammation
C-reactive protein (CRP)
Increased oxidant stress
Endothelial activation
Prothrombotic factors
Hyperhomocysteinemia
Cytokines
Advanced glycation end products
results from (1) vascular disease causing kidney failure, (2) kidney failure
causing vascular disease, or (3) common underlying factors promoting the
progression of kidney and CVD. It is likely that each of these mechanisms
apply.
CVD is already well established by onset of ESKD [18,21]. On starting
dialysis the prevalence of cardiomyopathy is very high, as is the presence of
symptomatic ischemic heart disease and heart failure. Symptomatic ischemic
heart disease was present in 38% and heart failure in 35% of Canadians at
rst dialysis [22]. Only 16% of new dialysis patients have normal hearts,
with concentric LVH present in 41% and systolic failure in 16% [23]. LVH
is already evident in 40% of patients with moderate CKD [24] and in 75% of
those commencing dialysis [25]. The high prevalence of CVD on starting
dialysis suggests that the predialysis phase of CKD is a state of high cardiac
risk. In fact, admission rates for congestive heart failure in patients with
CKD are seven times greater than in those without the disease [6].
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CURTIS et al
Cardiovascular disease: dierentiating between ischemic heart disease and

cardiomyopathy
CVD in CKD may be broadly classied clinically into two disease entities
that may overlap and vary from patient to patient: ischemic heart disease
and cardiomyopathy [26] (Fig. 1). Ischemic symptoms result from coronary
artery disease or nonatherosclerotic ischemic disease. Coronary artery
disease predisposes to diastolic dysfunction and to systolic failure. LVH is
present nearly always in dilated cardiomyopathy, but also causes diastolic
dysfunction in those with or without normal systolic function. In a recent
longitudinal study of kidney transplant recipients, a model of CKD, the rate
of ischemic cardiac events was similar to that seen in the Framingham study,
whereas the rate of heart failure events was substantially higher. This
suggests that CKD may not simply be a state of accelerated atherosclerosis,
and may be a predominantly cardiomyopathic state [27].
Cardiomyopathy
Cardiomyopathy is common in ESKD and its most common symptom is
pulmonary edema, a manifestation of pump failure that may result from
either systolic or diastolic dysfunction. Diagnosis may be made with
echocardiography [23] because the cardiomyopathy may be the consequence
of dilated cardiomyopathy with systolic failure or LVH with diastolic
dysfunction. Two major types of LVH may occur. The rst is concentric
LVH with normal chamber volume, arising from left ventricle (LV) pressure
overload, such as from hypertension, arteriosclerosis, and aortic stenosis.
The second is eccentric LV dilation resulting from LV volume overload. This
occurs in response to salt and water overload, anemia, and arteriovenous
stula. Hemodialysis with its associated hemodynamic stresses is the
Cardiomyopathy
Ischemic Heart Disease
Atherosclerotic
NonAtherosclerotic
Concentric
LVH
Diastolic
Dysfunction
LV
Dilatation
Systolic
Dysfunction
Pump Failure
Death
Fig. 1. The overlap of cardiac disease in CKD patients. LV, left ventricle.
515
quintessential model for overload cardiomyopathy, whose end stage is

systolic dysfunction.
LV growth starts before the initiation of dialysis and its prevalence is
inversely related to the level of declining kidney function. Anemia,
hypertension, and diabetes mellitus are risk factors for progressive LV
growth [28,29]. In kidney transplant recipients there is evidence that
systolic dysfunction, LV dilatation, and concentric hypertrophy present
while on dialysis improve after transplantation with concomitant improvement in uremic milieu. In renal transplant recipients, however, hypertension is a risk factor for LV growth, de novo heart failure, and de novo
ischemic heart disease [27,30]. Anemia additionally predisposes to de novo
heart failure, as does hypoalbuminemia [27].
Ischemic heart disease
Ischemia presents as myocardial infarction or angina resulting from
decreased perfusion of the myocardium. Coronary artery disease is dened
as the pressure of critical stenoses of the large coronary vessels, resulting
from atherosclerotic plaques. Although symptoms of ischemic heart disease
are most often attributable to the presence of critical coronary artery
disease, in about one quarter of the hemodialysis population these
symptoms may also result from nonatherosclerotic disease, caused by small
vessel disease and LVH.
The presence of symptomatic ischemic heart disease is not a signicant
mortality risk factor independent of congestive heart failure [31]. The
implication is that the underlying cardiomyopathy predisposing to heart
failure is prognostically more important than coronary perfusion disorders.
Arterial disease
The structure of arteries may be altered by mechanisms other than
atherogenesis. Arteriosclerosis is an intramural vascular remodeling with
hypertrophy of the media and subintimal brosis that occurs in response to
hemodynamic overload and hypertension. As a result, noncompliant conduit
vessels develop with an increase in vessel stiness and diameter. If persistent
and long-standing, arteriosclerosis may adversely aect left ventricular
structure and function by increasing cardiac workload and contribute
directly to ischemic symptoms [32].
Treatment strategies related to cardiovascular risk
Hypertension
About three quarters of CKD patients have hypertension, the prevalence
of which increases as glomerular ltration rate declines. Lowering blood
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CURTIS et al
pressure reduces mortality in those at risk for cardiovascular events,

including diabetics [3336]. Achieving a target blood pressure of less than
130/80 mm Hg in CKD also slows progression of kidney disease [13,33,
3741] and those with proteinuria greater than 1 g per 24 hours benet from
even lower blood pressure (\ 125/75 mm Hg) [13]. Three or four dierent
medications are often required to reach these goals.
Reninangiotensin system interruption
Angiotensin-converting enzyme (ACE) inhibitors have been clearly
shown to improve symptoms, morbidity, and survival in nonuremic
individuals with heart failure [42]. ACE inhibitors reduce cardiovascular
morbidity and death in CKD, as in those with normal glomerular ltration
rate [43]. The use of ACE inhibition reduces progression of CKD,
proteinuria, and regresses LVH [4447]. The benet of ACE inhibition is
applicable to those with diastolic and systolic dysfunction. ACE inhibitors
should also be used to prevent congestive heart failure in asymptomatic
patients whose LV ejection fraction is less than 35% [48] and in post
myocardial infarction patients with an ejection fraction of 40% or less [49].
Angiotensin receptor blockers also reduce ESKD and may delay death in
type 2 diabetics with nephropathy [50,51].
b-Blockers
b-Blockade is indicated for angina [52] and reduces morbidity and
mortality in both heart failure [53,54] and postmyocardial infarction [55],
and seems equally ecacious in patients with CKD [56]. It should be noted
that contraindications to their use (reactive airway disease, sinus-node
dysfunction, and cardiac conduction abnormalities) occur frequently in
CKD patients, especially in the later stages.
Aspirin
Aspirin prevents atherothrombotic events in patients at high risk of
vascular events [57,58] and has a role in primary prevention in diabetics
[33,58]. There have been no studies, however, of aspirin for either the
primary or secondary treatment of myocardial ischemia in the CKD
population. The risk of complications, mainly bleeding, probably increases
as kidney function declines and eects of uremia increase. Aspirin use for the
primary prevention of coronary artery disease cannot be recommended for
patients with CKD per se. For those patients with acute coronary
syndromes, myocardial infarction, or other high-risk individuals, the benets
likely outweigh the risks. There are little data regarding the use of clopidogrel
in CKD.
517
Diabetes management
Diabetes in patients with moderate to severe CKD predicts deterioration
in cardiovascular states, in patients with and without CVD at baseline [59].
Furthermore, it is an independent risk factor for ischemic heart disease
[27,60,61] and for cardiac failure [27] in kidney transplant recipients.
Controlling diabetes has benecial eects for at least early microvascular
disease [62,63]. Metformin showed benet for macrovascular disease in
obese type 2 diabetics [64], but is contraindicated in later stages of CKD.
Smoking
Approximately 25% of CKD patients and over 50% of dialysis and
transplant patients have a history of cigarette use [65]. Smoking status is
independently associated with cardiac disease, peripheral vascular disease,
and mortality. Importantly, smoking is modiable and cessation reduces
cardiovascular risk [66], may slow CKD progression [6769], and
improves quality of life [70], but may require intense intervention for
maximal eect [71].
Abnormal calcium and phosphate metabolism
Abnormal levels of calcium, phosphate, parathyroid hormone, and vitamin D in CKD may contribute to cardiomyopathy, LVH, LV brosis,
atherosclerosis, myocardial ischemia, and vascular and cardiac calcication
[72]. In prevalent dialysis patients increased phosphate and calcium
phosphate product were independent predictors of coronary artery calcication and mortality [73]. Whether this calcication represents calcication of
atherosclerotic plaques or a stage associated with arteriosclerosis is not clear.
The onset of these metabolic derangements occurs early on in the progression
of CKD and should be prevented or managed as they emerge. The ecacy of
interventions to normalize serum calcium and phosphate, however, has not
been demonstrated in randomized controlled trials with measurement of
major clinical event rates. Recently, the National Kidney Foundation
published clinical practice guidelines for appropriate surveillance and
treatment of bone metabolism and disease [74].
Statin therapy
Statin therapy in CKD seems to have a similar ecacy to that in nonCKD patients with CVD [7577]. The potential role of statin therapy in
CVD management independent of lipid lowering is receiving attention.
Their proposed properties include endothelial stabilization and antithrombogenic and anti-inammatory mechanisms that may modify their
eectiveness. The CKD population, similar to dialysis patients, is known
to have increased markers of inammation, such as CRP. This inammatory state is thought to confer an independent increased CVD risk
518
CURTIS et al
by oxidative stress and resultant atherosclerosis [77]. Although statins have

been shown to reduce CRP levels in patients with normal kidney function, it
is not known whether this translates into clinical benet independent of lipid
reduction.
Anemia
The role of anemia, and its treatment, is now a focus of congestive heart
failure management strategy and investigation in patients without CKD
[78]. Much more is known in patients with kidney disease. The combination
of CKD and anemia is independently associated with an increased risk of
coronary heart disease and stroke in middle-aged patients [79,80] and, in
CKD stage III or greater, anemia is associated with LV growth [24]. In
kidney transplant recipients, anemia is an independent risk factor for the
development of electrocardiographically diagnosed LVH [27] and of
symptomatic heart failure [30]. Treating anemia to a hemoglobin of 110
to 120 g/L improves quality of life, decreases hospitalization, and may
improve LVH [8186]. No strong evidence from randomized control trials
currently exists to support normalization of anemia with erythropoietin to
treat cardiac disease [8790].
Multiple risk factor intervention

The focus of CKD care must broaden to include CVD risk reduction in
addition to, or concomitant with, reducing the progression of kidney
decline. With increased understanding of kidney disease pathophysiology
and CVD within the CKD population, it has become clearer that treatment
and care options are increasingly complex. Given the multiplicity of goals of
care and the complexity of treatment options, an individual nephrologist is
unlikely to be able to manage CKD care alone. Implementing targeted
multiple risk factor intervention programs to manage cardiac disease in
CKD may well overwhelm the ability of individual nephrologists in the
absence of multidisciplinary teams. Publications using United States data
[91,92] demonstrate that care of patients with CKD known to nephrologists
continues to be suboptimal, and reasons for this must be further explored.
Given the complexity of the care, the increasing comorbidity of the patient
population, and the accumulating data describing best practices, a team
approach with well-dened roles, responsibilities, and objectives seems to be
logical and practical. Studies are underway to address these issues.
Summary
This article describes the relationship between CVD and CKD, the
current state of knowledge regarding medical interventions, and underscores
519
the importance of attending to both CVD and kidney disease aspects in each
individual.
The burden of cardiac disease in CKD patients is high with severe LVH,
dilated cardiomyopathy, and coronary artery disease occurring frequently.
This predisposes to congestive heart failure, angina, myocardial infarction,
and death. Multiple risk factors for cardiac disease exist and include
hypertension, diabetes, smoking, anemia, abnormal calcium and phosphate
metabolism, inammation, and LVH. The ecacy of risk factor intervention has not been established in these populations, although there is
good evidence for good blood pressure control, partial correction of anemia,
treatment of dyslipidemia, cessation of tobacco use, correction of divalent
abnormalities, and aspirin use. Appropriate use of ACE inhibitors,
b-blockers, and statins should be encouraged.
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Med Clin N Am 89 (2005) 525547
Etiology and Management of

Hypertension in Chronic Kidney Disease
Martin J. Andersen, MD,
Rajiv Agarwal, MBBS, MD, DNB, FASN, FAHA*
Division of Nephrology, Department of Medicine, Indiana University School of
Medicine and Richard L. Roudebush Veterans Aairs Medical Center,
1481 West 10th Street, 111N, Indianapolis, IN 46202, USA
The kidneys are vital in the pathogenesis of hypertension and are also
pathologically aected by the presence of hypertension. Hypertension
aects 24% of the adult United States population [1]. According to data
from the Third National Health and Nutrition Examination Survey, 3% of
the adult population has an elevated serum creatinine and 70% of these
patients have hypertension dened as blood pressure greater than or equal
to 140/90 mm Hg [2]. The prevalence of hypertension in chronic kidney
disease (CKD) depends on age, the severity of renal failure, and proteinuria
[3]. It also depends on the underlying renal disease; nearly 90% of patients
with diabetes and renovascular disease have hypertension. As patients with
CKD progress to end-stage renal disease (ESRD), 86% are diagnosed with
hypertension [4]. The intricate and inextricable relationship between CKD
and hypertension seems to cause cardiovascular disease that has assumed
epidemic proportions. This article discusses the etiology and treatment of
hypertension in CKD so that it can be better controlled.
Etiology of hypertension
Sodium and water
It has been recognized for at least 50 years that increasing sodium intake
leads to a variable but consistent increase in blood pressure in animals. This
Dr. Agarwal gratefully acknowledges the research support from National Institutes of
Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grant 5
RO1-062030-02. Dr. Andersen is supported by NIH training Grant 5T32DK062711-02.
E-mail address: ragarwal@iupui.edu (R. Agarwal).
doi:10.1016/j.mcna.2004.12.001
526
ANDERSEN & AGARWAL
heterogeneity in response was thought to be the interaction between genetic

and environmental factors by Dahl et al [5], and by ingenious inbreeding
experiments in Sprague Dawley rats fed a high-sodium diet, they could create
colonies within three generations that were hypertensive. Feeding a sodiumpoor diet, even in the predisposed animals, did not increase blood pressure,
but caused an elevation in blood pressure in the sodium-sensitive animals
conrming the importance of sodium in causing hypertension. The most
denitive experiments on the role of sodium being etiologically signicant
for hypertension in primates were performed over a span of 2.5 years
in chimpanzees fed a high-sodium diet [6]. Chimpanzees, who typically
consume a vegetarian, potassium-rich, sodium-poor diet, were gradually
supplemented with dietary sodium to a level of 15 g/d that was sustained over
16 months. At the end of supplementation period blood pressure increased
33/10 mm Hg together with suppression of plasma renin. Within 20 weeks of
stopping sodium supplementation, blood pressure returned to baseline.
Human data support the animal ndings noted previously. In primitive
societies, such as the New Guinea Highlanders, Yanomamo Indians in the
Amazon rain forest [7], Bushmen of Kalahari, or Kenyan tribal farmers,
sodium content in the diet is extremely low (110 mEq/d). Hypertension and
age-related blood pressure increase in these populations is not seen. In contrast, the mean dietary intake of sodium in Akita, Japan, is 450 mEq/d
(26 g/d) and a high incidence of hypertension and strokes are seen.
Furthermore, dietary sodium increase in preliterate societies associated with
urban migration is associated with rapid increase in blood pressure.
A meta-analysis of trials of sodium restriction in normotensive and
hypertensive individuals concluded that 50 mEq/d reduction in dietary
sodium (that can simply be achieved by taking away table salt) leads to fall
in systolic blood pressure of 5 mm Hg on average and by 7 mm Hg in those
who are more hypertensive [8]. Furthermore, at least 5 weeks of sodium
restriction are required to see such an eect. The reciprocal relationship
between sodium intake and blood pressure is regulated by the kidney [9].
The kidneys, in response to increased dietary sodium intake, decrease
sodium and water reabsorption in the proximal tubule and loop of Henle.
This increases urinary sodium and water output, a phenomenon recognized
as pressure natriuresis, and normalizes the blood pressure [10]. In people
with hypertension, the pressure natriuresis curve is shifted to the right.
The concept of volume overload in the genesis of hypertension was
popularized by Guyton et al [11,12]. Recognizing that mean arterial pressure
is the product of cardiac output and peripheral vascular resistance, it is
evident that an increase in mean arterial pressure can be either caused by an
increase in cardiac output or peripheral vascular resistance. Guytons group
was amongst the rst to demonstrate the central importance of the kidneys
in modulating systemic hemodynamics via sodium retention [11,12]. By
removing 40% of one kidney in dogs and infusing isotonic saline for 13 days,
Guytons colleagues created a model of hypertension. During the rst 3 days
HYPERTENSION IN CKD: ETIOLOGY & MANAGEMENT
527
of saline administration, blood pressures increased together with a rise in

cardiac output; however, peripheral vascular resistance fell. Subsequently,
cardiac output dropped while peripheral vascular resistance increased. These
results were explained by an increase in blood volume, an increase in mean
circulatory lling pressure, and a higher cardiac output at the initial stages
of volume expansion. This was followed by autoregulatory vasoconstriction
that resulted in increased peripheral vascular resistance. Perfusion of kidneys
at higher pressures caused pressure natriuresis, and restoration of cardiac
output. Hypertension was sustained even after the fall in cardiac output,
because of a persistently elevated peripheral vascular resistance.
The reninangiotensin system

Reduced volume, perfusion, or increased sympathetic tone is sensed by
the juxtaglomerular cells of the renal aerent arteriole, which secrete renin.
Renin, in turn, cleaves angiotensinogen to the decapeptide angiotensin I,
which angiotensin-converting enzyme (ACE) converts to the octapeptide
angiotensin II (Ang II). Ang II increases systemic vascular resistance by
activation of the Ang II subtype 1 receptors on vascular smooth muscle.
Ang II also causes eerent renal arteriolar vasoconstriction that increases
glomerular hydrostatic pressure. Ang II stimulates the adrenal glands to
release aldosterone, which stimulates renal sodium absorption. In the
sodium-depleted state, these actions preserve blood pressure and maintain
glomerular ltration rate, but in the sodium-replete state can result in renal
injury and hypertension. In addition to the well-known hemodynamic
actions of Ang II, endothelial, mesangial, and renal tubular activation;
oxidative stress (discussed later); and inammation and brosis can occur
with elevated levels of this hormone in a variety of kidney diseases. For
example, in areas of renal injury, ACE activity can be even higher than in
noninjured areas [13]. The resultant overexpression of Ang II can lead to
progressive renal damage and hypertension [14].
Oxidative stress
Reactive oxygen species, such as superoxide and hydrogen peroxide, are
important signaling molecules. Their production is regulated by Ang II
sensitive enzymes, such as the vascular NAD(P)H oxidases, and their
catabolism by antioxidant enzymes, such as superoxide dismutase, catalase,
and glutathione peroxidase [15,16]. Both superoxide and hydrogen peroxide
serve as second messengers to activate multiple intracellular proteins and
enzymes that, in turn, activate redox-sensitive transcription factors. Reactive
oxygen species participate in vascular smooth muscle cell growth and
migration; modulation of endothelial function, including endotheliumdependent relaxation and expression of adhesion molecules, chemoattractant
528
ANDERSEN & AGARWAL
compounds, and cytokines rendering a proinammatory phenotype; and

modication of the extracellular matrix.
Haugen et al [17] examined three models to assess the direct eect of Ang
II on the structure and function of the kidney by oxidative stress. In the rst
model, Ang II was administered by miniosmotic pumps to rats maintained
on standard diets. Oxidative stress and hypertension were observed. In the
second model, rats were made hypertensive with deoxycorticosterone
acetate and salt, but they were not given Ang II. In this model, the renin
angiotensin system is expected to be suppressed, and hypertension without
oxidative stress was noted. In the third model, rats maintained on
antioxidant-decient diets were studied while infused with Ang II.
Proteinuria and decreased creatinine clearance were noted in addition to
oxidative stress and hypertension. Kawada et al [18] studied the relationship
between prolonged and graded infusions of Ang II and blood pressure. In
mice, high-dose Ang II infusions caused a rapid increase in systolic blood
pressure. Intermediate doses of Ang II led to increased postglomerular
resistance, followed by elevated preglomerular resistance and hypertension.
Renal oxidative stress was increased at a later time point (Day 12 of
infusion), and administration of an antioxidant-reduced oxidative stress,
blood pressure, and renal vascular resistance. Others have demonstrated
that rats with renin-mediated hypertension have AT1 receptormediated
endothelial dysfunction associated with increased oxidative stress and
increased vascular xanthine oxidase activity [19]. In contrast, knockout mice
that are genetically decient in gp91(phox), an NADPH oxidase subunit
protein, show lower baseline blood pressures and demonstrate less oxidative
stressmediated vascular injury in response to Ang II [20]. Nishiyama et al
[21] have demonstrated that the blood pressureelevating eect of Ang II
is partly caused by inactivation of nitric oxide (NO) through the generation
of oxygen-derived free radicals. In humans with CKD, the authors have
found that blockade of reninangiotensin system can reduce oxidative stress
[22] and probrotic cytokines [23] independent of reduction in proteinuria
or blood pressure [24].
Taken together, these experiments oer direct evidence that Ang II
induces oxidative stress in vivo, which contributes to renal injury. This
injury seems to be predominantly localized to the renal proximal tubules.
NADPH oxidase-derived superoxide anion seems to be important for the
regulation of basal blood pressure and in the pathogenesis of hypertension.
Furthermore, these studies reveal a pressure-independent vascular hypertrophic response to Ang II and implicate that oxidative stress is causally
important in the genesis of renal parenchymal hypertension.
Nitric oxide and circulating inhibitors of nitric oxide
Endothelial-derived NO plays a critical role in the maintenance and
regulation of vascular tone and modulates key processes mediating vascular
529
disease including leukocyte adhesion, platelet aggregation, and vascular

smooth muscle proliferation [25]. Endothelial NO synthase enzymatically
produces NO from the substrate L-arginine. NO vasodilates the vasculature
by activation of guanylate cyclase, which subsequently produces cyclic
guanosine monophosphate [26]. Cyclic guanosine monophosphate activates
a protein kinase enzyme that phosphorylates and activates a calciumdependent potassium channel, leading to potassium eux and vasodilation
[27]. In hypertensive patients, this mechanism has been found to be defective
[2830]. Also, L-arginine supplementation can partially reverse renal failure
associated endothelial dysfunction [31].
Reactive oxygen species can impair the activity of NO. Superoxide
quenches NO to produce peroxynitrite, which is itself devoid of vasodilating
activity [32]. Peroxynitrite, in turn, reacts with tyrosine to produce
nitrotyrosine, a marker of oxidative stress [32]. In animals with induced
oxidative stress through glutathione depletion, blood pressures and nitrotyrosine levels are elevated, indicating the interaction of superoxide with
NO and the inhibition of vasodilation [33]. Studies further show that
endothelial-dependent vasodilation improves in hypertensive patients after
receiving antioxidant therapy [34].
A circulating inhibitor of NO synthase, asymmetric dimethylarginine,
competes with L-arginine for NO synthase. In humans with salt-sensitive
hypertension, administration of a high-salt diet increases plasma asymmetric
dimethylarginine and blood pressure [35]. Circulating asymmetric dimethylarginine is increased in subjects with CKD [36] and ESRD [37] and may
contribute to endothelial dysfunction and increased blood pressure. In
patients with ESRD, asymmetric dimethylarginine is correlated with
increased left ventricle thickness and reduced ejection fraction, consistent
with its ability to increase systemic vascular resistance [38].
As reviewed by Cooke [39], of the 300 lmol/d asymmetric dimethylarginine normally generated, only 50 lmol/d is excreted by the kidneys
in healthy volunteers, whereas the remaining amount is degraded enzymatically by dimethylarginine dimethylaminohydrolase. Pharmacologic
inhibition of dimethylarginine dimethylaminohydrolase with a small
molecule, 4124W, causes accumulation of asymmetric dimethylarginine
and generalized vasoconstriction. In contrast, overexpression of dimethylarginine dimethylaminohydrolase in genetically engineered mice reduces
asymmetric dimethylarginine, improves NO bioavailability, and reduces
systolic blood pressure. Oxidative stress that impairs dimethylarginine
dimethylaminohydrolase activity by oxidizing a sulfhydryl moiety critical
to its enzymatic activity leads to accumulation of asymmetric dimethylarginine and promotes endothelial dysfunction. Inammation, increased
homocysteine levels, reduced antioxidant defenses, and increased free
radicals in ESRD may provide an explanation for the relationship
between oxidative stress, endothelial dysfunction, and the generation of
hypertension [37].
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ANDERSEN & AGARWAL
The sympathetic nervous system

The sympathetic nervous system in the kidney stimulates the juxtaglomerular cells to release renin by b-adrenergic receptors and stimulates
sodium and water reabsorption. The sympathetic nervous system constricts
the vascular smooth muscle cells by a-adrenergic and dilates by the
b-adrenergic receptors [40]. In the heart, activation by the sympathetic
nervous system of b receptors leads to increased cardiac inotropy,
cardiomyocyte hypertrophy, and arrhythmogenicity [40].
Strong evidence has emerged that implicates enhanced sympathetic
activity as a cause of hypertension in patients with CKD and ESRD [41].
Microvascular and tubulointerstitial damage induced by repeated injections
of phenylephrine in animals leads to the development of sodium-sensitive
hypertension [42]. There is also ample evidence that sympathetic nervous
system is activated in CKD. Diminished vascular response to norepinephrine in animals with chronic renal failure provided initial indirect evidence of
increased sympathetic nerve activity that down-regulated adrenergic
receptors [43]. Later studies, however, provided more direct evidence of
elevated sympathetic tone in patients with ESRD [41]. This was made
possible by direct measurement of eerent sympathetic nerve activity [44].
Using microneurography, investigators have demonstrated that the
sympathetic activity is increased in those patients on chronic hemodialysis
who still have their native kidneys. In contrast, those patients with bilateral
nephrectomy have reduced sympathetic activity, lower calf vascular
resistance, and lower mean arterial pressure [41]. The kidney, although
devoid of excretory function, serves as an aerent organ to signal the
midbrain region to increase sympathetic activity. The central mechanisms of
increased sympathetic activity may involve dopaminergic neuronal transmission. Experiments in hypertensive hemodialysis patients show that
administration of the dopamine-releasing drug bromocriptine decreased
plasma norepinephrine and lowered mean arterial pressure [45]. In animals
with chronic renal failure, norepinephrine turnover rate is increased in the
posterior hypothalamic nuclei, and endogenous NO may be an important
regulator of sympathetic activity [46]. NO inactivation in the central nervous
system by an arginine analogue resulted in higher blood pressures and
increased renal sympathetic nerve activity in rabbits [47]. Baroreceptor
desensitization has also long been recognized in hypertensive patients with
ESRD and may contribute to elevated blood pressure [48].
Hormones
Endothelin
Endothelin-1 binds to endothelin-A and endothelin-B receptors in
vascular smooth muscle cells to initiate vasoconstriction [49]. Conversely,
endothelin-1 binds to endothelin-B receptors on endothelial cells to mediate
vasodilation [49]. Infusion of Ang II increases both endothelin-1 plasma
531
levels and blood pressure in animals [50]. Because NO prevents the

expression of endothelin-1 [51], these eects seem to be secondary to
oxidative stressinduced NO quenching by Ang II. Vasoconstriction and
blood pressure elevation are the end results. As expected, endothelin-A
receptor blockade reduces blood pressure.
Human studies have also shown the importance of endothelin-1 in hypertension. Compared with normotensive patients, endothelin-1dependent
vasoconstriction is higher in obese, hypertensive patients [52], whereas
black, hypertensive patients show increased endothelin-1 and vascular
smooth muscle endothelin-B receptor expression [53]. Treatment with
bosentan, an endothelin-A receptor blocker, in hypertensive patients lowers
blood pressure [54].
Parathyroid hormone
In a study of 123 elderly patients that compared 24-hour ambulatory
blood pressures (ABPs) and parathyroid hormone (PTH) levels, PTH
levels strongly correlated with mean 24-hour systolic blood pressures [55].
Duprez et al [56] noted that PTH levels signicantly correlated to mean
24-hour diastolic blood pressures and left ventricular hypertrophy in
hypertensive patients. Jorde et al [57] showed that PTH levels in middleaged women also correlated with both elevated systolic and diastolic blood
pressures.
The role of PTH in the pathogenesis of hypertension, however, has been
controversial. PTH can increase intracellular calcium and aggravate
hypertension [58], and parathyroidectomy may improve blood pressure
control [59]. Conversely, others have reported that elevated PTH levels can
reduce the pressor response to norepinephrine in animals with chronic renal
failure [60], and parathyroidectomy may not correct hypertension [61].
Two studies from Japan showed that sodium loading in hypertensive
patients caused increase in blood pressure, intracellular calcium, and PTH
levels [62,63]. Furthermore, the change in PTH levels with sodium loading
correlated signicantly with the elevations in blood pressure and intracellular calcium levels. The authors suggested that elevated intracellular
calcium levels may be caused by the elevated PTH levels. Because vascular
smooth muscle cells use calcium to initiate vasoconstriction [64], this in turn
may lead to the higher blood pressures.
A recent study, however, has disputed the ability of PTH to raise
intracellular calcium levels [65]. Others have suggested that the increase in
PTH levels were secondary to the lower calcium levels that resulted from
hemodilution from saline infusion [66]. When calcium levels were held stable
by infusing calcium during saline infusion, blood pressures increased despite
a fall in PTH. In fact, PTH infusion in hypertensive patients actually had
vasodilatory and natriuretic eects [67], and the higher urinary calcium
levels and serum PTH levels in hypertensive patients may simply reect
defects in renal calcium handling [68,69].
532
ANDERSEN & AGARWAL
To resolve these contradictions, Pang et al [70] have proposed that the

parathyroid glands, in addition to secreting PTH, may also secrete
parathyroid hypertensive factor. Parathyroid hypertensive factor may cause
vasoconstriction by increasing intracellular calcium levels, thereby leading
to elevated blood pressures. In contrast, the eects of PTH, the authors
argue, are vasodilatory. This model at least sets the stage for a testable
hypothesis that may help resolve the role of PTH in the pathogenesis of
hypertension.
Drugs and toxins
Erythropoietin
Erythropoietin can cause hypertension in around 20% of patients [71]. It
has also been noted to cause hypertensive urgency [72]. Originally,
erythropoietin-induced hypertension was attributed to the rise in hematocrit
and blood viscosity that occurred with treatment [73,74]. Yet, in both
animal and human studies, results have consistently shown that the rise in
blood pressure with erythropoietin administration is independent of
hematocrit [7578]. For example, Vaziri et al [79] have shown that if
erythropoietin is administered to anemic animals with chronic renal failure,
but hemoglobin is kept stable by feeding these animals an iron-decient diet,
hypertension still occurs. In blood vessels harvested from these animals
treated with erythropoietin, vasodilatory responses to NO donors were
impaired, but response to several vasoconstrictors was normal.
Erythropoietin increases the release of endothelin-1 from bovine
endothelial cells [80] and raises the blood pressures in spontaneously
hypertensive rats through endothelin-1mediated mechanisms [81]. This has
not, however, been consistently seen [82].
Vascular smooth muscle cells use intracellular calcium to initiate
vasoconstriction [64]. Platelet cytosolic calcium concentrations have been
shown to correlate with vascular smooth muscle cytosolic calcium concentrations and blood pressures [83]. Platelet cytosolic calcium serves as
a surrogate for smooth muscle calcium concentration. In this context,
erythropoietin increases platelet cytosolic calcium in animals [79] and in
hypertensive patients [84]. Erythropoietin can activate calcium channels by
tyrosine kinase [85]. Felodipine, a calcium channel blocker, lowered platelet
cytosolic calcium concentrations and blood pressures in rats treated with
erythropoietin [86].
Lead
Low-level lead exposure is associated with impaired renal function [87]
and hypertension [8891]. Oxidative stress and impaired endothelial
vasodilation seem to be important in the mechanism of lead-induced
hypertension. Lead-exposed rats had hypertension and biomarkers of oxidative stress that improved with the administration of an antioxidant [92].
533
Similarly, tempol, an antioxidant that reduces superoxide levels, lowered

blood pressures in lead-exposed rats while having no eect in the control rats
[93]. Finally, lead-exposed rats, in addition to having hypertension, have
reduced endothelial guanylate cyclase expression suggesting endothelial
dysfunction [94].
Cocaine
Cocaine blocks the uptake of catecholamines in presynaptic sympathetic
nerves [95], leading to peripheral vasoconstriction and elevated blood
pressure. Cocaine infusions in laboratory rats raised blood pressure in
a biphasic manner: after a rapid initial increase in blood pressure, a more
sustained response ensued [96]. Treatment with phentolamine, an aadrenergic receptor blocker, or pentolinium, a ganglionic blocker, in these
rats prevented cocaine-induced elevations in blood pressures. Furthermore,
although the vasoconstrictive eects of norepinephrine were unaected, those
of cocaine were attenuated when isolated carotid artery preparations were
stripped of endothelium or pretreated with a NO synthase inhibitor, NGmonomethyl-L-arginine [97]. These results indicate that the blood pressure
raising eect of cocaine is at least in part caused by its ability to impair
endothelial function.
Cyclosporine
Cyclosporine, a calcineurin immunosuppressive agent, causes aerent
arteriolar vasoconstriction and tubulointerstitial brosis [98] that can lead to
hypertension and reduced glomerular ltration rate. NO deciencies may play
a primary role in the pathogenesis of cyclosporines toxicity. Cyclosporine
increases the production of ROS (primarily superoxide and hydrogen
peroxide) in vitro that can be reduced by free radical scavengers [99].
Cyclosporine administration to laboratory rats increased Ang II superoxide
levels and blood pressure [100]. Nephrotoxicity of cyclosporine can be
abrogated in laboratory rats by antioxidant therapy [101].
Nonsteroidal anti-inammatory drugs
Prostaglandins promote vasodilation and enhance natriuresis [102].
Nonsteroidal anti-inammatory drugs block the synthesis of prostaglandins
and lead to an elevation in blood pressure of about 5 mm Hg [102,103]. The
elderly, the hypertensive, and those with CKD carry an increased risk
of developing hypertension with nonsteroidal anti-inammatory drugs.
Aspirin and sulindac seem to have the least eect on increasing blood
pressure [103]. Increased vascular resistance and expanded extracellular volume have both been incriminated in the genesis of nonsteroidal
anti-inammatory druginduced hypertension. Like nonsteroidal antiinammatory drugs, the coxcibs can also increase blood pressure and cause
renal injury [104,105].
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ANDERSEN & AGARWAL
Summary of pathophysiology of hypertension and chronic kidney disease

The pathophysiology of hypertension and CKD can be summarized as
follows: renal injury occurs because of a variety of reasons that include
activation of the reninangiotensinaldosterone axis, the sympathetic
nervous system, and toxins (Fig. 1). Some of these factors (eg, renin
angiotensin system, sympathetic system, cocaine use) can by themselves
aggravate hypertension. Tubulointerstitial inammation results in the
release of oxidants by the invading inammatory cells, the inactivation of
local NO, and the heterogeneous activation of the intrarenal renin
angiotensin system. Tubular and vascular barotrauma characterized by
aerent arteriolopathy leads to a right-shifted pressure natriuresis curve.
This relieves the renal ischemia, but at the expense of higher blood pressure,
leading to the development of hypertension that causes further renal injury.
Dietary sodium excess, by inactivation of dimethylarginine dimethylaminohydrolase, can reduce NO activity and further accelerate tubular and
microcirculatory damage. Extracellular volume expansion by sodium
Fig. 1. The pathophysiology of hypertension and CKD. CVD, cardiovascular disease;

DDAH, dimethylarginine dimethylaminohydrolase; ECF, extracellular uid volume; NSAIDs,
nonsteroidal anti-inammatory drugs; RAAS, reninangiotensinaldosterone system; ROS,
reactive oxygen species; SNS, sympathetic nervous system.
535
overload can by itself aggravate hypertension. Renal inammation eventually leads to brosis, progressive CKD, and ESRD. CKD is accelerated by
underlying CVD and is a known risk factor for CVD.
Johnson et al [106] have suggested that subtle acquired renal injury is an
essential part of all salt-sensitive hypertension, whereas Brenners hypothesis
that low nephron dose is central to the pathogenesis of essential hypertension
is nding growing support [107]. Essential hypertension may simply be
a disease of the nephrons (low numbers or impaired function) and may
account for a signicant proportion of salt-sensitive hypertension seen in the
general population [108].
Management of hypertension
Assessment of blood pressures
Blood pressure obtained in the physicians oce (clinic blood pressures
[CBPs]), has been the basis of most clinical trials and most physicians guide
antihypertensive therapy based on CBP. Accurate readings of CBP,
however, are often not obtained. According to the Seventh Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 7), CBP should be obtained only from patients who
have been sitting for at least 5 minutes and who have had their feet on the
oor and arms at heart level [109]. Bladders of blood pressure cus should
encircle greater than or equal to 80% of patients arms to avoid spuriously
high CBP values. Finally, two measurements, taken at least 2 minutes apart,
should be obtained and averaged to determine the patients CBP. These
recommendations are often not followed.
Home blood pressures (HBP) are another way to assess blood pressure in
patients with CKD. Concern has been noted in the past about the reliability
of patients being able to perform and record their HBP accurately [110]. A
study by Mengden et al [111] revealed that more than half of hypertensive
patients incorrectly record their HBP values into diaries. HBP monitors that
electronically store the HBP data are preferred [112]. Finger and wrist HBP
devices are to be avoided because they tend to be inaccurate. Instead,
appropriately sized arm cus should be used, and the patients should take
their HBP over a 7-day period with at least a total of 12 readings recorded
during that time [112]. According to prior studies, HBP should be
performed at least twice a day with two measurements made at each sitting
[113,114]. Furthermore, because of their likelihood of being inaccurate, the
rst days HBP should not be considered when making clinical judgments.
ABP recordings provide even more information on the diurnal nature of
the blood pressure variation. The European Society of Hypertension
recommends that ABP monitoring be performed with an appropriately sized
cu over a 24-hour period with readings made every 20 to 30 minutes,
a timeline that prevents interference with daily activities, but allows for
536
ANDERSEN & AGARWAL
a sucient amount of readings to be made [112]. At least 14 ABP measurements should be made during the day, and at least seven measurements
should be made during the night to obtain a minimal amount of data.
If there are fewer recordings, the ABP monitoring should be repeated.
Daytime and nighttime divisions can be determined either from patient
diaries or arbitrarily set time periods devised by the physicians.
When measuring CBP, ABP, or HBP, it is important to use validated
devices (ie, those approved by the American Association for the Advancement of Medical Instrumentation and the British Hypertension Society)
[115]. It is recommended that physicians use only those cus that have
successfully passed the testing criteria of both societies.
Treatment decisions: clinic blood pressures, ambulatory blood pressures,
and home blood pressures
Currently, all guidelines for antihypertensive therapy are based on CBP
[109] because all major studies on the cardiovascular risks of hypertension
use CBP exclusively [116118]. Other blood pressure measurement
techniques, however, oer advantages over CBP. Repeated measurements
of blood pressure, with ABP or HBP, allow better assessment of patients
true blood pressures [112]. Furthermore, those patients who have elevated
blood pressure only in the physicians oce (white coat hypertension) may
be correctly identied. Also, those patients who have a normal blood
pressure in the physicians oce but elevated blood pressure at home
(masked hypertension) can be recognized. ABP allows the assessment of
diurnal blood pressure trends. Observational studies show that nocturnal,
nondipping blood pressures, dened as less than 10% reduction of
nocturnal systolic blood pressure, are associated with increased cardiovascular risk [119]. CBP, unable to measure nighttime blood pressures and
subject to measurement error, may underestimate this association between
blood pressure and cardiovascular risk [120]. Most importantly, studies
reveal that ABP correlate better with cardiovascular disease than CBP [121
123]. In one such study [124], hypertensive patients were divided by CBP
into JNC VI classes of hypertension (stages I, II, or III). Within each class,
there were patients with normotension on ABP monitoring, dened by
a systolic ABP less than 135 mm Hg. The normotensive patients had
signicantly fewer cardiovascular events than those patients who did not. In
multivariable analysis, ABP emerged as an independent predictor of
cardiovascular risk even after accounting for CBP. Data are also emerging
that the lack of nocturnal dipping in patients with type 1 diabetes mellitus
may be a marker of future diabetic nephropathy [125].
HBP monitoring provides a cost-eective tool for the assessment of
blood pressure [126]. HBP are generally lower than CBP; CBP of 140/90 mm
Hg generally correlates with HBP of 135/85 mm Hg [113,127131].
Additionally, HBP is more reproducible over time compared with CBP,
537
making HBP more useful in predicting cardiovascular disease [132]. For

example, Mule et al [133] reported that both ABP and HBP were superior to
CBP in predicting target organ damage (as measured by left ventricular
mass index, albumin excretion rate, and an index of cardiac, renal, and
retinal parameters) in hypertensive patients. Furthermore, Ohkubo et al
[134] performed a population-based, observational study of 1789 Japanese
subjects, aged greater than or equal to 40 years, who were followed for
a mean 6.6 years. HBP and CBP were obtained in these subjects at baseline.
After adjusting for cardiovascular risk factors, the authors found that only
the average of multiple (taken more than three times) systolic HBP values
were signicantly and strongly related to cardiovascular mortality risk,
indicating that HBP had a stronger predictive power for cardiovascular
mortality than did screening CBP.
Because of the growing data supporting ABP and HBP, all three blood
pressure measurements are important in managing hypertension. ABP
monitoring, however, currently is only reimbursed for the evaluation of
white coat hypertension. White coat hypertension occurs in patients who
have elevated CBP, but normal 24-hour ABP [112]. Approximately 10% of
all patients diagnosed with hypertension have white coat hypertension [112].
These discrepancies between blood pressures may be caused possibly by
increased sympathetic activity in these patients during clinic visits [135].
Whatever the etiology underlying white coat hypertension, these patients
cardiovascular risk is essentially the same as the normotensive population
[136]. Diagnosing white coat hypertension prevents inappropriate antihypertensive therapy.
A distinction needs to be made between white coat hypertension and the
white coat eect. The white coat eect occurs in patients with hypertensive
CBP whose ABP, although lower than their CBP, are still abnormally high
[112]. The white coat eect is quite common in hypertensive patients,
occurring in greater than 70% [112]. The importance of diagnosing the white
coat eect is that patients diagnosed with severe hypertension by CBP may
only have moderate hypertension on ABP monitoring. This provides patients
with a better prognosis. The magnitude of the white coat eect does not
correlate with left ventricular hypertrophy, attesting to its benign nature [136].
Blood pressure goals
The goals of treatment of hypertension are to reduce cardiovascular
morbidity and mortality. Whereas eective hypertensive treatment has
resulted in the decline of the prevalence of left ventricular hypertrophy and
cardiovascular mortality [137], the absolute risks for cardiovascular
mortality are still high in the industrialized world [138]. A meta-analysis
of cardiovascular morbidity and mortality in 1 million hypertensive adults
revealed that cardiovascular disease occurs in a continuous and graded
manner with higher blood pressures, starting from at least a threshold of
538
ANDERSEN & AGARWAL
usual blood pressure of 110/70 mm Hg and a single blood pressure of 115/

75 mm Hg even among the very old [116].
JNC VII has delegated reduced glomerular ltration rate as an
independent cardiovascular risk factor. At the extreme end of the spectrum
are ESRD patients who have very high cardiovascular morbidity and
mortality: 40% have coronary artery disease; 75% have left ventricular
hypertrophy; and 9% die every year from cardiovascular causes [139].
Data show that even mild renal failure (serum creatinine 1.4 mg/dL but
\ 2.4 mg/dL) in high-risk patients (namely patients with vascular disease or
diabetes mellitus and one other risk factor) had a 40% increase in the risk of
cardiovascular death, myocardial infarction, or stroke compared with those
patients with lower serum creatinine [140]. Whereas large data sets are not
available for vascular protection with blood pressure control in patients
with CKD, data nevertheless strongly support the need for blood pressure
control at least for reducing progression of kidney disease [141,142].
JNC VII guidelines recommend that patients with diabetes mellitus or
CKD, dened as a glomerular ltration rate less than 60 mL/min/1.73 m2
or albuminuria greater than 300 mg/d, have CBP targeted to less than 130/
80 mm Hg [109]. Data from the Modication in Diet in Renal Disease
Study, a study in which patients with CKD were randomized to various
protein restriction and blood pressure groups, revealed that those patients
with greater than 1 g/d of proteinuria had better outcomes when their blood
pressures were lowered to less than 125/75 mm Hg [143]. The National
Kidney Foundation has recommended this lower CBP goal in CKD patients
with proteinuria [144]. Although guidelines for ABP and HBP are not as
clearly dened for hypertensive CKD patients, ABP and HBP greater than
135/85 mm Hg are considered hypertensive by JNC VII [109]. The European
Society of Hypertension notes that ABP in high-risk groups should be less
than 130/80 mm Hg [112].
It is worth noting that systolic hypertension is of central importance for
blood pressure management. In a retrospective of patients with hypertension, systolic blood pressures correlated more strongly for cardiovascular
outcomes than diastolic blood pressures [117,145]. In the Multiple Risk
Factor Intervention Trial, a study developed in the 1970s to reduce
cardiovascular disease in men, relative risks for coronary heart disease
mortality in patients were increased with higher systolic blood pressures
compared with those with higher diastolic blood pressures. In the
Cardiovascular Health Study, a study that evaluated the cardiovascular
event rate of 5888 patients greater than or equal to 65 years in relationship
to blood pressure [118], higher systolic blood pressures, diastolic blood
pressures, and pulse pressures were all associated with increased cardiovascular events; however, systolic blood pressures had higher relative risks
for stroke and myocardial infarction than either diastolic blood pressures
or pulse pressures. Also, only systolic blood pressures in this study were
associated with total mortality.
539
Blood pressure management

Lifestyle modications, such as restriction of dietary sodium intake,
exercise, weight loss, limitation of alcohol intake, and cessation of smoking,
are of great importance but are often neglected in the management of
hypertensive CKD patients. Each of these modiable factors (high sodium
intake [146,147], increased body mass index [148], smoking [149,150], and
excessive alcohol intake [151]) has been independently linked to kidney
disease. The goal of antihypertensive therapy in CKD patients is to slow the
progression of renal disease and reduce cardiovascular morbidity and
mortality. Despite the general recognition that blood pressure control is the
single most eective method to delay progression of chronic kidney disease,
only 75% of patients with CKD are treated and only 11% controlled to a goal
blood pressure of less than 130/80 mm Hg. Forty-eight percent of such
individuals are prescribed only one antihypertensive drug. ACE inhibitors and
angiotensin receptor blockers (ARBs) are the backbone of antihypertensive
therapy in patients with CKD [109]. A meta-analysis of 1860 patients with
nondiabetic kidney disease also showed that ACE inhibitor use reduced the
risk for progression to ESRD by 31% [152]. ACE inhibitors have been shown
to slow the progression of diabetic nephropathy in type I and II patients [153
155]. In addition, ARB use in type II diabetic patients has been shown to be
eective in slowing the progression of diabetic nephropathy [153,154,156].
These data indicate that disruption of the reninangiotensinaldosterone axis
is benecial in high-risk patients with kidney disease because these agents,
besides lowering blood pressures, favorably alter glomerular hemodynamics
[153,157]. ACE inhibitors, in addition, abrogate sympathetic activation seen
in CKD [158]. Furthermore, reduction in proteinuria is considered benecial
for reduction of cardiorenal risk [159].
A meta-analysis of the major antihypertensive trials of the past decade
shows improved outcomes with better blood pressure control in patients with
essential hypertension [160]. Similar data are emerging that demonstrate
reduction in renal risk with lower blood pressure achieved in patients with
nephropathy. Control of blood pressure seems critical to the success of any
antihypertensive program. The National Kidney Foundation recommends
that when CKD patients have blood pressures greater than 15/10 mm Hg
above their goal blood pressures, two dierent agents should be started [144].
A good combination in this situation is a thiazide diuretic combined with
either an ACE inhibitor or an ARB. If the creatinine is high (glomerular
ltration rate \ 30 mL/min), a loop diuretic should be substituted in lieu of
a thiazide [161,162]. If blood pressures continue to be high, calcium channel
blockers or b-blockers can be sequentially added to the regimen followed by
other agents, such as clonidine, and vasodilators like minoxidil or hydralazine.
If patients have substantial proteinuria, both ACE inhibitors and ARBs can
be combined to reduce the proteinuria [163165]. This strategy, however,
needs to be tested in prospective trials to evaluate its risk-benet ratio.
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ANDERSEN & AGARWAL
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Med Clin N Am 89 (2005) 549561
Complications of Chronic Kidney

Disease: Anemia, Mineral Metabolism,
and Cardiovascular Disease
Shona Pendse, MD,
Ajay K. Singh, MB, MRCP(UK)*
Renal Division, Brigham and Womens Hospital, Harvard Medical School,
The publication of the Kidney Disease Outcome Quality Initiative

(K/DOQI) clinical practice guidelines for chronic kidney disease (CKD) in
2002 heralded a focus on CKD. Public bodies have embraced the
importance of CKD. The US Department of Health and Human Services
has made CKD a national focus area in its Healthy People 2010 report [1,2].
There is now a National Kidney Disease Education Program in place. The
National Kidney Foundation has embarked on an unprecedented national
screening initiative termed Kidney Early Evaluation Program that has
successfully screened over 40,000 individuals in the United States. Studies
using the Third National Health and Nutrition Examination Survey
(NHANES) estimate that 6.2 million Americans have serum creatinine
greater than 1.5 mg/dL [3]. The K/DOQI work group more recently
reassessed the NHANES III data and released estimates of the prevalence of
each of the ve stages of CKD [2,46]. Their repeat analysis suggests that 8.3
million individuals in the United States have CKD based on decreased
glomerular ltration rate (GFR) (less than 60 mL/min/1.73 m2) with an
additional 11.2 million individuals who have persistent proteinuria with
normal or mildly decreased GFR (60 mL/min/1.73 m2 or higher). Their
gures suggest that 3.3% of the population 20 years of age or older have
CKD stage 1 disease; 3% have stage II; 4.3% have stage III; 0.2 have stage
IV; and 0.2% have stage V (with stage V including those on dialysis) [2,46].
The early stages of CKD represent 10% of the United States population, as
E-mail address: asingh@partners.org (A.K. Singh).
doi:10.1016/j.mcna.2004.12.004
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PENDSE & SINGH
compared with less than 0.5% of the population with advanced (stages IV
and V) disease.
The impact of impaired kidney function on outcome has until recently
been underappreciated. Recent work indicates emphatically that there is
a graded relationship between the GFR and mortality, cardiovascular
events, and hospitalizations [7,8]. Although a poor and relatively unchanged
survival rate has been appreciated in the end-stage renal disease (ESRD)
population for several decades (5- and 10-year survival rates of 38% and
21%, respectively) [9,10], mortality is also an important problem in preESRD CKD patients [1116]. As patients progress to more advanced stages
of CKD, while the incidence of renal replacement therapy increases, there is
a twofold to threefold higher mortality. Furthermore, the level of renal
function seems to be one of the most important factors determining survival
after a myocardial infarction. Collectively, these studies suggest that
renalism, a term coined by Chertow et al [17], modulates outcome in
a signicant way and beyond the eect of a number of other factors [8].
In terms of public health dollars, kidney disease is an important problem.
ESRD patients represent less than 0.5% of the Medicare population, but
care of these patients necessitates more than 5% of the Medicare budget.
Kidney disease becomes more costly as the patient approaches ESRD. The
absence of optimal pre-ESRD care, particularly if referral to a nephrologist
has not occurred, accentuates the cost. Most patients with CKD are seen
late in the course of CKD by a nephrologist and are frequently seen during
the few months preceding the initiation of dialysis. Late referral to
nephrology occurs despite the fact that factors associated with adverse
outcomes in ESRD, such as bone disease, anemia, hypertension, and
malnutrition, are present very early in the course of CKD, well before the
development of ESRD and the need for initiation of dialysis [18,19].
Comorbidities in CKD patients seem to have a very signicant eect on
mortality [2024]. Patients who have CKD in the presence of anemia,
congestive heart failure, and/or diabetes mellitus have a mortality several fold
higher than an otherwise uncomplicated CKD patient [12,14,15,20,2426].
This article focuses on the importance of three major complications of
CKD: (1) anemia, (2) calcium-phosphorous regulation and bone disease,
and (3) cardiovascular risk proling and treatment. The arguments for early
and eective intervention have been amply made with respect to these three
complications. Yet, substantive trial data are sorely needed to provide the
denitive evidence that eective treatment of these complications results in
better outcomes.
Anemia of chronic kidney disease
Anemia is usually observed when the GFR falls below 60 mL/min/
1.73 m2 and worsens as both renal function and erythropoietin production
decline. In a multicenter study in Canada, the prevalence of anemia was
CKD: ANEMIA, MINERAL METABOLISM, & CVD
551
found to be approximately 25% in patients with creatinine clearance greater

than 50 mL/min [27]. By the time a patient reaches a GFR of 15 to
29 mL/min/1.73 m2, approximately 44% of patients are anemic (anemia
dened as a hemoglobin of \ 12 g/dL in men and \ 11 g/dL in women), and
by stage 5 CKD approximately 90% of patients are anemic [16,28,29].
NHANES survey data indicate that anemia is more common among nonHispanic black men and women compared with other racial groups even
after adjusting for renal function. Studies also suggest that diabetic CKD
patients may have anemia that is more severe than in nondiabetics after
adjusting for kidney function. CKD patients usually become symptomatic
when the hemoglobin level falls below 11 g/dL. The most common
symptoms are tiredness and fatigue. Anemia may also be associated with
cardiovascular manifestations, however, such as left ventricular hypertrophy
(LVH), worsening congestive heart failure, and myocardial ischemia.
Several studies suggest that anemia in CKD patients is associated with
reductions in health-related quality of life, impaired cognitive function, and
abnormalities in immune responses. The role of anemia as a major risk
factor in driving poor CVD outcomes has been suggested by several
observational and a few small prospective interventional studies.
The treatment of anemia in patients with kidney disease was transformed
by the cloning of erythropoietin in 1986 and its commercial availability
in 1989. Before this, anemia was either not being treated or various maneuvers, such as repeated blood transfusions or the use of anabolic steroids,
were the mainstay, especially among dialysis patients. Presently, treatment for anemia in both pre-ESRD and ESRD patients is strongly
recommended.
Anemia and its impact on mortality

There are substantial observational data to support a relationship
between anemia and mortality. A causal relationship between anemia and
mortality, based on adequately powered randomized trials, however, has
not been proven. Furthermore, data on the relationship between anemia and
survival has been almost completely focused on the ESRD population.
Among dialysis patients, several studies have documented that hemoglobin
levels of 10 g/dL or less is associated with a higher risk of death when
compared with levels greater than 10 g/dL. Indeed, hematocrit levels
maintained between 33% and 36% has been suggested in a number of
studies to be associated with the lowest risk of death. The argument favoring
treatment of anemia is based on outcome benets of meaningful magnitude
based largely in observational studies with large sample size; careful
modeling with adjustment for many factors; and the publication of smaller
prospective studies using surrogate outcomes to show benet (eg,
improvement in LVH with the treatment of anemia).
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Anemia and cardiovascular disease

LVH has been proposed as a major consequence of the anemia of CKD.
In a cross-sectional study by Levin et al [28], the prevalence of LVH detected
by echocardiography was observed to be 26.7% in patients with creatinine
clearance above 50 mL/min, 30.8% in patients with creatinine clearance 25
to 49 mL/min, and 45.2% in patients with clearances below 25 mL/min. In
a multivariate analysis by the same investigators, hemoglobin concentration
was found to be an independent risk factor for the development of LVH,
with 32% increased risk for LVH for every 0.5 g/dL decrease in hemoglobin,
as was creatinine clearance, with a 3% increase in risk of LVH for every
5 mL/min decline in GFR (P = .0168). Furthermore, only 15% of patients
have normal left ventricular structure and function at the start of dialysis,
and mortality caused by cardiovascular disease is 20- to 40-fold higher in
patients with ESRD than in the general population [30,31]. These ndings
suggest that patients are exposed to anemia for a lengthy period of time
before the development of ESRD, and that correction during this period
may be critical to the optimization of outcomes for these patients. Fink et al
[32] found that patients who received erythropoietin before initiation of
dialysis had improvement in survival compared with patients who did not
receive epoetin during this period. This work was based on data from
Medical Evidence Forms (Health Care Financing Administration 2728, now
the Centers for Medicare and Medicaid Services), which only species
whether or not epoetin was given in the pre-ESRD period, but does not
specify the length of time of treatment. A study of 11 patients with CKD
done by Portoles et al [13,33] demonstrated that partial improvement of
anemia was associated with signicant decrease in left ventricular mass
index from 178.2 20.6 g/m2 to 147.3 20.6 g/m2 and a trend toward
decreased left ventricular thickness. Another study by Hayashi et al [34]
showed similar reduction in left ventricular mass with anemia correction.
This study observed that left ventricular mass index tended to decrease after
a partial correction of anemia (hematocrit 32.1% 1.8%) at 4 months
(from a baseline of 140.6 12.1 g/m2 to 126.9 10 g/m2 after partial
correction), whereas it tended to signicantly decrease after normalization
of hematocrit at 12 months (hematocrit 39.1% 2.4%) to 111.2 8.3 g/m2.
A retrospective review of 89,193 Medicare patients with ESRD by Xue et al
[11] showed that patients who received consistent predialysis therapy with
erythropoietin had higher hematocrit at the start of dialysis and lower risk
of mortality 1 year after the start of dialysis.
The issue of the optimal target hemoglobin has been greatly debated over
the past few years. The United States National Kidney Foundation Dialysis
Outcomes Quality Initiative guidelines, initially published in 1997 and
revised in 2001, recommend a target hematocrit between 33% and 36% or
a hemoglobin concentration of 11 to 12 g/dL [3537]. The European Best
Practice Guidelines recommend a target hemoglobin of greater than 11 g/dL
553
or hematocrit greater than 33%, without a guideline for the upper limit
[38,39]. The United States Normal Hematocrit study evaluated 1233
hemodialysis patients with clinical evidence of congestive heart failure or
ischemic heart disease [40]. Of these, 618 patients were assigned to receive
increasing doses of epoetin to achieve and maintain a hematocrit of 42%,
and 615 were assigned to receive doses of epoetin adjusted to maintain
a hematocrit of 30, for a median duration of 14 months. After 29 months of
follow-up, there were 183 deaths and 19 rst nonfatal myocardial
infarctions in the normal-hematocrit group in contrast to 150 deaths and
14 nonfatal myocardial infarctions among those in the low-hematocrit
group. The risk ratio for the normal-hematocrit group as compared with the
low-hematocrit group was 1.3 with a 95% condence interval of 0.9 to 1.9.
The investigators halted the study prematurely given these unexpected
results and concluded that normalization of hematocrit was not recommended for hemodialysis patients with evidence of congestive heart failure
or ischemic heart disease [40]. In a study of nine predialysis patients,
Hayashi et al [34] found a reduction in left ventricular mass with partial
followed by full anemia correction.
Despite evidence supporting the treatment of anemia, especially for the
prevention of cardiovascular disease events and in reducing mortality, it is
clear that anemia is not optimally being corrected in most CKD patients,
both before and after referral to nephrologists. Valderrabano et al [41] in
their predialysis survey on anemia management performed a retrospective
chart review of 4333 new dialysis patients in 21 European countries, South
Africa, and Israel. They found that, at rst visit to a dialysis center, 68%
had hemoglobin levels at or below 11 g/dL, and only 26.5% of patients
received epoetin before the start of dialysis. Furthermore, they found that
more than 30% of the patients had been followed by a nephrologist less than
6 months before initiation of dialysis. In a review of more than 150,000
dialysis patients in the United States, Obrador et al [4144] observed that
a similar percentage (23%) of patients had been given epoetin before
initiation of dialysis. A review of more than 89,000 Medicare patients in the
United States by Xue et al [11] found an even lower percentage (15.6%) of
patients received erythropoietin in the pre-ESRD period.
Darbepoetin-a, the most recent therapeutic agent for renal anemia, was
commercially launched in 2001. The premise for the introduction of
darbepoetin-a is the observation that the greater the number of sialic acid
residues on erythropoietin, the greater the in vivo stability, and hence longer
the serum half-life [45]. Several clinical trials have demonstrated the
eectiveness of darbepoetin-a, both intravenously and subcutaneously, at
maintaining similar hemoglobin levels with less frequent dosing, usually
once-weekly for patients on three times per week recombinant erythropoietin [4653]. Notably, however, epoetin-a with a half-life one third of
darbepoetin-a (8 hours versus nearly 24 hours) seems also to be amenable to
extended dosing. In the PROMPT study, approximately 90% of patients
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maintain their hemoglobin at greater than 11 g/dL after conversion from

weekly subcutaneous administration epoetin-a to every other week
administration. Interestingly, over 75% of patients maintain the target
hemoglobin of greater than 11 g/dL dosed every 3 or 4 weeks.
Mineral metabolism and renal bone disease
The management of renal osteodystrophy and secondary hyperparathyroidism has undergone tremendous changes over the past several decades.
Studies undertaken in the early 1970s by Slatopolsky et al [54,55] in uremic
dogs demonstrated the eect of hypocalcemia in the development of
hyperparathyroidism, and that restriction of phosphorous intake in the
setting of advancing renal dysfunction prevented its occurrence. This was
then followed by a study by Goldsmith et al [56] that showed that infusions
of calcium could suppress parathyroid hormone (PTH) secretion in
hemodialysis patients. This led to a newly acquired ability to manage
secondary hyperparathyroidism with calcium repletion through supplementation of both calcium and calcitriol, phosphorous restriction in the diet,
and the use of highly potent aluminum-based phosphate binders [5760]. In
the following decade, growing concern as to the toxic eects of aluminum,
particularly in patients whose intrinsic ability to clear aluminum by the
kidneys was impaired, led physicians to be wary of the use of these products
as phosphate-binders, and once calcium-based binders became available in
the 1980s, these became largely the agent of choice [6163]. Although these
agents were not quite as eective as their aluminum-based counterparts,
they were considered safer given the risks of aluminum toxicity and
aluminum-related bone disease, characterized by a low-turnover state with
osteomalacia and adynamic bone [6467]. Adequate binding of dietary
phosphate with these calcium-based binders, however, because of their
reduced potency in comparison to aluminum-based binders, necessitated
large daily doses of calcium, which resulted in positive calcium balance and
diculties with hypercalcemia.
Over the past decade the focus of calcium-phosphorous management in
CKD has shifted to concerns regarding the signicant increase in
cardiovascular risk associated with extraskeletal calcication, particularly
in the coronary vasculature. Several landmark studies have highlighted this
issue. Braun et al [68] reported the prevalence of aortic and mitral valve
calcication, as determined by electron-beam CT, to be 55% and 59%,
respectively, in a series of patients on dialysis. In a later study, Block et al
[69] found that elevated calcium-phosphorous product over 55 was
associated with a signicant increase in mortality in these patients, and
those individuals in the highest quintile of the calcium-phosphorous
product, greater than 72, had a relative mortality risk of 1.34 relative to
those with products of 42 to 52. Goodman et al [70] used electron-beam CT
to evaluate the presence of coronary calcication in 39 young patients on
555
dialysis and 60 normal subjects and found that 14 of the patients on dialysis
had coronary calcication in contrast to only 3 of the normal subjects.
Furthermore, those patients with coronary calcication were found to be
older (26 3 versus 15 5 years, P \ .001) and to have been on dialysis for
a longer duration (14 5 versus 4 4 years, P \ .001). In addition, elevated
calcium-phosphorous product and use of calcium-based phosphate binders
were both found to be correlated with coronary calcication. In a follow-up
CT scan done in a subgroup of 10 of the patients with calcication, the
calcication score was increased close to twofold (125 104 initially to 246
216, P = .02), over a mean interval of 20 3 months [70].
These new concerns led to the search for non-aluminum and noncalciumbased therapy for phosphate binding. Sevelamer hydrochloride
(Renagel; Genzyme, Cambridge, MA), approved by the Food and Drug
Administration in 1998, was found in numerous clinical trials to control
serum phosphorous and calcium-phosphorous product eectively in dialysis
patients, while avoiding the positive calcium balance and hypercalcemia
induced by calcium-based binders [7177]. In addition, sevelamer has been
found to result in improvement in lipid prole, including reduction in total
cholesterol and low-density lipoprotein along with increase in high-density
lipoprotein levels [73,78]. This treatment was also found to result in fewer
hospitalizations and a corresponding reduction in medical costs, as
demonstrated by Collins et al [79] in a case-control study on Medicare
patients. They evaluated 152 patients on hemodialysis treated with
sevelamer with 152 non-sevelamertreated dialysis patients as their controls,
and found a 46% to 54% decrease in relative risk of hospitalization in the
sevelamer-treated patients compared with the control group, along with
a reduction in cost of $3368 (Medicare expenditures per member, per
month) in the sevelamer-treated patients compared with $4745 in the control
patients.
Vitamin D supplementation has been an essential element in the care of
renal patients since the early 1980s, after studies by Slatapolsky et al [8087]
showed the benet of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on secondary hyperparathyroidism. Numerous studies have shown calcitriol and
1a-hydroxyvitamin D3 to be eective in the prevention and treatment of
secondary hyperparathyroidism in renal patients. In a prospective, doubleblind, placebo-controlled trial of patients with mild to moderate renal
failure (creatinine clearances of 20 to 59 mL/min), however, bone biopsies
done at baseline and 1 year posttreatment showed signicant inhibition of
bone turnover in the calcitriol-treated group compared with placebo [88]. In
addition to this issue of precipitation of adynamic bone disease, also
concerning was its ability to cause positive calcium balance and
hypercalcemia. In response to these concerns, calcimimetic agents were
developed that modulate the extracellular calcium-sensing receptors found
on parathyroid cells, on calcitonin-secreting C-cells of the thyroid, in the
kidneys, and in the brain and bone cells, causing these receptors to become
556
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more sensitive to the inhibitory eects of calcium on PTH secretion [8991].

One such agent is paricalcitol (19-nor-1,25-dihydroxyvitamin D2), approved
by the Food and Drug Administration in 1998. This was found to suppress
PTH levels eectively while avoiding the changes in calcium and
phosphorous levels associated with calcitriol [92,93]. In addition, this agent
was found to suppress PTH levels in a prospective study of 39 patients with
calcitriol-resistant secondary hyperparathyroidism. The mean iPTH level
decreased from a baseline of 901 58 pg/mL during the initial 2 months to
165 24 pg/mL at 16 months. Alkaline phosphatase levels decreased from
280 27 IU at baseline to 65 12 IU at 16 months. Mean calcium and
phosphorus levels did not change signicantly over the 16 months [92,93]. In
a recent large historical cohort study of hemodialysis patients done by Teng
et al [94], the 36-month survival rate was compared among 29,021 patients
on paricalcitol treatment and 38,378 patients on calcitriol between 1999 and
2001. Their ndings revealed a signicant survival advantage in the
paricalcitol-treated patients (mortality rate of 0.180 per person year in the
paricalcitol group compared with 0.223 in the calcitriol-treated patients),
which was independent of baseline calcium, phosphorous, and PTH levels.
In the adjusted analysis they found a 16% reduction in mortality in the
paricalcitol-treated patients compared with the calcitriol-treated group. The
dierence in survival was signicant at 12 months and increased with time.
They also performed a subgroup analysis of patients who switched from one
agent to the other, and found a signicant survival advantage in those
patients who transitioned from calcitriol to paricalcitol (73% 2-year survival
rate) as opposed to those who switched to calcitriol from initial therapy with
paricalcitol (64% survival at 2 years).
Cardiovascular risk proling and treatment
The high prevalence of cardiovascular disease in dialysis patients has
been well-described, particularly LVH [30,9598]. Parfrey et al [99] found
that the likelihood of de novo heart failure after the initiation of dialysis is
approximately 80% within the rst year, and that the combination of
congestive heart failure and LVH is a predictor of poor survival [30,97,100].
This cardiovascular risk was observed to be 65-fold higher in dialysis patients
in the 45- to 54-year age category compared with the general population
[101,102]. In patients with very mild degrees of renal insuciency, this
increase in risk was found to be approximately threefold [103].
This increase in cardiovascular risk in patients with CKD is multifactorial, arising as a result of calcium-phosphorous dysregulation and
extraskeletal calcications; anemia with its associated increase risk of
LVH; along with the well known associations with CKD of hypertension,
diabetes, and dyslipidemia. Also included in this list of contributors is
hyperhomocysteinemia, a common metabolic consequence of renal failure.
A 10 lmol/L increase in plasma homocysteine concentration has been found
557
to be associated with a 1.8-fold increased risk of cardiovascular events. The

plasma concentration of asymmetric dimethyl-L-arginine, an inhibitor of
nitrous oxide synthase found endogenously, has been found to be increased
early in the course of renal disease, even in the presence of a normal GFR
[104]. A 2.7 lmol/L increase in plasma levels, which is the average dierence
in concentration between patients with CKD and normal subjects, has been
associated with a greater than threefold increase in risk of cardiovascular
events [105].
The future: the new arena of chronic kidney disease management, a focus on
cardiovascular risk minimization
CKD management has evolved a great deal over the past several years.
There is now mounting evidence that suggests that patients have a much
higher risk of cardiovascular disease than the general population even at the
earliest stages of CKD. It is increasingly becoming evident that complications thought to exist only in advanced kidney disease, such as anemia and
calcium-phosphorous dysregulation, are actually present much earlier in the
course of renal dysfunction, and that correction of these factors in these
early stages results in optimization of outcomes in these patients. It is
critical, however, that knowledge in these arenas be increased, because many
questions still remain unanswered.
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Med Clin N Am 89 (2005) 563585
Treatment of Acute Coronary

Syndromes in Patients Who Have
Rory OHanlon, MB, BMedSci, MRCPIa,
Donal N. Reddan, MB, MHS, MRCPIb,c,*
a
Division of Cardiology, University College Galway Hospital, Galway, Ireland

b
Division of Nephrology, University College Galway Hospital, Unit 1,
Merlin Park Hospital, Galway, Ireland
c
Division of Nephrology, Department of Medicine, Duke University,
Durham, NC, USA
Chronic kidney disease (CKD) is an important risk factor for

cardiovascular morbidity and mortality [1], yet evidence regarding treatment
of ischemic heart disease among CKD patients remains limited. Mild CKD
dened as a glomerular ltration rate (GFR) less than 60 mL/min/1.73m2 is
nearly 10 times more prevalent than end-stage renal disease (ESRD). The
National Health And Nutrition Epidemiology Survey estimates that renal
disease aects at least 3 million people in the United States alone [2], and
although the impact of dialysis-dependent renal failure on cardiovascular
diseases has been studied to some extent, milder forms of CKD may not yet
have been suciently investigated. Analyses of the associations of CKD are
dicult to compare because of unclear denitions of what constitutes CKD
and how to measure it exactly. Often in the cardiovascular literature a serum
creatinine less than 1.5 mg/dL has been used to identify normal renal
function and a creatinine greater than or equal to 1.5 mg/dL has been used
to identify CKD. The consistent use of GFR measured either directly or
indirectly using approximation formulae, as opposed to serum creatinine,
increases the accurate identication of patients with abnormal renal
function and identies a greater number of patients with CKD. The
approximation formula currently recommended by the National Kidney
* Corresponding author. Division of Nephrology, University College Galway Hospital,

Unit 1, Merlin Park Hospital, Galway, Ireland.
E-mail address: donal.reddan@whb.ie (D.N. Reddan).
doi:10.1016/j.mcna.2004.11.008
564
OHANLON & REDDAN
Foundation is the equation developed by the Modication of Diet in Renal

Disease Study Group, because this has an even greater correlation with
renal function than the Cockroft-Gault formula [3,4].
ESRD mortality continues to approximate 19.5% at 1 year with 50% of
deaths attributable to cardiac disease. Mortality following myocardial
infarction (MI) is 16- to 19-fold higher among patients with ESRD
compared with the general population [5]. The association between CKD
and poor cardiovascular outcomes may at least partially be attributable to
advanced age and greater prevalence of comorbidities, such as hypertension
and diabetes. But CKD itself has also been shown to be an independent
predictor of cardiovascular mortality in a number of analyses [68].
Acute coronary syndrome (ACS) constitutes a clinical syndrome that is
usually, but not always, caused by atherosclerotic coronary artery disease
(CAD). This term has evolved to refer to any constellation of clinical
symptoms that are compatible with acute myocardial ischemia. It encompasses acute ST-elevation MI (STEMI), nonST-elevation MI (NSTEMI),
and unstable angina. The approach in this article to the treatment of ACS in
patients with CKD focuses on the treatment of STEMI and NSTEMI
unstable angina. The grouping together of NSTEMI and unstable angina
simplies the process of management because these conditions are managed
in the same manner initially.
For patients with ACS there is a wide range of therapeutic modalities
with varying indications. CKD patients are less likely to receive aggressive
therapy, such as thrombolytic therapy or primary angioplasty, even
though they may gain substantially from such treatments [9]. Benets of
therapy must be balanced with perceived risk of adverse outcomes caused
by therapy [10], but benets are often dicult to quantify because clinical
trials have typically excluded patients with more severe CKD [11,12]. The
optimal methods of restoring perfusion-revascularization in patients with
CKD are controversial. A summary of the recommendations is outlined
in Box 1.
Diagnosis
History
Patients presenting to the emergency department with symptoms
suggestive of myocardial ischemia should be urgently triaged and assessed
or managed according to the American College of Cardiology (ACC)
American Heart Association (AHA) guidelines for acute myocardial
infarction (AMI) [13,14].
The suspicion of ACS is rst based around the presenting history. The
characteristics of angina are described in the ACC/AHA/ACP-ASIM
Guidelines for the Management of Patients With Chronic Stable Angina
[15]. Patients with ACS may have all the features of typical angina except
ACS TREATMENT IN CKD PATIENTS
565
Box 1. Acute coronary syndrome management suggestions

among patients with chronic kidney disease
Oxygen therapy and nitrate therapy
No dose adjustment
Aspirin
300 mg immediately followed by 75 mg once daily
300 mg clopidogrel stat in STEMI; consider in all patients
undergoing direct infarct percutaneous coronary
intervention
Morphine sulfate
GFR > 50: no dose adjustment
GFR = 1050: use 75% of normal starting dose
GFR < 10: use 25%50% of normal starting dose
b-Blockade
Atenolol: maximum dose of 50 mg once daily if GFR = 1535.
Maximum dose 25 mg once daily if GFR < 15
Bisoprolol: 2.5 mg once daily if GFR < 40 and careful
uptitration
No dose adjustments for metoprolol or carvedilol
Thrombolysis
No dose adjustment in CKD
GFR < 30: consider once daily enoxaparin if tenecteplase is
thrombolytic of choice
Percutaneous coronary intervention
Consider as first choice in STEMI. Abciximab safe as adjunct.
Stenting preferable and consider drug-eluting stent to reduce
chance of repeat revascularization and contrast nephropathy.
Consider bivalirudin as alternative to heparin.
Low-molecular-weight heparin
Once daily enoxaparin if GFR < 30
that the episodes are new or are more severe, prolonged, or may occur at
rest. Atypical features in history including pleuritic chest pain or
reproduction of chest pain on palpation do not exclude ACS. In one study
22% of patients presenting with pleuritic chest pain actually had suered an
ACS and 7% with chest pain reproducible by palpation were ultimately
found to have had an ACS [16]. Patients with CKD are at a higher risk for
silent ischemia and atypical presentation during an ACS [17]. Angina is
often absent in patients with ESRD and CAD and was present in only 17%
in one study [18]. The silent ischemia presentation is also more prevalent in
566
OHANLON & REDDAN
diabetic subgroups, which are represented more frequently in the CKD

population. A high index of suspicion for diagnosis of ACS is prudent in
patients with CKD given the increased incidence of cardiovascular disease in
this subgroup. Risk factors for ischemic heart disease are more prevalent
in patients with CKD and, as among diabetics, symptoms even partially
suggestive of cardiac pathology should be taken seriously and investigated.
Electrocardiogram
Electrocardiogram (ECG) is critical not only to add support to the
clinical suspicion of a possible STEMI-NSTEMI but also provides
prognostic information [19]. Although imperfect, the 12-lead ECG lies at
the center of the decision pathway for the evaluation and management of
patients with acute ischemic discomfort. Patients with ST-segment elevation
of greater than or equal to 0.1 mV in greater than or equal to two
contiguous leads have an AMI in greater than 90% of cases and should be
considered candidates for acute reperfusion therapy [20]. The interpretation
of ECG changes in ACS should be based on the ACC-AHA guidelines
[13,14]. In patients with CKD the prevalence of baseline ECG abnormalities
is increased and diculties in interpretation and diagnosis are common. To
begin with, given the high incidence of hypertension and left ventricular
hypertrophy in the CKD population ECGs are often dicult to interpret
(baseline ST depression, T-wave inversion, left bundle branch block) in the
presence of chest pain. Concurrent medications, electrolyte abnormalities,
and conduction abnormalities can also lead to ECGs that are dicult to
interpret in the setting of suspected myocardial ischemia. Interestingly,
however, in albeit a small study, Van Lente et al [21] showed no dierences
in ECGs in patients presenting with suspected ACS with normal versus
abnormal renal function.
Cardiac markers
The interpretation of elevated serum cardiac markers of myocardial
necrosis in patients with CKD is controversial. The more traditional
markers of myocardial cell necrosis, such as creatine kinase (CK),
myocardial band isoenzyme (MB)-fraction of CK, and myoglobin, are
commonly increased in CKD patients even in the absence of clinically
suspected myocardial ischemia [22,23]. Although cardiac troponins are
more specic markers of myocardial necrosis, they are frequently elevated
in patients with renal failure in the absence of myocardial necrosis [24,25].
Unfortunately, most studies that have demonstrated the importance of
cardiac troponin elevation in risk stratication, prognosis, and therapeutic
use have excluded patients with CKD [26,27], although technically a large
number of patients with mild CKD are actually included in the
randomized population included in the analysis. Freda et al [28] report
that troponin T elevations are present in up to 71% of patients with ESRD
567
without clinical or electrocardiographic evidence of acute ischemia using

the rst-generation assays and that more sensitive second-generation assays
led to greater specicity. Troponin I, however, was elevated in only 7% of
patients with ESRD. Using the most current assays, troponin T is more
frequently elevated than troponin I in renal failure patients.
The contribution of small areas of clinically silent myocardial necrosis to
the elevated troponin levels in CKD patients may be underrecognized.
Pathologic evidence exists documenting the presence of such microinfarctions in patients with elevated troponins [29]. It is possible that given
the high incidence of CAD and left ventricular hypertrophy in CKD
patients that they are more likely to suer such clinically silent events
[30,31]. In one study, all patients with CKD, elevated troponin T, and no
clinical evidence of AMI had cardiac pathology consisting of either recent
MI-microinfarct, healing microinfarct, heart failure or degenerative
changes, or other myocardial pathology [32].
Elevation of cardiac troponin in CKD patients has been attributed to
decreased renal clearance but this may not be entirely the case [33,34].
Troponin T (bound and free) is relatively large molecules similar to albumin
making it unlikely that clearance is renal dependant. Furthermore,
improvement in renal function after renal transplant has been reported
not to alter the occurrence of elevated serum troponin [35]. Indeed, most
studies have failed to show a relationship between serum creatinine and
overall frequency or degree of troponin elevation. Recently, however, Diris
et al [36] have demonstrated that troponin I is fragmented into molecules
small enough to be cleared by the kidneys of healthy subjects and that
impaired renal function causes accumulation of these troponin I fragments,
suggesting that this is the likely explanation of the unexplained elevations of
serum troponin I found in patients with severe renal failure. Troponin is
an important prognostic marker in patients with ESRD and no suspicion
for myocardial ischemia because it is associated strongly with all-cause mortality and fatal cardiovascular disease outcomes [37].
In the setting of ACS and patients with CKD the interpretation of
elevated serum troponin is more challenging. Studies have conrmed that in
this setting troponin T and troponin I are more sensitive and specic than
CK-MB for predicting myocardial ischemia but less predictive of adverse
outcomes than in patients with normal renal function [21,38,39]. In a recent
analysis of over 7000 patients from the Global Use of Strategies To Open
(GUSTO IV) occluded coronary arteries ACS trial, the prognostic value of
cardiac troponin T was not diminished in patients presenting with CKD and
suspected ACS [40]. Patients who present with ACS and CKD in
combination with elevated troponin T had the highest overall risk of death
or AMI.
Elevated troponins in the setting of ACS are powerful predictors of
morbidity and mortality and a time-appropriate rise and fall of the
biomarker is important in the diagnosis of ACS in both the CKD and
568
OHANLON & REDDAN
non-CKD population. These elevations should rarely be considered

spurious because elevated biomarkers are powerful predictors of mortality.
Importantly, two important implications arise from the increased frequency
of elevated troponins in patients with CKD. Given that CKD is common in
patients with coronary disease, the ability of cardiac troponin levels to
predict the outcome irrespective of creatinine clearance (CrCl) rate expands
their clinical usefulness. Second, elevated troponins are used to risk stratify
and guide therapeutic decisions in ACS patients, such as low-molecularweight heparins, glycoprotein (GP) IIb-IIIa inhibitors, and aggressive
treatment following cardiac catheterization. In particular, these therapies
are emerging as being particularly benecial in ACS and elevated troponin
subgroups [4143]. More patients in the future with CKD-ACS and elevated
troponins may be treated more aggressively based on the high risk
associated with the combination.
Initial management
The optimal management of ACS-NSTEMI has the twin goals of the
immediate relief of ischemia and the prevention of serious adverse
outcomes, such as death, MI, or reinfarction. This is best accomplished
with an approach that includes anti-ischemic therapy, antiplatelet and
antithrombotic therapy, ongoing risk stratication, and the use of invasive
procedures. Routine measures for patients presenting with suspected ACS
after rapid triage and determination of eligibility for reperfusion therapy is
to administer oxygen, nitroglycerin, and aspirin, and provide adequate
analgesia. Patients with CKD should be managed in the same way.
Established standards of care for ACS in non-CKD groups should still be
followed in the CKD population.
Anti-ischemic therapy
The administration of oxygen, nitrates, aspirin, and opiate analgesia
should apply for all patients presenting with a suspected ACS regardless of
renal function. ACC-AHA guidelines, however, recommend morphine
sulfate administered intravenously at a rate of 2 to 4 mg every 5 minutes.
Patients with renal failure are sensitive to the sedative and respiratory
depressant eects of opioids, and a major problem is the accumulation of
active or toxic metabolites. Morphine is metabolized in the liver mainly to
morphine-3-glucoronide and morphine-6-glucoronide, the latter of which is
the potent analgesic. Accumulation of morphine metabolites in renal failure,
particularly morphine-6-glucoronide, leads to morphine intoxication (eg,
prolonged central nervous system and respiratory depression and neurologic
side-eects, such as myoclonus) [44]. Starting doses of 25% to 50% of the
normal starting dose have been suggested in severe renal failure (GFR \ 10
mL/min) [45]. For GFR greater than 50 mL/min no dose adjustments are
569
necessary, and for a GFR of 10 to 50, 75% of the regular dose should be
used [46,47].
The use of b-blockers in ACS serves to blunt the heart rate and
contractility responses to chest pain and decrease cardiac work and
myocardial oxygen demand. They should be started early in the absence of
contraindications. There is no evidence that any member of the b-blocker
class is more eective than another, except that b-blockers without intrinsic
sympathomimetic activity are preferable. An overview of double-blind,
randomized trials of b-blocker use in patients with a threatening or
evolving MI suggests an approximately 13% reduction in the risk of
progression to AMI [48]. Many of the recommendations of b-blocker use in
ACS patients, however, have been extrapolated from experience and data
showing benet in CAD patients who have other types of ischemic
syndromes (stable angina, AMI, or heart failure). For patients with CKD
the choice of b-blocker may be more relevant. Carvedilol, a nonselective
b-blocker with a-1 blocking activity, has recently been shown to improve
renal blood ow in heart failure and hypertensive patients and improve
insulin sensitivity, actions not observed in other b-blockers. Giugliano et al
[49] studied the metabolic and cardiovascular eects of carvedilol and
atenolol in noninsulin-dependent diabetic and hypertensive patients. The
study was undertaken based on the premise that diabetic patients are
considered less suitable for b-blockade because of an increased risk of
impaired glucose tolerance attributed to a worsening of insulin resistance
and the deterioration of lipoprotein metabolism caused by these agents [50].
They found that fasting glucose and insulin levels decreased during
carvedilol treatment and increased during atenolol treatment. The
hemoglobin A1c level decreased by 1.4% in the carvedilol group and
increased by 4% in the atenolol group. Glucose disposal increased by 20%
during carvedilol treatment but decreased by 16% during atenolol
treatment. This advantage has led authors to suggest carvedilol to be
the b-blocker of choice in diabetic patients and diabetics with CKD [51].
In comparative studies with an angiotensin-converting enzyme inhibitor,
b-blocker, diuretic, or calcium-channel blocker, carvedilol was shown to
reduce microalbuminuria to a greater extent than the other agents tested
[52]. Data also indicate that GFR and renal blood ow are not signicantly
changed and renovascular resistance is decreased following chronic use of
carvedilol in patients with essential hypertension [53]. For this reason, if no
contraindications for b-blockade exist in a patient with an ACS and CKD
carvedilol may be more ecacious in the short and long term, especially in
diabetic subgroups.
The choice of b-blockade is also inuenced by the pharmacokinetics and
clearance of the medication. In general, lipophilic b-blockers are metabolized in the liver, whereas hydrophilic agents are eliminated in the kidneys as
unchanged drugs. Doses have to be adjusted according to renal function in
the case of atenolol, carteolol, nadolol, sotalol, and acebutolol. Bisoprolol is
570
OHANLON & REDDAN
eliminated 50% by the liver and 50% by the kidneys [54]. Manufacturer
guidelines recommend a maximum daily dosage of atenolol of 50 mg if the
CrCl is between 15 and 35 mL/min and 25 mg once daily if the CrCl is less
than 15 mL/min. The dose of bisoprolol should be 2.5 mg once daily in
patients with cirrhosis or a CrCl less than 40 mL/min and caution should be
used in dose titration. There are no recommendations for altering doses for
metoprolol or carvedilol in patients with CKD.
Antiplatelet therapy
Antithrombotic therapy is essential to modify the disease process and its
progression to death, MI, or recurrent MI. A combination of aspirin,
unfractionated heparin, and a platelet GP IIb-IIIa receptor antagonist
represents the most eective therapy. The intensity of treatment is tailored to
individual risk, and triple antithrombotic treatment is used in patients with
continuing ischemia or with other high-risk features and in patients deemed
for an early invasive strategy. Unfortunately, data on the use of these agents
in patients with CKD are sadly lacking.
Aspirin forms part of the early management of all patients with suspected
AMI and should be given promptly at a dose between 160 and 325 mg and
continued daily indenitely. The Second International Study of Infarct
Survival has shown conclusively the ecacy of aspirin alone for treatment of
evolving AMI, with a 35-day mortality reduction of 2.4% [55]. When
combined with streptokinase the reduction in mortality was 42%. In a
dose of 160 mg or more aspirin produces a rapid clinical antithrombotic
eect caused by immediate and near-total inhibition of thromboxane
A2 production. At present there are no recommendations to change this
dosage in patients with CKD and there are scant data on the ecacy of
aspirin in CKD. Although the risk of vascular thrombotic events is high in
patients with CKD, there is also an increased risk of both intracranial
hemorrhage and gastrointestinal bleeding with aspirin use; whether the
risk:benet ratio still favors aspirin use among patients with CKD is uncertain [56,57]. One example of a dierence in the biologic eect of aspirin in
patients with and without CKD was revealed in a study in which 100 mg/m2
of aspirin increased the bleeding time in CKD patients, which is not seen in
those with normal renal function [58]. A recent study of 1724 patients who
presented with an AMI who were categorized into quartiles based on their
renal function again demonstrated that aspirin and b-blocker use was lower
in patients with the lowest CrCl [59]. Importantly, also there was a signicant
risk reduction associated with aspirin and b-blocker use across all quartiles
of renal function. Berger et al [60] also performed a similar study on the use
and ecacy of aspirin and b-blockade in patients with ESRD and an AMI.
The uses of aspirin, b-blockade, and angiotensin-converting enzyme inhibition were less likely in those with ESRD despite the fact that the benet of
these therapies on 30-day mortality was similar among ESRD patients and
571
non-ESRD patients. These studies suggest that aspirin and b-blockers are
eective among patients with CKD. In patients with normal renal function,
newer antiplatelet therapies, such as clopidogrel in combination with
aspirin, reduce major adverse cardiovascular events more than aspirin alone
in those with NSTEMI and postangioplasty and stent insertion [61,62]. The
platelet eects of clopidogrel are irreversible but take several days
completely to manifest. Indeed, in some centers the use of clopidogrel
bisulfate is a relative contraindication to performance of renal transplant
surgery. The combination of aspirin and clopidogrel has not as yet been
studied in the treatment of acute STEMI. Patients with mild or moderate
CKD, however, may not have the same benecial eects from standard
therapy with clopidogrel and aspirin [63]. Further studies are needed to
determine prospectively if there is a role for clopidogrel therapy in the
prevention of cardiovascular events among patients with CKD. Interestingly, the use of 75 mg per day clopidogrel in dialysis patients in one study
was not shown to prolong time to hemostasis on removal of the dialysis
needle, nor was it associated with an increase in bleeding [64]. Of note, this
was not a study looking at the combination of aspirin and clopidogrel. For
the time being, without any evidence to the contrary, clopidogrel, 300 mg,
should be administered with between 160 and 300 mg of aspirin for all
patients presenting with ACS-NSTEMI and both thereafter are administered at 75 mg per day in patients with normal renal function and patients
with CKD. The addition of a platelet GP IIb-IIIa inhibitor in patients
receiving aspirin, clopidogrel, and heparin in the CURE trial was well
tolerated; however, fewer than 10% of patients received this combination.
Additional information on the safety of the addition of heparin (lowmolecular-weight heparin or unfractionated heparin) and a GP IIb-IIIa
inhibitor in patients already receiving aspirin and clopidogrel is probably
required. Also, it is not known whether clopidogrel improves the outcome in
patients who received GP IIb-IIIa antagonists not deemed for early
revascularization.
Anticoagulants
Anticoagulants available for parenteral use include unfractionated
heparin; various low-molecular-weight heparins; and a number of direct
thrombin inhibitors, such as hirudin and bivalirudin. The heparins
are important in both STEMI and NSTEMI. In general, these strategies
are aimed at preventing the generation of or blocking the activity of
thrombin, which plays a pivotal role in thrombotic events, and antithrombotic agents have been used in both medical and interventional therapeutic
approaches for ACS since the 1960s. The approach to anticoagulation for
patients with CKD and ACS is more complex and has been recently
reviewed [65]. Because patients with renal disease and subgroups of these
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OHANLON & REDDAN
patients are usually excluded from clinical trials for ACS, knowledge about
pharmacokinetics for drugs and the best approach to treating these patients
is insucient. The choice of heparin is important in CKD patients.
Unfractionated heparin is often used in the management of patients with
unstable angina and NSTEMI. Unfractionated heparin has important
pharmacokinetic limitations that are related to its nonspecic binding to
proteins and cells. These properties lead to a poor bioavailability at low
doses and a marked variability in anticoagulant response among patients
[66]. Clinical trials have indicated that a weight-adjusted dosing regimen
could provide more predictable anticoagulation than the xed-dose regimen
[67,68]. The regimen suggested is a bolus of 60 to 70 U/kg (maximum
5000 U) and an initial infusion of 10 to 15 U/kg (maximum 1000 U/h) for
a target activated partial thromboplastin time value of between 60 and 80
seconds [66]. The metabolism and excretion of unfractionated heparin is by
the liver and kidney [69] and at higher doses the proportion of the drug that
is renally cleared increases [69]. High peak levels and prolonged heparin
activity have been reported in patients with impaired renal function (serum
creatinine > 120 mmol/L) undergoing aortic surgery, which results in an
increase in the requirement for blood replacement [70]. The US Food and
Drug Administration labeling for heparin does not carry any warnings
about renal insuciency, however, and neither the package insert nor
standard recommendations on dosing recognize the need for doseadjustment in cases of CKD [71]. In the setting of thrombolysis
unfractionated heparin is given with all the thrombolytics except tenecteplase, which is licensed to be given with low-molecular-weight heparin
(enoxaparin) based on the ASSENT III trial results [72]. The use of lowmolecular-weight heparin has simplied greatly the treatment of ACSNSTEMI and STEMI (if tenecteplase is the thrombolytic agent of choice) in
that it is easy to administer, is prescribed at xed doses, does not in general
require any monitoring of anticoagulant eects, and carries a reduced risk of
heparin-induced thrombocytopenia or osteoporosis [73]. Because lowmolecular-weight heparin is renally cleared, however, it should be used
with caution in patients with CKD. Small clinical trial results have
conicting data on kinetics of low-molecular-weight heparin in patients with
CKD. Some of these studies have shown that after a single subcutaneous
injection of low-molecular-weight heparin, the half-life of the drug is
signicantly prolonged [74,75]. In addition, there are no published multidose
pharmacokinetic studies on low-molecular-weight heparin that evaluate the
possible accumulation of anticoagulant activity in patients with severe renal
impairment. There are, however, numerous reports of hemorrhagic
complications that have occurred in patients treated with low-molecularweight heparin with concurrent CKD [76]. Because low-molecular-weight
heparin levels cannot be measured directly, anti-factor Xa levels are
measured as a biomarker of low-molecular-weight heparin treatment [77].
Unfortunately these assays are not readily available. Product information
573
for enoxaparin states that at prophylactic doses the elimination of

enoxaparin is not signicantly modied in patients with mild (CrCl 5080
mL/min) to moderate (CrCl 3050 mL/min) renal impairment but caution is
advised. For those with a CrCl of less than 30 mL/min therapeutic doses
should be administered once per day rather than the normal twice daily
approach. No pharmacokinetic parameters are available at higher doses in
patients with mild, moderate, or severe renal insuciency.
Direct thrombin inhibitors may be an alternative to heparin in the
management of cardiovascular disease in cases where heparin use may be
associated with an increase in bleeding risk, such as in CKD. Although
argatroban may seem to be advantageous because it is primarily hepatically metabolized, it has not been tested in large percutaneous coronary
intervention (PCI) or ACS populations. Bivalirudin is a semisynthetic
inhibitor of thrombin approved by the Food and Drug Administration for
use as anticoagulation in patients with ACS undergoing PCI. Although
renally excreted, there are Food and Drug Administration approved
adjustments for all degrees of renal impairment, including dialysisdependence, provided by the manufacturer [78]. Dosage adjustment is
advisable in patients with moderate and severe renal impairment who
receive bivalirudin because of increased plasma levels in CKD and
evidence of strong correlation between activated partial thromboplastin
time and plasma bivalirudin levels [78]. In patients with mild to moderate
CKD, bivalirudin may be an alternative to unfractionated heparin because
of the lower bleeding risk associated with bivalirudin. Clinical trials
examining the use of bivalirudin for ACS have shown it to be superior to
heparin for thrombin inhibition, and it has a signicantly reduced
incidence of bleeding in patients with ACS and in patients undergoing
PCI [79,80]. The Hirulog and Early Reperfusion or Occlusion-2 study set
out to compare bivalirudin and heparin in patients undergoing brinolysis
with streptokinase for AMI [81]. In this study bivalirudin was associated
with an increase in mild to moderate bleeding rates and was not associated with a reduction in mortality. Dosage adjustment is advisable in
patients with moderate to severe renal impairment because of increased
plasma levels and evidence of a strong correlation between activated
partial thromboplastin time and plasma bivalirudin levels (D. Sicca,
unpublished observations). Because patients with CKD have a higher
incidence of major bleeding independent of anticoagulant therapy, any
therapy that may increase this risk needs to be considered carefully.
Studies to evaluate these and other compounds used in the management of
patients with cardiac and renal disease are needed to guide clinicians to
avoid untoward harm from improper dosing. Importantly, no trial as yet
has showed a statistically signicant reduction in their primary end point
with the use of hirudin or bivalirudin in patients with unstable angina,
NSTEMI, or ACS [82,83]. No direct antithrombin has as yet been
approved for management of unstable angina, NSTEMI, and ACS.
574
OHANLON & REDDAN
Thrombolysis
When considering a patient for pharmacologic reperfusion with
intravenous thrombolysis, an important consideration is the risk of
systemic or intracranial bleeding as a result of the treatment. The
likelihood of patients with CKD and ACS of receiving therapies proved
to reduce mortality is inversely related to the severity of renal failure [84].
Thrombolysis is a potential benecial therapy in CKD-ACS patients and
2-year mortality data available from the USRDS comparing CKD-ACS
patients who do not receive coronary reperfusion therapy with CKDACS patients who did showed mortality gures of 78% and 60%,
respectively. In a comorbidity-adjusted Cox model, thrombolytic therapy is
associated with a 28% reduction in all-cause death risk [85]. The fear of
potential complications, such as hemorrhage, and the unavailability of
clinical trial outcome data for thrombolysis in patients with ACS and
coexistent CKD has potentially contributed to the reduced chance of these
patients receiving benecial therapies and hence possibly also the poor
outcome of CKD patients post-ACS. Withholding treatment in this group
may have negative consequences. Thrombolytics are in fact used safely in
dialysis populations for the treatment of occluded-thrombosed hemodialysis access grafts [8688].
The tissue plasminogen activators tenecteplase and reteplase constitute
the newest and most conveniently administered bolus brinolytics (streptokinase is no longer available as a thrombolytic therapy in the United
States since it has gone o the market). Their simplicity in administration
reduces the potential for medication errors and simplies the process of
prehospital thrombolysis [89]. Trials involving tenecteplase, however,
excluded patients with CKD [89,90]. The metabolism of thrombolytics is
primarily hepatic and currently there are no dosage adjustments suggested
by the manufacturers based on a patients CrCl.
Percutaneous coronary intervention

Patients with CKD have a predisposition toward accelerated atherosclerosis [91]. Although studies have shown improved prognosis in CKD
patients undergoing surgical or percutaneous revascularization, several
small studies focusing on ESRD patients undergoing balloon coronary
angioplasty have shown poor success rates and long-term event-free survival
among dialysis patients [92,93]. Since the advent of coronary stents and
a variety of debulking techniques the outcome post-PCI has vastly improved
in complex lesions [94,95]. Rubenstein et al [96] studied the immediate and
long-term outcomes of patients with varying degrees of renal failure
undergoing percutaneous revascularization with and without stents. They
identied 362 (11%) of 3334 patients undergoing percutaneous coronary revascularization with preprocedural creatinine levels greater than 1.5 mg/dL.
575
This group of patients tended to be older, had more severe disease, and
greater comorbidities. Importantly, the CKD patients were more likely to
present with MI, cardiogenic shock, and congestive cardiac failure and less
likely to present with stable or unstable angina. In the CKD group stent use
increased from 9% to 56% between 1994 and 1997 and the procedural
success rate from 84% to 95%, suggesting that renal failure patients may
derive a benet from stenting. In this study CKD was identied as an
independent predictor of in-hospital major adverse cardiac events. In their
long-term follow-up, survival and event-free survival were signicantly
worse in the renal failure group, and 1-year actuarial survival was 75% in
the renal group versus 95% in the matched group.
For those undergoing primary angioplasty in the setting of an AMI,
CKD is associated with a markedly increased risk of mortality and bleeding
and restenosis. Sadeghi et al [97] studied the results of the Controlled
Abciximab and Device Investigation to Lower Late Angioplasty Complications trial to determine what eect baseline renal impairment had on
outcomes of patients undergoing direct infarct angioplasty. A total of 2802
patients of any age with AMI within 12 hours were randomized to balloon
angioplasty abciximab versus stenting abciximab. CKD based on
a cuto CrCl of less than or equal to 60 mL/min was present in 18% of
patients. This gure demonstrates the high prevalence of CKD in patients
presenting with ACS. Patients with CKD had a greater than ninefold
increase in mortality at 30 days and a vefold increase in mortality at 1 year.
Mortality increased incrementally for every 10 mL/min decline in baseline
renal function. It was noteworthy that patients with CKD (CrCl \ 60 mL/
min) had notably higher rates of major hemorrhage (6.7% versus 2.8%);
thrombocytopenia; and need for blood transfusions (8.4% versus 3.6%)
(independent of abciximab). In the CKD group the incidence of severe
restenosis with balloon angioplasty alone was 26.5% versus 15.1% in the
stented group.
The inuence of CKD on therapeutic modality in patients with CAD was
studied by Reddan et al [98] among 3661 patients who underwent cardiac
catheterization between 1995 and 2000 and subsequently followed regarding
the type of intervention undertaken whether it was medical therapy,
angioplasty stenting, or coronary artery bypass graft. The inuence of
renal function on outcome was assessed. Of those patients in this study who
underwent PCI, 91.5% had stent implantation. Patients with CKD in this
cohort again had greater comorbidities. The frequency of left main stem
disease, triple vessel disease, or severe CAD was higher in patients with
CKD consistent with other studies. Of the patients with normal renal
function, 47.6% underwent PCI as initial intervention versus 35.7% with
mild CKD (CrCl 6089 mL/min), and only 15.7% with severe CKD (CrCl
1529 mL/min). Furthermore, patients with CKD were more likely to
receive medical therapy as the intervention of choice postcardiac
catheterization (29.2% of those with mild CKD to 51.4% with severe
576
OHANLON & REDDAN
CKD) compared with those with normal renal function (25%). Decreasing
renal function was an independent predictor of mortality, with declines of
10 mL/min in CrCl below 85 mL/min associated with a 14% increase in
mortality risk.
In this study PCI was associated with a survival benet over medical
therapy in patients with normal renal function and CKD but the benet was
less evident at lower levels of renal function. Treatment with coronary artery
bypass graft was associated with a greater survival benet over both PCI
and medical management in the severe CKD group. These ndings are
consistent with previous studies demonstrating a dierential treatment
benet from PCI and coronary artery bypass graft among patients with
ESRD [99,100]. What is unknown, however, is if the new generation of
drug-eluting stents will change outcomes in patients with moderate to
severe CKD.
The question regarding primary angioplasty versus thrombolysis for
AMI has been addressed in a number of trials. The superiority of primary
angioplasty seems to have been demonstrated over thrombolysis with regard
to restoration of normal coronary blood ow, and lower rates of recurrent
ischemia, infarction, stroke and death [101103]. Although no prospective
trials have studied the benet of stent implantation in direct infarct
angioplasty in patients with CKD, Grines et al [104] did compare immediate
and 6-month angiographic outcomes along with the end points of death,
reinfarction, disabling stroke, or target-vessel revascularization because of
ischemia in patients undergoing direct infarct angioplasty with and without
stent implantation. Patients with renal failure were not included. There
was a reduction in the recurrence of angina and repeat target vessel
revascularization plus the combined end points in the stented group at 6
months and the luminal diameter of the vessel was larger poststenting than
with angioplasty alone. Similar results have been shown in various other
studies but unfortunately not including patients with CKD [105,106].
Although there is as yet no evidence in favor of direct infarct angioplasty
in CKD patients, this population should be treated as a very-high-risk group
post-MI given the poor overall mortality of these patients post-MI. Because
direct infarct angioplasty with stent implantation has demonstrated
advantages over thrombolysis and balloon angioplasty alone, it seems
prudent to also recommend this approach for patients with CKD. In the
new device era we have yet to see if direct infarct angioplasty with drug
eluting stents confers an added benet over bare metal stents, and
particularly in CKD patients. The very impressive reduction in restenosis
in patients treated with drug-eluting stents included those high-risk patients,
such as diabetics and small target vessels [107]. Restenosis is a considerable
obstacle to overcome in CKD and ESRD patients who undergo PCI and
stenting, leading to the recommendation that CKD patients should undergo
coronary artery bypass graft as the revascularization procedure of choice
[99,100]. As more evidence is published on drug elution perhaps these
577
recommendations will change. Although the drug-coated stent trials did not
enroll ESRD patients, the reports from the Randomized Study with the
Sirolimus Coated Bx Velocity Balloon Expandable Stent in the Treatment of
Patients with De Novo Native Coronary Artery Lesions trial [108] have
been exciting with 0% restenosis at 6 months in 120 patients receiving
sirolimus-coated stents as compared with 26.6% of those in the standardstent group. There were no episodes of stent thrombosis. During a follow-up
period of up to 1 year, the overall rate of major cardiac events was 5.8% in
the sirolimus-stent group and 28.8% in the standard-stent group. In trials
studying predictors of restenosis in patients with complex CAD receiving
drug-eluting stents CKD was not reported as a predictor of restenosis [109].
Contrast nephropathy is a recognized complication of PCI. The adverse
eect occurs infrequently in healthy patients but is regarded as a problem in
patients with underlying renal dysfunction. A number of studies have
examined approaches to reducing the nephrotoxicity of contrast agents used
in PCI and N-acetylcysteine [110]. Intravenous uids [111] and the use of
third-generation iso-osmolar nonionic contrast agents [112] have shown
promising results and should be considered for all CKD patients. The
reduction in restenosis seen with drug-eluting stents suggests a reduced need
for reintervention and hence may be an attractive choice for all CKD
patients undergoing PCI.
Glycoprotein IIb-IIIa inhibitors
Disruption of atherosclerotic plaque, which either occurs spontaneously
in patients with ACSs or during a PCI, triggers platelet aggregation and
intracoronary thrombus formation, and can result in MI or death.
Activation of the platelet GP IIb-IIIa receptor is the nal common pathway
in the process leading to platelet aggregation, and inhibitors of this receptor
have been shown to protect against periprocedural death or MI in patients
undergoing PCI for various indications [113116]. Most studies that have
demonstrated CKD to be a risk factor for poor outcome post-MI preceded
the era of recent therapeutic advances in the management of ACS using
agents such as GP IIb-IIIa antagonists, which have been shown to improve
the clinical outcome for the general population [117]. As with other
therapies with proved benet in patients with normal renal function, the
therapeutic benet of GP IIb-IIIa antagonists in patients with CKD is
unknown. Freeman et al [118] studied 889 patients admitted with a diagnosis
of ACS and a calculated CrCl based on the Cockcroft-Gault formula
(CrCl = [140-age] weight (kg)/ [serum creatinine (mg/dL) 72]. Of the
889 patients studied, 34.9% had CKD. The use of GP IIb-IIIa inhibitors
decreased from 39.1% in patients with CrCl greater than 90 mL/min to
12.7% in those with CrCl less than 30 mL/min. In adjusted analyses the use
of GP IIb-IIIa antagonists was not associated with an increased risk of inhospital mortality associated with CKD. Moreover, when controlling for
578
OHANLON & REDDAN
levels of CKD and other covariates, there was a signicant protective eect
on in-hospital mortality associated with the use of GP IIb-IIIa antagonists.
But with worsening renal function there was an increase in major-bleeding
events, and when controlling for level of CrCl, there was a twofold increase
in the odds of a major bleeding event with the use of GP IIb-IIIa
antagonists. Eptibatide has also been demonstrated to be eective and may
be even more eective among patients with CKD [119].
Given the increased risk of adverse overall outcomes in the CKD
population post-MI, the incremental benet of IIb-IIIa antagonism may
outweigh the potential adverse eects. Studies of the pharmacokinetics of
these agents show that they are largely cleared by renal mechanisms [120
122]. Dosing recommendations vary in the presence of CKD but are not
uniform. In healthy subjects the plasma clearance of tiroban ranges from
213 to 314 mL/min and renal clearance accounts for 39% to 69% of plasma
clearance. In patients with CAD the plasma clearance ranges from 152 to
267 mL/min, and renal clearance accounts for 39% of plasma clearance.
Furthermore, clearance in the elderly (>65 years) with CAD is about 19%
to 26% lower than that of younger subjects. In patients with CrCl less than
30 mL/min the plasma clearance is signicantly decreased (>50%) and
company recommendations suggest a reduction of 50% of the total dose in
this CKD population. Product information for eptibatide states that it
should not be given to patients with a serum creatinine greater than 4 mg/
dL. The results of the GUSTO-IV trial do not support the use of abciximab
in patients presenting with ACS. What is attractive about the small
molecules (tiroban, eptibatide) is that their actions are short lived and
wear o quickly on discontinuation of the drug, whereas with abciximab,
because of its high binding anity to the GP IIb-IIIa receptor, its activity is
maintained for many hours after discontinuation of therapy. Given the
higher bleeding risk with these agents in the presence of CKD the small
molecules eects may be reversed quickly on stopping the drug should the
complication arise, whereas abciximab bleeding eects may be present for
longer.
The Platelet Receptor Inhibition for Ischemic Syndrome Management
Patients-Limited by Unstable Signs and Symptoms trial, which studied the
combination of tiroban in combination with heparin versus heparin alone
in the treatment of patients with unstable angina and nonQ-wave MI,
patients with CrCl greater than 2.5 mg/dL were excluded [123]. Januzzi et al
[124], however, examined the interaction between renal failure, prognosis,
and bleeding risk among patients treated with the small molecule tiroban
and found that there was no synergistic relationship between the use of
tiroban and degree of renal impairment for the development of
hemorrhagic complications. Boersma et al [125] performed a meta-analysis
of six of the IIb-IIIa antagonist trials involving 31,402 patients and
concluded that in patients with unstable angina and NSTEMI not routinely
scheduled for early revascularization and at high risk of thrombotic
579
complications, treatment with a GP IIb-IIIa inhibitor might therefore be

considered. Their benet is modest in patients not routinely scheduled for
PCI, and they are of questionable benet in patients who do not
undergo PCI.
Among patients with troponin-positive NSTEMI and a GFR less than 30
mL/min tiroban at a 50% reduced dose seems a reasonable suggestion. For
those with STEMI the benet of IIb-IIIa antagonism should be considered
with caution and abciximab or eptibatide are reasonable agents to use.
Summary
Patients with CKD and CAD have traditionally been a dicult
population to diagnose and treat in the setting of ACS. In addition to
having poorer outcomes post-ACS, data are lacking regarding best
treatments available. Aggressive interventional and medical treatments in
this group with already poor outcomes are not necessarily contraindicated
and should always be considered. The appalling outcome for CKD patients
post-ACS is improved by many therapies shown to benet in the non-CKD
patients. Data suggest that troponins are useful markers in CKD patients,
that major bleeding is not increased with the use of GP IIb-IIIa antagonists,
that thrombolytics have been used successfully in CKD patients, and that
PCI electively and as a primary treatment for ACS is successful and
probably more benecial than no treatment.
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Traditional and Nontraditional

Cardiovascular Risk Factors
in Chronic Kidney Disease
Panagiotis T. Vlagopoulos, MD, Mark J. Sarnak, MD*
Division of Nephrology, TuftsNew England Medical Center, Box 391,
750 Washington Street, Boston, MA 02111, USA
Cardiovascular disease (CVD) is the major cause of morbidity and

mortality in chronic kidney disease (CKD). CVD accounts for nearly 50%
of all-cause mortality in prevalent dialysis patients and after stratication
for age, race, and gender, CVD mortality is approximately 10 to 30 times
higher than in the general population [13].
There is also a high prevalence of CVD in incident dialysis patients and in
stages 1 to 4 CKD suggesting that CVD begins before the onset of end-stage
renal disease (ESRD) [49]. In one population-based study of CKD in the
United Kingdom, CVD was the most common cause of death, occurring in
46% of cases [10]. It is now well appreciated that subjects with stages 1 to 4
CKD are more likely to die of CVD than to develop ESRD (Table 1)
[3,11,12].
Cardiovascular risk factors predispose to three major pathologic forms of
CVD in CKD. The rst is an alteration in the structure of the myocardium,
including eccentric left ventricular hypertrophy (LVH), concentric LVH,
and left ventricular remodeling. In subjects with CKD, risk factors for concentric LVH include pressure overload secondary to hypertension, arteriosclerosis, or aortic stenosis. Risk factors for eccentric LVH include volume
overload secondary to uid retention, anemia, or arteriovenous stulae
[8,13]. The second form of CVD in patients with CKD is atherosclerosis,
and the third is arteriosclerosis or disease of the large vessels, such as the
aorta. The remodeling of blood vessels and loss of elasticity leads to the
development of sti noncompliant vessels. The latter is now recognized as
an important independent risk factor for CVD in dialysis patients [14,15].
E-mail address: msarnak@tufts-nemc.org (M.J. Sarnak).
doi:10.1016/j.mcna.2004.11.003
588
VLAGOPOULOS & SARNAK
Table 1
Percent of subjects reaching end-stage renal disease and all-cause mortality in subjects with
chronic kidney disease
CKD stage
(N = 27,998)
ESRD
Death prior to ESRD
1.1
19.5
1.3
24.3
19.9
45.7
Modied from Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and
outcomes among a population with chronic kidney disease in a large managed care
organization. Arch Intern Med 2004;164:65963.
Because of the high prevalence of and mortality rate from CVD in CKD,
several guidelines have now recommended that patients with CKD be
considered in the highest-risk group for CVD and that CKD be considered
a coronary heart disease equivalent [1618].
This article focuses attention on the major modiable risk factors in
CKD. CVD risk factors in kidney transplant recipients are not discussed.
Denition of traditional and nontraditional risk factors

Risk factors for CVD in CKD may be divided into two broad categories:
traditional risk factors and nontraditional risk factors (Table 2) [7].
Traditional risk factors can be dened as those that have primarily been
described in the Framingham cohort. They include factors that are widely
used by health care providers to stratify CVD risk in the general population:
older age, male gender, hypertension, diabetes, smoking, hyperlipidemia,
and LVH. Nontraditional risk factors are not used in Framingham coronary
risk equations and increase in prevalence as kidney function declines. They
may be recognized as risk factors in the general population, such as inammation and hyperhomocysteinemia, or be unique to patients with CKD,
such as anemia and calciumphosphorus imbalance [9].
Predictive potential of the Framingham coronary risk equation in chronic

kidney disease
It remains unknown how accurately the Framingham coronary risk
equation predicts coronary outcomes in patients with CKD. Although
several studies have suggested that the Framingham coronary risk score may
not suciently capture the risk of CVD in patients with CKD [1921], many
of these studies are limited by their cross-sectional nature. If the
Framingham coronary risk score indeed does not accurately predict CVD
in patients with CKD, what are the potential explanations? First, other
factors including nontraditional risk factors may play an important role in
promoting CVD. Second, traditional risk factors may have a qualitatively
CARDIOVASCULAR RISK FACTORS IN CKD
589
Table 2
Traditional and nontraditional cardiovascular risk factors in chronic kidney disease
Traditional
Nontraditional
Older age
Male sex
Hypertension
Higher LDL cholesterol
Lower HDL cholesterol
Diabetes
Smoking
Physical inactivity
Menopause
Family history of CVD
LVH
Albuminuria
Hyperhomocysteinemia
Anemia
Abnormal calcium-phosphate metabolism
Extracellular uid volume overload and electrolyte imbalance
Oxidative stress
Inammation
Malnutrition
Thrombogenic factors
Sleep disturbances
Altered nitric oxide-endothelin balance
Modied from Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease:
a new paradigm. Am J Kidney Dis 2000;35(4 Suppl 1):S117131.
and quantitatively dierent relationship with CVD in patients with CKD

compared with the general population [22]. For example, individuals with
CKD may have had a longer and more severe exposure to hypertension than
subjects without CKD. Third, the prevalence of cardiac risk factors and the
rates of CVD are dierent in CKD.
The following sections discuss modiable risk factors for CVD in CKD.
For the purposes of this article, for most risk factors the CKD population is
divided into stage 5 CKD and stages 1 to 4 CKD.
Traditional risk factors for cardiovascular disease

Hypertension
Chronic kidney disease stage 5
Hypertension is widely prevalent in the dialysis population. It is estimated
that 50% to 90% of dialysis patients have a blood pressure greater than
140/90 mm Hg [19,23]. Hypertension in hemodialysis (HD) patients is mainly
systolic, likely reecting the presence of sti noncompliant vessels [24].
Several observational studies suggest that high blood pressure is a risk
factor for mortality in dialysis-dependent patients [25,26]. Other studies,
however, have implicated low blood pressure as a risk factor for mortality
[2729]. Zager et al [30] noted that the risk of mortality was U shaped. That
is, the risk was higher in those with postdialysis systolic blood pressure
greater than or equal to 180 mm Hg, but also in those with a predialysis or
postdialysis systolic blood pressure below 110 mm Hg. The most likely
explanation for the mortality risk of low blood pressure in dialysis patients
is that low blood pressure is a marker of comorbid conditions, such as
structural heart disease or severe autonomic neuropathy. The underlying
comorbid conditions, rather than the low blood pressure itself, may be
590
responsible for the increase in mortality. Mazzuchi et al [26] demonstrated

that duration of follow-up is also an important factor in determining the
risk associated with blood pressure. In their study of an incident HD
population that had survived at least 2 years of dialysis before study entry,
low blood pressure (diastolic blood pressure \ 74.5 mm Hg) was a risk
factor for early mortality (years 3 and 4 of dialysis), and systolic blood
pressure greater than or equal to 160 mm Hg was a risk factor for late
mortality (greater than or equal to 5 years of dialysis). The authors suggested that dierences in duration of follow-up may explain the discrepant
results of prior studies.
Several studies suggest that higher pulse pressure, a measure of sti
noncompliant vessels, is an independent risk factor for mortality in dialysis
patients [15,31,32] and may be superior to systolic blood pressure or
diastolic blood pressure alone in predicting CVD risk.
The optimal blood pressure target in the dialysis population is not
known. There are no controlled trials to assess the impact of blood pressure
control on CVD outcomes or mortality. In the absence of denitive data, the
National Kidney Foundation Task Force on CVD recommended a target
similar to the general population (140/90 mm Hg), recognizing that in some
cases the target may need to be higher so as to avoid intradialytic
hypotension [16]. The Task Force also recommended that the mainstay of
therapy should be control of volume status through dietary means and
ultraltration. In patients who remain hypertensive despite aggressive
volume removal, antihypertensive medications should be initiated. There
are no large trials in dialysis patients that support the choice of any particular
antihypertensive agent. It seems reasonable to guide therapy based on comorbid conditions and by extrapolating data from the general population.
Chronic kidney disease stages 1 to 4
The prevalence of hypertension in individuals with stages 1 to 4 CKD is
about 70% to 80% [33,34] and increases as glomerular ltration rate (GFR)
declines (Fig. 1) [35]. Elevated systolic blood pressure is an independent risk
factor for CVD outcomes in both diabetic [36,37] and nondiabetic CKD
[38,39]. In a secondary analysis of the Modication of Diet in Renal Disease
study, each 10mm Hg increase in systolic blood pressure was associated
with a 1.35-times greater risk of hospitalization for CVD events. The
increased risk persisted after adjustment for baseline covariates, including
other traditional cardiac risk factors [39].
It has been well-established that angiotensin-converting enzyme (ACE)
inhibitors and angiotensin receptor blockers slow the progression of CKD,
particularly when proteinuria is present [4048]. In a post hoc analysis of the
Heart Outcomes and Prevention Evaluation study, the ACE inhibitor
ramipril also reduced CVD outcomes in a subgroup of patients with CKD
who also had pre-existing vascular disease or diabetes combined with an
additional cardiovascular risk factor [49].
591
140/90 mmHg or BP medication

95% confidence interval
160/100 mmHg
95% confidence interval
Proportion of Population (%)
100
90
80
75%
77%
70
68%
60
55%
50
45%
40%
40
39%
42%
30
20
21%
15%
10
12%
10%
8%
7%
6%
6%
0
15
30
60
90
120
Estimated GFR (mL/min/1.73 m2)

Fig. 1. Prevalence of high blood pressure by level of GFR, adjusted to age 60 years (NHANES
III). Predicted prevalence of high blood pressure among adult participants age 20 years and
older in NHANES III, 19881994. Values are adjusted to age 60 years using a polynomial
regression. 95% condence intervals are shown at selected levels of estimated GFR. BP, blood
pressure. (From K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,
classication, and stratication. Am J Kidney Dis 2002;39(2 Suppl 1):S1266; with permission.)
Based on these and other data, the Kidney Disease Outcomes Quality
Initiative (K/DOQI) Clinical Practice Guidelines on Hypertension and the
use of Antihypertensive Agents in CKD [50] recommended a target blood
pressure of less than 130/80 mm Hg with the preferred antihypertensive
agents being ACE inhibitors and angiotensin receptor blockers. The Seventh
Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure had similar guidelines
for individuals with stages 1 to 4 CKD [17].
Dyslipidemia
Dyslipidemia is discussed briey. For a more in-depth review, the reader
is referred to the article by Farbakhsh and Kasiske elsewhere in this issue.
The prevalence of dyslipidemia in the dialysis population is high.
Approximately 50% of HD patients and nearly 70% of peritoneal dialysis
patients have low-density lipoprotein (LDL) cholesterol levels above
100 mg/dL and nonhigh-density lipoprotein (non-HDL) cholesterol over
130 mg/dL. The characteristics of the lipid prole dier in these two
patient populations [51]. Peritoneal dialysis patients tend to have a more
atherogenic lipid prole than HD patients, with increased levels of LDL
592
cholesterol, apolipoprotein B, oxidized LDL cholesterol, triglycerides, and

lipoprotein(a), and decreased HDL cholesterol. One reason for the increased
atherogenicity of the lipid prole in peritoneal dialysis patients compared
with HD patients may be the absorption of glucose across the peritoneal
membrane from peritoneal dialysate [52].
The relationship between total cholesterol levels and CVD outcomes has
not been consistent. Some studies show no association between total
cholesterol and CVD [4,20], whereas others have demonstrated that higher
total and LDL cholesterol are associated with CVD outcomes [53]. Still
other studies have demonstrated J- or U-shaped relationships between
serum cholesterol and CVD outcomes. For example, in a study of more than
12,000 prevalent HD patients, the lowest relative risk for all-cause mortality
was found in patients with serum total cholesterol 200 to 250 mg/dL [27].
The most common explanation for the seemingly paradoxical relationship between serum cholesterol and CVD outcomes in the latter studies is
that there is confounding from malnutrition and inammation in those with
low cholesterol levels. In fact, a malnutrition-inammation complex
syndrome in dialysis-dependent patients has been proposed that may
explain this reverse epidemiology [5456]. In support of this theory is a study
of 1167 Japanese HD patients who were followed for 10 years. Low
cholesterol was associated with all-cause mortality, whereas high cholesterol
was associated with death from cardiovascular events. Low cholesterol was
also associated with lower serum albumin and elevated C-reactive protein,
implying that the low cholesterol may have been a marker of malnutrition
and inammation [57]. Additional evidence of the potential confounding
eect of the malnutrition-inammation complex syndrome was demonstrated in a recent analysis of the Choices for Healthy Outcomes in Caring
for ESRD Study, a national prospective cohort study of approximately 1000
incident dialysis patients [19]. Higher total cholesterol was associated with
a lower risk of all-cause and CVD mortality in all patients, and in
a subgroup with serologic markers of inammation and malnutrition.
Hypercholesterolemia was an independent risk factor, however, for the same
outcomes in a subgroup of patients without serologic evidence of
inammation or malnutrition (Fig. 2) [58].

The prevalence of dyslipidemia in stages 1 to 4 of CKD varies according
to level of GFR and the degree of proteinuria [59]. Few studies have
examined the association between hyperlipidemia and CVD events in the
CKD population. In one prospective study of 147 patients with CKD who
were followed for nearly 10 years, low HDL cholesterol was an independent
risk factor for CVD events [38].
There are no large, randomized, controlled trials demonstrating that
treatment with lipid-lowering agents reduces CVD events in this population.
593
60
Presence of inflammation/Malnutrition
Mortality Rate per 100 Patients
Mortality Rate per 100 Patients
Overall
All-Cause Mortality
50
40
30
20
10
0
120
140
160 180 200 220

Cholesterol, mg/dL
240
Absence of inflammation/Malnutrition
60
CVD Mortality
50
40
30
20
10
0
120
140
160 180 200 220

Cholesterol, mg/dL
240
Fig. 2. Estimated 3-year all-cause and cardiovascular disease (CVD) mortality by cholesterol
level. Serum cholesterol is modeled as a fth-order polynomial, and all values are predicted
from Cox models adjusted to age, sex, race, modality, and smoking status of the entire study
group at each cholesterol level. To convert cholesterol from mg/dL to mmol/L, multiply values
by 0.0259. (From Liu Y, Coresh J, Eustace JA, et al. Association between cholesterol level and
mortality in dialysis patients: role of inammation and malnutrition. JAMA 2004;291:4519;
with permission.)
Tonelli et al [60], however, did perform a post hoc subgroup analysis in

approximately 1700 subjects with CKD (dened as creatinine clearance 75
mL/min using the Cockroft-Gault equation) who had participated in the
Cholesterol and Recurrent Events study, a randomized trial of pravastatin
versus placebo in over 4000 subjects with a history of prior myocardial
infarction [61]. After a median follow-up of nearly 6 years, the pravastatin
group had a signicantly lower risk of CVD events compared with the
placebo group (adjusted hazard ratio 0.72), after adjusting for potential
confounders [60]. The authors concluded that pravastatin seems to be
eective for secondary prevention of CVD in subjects with mild CKD.
The National Kidney Foundation K/DOQI has developed guidelines for
the treatment of dyslipidemia in patients with CKD [51]. The recommendations state that patients with stage 1 to 4 CKD should be managed according
to the National Cholesterol Education Program Adult Treatment Panel III
guidelines [62], except that CKD is considered a coronary heart disease risk
equivalent, with target LDL cholesterol less than 100 mg/dL. Stage 5 CKD is
also considered a CHD risk equivalent with target LDL cholesterol less
than 100 mg/dL. The K/DOQI and Adult Treatment Panel III guidelines
had a few other key dierences, which are not mentioned here [51].
K/DOQI recognized the importance of large-scale prospective, randomized trials in patients with CKD to assess the ecacy of lipid-lowering
therapy. The Study of Heart and Renal Protection involving approximately
9000 patients with CKD (one third dialysis patients and two thirds predialysis patients) [63], the Die Deutsche Diabetes Dialyse Studie involving
1200 HD patients with type 2 diabetes [64], and the AURORA (A Study to
Evaluate the Use of Rosuvastatin in Subjects On Regular Hemodialysis: an
594
Assessment of Survival and Cardiovascular Events) Study, which includes

close to 3000 HD patients [65], are all placebo-controlled trials that will
assess the impact of lipid-lowering therapy on CVD outcomes in CKD.
Diabetes mellitus
Diabetes is the leading cause of ESRD in the United States, accounting
for approximately 40% of cases [66]. In dialysis patients, the presence of
diabetes is an independent risk factor for ischemic heart disease, heart
failure, and all-cause mortality [20,67]. Diabetic patients also have worse
long-term outcomes after coronary interventions than nondiabetic patients
[68,69]. There have been no controlled studies that examine the relationship
between glycemic control and CVD outcomes in this population. Although
poor glucose control may hasten the progression of diabetic retinopathy and
peripheral neuropathy, increase the risk for infection, and worsen hyperkalemia, the net risk benet of strict glycemic control needs to be assessed
on an individual basis, because of the higher risk of severe adverse eects
associated with hypoglycemia.
Diabetes is the most common cause of stages 1 to 4 CKD, and is a risk
factor for CVD in this population [70]. Higher levels of proteinuria in
diabetic CKD have been linked to a higher risk of CVD and all-cause
mortality [71]. There is no denitive evidence that strict glycemic control
reduces CVD events. In the UK Prospective Diabetes Study, which
examined the eect of intensive glycemic control in a cohort of nearly
4000 patients with type 2 diabetes, some of whom had early CKD at study
entry, the risk of microvascular but not macrovascular outcomes (CVD) was
reduced by intensive glycemic control [72].
Smoking
Nearly 20% of dialysis-dependent patients are self-reported active
smokers, and up to 50% are current or former smokers [19,20,73]. Smoking
is associated with CVD and peripheral vascular disease in cross-sectional
studies [4,74]. In a recent analysis of the United States Renal Data System
Wave 2 Study, active smoking at study inception was shown to be an
independent risk factor for new-onset congestive heart failure, new-onset
peripheral vascular disease, and mortality [75].
Approximately 25% of individuals with stages 1 to 4 CKD are current or
former smokers [21,70]. Smoking has been associated both with kidney
disease progression [76] and CVD in subjects with CKD [38]. Smoking may
595
also be associated with the development of atherosclerotic renal artery

disease [77]. Cessation of smoking should be actively pursued in patients at
all stages of CKD.
Left ventricular hypertrophy
LVH is widely prevalent in the dialysis population. Up to 70% of
incident and 50% to 75% of prevalent dialysis patients have LVH by
cardiac echocardiography [7880]. As in the general population, LVH is an
independent risk factor for CVD outcomes and all-cause mortality in the
dialysis population [8184].
Observational data suggest that modication of risk factors, such as
anemia, volume overload, and hypertension, may lead to regression of LVH
in dialysis patients [8588]. One randomized trial, however, did not demonstrate regression of LVH with higher levels of hemoglobin [89].
The prevalence of LVH increases as CKD advances, reaching approximately 75% at dialysis initiation [6]. LVH is associated with increased
morbidity and mortality [5]. Therapy for LVH is not dierent from that
used in the general population, and includes blood pressure control, ACE
inhibitors or angiotensin receptor blockers, and b-blockers. It remains to be
determined whether correction of anemia leads to prevention or regression
of LVH in CKD (see later).
Physical inactivity
Dialysis patients have decreased exercise tolerance [90,91] and a lower
level of physical activity compared with age-matched healthy sedentary controls [92]. Potential reasons for this include multiple comorbid conditions,
anemia, postdialysis fatigue, and other adverse eects of the uremic milieu.
Dialysis patients also have muscle atrophy, documented quantitatively by
MRI, when compared with healthy sedentary controls [93].
A secondary analysis of the Dialysis Morbidity and Mortality Study
Wave 2 noted that sedentary behavior was associated with an increased risk
for death at 1 year, after adjusting for other variables known to be associated with survival [94].
Physical training may have benecial cardiac eects in dialysis patients.
In a randomized-controlled trial, dialysis patients assigned to a 6-month
exercise training program had increased cardiac vagal activity and a decrease
in vulnerability to arrhythmias compared with controls [95]. In another
controlled trial, resting left ventricular ejection fraction improved to
a signicant degree (5%), after a 6-month exercise regimen in a cohort of
dialysis patients [96]. Finally, 12 months of endurance exercise training in
596
another study led to an improvement in lipid proles, glucose metabolism,

blood pressure, anemia, and depression [97].
Despite the absence of long-term data on CVD outcomes, moderate
exercise programs should be encouraged [98100]. Because of the high
prevalence of CVD in dialysis patients, caution should be used when
initiating an exercise program and screening stress tests may be required.
There are few data on the importance of physical activity in this
population. The Surgeon General has recommended 30 minutes of physical
activity of moderate intensity on most or all days of the week for the general
population [101]. In the absence of data to the contrary, these recommendations apply to subjects with stages 1 to 4 CKD.
Nontraditional cardiac risk factors
Albuminuria
The presence of albuminuria is used to dene CKD [35]. Albuminuria is
associated with CVD surrogates and is a risk factor for CVD outcomes and
all-cause mortality in both diabetic and nondiabetic subjects [102106].
Several studies now suggest that this risk extends below the microalbuminuria range (Fig. 3) [102,104].
There are several explanations for the association of microalbuminuria
with CVD [107]. Microalbuminuria may be a marker of generalized vascular
and endothelial dysfunction and impaired arterial dilatory capacity [108
110]. Microalbuminuria may also be associated with a higher prevalence of
traditional and nontraditional CVD risk factors, such as dyslipidemia
[111,112], the metabolic syndrome [113], and inammation [114].
In proteinuric kidney diseases, ACE inhibitors and angiotensin receptor
blockers have been shown to decrease the degree of proteinuria and slow the
progression of kidney disease. In patients with microalbuminuria, it remains
unknown whether ACE inhibitors or angiotensin receptor blockers reduce
the risk for adverse CVD outcomes independent of blood pressure
reduction. The Prevention of Renal and Vascular Endstage Disease
Intervention Trial study, a double-blind, randomized, placebo-controlled
trial evaluating the use of an ACE inhibitor or statin in nonhypertensive,
nonhypercholesterolemic subjects with microalbuminuria, will attempt to
answer this question [115].
Homocysteine
The prevalence of hyperhomocysteinemia in the dialysis population is
estimated to be 80% to 85% [116118]. In the earlier stages of CKD levels of
homocysteine are inversely associated with level of kidney function with
correlations ranging from approximately 0.4 to 0.7 [119,120].
597
Cardiovascular death
6.0
5.5
5.0
Hazard Ratio
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1
10
100
1000
Urinary Albumin Concentration (mg/L)
Non-cardiovascular death
6.0
5.5
5.0
Hazard Ratio
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1
10
100
1000
Urinary Albumin Concentration (mg/L)
Fig. 3. Adjusted eect of urinary albumin concentration on hazard function. Solid line shows
estimated relation when logarithmic hazard is modeled as linear function of log (urinary
albumin concentration). Dotted lines are 95% condence interval limits for more general
functional relation, as estimated by P-splines. Hatched area represents upper and lower limit of
current denition of microalbuminuria (20200 mg/L). (From Hillege HL, Fidler V, Diercks
GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality
in general population. Circulation 2002;106:177782; with permission.)
Hyperhomocysteinemia has been associated with CVD in several studies

in the dialysis population [121,122]. Other studies, however, have noted
inverse associations between homocysteine and outcomes [123125]. The
most common explanation for the latter nding is that low homocysteine
may be a marker of malnutrition in dialysis patients [126].
Homocysteine levels are often resistant to B vitamin and folate supplementation in stage 5 CKD, particularly at conventional doses of these
vitamins. High-dose folate supplementation may lower but does not usually
598
normalize homocysteine levels [127129]. Very high ux dialyzers and

daily nocturnal HD have been shown to decrease homocysteine levels
[130,131]. Intravenous acetylcysteine given during HD sessions resulted in
lower plasma homocysteine levels, improved pulse pressure, and evidence of
improved endothelial function compared with placebo in one study [132].
Oral N-acetylcysteine failed to lower homocysteine levels in HD patients,
however, in another study [133].
It is not known, either in the general population or in the dialysis
population, whether lowering homocysteine levels decreases CVD outcomes.
In a randomized trial of the eect of 1, 5, or 15 mg of folic acid on CVD events
and all-cause mortality in a cohort of 510 dialysis patients with a median
follow-up of 2 years, there was no dierence in outcomes among groups
(Fig. 4) [134]. Homocysteine levels were lowered to a greater degree with highdose folic acid; however, the percentage of patients who normalized their
homocysteine levels did not vary between treatment groups. The Homocysteine Study, a large randomized, placebo-controlled multicenter trial
designed to assess the eect of folate and B vitamins on all-cause mortality
and CVD outcomes in dialysis patients and patients with advanced CKD, is
in progress [135]. There is currently insucient evidence to recommend
aggressive treatment of hyperhomocysteinemia in patients with CKD.
Anemia
Anemia is discussed briey. For a more in-depth review, the reader is
referred to the article by Pendse and Singh elsewhere in this issue.
Cumulative Event-free Survival
1.00
0.75
0.50
Folic Acid 1 mg
Folic Acid 5 mg
Folic Acid 15 mg
0.25
0.00
0
200
400
600
800
1000
Days of Follow-up
Fig. 4. Event-free survival by folic acid group. (From Wrone EM, Hornberger JM, Zehnder JL,
et al. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal
disease. J Am Soc Nephrol 2004;15:4206; with permission.)
599

Chronic anemia, which usually begins at stage 3 of CKD, results in
several short- and long-term adaptations, which help to maintain adequate
tissue oxygenation. One such adaptation is vasodilatation, which leads to an
increase in cardiac preload and a decrease in afterload, both resulting in an
increase in cardiac output [136,137]. In the short term, these compensatory
mechanisms are benecial, because tissue oxygenation is maintained. In the
long term, however, these compensatory mechanisms may be maladaptive,
resulting in LVH. Anemia has been associated with LVH at all stages of
CKD in both cross-sectional and prospective studies [78,138140].
There is also evidence that anemia may be a risk factor for CVD
outcomes in patients with CKD. In analyses from the Atherosclerosis Risk
in Communities Study, the combination of anemia and CKD conferred
a synergistic risk for stroke and coronary disease compared with each risk
factor alone [141,142]. Anemia has also been shown to be an independent
risk factor for all-cause mortality in dialysis patients [140].
It remains unknown whether treatment of anemia reduces LVH and
decreases CVD outcomes in patients with CKD. In HD patients with
established CVD, randomization to a hematocrit value of 42% versus 30%
resulted in a slightly although not signicantly increased risk of myocardial
infarction and all-cause mortality [143]. Similarly, in a study in which HD
patients were randomized to hemoglobin levels of 10 or 13.5 g/dL, there was
no dierence between the groups in regression of LVH [89]. Finally, in a 2year study of patients with CKD stages 3 to 4 who were randomized to
a hemoglobin level of 9 to 10 g/dL or 12 to 13 g/dL, there was no dierence
between groups in the development or progression of LVH [144].
There are three ongoing trials in stages 3 and 4 CKD evaluating whether
treatment of anemia reduces CVD outcomes: (1) Trial to Reduce Cardiovascular Events with Aranesp Therapy [145], (2) Correction of Hemoglobin and
Outcomes in Renal Insuciency [146], and (3) Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta [147].
Calciumphosphorus metabolism
The pathophysiology of calciumphosphorus metabolism is discussed
briey. For a more in-depth review, the reader is referred to the article by
Goodman elsewhere in this issue.
As GFR declines, phosphorus levels increase, calcium levels decrease,
and parathyroid hormone levels increase. Calcium-containing phosphate
binders were until recently the primary agents used to control hyperphosphatemia, and vitamin D or vitamin Danalogues were used to control
hyperparathyroidism. This strategy may lead to a state of positive calcium
balance and a high calciumphosphorus product, which may result in
metastatic calcication of the large vessels, such as the aorta and the
carotids, and the coronary vessels and valves [8].
600

Abnormalities in calcium, phosphorus, and parathyroid hormone have
all been linked to adverse outcomes in dialysis patients. Both high and low
serum calcium have been implicated as independent risk factors for all-cause
mortality and CVD outcomes in the dialysis population [27,148]. In a large
retrospective study of approximately 6500 HD patients from the USRDS,
a serum phosphorus level greater than 6.5 mg/dL was an independent risk
factor for all-cause mortality [149]. Similar results were noted for mortality
from cardiac causes [150].
Several studies have used electron-beam CT to assess calcication of the
coronary arteries and valves of dialysis patients [151153]. The conclusions
from these studies are that the prevalence and severity of coronary artery
calcication is higher in dialysis patients than in the general population
[151], that calcication is widely prevalent even in young dialysis patients
[152], and that higher calcium intake and a higher serum calcium
phosphorus product may be risk factors for calcication [152,153]. In
dialysis patients, calcication may be present both in the intima and the
media of the vessel wall. As a result, electron-beam CT calcication may
not reect atherosclerosis (intimal calcication) as it does in the general
population. In fact, coronary artery calcication measured by electron-beam
CT correlate poorly with the degree of vessel stenosis assessed by coronary
angiography in one study [154]. Nevertheless, Raggi et al [153] demonstrated
that high coronary artery calcication scores were associated with the
prevalence of clinical atherosclerotic vascular disease, such as myocardial
infarction and angina in HD patients. Vascular calcications have also been
associated with stiening of the arteries [155], which in turn may lead to
higher pulse pressure, LVH, decreased coronary perfusion, and increased
risk for CVD outcomes [156,157].
There are no randomized trials that have evaluated whether treatment of
calciumphosphorus abnormalities or reduction in the use of calcium-based
phosphate binders reduces the risk of CVD outcomes. In one study HD
patients were randomly assigned to treatment with either sevelamer, a
nonabsorbable noncalcium-containing phosphate binder, or to calciumbased phosphate binders for 52 weeks, and then evaluated by electron-beam
CT [158]. At week 52, the median percent increase in coronary artery and
aortic calcium score was signicantly lower in the sevelamer group. More
research is needed to clarify whether these results translate into a reduction
in CVD outcomes.
Current guidelines in dialysis patients recommend that serum phosphorus
be maintained between 3.5 and 5.5 mg/dL, that calciumphosphorus product be maintained below 55 mg2/dL2, and that parathyroid hormone be
maintained between 150 and 300 pg/mL [159]. Calcium-based phosphate
binders should in general be avoided in patients with hypercalcemia,
excessive calcication, low parathyroid hormone level, or a signicantly
elevated calciumphosphorus product.
601
Calcimimetics, which target the calcium-sensing receptor and lower

parathyroid hormone levels without increasing calcium and phosphorus
levels, are novel agents that have recently been approved for use in the
United States [160].
The authors are not aware of any data regarding associations between
calciumphosphorus metabolism and CVD outcomes in the earlier stages of
CKD.
Oxidative stress and inammation
Oxidative stress, dened as an imbalance between oxidants and the
antioxidant defenses of the body, and inammation have been proposed as
key processes in the pathogenesis of atherosclerosis and CVD in the general
population [161163]. Oxidative stress has also been proposed as a unifying
concept of cardiovascular disease in CKD [164].
There is evidence that dialysis patients are in a state of oxidative stress.
Contributing factors to this condition include inammation [165], malnutrition, uremic toxins, and potentially the blood-membrane interaction in
HD patients [166]. Dialysis patients also have decreased levels of antioxidant defenses, including vitamins E and C, and glutathione [164]. Furthermore, levels of C-reactive protein, a marker of inammation, are often
elevated in dialysis patients [167,168].
Elevated C-reactive protein is a strong predictor of all-cause mortality and
adverse CVD outcomes in dialysis patients [169171]. C-reactive protein and
other inammatory markers have also been associated with coronary artery
calcication in peritoneal dialysis patients [172] and cardiac hypertrophy in
HD patients [173]. Furthermore, the presence of an inammatory state, as
measured by elevated C-reactive protein levels, attenuated the improvement
conferred by antihypertensive medications and erythropoietin on aortic
stiness and LVH in a study of dialysis patients [174].
Statins have been associated with anti-inammatory eects in addition to
their lipid-lowering eects, and may lower C-reactive protein both in the
general population and in dialysis patients [175177]. There are no data,
however, that have demonstrated that treatment of inammation reduces
CVD outcomes in dialysis patients.
Although antioxidants have not convincingly reduced CVD outcomes in
the general population [178], two small, randomized controlled trials in HD
patients have shown a benet of the antioxidants vitamin E (Fig. 5) [179]
and N-acetylcysteine [180] in reducing CVD events. Larger trials are needed
to conrm these ndings.
602
Proportion free of CVD endpoints
1.0
0.8
p=0.014
0.6
0.4
Placebo
Vitamin E
0.2
0.0
0
Number at risk
Placebo
99
Vitamin E 97
100
200
300
400
Time (days)
500
600
700
97
94
86
91
74
79
60
67
59
63
57
60
67
71
Fig. 5. Kaplan-Meier survival curves for the primary cardiovascular disease end point. (From
Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.
Lancet 2000;356:12138; with permission.)
Other strategies that have been shown to reduce the levels of oxidative
stress include the use of vitamin Ecoated dialyzers [181,182] and the use of
specialized water for the dialysis procedure, which has the ability to
scavenge reactive oxygen species [183].
Increased oxidative stress and inammation manifest early in CKD
[184,185]. In a large study using data from the National Health and
Nutrition Examination Survey III, C-reactive protein levels were elevated in
subjects with CKD compared with those with normal kidney function [186].
Furthermore, in a cross-sectional study, C-reactive protein levels were
independently associated with the presence of CVD in subjects with CKD
[187]. It remains unknown whether therapy to reduce inammation or
oxidative stress reduces CVD outcomes in the earlier stages of CKD.
Summary
CKD is a public health problem, with as many as 20 million individuals
aected in the United States. Patients with CKD should be considered in the
highest-risk group for development of CVD, and aggressive treatment of
both traditional and nontraditional risk factors should be instituted.
Additional randomized controlled trials are, however, urgently needed to
evaluate potential treatments in this population.
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Med Clin N Am 89 (2005) 613630
Gender Dierences in Hypertension

and Kidney Disease
Daisy Reyes, MD, Susie Q. Lew, MD,
Paul L. Kimmel, MD, FACP, FASN*
Division of Renal Diseases and Hypertension, Department of Medicine,
George Washington University Medical Center,
2150 Pennsylvania Avenue, NW, Room 4-425,
Washington, DC 20037, USA
It is estimated that in the United States 50 million people have

hypertension [1], 20 million have chronic kidney disease [2], more than
300,000 have end-stage renal disease (ESRD), and tens of thousand have
functioning renal transplants [3]. Gender dierences in physiologic states
and in disease are being investigated to understand the pathogenesis and
pathophysiology of hypertension and nephropathy, which in turn may aect
management and outcomes. This article reviews dierences between the
genders in hypertension, renal function, prevalence of renal disease,
progression of renal disease, and ESRD, including renal transplantation.
Blood pressure
Gender dierences in blood pressure
Hypertension is a major cause of cardiovascular disease and an important
contributor to morbidity and mortality. Data from Third National Health
and Nutrition Examination Survey (NHANES III) showed that 24% of the
United States adult population has high blood pressure [4]. Men have
a slightly higher prevalence of high blood pressure compared with women
across all ethnic groups (24.7% versus 23.4%) [4]. Hypertension is more
common in men than in women before menopause [5]. After menopause,
however, hypertension is more prevalent in women [4,6,7]. In the NHANES
III population, in people over 70 years old, the prevalence of high blood
E-mail address: pkimmel@mfa.gwu.edu (P.L. Kimmel).
doi:10.1016/j.mcna.2004.11.010
614
REYES et al
pressure was higher in women than men. In the elderly population, 56% of
non-Hispanic black women were hypertensive compared with 50% of men,
55% of non-Hispanic white women were hypertensive compared with 50%
of men, and 63% of Hispanic women were hypertensive compared with 49%
of men [4]. Men have a higher incidence of uncontrolled hypertension [4].
Men have a higher risk of developing target organ damage compared with
age-matched premenopausal women [8]. These gender dierences in blood
pressure start to appear in adolescence, and persist through adulthood [9].
Blood pressure rises with increasing age in children and adolescents when
monitored using ambulatory blood pressure devices. After puberty, boys
have higher blood pressures than do age-matched girls [9].
Mechanisms underlying gender dierences in high blood pressure
The mechanisms underlying gender dierences in blood pressure control
are not completely understood. It has been postulated that the disparity in
the mean blood pressures between men and women is caused, in part, by sex
hormones. Receptors for androgens and estrogens have been found on
vascular endothelium and smooth-muscle cells of several mammalian
species, suggesting that these hormones may inuence vascular function [10].
Estrogen and high blood pressure
It has been postulated that female sex hormones, particularly estrogens,
may protect against the development of high blood pressure in women. In the
NHANES-III population, menopause was characterized by increases in
blood pressure [3]. One proposed mechanism by which estrogens decrease
blood pressure is through the formation and release of vasoactive substances.
In a study that evaluated the relationship between endothelium-dependent
vasodilatation and advancing age in men and women, the ndings suggested
that menopause aects endothelium-dependent but not endotheliumindependent vasodilatation in normotensive and hypertensive women [11].
In hypertensive subjects and postmenopausal women, the response to the
endothelium-dependent vasodilator acetylcholine was blunted, whereas the
vasodilating eect of sodium nitroprusside was similar in both groups. In
normotensive men, endothelial responses started to decline in the third
decade in a gradual fashion. In normotensive women, however, advancing
age only slightly aected endothelium-dependent vasodilatation until
menopause, at which time there was a steep decline in this response.
Acetylcholine can trigger endothelium-dependent vasodilatation through the
release of nitric oxide (NO), suggesting that endogenous estrogens might
have a direct eect on endothelial cell function.
Another proposed mechanism through which estrogens may protect
against hypertension is by inuencing cardiovascular and neuroendocrine
responses. Postmenopausal women show larger stress-induced changes in
GENDER IN HYPERTENSION & KIDNEY DISEASE
615
blood pressure than premenopausal women [12,13]. Postmenopausal women

had greater blood pressure responses and had higher levels of norepinephrine during mental stress than premenopausal women [13]. A possible
mechanism by which estrogen may inuence the cardiovascular stress
response is by aecting b-adrenergic sensitivity or receptor number. Animal
studies have shown that, under the inuence of estrogens, there is
diminished response of b-adrenergic receptors to catecholamines [14].
Testosterone and high blood pressure
There is evidence from both animal and human studies that testosterone
plays an important role in mediating gender dierences in blood pressure.
Studies using ambulatory blood pressure monitoring techniques in children
have shown a more pronounced increase in blood pressure after puberty in
boys compared with age-matched girls [9]. Castration of male spontaneously
hypertensive rats (SHR) at a young age attenuated the development of
hypertension [15]. Ovariectomized female SHR, however, had no change in
mean arterial pressure compared with intact females [16].
Testosterone may aect blood pressure by causing a shift in the pressurenatriuresis relationship [17]. When there is a normal pressure-natriuresis
relationship, increased arterial blood pressures elicit a marked increase in
urinary sodium excretion [18,19]. Male SHR excrete lower levels of sodium
than females at the same blood pressures [15,20,21]. Castration of males
shifted the pressure-natriuresis relationship back to the values obtained in
intact females, whereas testosterone treatment of ovariectomized females
resulted in an increase in blood pressure and a hypertensive shift in the
pressure-natriuresis relationship [15]. Such ndings suggest that testosterone
inuences renal sodium handling. Testosterone receptors have been found in
proximal tubules, supporting a possible role of testosterone in sodium
reabsorption in this tubular segment [22].
An important modulator of pressure-natriuresis is the renin-angiotensinaldosterone system (RAS). Gender dierences in components of the RAS
have been shown to exist in animal and human studies. In a normotensive
population, plasma renin activity (PRA) was 27% higher in men compared
with women, regardless of age or ethnic heritage [23,24]. Male SHR have
increased PRA compared with female SHR [15], and castration decreases
PRA [25,26]. Treating ovariectomized female rats with testosterone
increases PRA [25,26]. These data suggest that testosterone stimulates the
RAS, which blunts the pressure-natriuresis relationship.
There are data supporting a role for the androgen receptor in mediating the
hypertensive eects of testosterone. In a study done in SHR to determine the
role of androgen receptors in hypertension, administration of the androgen
receptor antagonist utamide attenuated hypertension [27]. In the same
study, nasteride, a 5[alpha]-reductase inhibitor that blocks the conversion
of testosterone to dihydrotestosterone (DHT), was also given to rats to
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REYES et al
determine if the hypertensive eects were mediated by testosterone or its

metabolite, DHT. Finasteride had no eect on mean arterial pressure,
suggesting that conversion to DHT is not necessary to promote hypertension
in male SHR.
Oral contraceptives and high blood pressure
Small elevations in blood pressure, between 4 and 9 mm Hg in systole and
diastole, are observed in almost all women taking oral contraceptives (OC)
[2832]. OC can induce hypertension in approximately 5% of users [33]. The
risk increases with higher doses of estrogen and progestin. Data from the
Nurses Health Study II used to study the relationship between OC use and
the risk of hypertension showed the risk of developing hypertension was
higher among OC users compared with nonusers [31]. OCs currently contain
lower doses of hormones, which are associated with a lower risk of developing hypertension. Blood pressure levels usually return to normal on
withdrawal of OCs [31].
The mechanisms whereby OCs cause elevations in blood pressure are not
well understood. The RAS has been implicated as a possible mediator of this
eect [31,33]. Involvement of the RAS in the pathogenesis of OC-mediated
hypertension was suggested by the nding of increased plasma levels of renin
and angiotensinogen in women receiving estrogen therapy [34]. Not all women
taking OCs, however, develop high blood pressure, even in the presence of
elevated levels of renin and angiotensin. Some studies have also failed to
demonstrate a prominent role of the RAS in OC-induced hypertension [35].
Additional factors are necessary for the development of hypertension in
women taking these agents [33]. Sodium retention is another potential
mechanism by which OCs could lead to an increase in blood pressure [36].
When healthy normotensive women treated with chronic OC ingested highsalt diets for 1 week, there was a signicant increase in mean weight gain,
compared with women on chronic OC therapy and low-salt diets [36].
Even when there is an elevation in blood pressure, these elevations are
small on average and usually clinically insignicant. Existing hypertension
may be worsened, however, by use of OCs. Women who wish to use OCs
should be monitored periodically. If hypertension develops in women taking
OCs, the drug should be stopped. Blood pressure usually normalizes within
a few months [31]. If the risks of pregnancy are too great and no other
method of contraception is suitable, then OCs may have to be continued and
treatment with an antihypertensive agent should be initiated.
Hormone-replacement therapy and high blood pressure
Menopause and estrogen deciency are associated with an increased risk
of cardiovascular disease in women [11]. The mechanisms responsible for
the cardioprotective eect of estrogens are not completely understood. The
617
benecial eect of estrogens on lipid prole does not completely explain the
possible cardioprotective eects of estrogen [12,37]. Estrogens can directly
aect vascular endothelial function, resulting in vasodilatation [11,3840].
Hormone-replacement therapy improves endothelium-dependent vasodilatation by increasing levels of NO [41]. Hormone-replacement therapy increases bradykinin levels, which may also inuence vascular tone [42]. Estrogens
also attenuate the eects of endothelin-1, a powerful vasoconstrictor [43].
In view of the potential eects of OCs on blood pressure, there have been
concerns about the use of hormone-replacement therapy and the development
of hypertension. Clinical data suggest that the risk of developing hypertension
caused by hormone-replacement therapy is low. In the Postmenopausal
Estrogen/Progestin Intervention trial, designed to determine the eect of
hormone-replacement therapy on several known cardiovascular risk factors,
875 postmenopausal women were randomized to receive placebo, unopposed
estrogen, or estrogen-progestin regimens. In this trial there were no
statistically signicant dierences in systolic blood pressure among treatment
groups [44]. Another large, randomized, blinded study of postmenopausal
woman designed to evaluate whether the use of hormone-replacement
therapy was associated with increased cardiovascular events failed to show
any signicant dierences in blood pressure among users of estrogen alone,
estrogen and progestin, or nonusers [45]. In summary, the data available
suggest that hormone-replacement therapy is an uncommon cause of
hypertension in postmenopausal women. The presence of hypertension is
not a contraindication to hormone-replacement therapy.
Gender considerations in the treatment of hypertension
Lifestyle modications
There are gender dierences in ecacy of weight reduction for blood
pressure control. Analysis of the data was performed for the eects of
lifestyle modication in the Treatment of Mild Hypertension Study,
assessing gender-specic risks and benets of treating stage 1 hypertension
when groups were treated by lifestyle modication with placebo or with one
of ve classes of antihypertensive medication [46]. In this study, men lost
signicantly more weight than women. Women were less likely than men to
achieve blood pressure control with lifestyle intervention alone. Even though
the eects of weight reduction in blood pressure control in women have not
been extensively studied, small clinical trials have shown benets [47].
Drug therapy for high blood pressure
Results from clinical trials of antihypertensive treatment have suggested
that there are gender dierences in cardiovascular outcomes. A metaanalysis of the eects of antihypertensive treatment on cardiovascular
outcomes in women and men showed that antihypertensive therapy reduced
the incidence of stoke in women [8]. A reduction in coronary events was not
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REYES et al
seen in women compared with men, which was attributed to the lower risk
of coronary artery disease in women. The Treatment of Mild Hypertension
Study trial, however, showed similar benets, with lower rates of clinical
events in both men and women who received drug treatment [46]. This study
also showed similar drug tolerability in men and women. There were no
dierences in blood chemistries, lipid proles, side eects, and risk of clinical
events between genders.
There are still very few data describing gender dierences in response to
antihypertensive therapy. The decision to initiate pharmacologic therapy
should be made based on the patients level of blood pressure elevation, the
presence of target organ damage, the presence of cardiovascular disease, or
other cardiovascular risk factors regardless of gender.
Renal structure and function

Gender dierences in renal structure and function
Although male kidneys weigh more than female kidneys, gender is not an
independent determinant of kidney weight [10]. Rather, the increase in
kidney weight in men (determined from human renal tissue obtained at
autopsy or resection) is dependent on the larger body surface area of men
[10]. There are no dierences in the number of glomeruli between male and
female rats [48,49] or men and women [10]. Male rats have larger glomeruli
than females [50]. There was no dierence in kidney weight or volume in
relation to body weight between male rats and female rats treated with
DHT. The cortex of male rats and DHT-treated female rats compared with
female rats was greater in volume, because of more extensive development
of proximal tubules [50]. Men have larger glomeruli than women and have
a greater total glomerular volume [10,50].
In early studies of glomerular ltration rate (GFR) in humans with and
without renal disease, men had higher GFRs than women when corrected
for body surface area [51,52]. When only healthy kidney donors were
evaluated, however, there was no dierence in GFR between the genders,
even when corrected for body surface area [53]. When humans were given
testosterone or estrogen, there were no signicant changes in GFR or renal
blood ow [54,55].
Renal disease
Gender dierences in the epidemiology of chronic kidney disease
In the NHANES III population, the prevalence of an elevated serum
creatinine concentration was greater in adult men (3.3%) compared with
women (2.7%) [56]. When estimated GFR and persistent albuminuria were
619
used to diagnose renal disease, the prevalence of kidney disease (GFR \ 60

mL/min/1.73 m2) was greater in women than men (5.33% versus 3.58%) [2].
This dierence, however, disappeared after adjusting for age [2]. The
prevalence of microalbuminuria, dened by urinary albumin concentration
in the range of 30 to 300 mg per 24 hours, was also greater in women
(10.3%) than men (9.5%) [57].
Despite these ndings in women, more men develop ESRD every year,
requiring renal replacement therapy [3]. A total of 96,295 patients initiated
therapy for ESRD in 2001. Of that group, 51,828 were men (53.8%) and
44,453 were women (46.2%) [3]. A total of 90.6% were treated with
hemodialysis and 8.5% were treated with peritoneal dialysis. A total of
97.5% of incident patients started dialysis and 2.5% of incident patients had
a functioning graft. Of the dialysis patients, 91.8% of incident patients were
treated with hemodialysis and 7.7% were treated with peritoneal dialysis.
Further, 53.7% of incident dialysis patients were men, 46.2% of incident
hemodialysis patients were women, and 52.4% of incident peritoneal
dialysis patients were men.
The point prevalent count of reported ESRD in 2001 was 406,081:
222,799 were men (54.9%) and 183,257 were women (45.1%). A total of
72% of the prevalent population was treated with dialysis and 28% had
functioning renal allografts. On December 31, 2001, 292,201 patients were
treated with dialysis: 53.2% were men. A total of 91.5% of dialysis patients
were treated with hemodialysis. A total of 113,866 patients had functioning
renal transplants: 59.3% were men and 40.7% were women.
The prevalent ESRD rate per million is higher for men than women, 1670
compared with 1163, adjusted for age, race, and ethnicity. The number of
incident cases and the incident ESRD rate is higher for men than women. The
ESRD incident rate from 1998 to 2001 (per 10 million, adjusted for
demographic characteristics and diagnosis) was 404 for men and 280 for
women. The ESRD incident rate, from 1998 to 2001, per 10 million, adjusted
for age and race for men and women, respectively, was 1157 and 663 for
hypertensive renal disease, 1570 and 1331 for diabetic renal disease, 338 and
212 for glomerulonephritis, and 87 and 69 for polycystic kidney disease.
Gender dierences in the progression of renal disease
The rate of progression of chronic renal disease is more rapid in men than
women [5866]. In studies where it was measured, there was nearly 50%
more rapid decline in creatinine clearance in men than women [58,59,61].
The impact of gender on renal disease progression may reect environmental and socioeconomic dierences, and both genetically determined
dierences between the sexes in renal structure and function, and receptormediated direct eects of sex hormones on the kidney.
Several potential mechanisms have been implicated in the pathogenesis of renal disease progression. Estrogen decreases the proliferation and
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REYES et al
prosclerotic properties of mesangial cells and decreases synthesis of types I

and IV collagen, whereas testosterone increases proliferation of mesangial
cells and stimulates collagen synthesis [6772]. Silbiger et al [72] demonstrated that estradiol may act to suppress collagen synthesis by inhibiting the
eect of transforming growth factor-b. In another study, selective estrogen
receptor modulators suppressed collagen synthesis in murine mesangial cells
in culture, with a potency of eect similar to that of estradiol [69].
Accumulation of extracellular matrix in the mesangium may also result
from decreased extracellular matrix degradation. Metalloproteinase-2 and
metalloproteinase-9 are matrix-degrading enzymes. Levels of metalloproteinase-9 increased in human mesangial cells after exposure to estrogen.
These eects were blocked by the selective estrogen receptor modulator
tamoxifen [73]. These data suggest that one of the mechanisms by which
estrogen may protect against the progression of renal disease is by
decreasing accumulation of matrix protein.
Estrogen increases NO synthesis [74,75] and decreases the activity of the
RAS [7679]. NO has a role in the regulation of glomerular ultraltration by
modulating the tone of mesangial cells and aerent arterioles [80]. NO also
inhibits glomerular remodeling by inhibiting extracellular matrix production
by glomerular mesangial cells, an event that may result in the development
of glomerulosclerosis [81]. In addition, Xiao et al [81] showed, in an in vitro
experiment, that estradiol stimulates NO synthesis by glomerular endothelial cells. By stimulating NO synthesis, estrogens may diminish factors that
predispose to the development of glomerulosclerosis.
Components of the RAS may be important modulators of the
progression of renal disease. Angiotensin II inuences mesangial cell
proliferation and matrix production, increases systemic blood pressure,
and inuences renal hemodynamics [64,79,82]. When oophorectomized rats
were treated with estrogen for several weeks, a marked decrease in
angiotensin-converting enzyme mRNA was seen in both kidney cortex
and medulla, compared with tissue of placebo-treated controls [76]. In this
study, the angiotensin-converting enzyme levels and activity were also
decreased in kidney tissue extracts obtained from estrogen-treated rats
compared with controls [76], suggesting that estrogens modulate intrarenal
angiotensin-converting enzyme activity and levels. Miller et al [79] studied
the dierences in RAS components in healthy men and women and their
hemodynamic response to angiotensin II infusion. At baseline, no signicant
dierences were seen in eective renal plasma ow, renal blood ow, or
ltration fraction. Renal plasma ow decreased in both men and women
with angiotensin II infusion. Men responded to angiotensin II infusion with
an increase in ltration fraction, but no change in GFR [79]. Women,
however, had no change in ltration fraction, but had a signicant decrease
in GFR. The discrepancy in ltration fraction may indicate an increased
intraglomerular pressure in men, which may contribute to progression of
renal disease.
621
Testosterone has been shown to increase PRA and angiotensinogen

mRNA levels in the liver and kidney in testosterone-treated rats [8385].
Endothelin is a potent vasoconstrictor that may have mitogenic properties,
and which has been implicated in the pathogenesis of hypertension and
atherosclerosis [86]. In humans, testosterone has been shown to increase
plasma endothelin levels [86]. Physiologic levels of testosterone have also
been shown to promote apoptotic damage in human proximal tubule cells
[87]. Gender has also been an important factor in the development of agedependent glomerular damage [88]. Testosterone promotes age-dependent
glomerular damage in rats, whereas orchiectomy is protective [89]. In shamoperated rats, orchiectomy improved parameters of glomerular injury.
Ovariectomy, however, worsens glomerular injury to the same extent as seen
in castrated rats [90].
Human and animal studies have demonstrated that estrogen has
immunomodulatory eects on the immune response [91,92]. By inuencing
the inammatory cascade, sex hormones may aect interstitial inammation, which may contribute to the progression of renal disease [65]. Potential
mechanistic factors implicated in the pathogenesis of renal disease
progression, which need additional investigation, include eects of sex
hormones on the synthesis, release, and action of cytokines, vasoactive
agents, and growth factors, and on antioxidant action in the mesangial
microenvironment.
Gender dierences in specic renal diseases and end-stage renal disease
program
In patients with idiopathic membranous glomerulonephritis, IgA
nephropathy, and polycystic kidney disease, most reports suggest that
women have more favorable outcomes, with a slower rate of progression of
nephropathy and prolongation of the development of ESRD [66,93]. In
a meta-analysis of clinical studies done through 1998, Neugarten et al [66]
analyzed the eect of gender on the progression of nondiabetic chronic renal
disease. The diagnoses evaluated in these studies included polycystic kidney
disease, IgA nephropathy, membranous nephropathy, and other causes of
chronic renal disease. This meta-analysis showed that renal disease
progressed faster in men compared with women in all four categories [66].
Data from the United States Renal Data System demonstrate a similar
pattern. The incidence of ESRD reported from 1997 to 2001, by primary
diagnosis, conrms that more men than women developed ESRD because of
IgA nephropathy (67.7% versus 32.3%); membranous nephropathy (67.2%
versus 32.8%); and polycystic kidney disease (53.4% versus 46.6%). The
incidence of ESRD reported from 1997 to 2001 caused by hypertension was
56.2% for men and 43.8% for women [3].
In patients with diabetes mellitus, a gender advantage with respect to the
development or prevalence of proteinuria or progression of renal disease has
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REYES et al
not been well characterized. Seliger et al [65] summarized selected clinical

studies of gender and the clinical outcome of diabetic nephropathy, showing
conicting results. United States Renal Data System data show that the
incidence of ESRD caused by type 2 diabetes mellitus was 48.6% in men
and 51.4% in women, whereas in type 1 diabetes, the incidence of ESRD
was 53.1% in men and 46.9% in women [3]. The incidence of ESRD for
vasculitis, lupus nephritis, and scleroderma during 1997 to 2001 was 68.4%,
82.3%, and 77.5% in women. The incidence of ESRD attributed to analgesic abuse nephropathy was 60.4% in women.
Disparities in death rates between men and women in the ESRD program
are diminishing. From 1980 to 1998, the death rate for men in the ESRD
program exceeded that of women. In 1999 and 2000, death rates for men
and women were essentially equivalent. There were 76,584 ESRD patient
deaths in 2001. A total of 40,175 men (52.5%) and 36,371 women died
(47.5%) [3]. The annual ESRD death rate per 1000 patient years at risk in
2001 was 182 for men and 183 for women, adjusted for age, primary
diagnosis, and race. The reasons for these secular trends are unclear.
The annual hemodialysis death rate per 1000 patient years at risk in 2001,
adjusted for age, primary diagnosis, and race was 246 for men and 216 for
women. The annual peritoneal dialysis death rate per 1000 patient years at
risk in 2001, adjusted for age, primary diagnosis, and race was 258 for men
and 262 for women.
In hemodialysis patients, dierences between the genders in psychosocial
function may also aect outcome. For example, Kimmel et al [94] showed in
a small study of urban hemodialysis patients that level of depressive aect
was correlated with medical severity, and depression and level of circulating
cytokines were associated with mortality in women, but not in men. Marital
satisfaction correlated with b-endorphin levels in women, but not men, in
the study. Marital conict was associated with mortality in women in the
study, but not men. The authors concluded depression and psychologic
and marital distress are important stressors for women hemodialysis
patients.
Transplantation
Gender dierences in organ donation
More women than men donate kidneys for living donor kidney
transplantation [9597]. There are disproportionately more female-to-male
donations and fewer male-to-female donations. Women comprised 68% of
spousal and 56% of related and unrelated nonspousal donors [95]. Gender
disparities in living donor transplantation result from a higher proportion of
wife-to-husband donations and disproportionate female-to-male donations
among biologic relatives and unrelated pairs.
623
There is a greater proportion of female-to-male living unrelated donor

transplants compared with the living related donor group (46% versus 30%)
[96]. There is a smaller proportion of female-to-female living unrelated
donor transplants compared with the living related donor group (10%
versus 25%). When spousal pairs were excluded from the analysis, there was
a higher proportion of male-to-male (48% versus 27%) donations, and
a lower proportion of male-to-female (18% versus 9%) and female-tofemale (25% versus 17%) transplants in the living unrelated donor group.
The reasons underlying the gender discrepancy in kidney donation are
unclear. It has been suggested that men may be excluded more often as
donors, because of higher prevalence of hypertension and coronary artery
disease [98]. In a study that analyzed spouses and rst-degree relatives as
living donors for an immediate family recipient, there were no signicant
dierences in exclusion because of medical illness or blood group type
incompatibility between male and female potential donors. More acceptable
women donors proceeded to HLA typing compared with men [98]. There
were a greater percentage of acceptable women donors (28.3%) compared
with men (20.3%) who went on to donate a kidney. When spouses were
included, 36% of wives versus 6.5% of husbands had kidneys acceptable for
donation. These data suggest that medical factors did not signicantly
contribute to the gender dierences in organ donation. Economic factors,
however, may contribute to a decreased proportion of male organ donation.
More acceptable male donors were employed full time compared with
women. Donation by the family member responsible for generating the
income in the family may be seen as a nancial burden.
Gender dierences in organ access
Several studies show that women are less likely to be kidney transplant
recipients than men. The reasons for this gender disparity are multifactorial.
Medical, immunologic (higher percentage of panel-reactive antibodies), and
economic disparities and dierences in attitudes toward transplantation have
been suggested as explanations [99]. Barriers to cadaveric renal transplants
existed for women [100]. Gender selection bias by physicians or other health
care personnel could also play a role. To be placed on the transplantation list,
a patient must be considered by his or her physician and have a medical
evaluation to conrm medical suitability. No dierence in time to inclusion
on the waiting list was seen between men and women aged less than 45 years.
Women between the ages of 46 and 55 years and 56 and 65 years old were
33% and 29% less likely to be included on the transplant list than women less
than 46 years old. Once they were listed, women were 26% less likely to
receive a kidney than men [100,101]. This has remained true over two
decades. These ndings are also not limited to the United States. In a study
performed in Sweden, of 1095 consecutive kidneys transplanted, 63.7% were
received by men [102]. Women are 10% less likely to receive a living related
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REYES et al
transplant than men [97]. Not only were women less likely to receive a living
related donor kidney transplant, but white women had a fourfold higher rate
of receiving a kidney than black women [103].
Gender dierences in organ recipient outcome
Male recipients of male donor kidneys have signicantly higher graft
survival than patients with other donor-recipient combinations [95]. Kidneys
from female donors have a worse 1-year graft survival compared with
kidneys from male donors. This dierence in survival is seen regardless of
donor status (cadaver versus living related donor kidney). This dierence was
thought to be caused in part by a mismatch between the number of donors
glomeruli and recipients functional demand [104,105]. Having fewer
nephrons might result in compensatory hyperltration-mediated glomerular
injury, causing progressive loss of glomeruli and graft failure. Neugarten et al
[104] evaluated graft survival in 1049 renal transplants, most of whom
received kidneys from cadaver donors. In this study, there were no
dierences in graft survival between female or male donor kidneys
transplanted into recipients of either gender who were not treated with
cyclosporine as an immunosuppressive agent. Kidneys from female donors in
the cyclosporine-treated group had worse graft survival compared with
kidneys from male donors, despite similar average recipient cyclosporine
dose and mean plasma cyclosporine level [104]. These data suggest that other
factors must play a role in the development of graft failure. Female kidneys
may be more susceptible to cyclosporine toxicity than male kidneys. Other
possible explanations include greater susceptibility of female kidneys to
ischemic and immunologic injury. It has been thought that female kidneys
may be more antigenic and stimulate a greater immune response [104].
Graft and patient survival were found to be signicantly better in female
renal transplant recipients compared with male recipients [106]. Graft
survival, however, censored for death, was not signicantly dierent by
gender. By multivariate analysis, women had a 10% increased risk of acute
rejection, but a 10% lower risk of graft loss secondary to chronic allograft
failure. The risk of chronic allograft failure increased with age in both
genders, but this eect was greater for men than for women. Animal data
suggest that testosterone enhances the development of chronic allograft
nephropathy [107,108]. Co-morbid conditions that dier between the
genders may also aect the outcome of renal transplantation. For instance,
hypercholesterolemia is an independent risk factor for kidney graft loss
from chronic rejection in male patients with previous acute rejection [109].
Summary
Gender dierences exist in hypertension, the prevalence of several renal
diseases, progression of established renal disease, and within the ESRD
625
program, including renal transplantation. Sex hormones play key roles in

the pathogenesis and outcome of disease processes. Observational data
suggest gender dierences in the prevalence and outcome of several renal
diseases. The molecular mechanisms associated with physiologic phenomena needed to explain gender dierences in renal disorders, however, remain
largely obscure. The interaction of psychosocial, economic, medical, and
genetic dierences associated with discrepancies between the genders in the
process of receiving a renal transplant and sustaining graft function are
currently unclear. Additional studies are needed in these and other areas to
explain gender dierences in the incidence, prevalence, and outcome of renal
disease.
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Med Clin N Am 89 (2005) 631647
Calcium and Phosphorus Metabolism

in Patients Who Have Chronic
Kidney Disease
William G. Goodman, MD
Division of Nephrology, Department of Medicine, David Geen School of Medicine
at the University of California at Los Angeles, University of California
at Los Angeles Medical Center, 7-155 Factor Building, 10833 Le Conte Avenue,
Los Angeles, CA 90095, USA
Disturbances in calcium and phosphorus metabolism are almost invariable consequences of chronic kidney disease (CKD) [1]. This is not
unexpected because the kidneys serve to maintain total body calcium and
phosphorus balance by modulating the amounts of each mineral that are
excreted daily in the urine. Cells of the proximal nephron are primarily
responsible for the synthesis of calcitriol, or 1,25-dihydroxyvitamin D, the
most potent metabolite of vitamin D. Calcitriol circulates in plasma and
functions as a systemic hormone by interacting with its receptor, the vitamin
D receptor (VDR), which is expressed in a wide variety of tissues.
Abnormalities in vitamin D metabolism in general and inadequate renal
calcitriol production in particular among patients with CKD have diverse
manifestations, which include impairments in intestinal calcium absorption,
increases in parathyroid hormone (PTH) gene expression and PTH
synthesis, and alterations in bone cell metabolism [1]. Because the capacity
to regulate calcium and phosphorus metabolism becomes compromised
progressively as kidney function declines, calcium and phosphorus
homeostasis is disrupted and serum calcium or phosphorus levels are
perturbed in many patients with CKD.
Certain disturbances in mineral metabolism develop relatively early
during the course of progressive renal disease. Others occur only at more
advanced stages, and some are unique to patients who require treatment
with dialysis. Both the extent to which calcium and phosphorus metabolism
is disrupted and the severity of abnormalities in vitamin D metabolism and
This work was supported in part by United States Public Health Service grant DK-60107.
E-mail address: wgoodman@ucla.edu
doi:10.1016/j.mcna.2004.12.005
632
GOODMAN
parathyroid gland function varies considerably among patients. Several

factors are responsible including gender, race, and the underlying type of
kidney disease.
The level of interest in, and concerns about, abnormalities in calcium and
phosphorus metabolism among patients with CKD has increased substantially in recent years. This is based, at least in part, on a growing body of
evidence indicating that selected disturbances in calcium and phosphorus
metabolism or the therapeutic interventions used to manage them are
associated with adverse clinical outcomes, particularly from cardiovascular
causes in patients undergoing dialysis regularly. Strategies for clinical
management are being revised, and recent recommendations dier substantially from those used previously with a renewed emphasis on safety. In
this regard, an advisory panel working under the auspices of the National
Kidney Foundation has introduced a set of recommendations for managing
bone disease and mineral metabolism in patients with CKD. The guidelines
have been published, and they are available by way of the Internet at the
website of the National Kidney Foundation [2]. These recommendations are
an integral part of the broader and ongoing Kidney/Dialysis Outcomes
Quality Initiative that provides current information and educational
materials to health care providers about the clinical management of patients
with CKD.
Recent observations indicate that 10% to 11% of the general population
in the United States has CKD as documented either by elevations in serum
creatinine levels or by the presence of proteinuria [3]. Many of these
individuals are managed by primary care physicians not only at early but
also at later stages of the disease. It is hoped that greater awareness of,
access to, and use of the Kidney/Dialysis Outcomes Quality Initiative
guidelines for managing bone disease and mineral metabolism will improve
the clinical care of patients with CKD and promote the widespread use of
therapeutic interventions designed to prevent or retard the development of
serious medical complications that arise when management is inadequate.
Calcium metabolism
Calcium ions play a pivotal role both in cell membrane function and in
intracellular signal transduction. Because variations in the level of calcium
in extracellular uids can adversely aect these important physiologic
processes, calcium metabolism is controlled quite tightly with the ultimate
goal of maintaining blood ionized calcium concentrations within a very
narrow physiologic range [4]. The parathyroid glands serve as the primary
regulator of blood ionized calcium levels on a minute-to-minute basis by
modulating the amounts of calcium that enter or leave extracellular uid.
This is achieved by very short-term variations in PTH secretion that have
immediate eects on renal tubular calcium transport and on the exchange of
calcium between bone and extracellular uid. More sustained changes in
633
CKD: CALCIUM & PHOSPHORUS METABOLISM
plasma PTH levels lasting many hours or several days elicit additional
adaptive adjustments in intestinal calcium absorption that serve further to
maintain constant levels of ionized calcium in blood.
Overview of calcium metabolism and the regulation of plasma calcium
concentrations
Calcium is the most abundant cation in the body. More than 99% of
calcium, or approximately 1.2 to 1.4 kg, is located in bone, predominantly in
the form of hydroxyapatite. By contrast, less than 1% of calcium is found in
extracellular uid (Fig. 1). Intracellular calcium concentrations are quite
low. Intracellular stores account for a very small fraction of the total body
calcium content.
A limited amount of calcium, approximately 150 to 200 mg, is exchanged
daily between bone and extracellular uid as part of the ongoing process of
skeletal remodeling (Fig. 1) [5,6]. Under basal conditions in adults, the
amounts entering and leaving bone are nearly identical, and net skeletal
calcium balance is neutral. Although marked changes in bone remodeling
can aect serum calcium levels in certain clinical conditions, a separate more
rapidly exchangeable skeletal pool of calcium participates in the regulation
of blood calcium levels (Fig. 1) [5,6]. The ux of calcium between this
rapidly exchangeable skeletal pool and extracellular uid is aected by
several hormones including PTH, providing a mechanism to buer changes
in blood calcium concentration that follow short-term variations in calcium
entry into or egress from the extracellular uid.
Rapidly
exchangeable
pool
1000 mg
1.2-1.4 kg
(>99%)
1200-1400 mg
(<1%)
Extracellular Fluid
Intestine
800 mg
200 mg
150-200 mg
Bone
Kidney
200 mg
Fig. 1. A depiction of the distribution of calcium in bone and extracellular uid, and the net
amounts of calcium that enter and leave the extracellular uid each day from bone and the
gastrointestinal tract. The movement of calcium between extracellular uid and a rapidly
exchangeable skeletal calcium pool serves to maintain constant levels of ionized calcium in
blood. Under steady conditions, calcium excretion in the urine closely approximates net
intestinal calcium.
634
GOODMAN
Calcium in extracellular uid exists in three distinct phases. Approximately 40% is bound to plasma proteins, primarily albumin, whereas another
10% exists as soluble complexes with organic anions, such as citrate. The
physiologically most important component of calcium in extracellular uid is
the ionized fraction. Free calcium ions interact directly with cell membranes,
with calcium channels, and with the calcium-sensing receptor (CaSR), and it
is the level of ionized calcium in blood that is regulated tightly.
The range of normal for blood ionized calcium concentrations in healthy
persons is approximately 4.4 to 5.2 mg/dL, or 1.1 to 1.3 mmol/L. Constant
levels are maintained in persons with normal renal and parathyroid gland
function by adjusting calcium excretion in the urine to accommodate
changes in calcium entry into the extracellular uid from the gastrointestinal
tract and bone (Figs. 1 and 2). Increases in the reabsorption of calcium from
tubular uid, primarily in the distal nephron, provide additional calcium to
the extracellular uid when intestinal calcium absorption is reduced or when
calcium release from bone is diminished. Conversely, reductions in calcium
reabsorption in both the proximal and distal nephron promote calcium
excretion in the urine when excess amounts of calcium enter the extracellular
uid from the gastrointestinal tract or from bone. These adaptive responses
Parathyroid glands
PTH
PTH
(+) CaSR
(-) CaSR
[iCa+2]
(-)
Bone
[iCa+2]
(-)Ca
Plasma
(-)
Kidney
(-)Ca
(-) 1OHase
Bone
(+)
Kidney
(+)
(+)Ca
(+)Ca
1,25(OH)2D
(+) 1OHase
1,25(OH)2D
(+)
(-)
Intestine
(+)Ca
(-)Ca
Intestine
Urine Calcium
Fig. 2. A summary of the adaptive responses to a change in blood ionized calcium. Decreases in
blood calcium levels provoke PTH secretion, which reduces calcium excretion in the urine by
enhancing calcium reabsorption in the distal nephron. PTH also mobilizes calcium from bone,
and both responses increase the amount of calcium entering extracellular uid. By contrast,
increases in blood calcium levels diminish PTH secretion leading to an increase in calcium
excretion in the urine and to a reduction in calcium release from bone. The amount of calcium
that enters the extracellular uid decreases.
635
are caused by very short-term changes in PTH secretion that are mediated
by a CaSR located within the plasma membrane of parathyroid cells [7].
The CaSR is expressed abundantly in parathyroid tissue and it represents
the molecular mechanism by which parathyroid cells detect very small
changes in blood ionized calcium concentration and modulate PTH
secretion accordingly. Reductions in blood ionized calcium concentration
inactivate the CaSR and promote PTH release (Fig. 2). As a result, renal
tubular calcium reabsorption is enhanced and calcium excretion in the urine
falls. In addition, PTH promotes calcium mobilization from the rapidly
exchangeable skeletal calcium pool. Both responses occur within minutes to
hours and serve to raise blood ionized calcium concentrations toward
baseline values. If plasma PTH levels remain elevated for longer periods,
1,25-dihdroxyvitamin D synthesis by the kidney increases and intestinal
calcium absorption rises, providing an additional source of calcium to
maintain its level in extracellular uid (Fig. 2).
In contrast, increases in blood ionized calcium concentration activate the
CaSR and inhibit PTH secretion (Fig. 2). Calcium excretion in the urine rises,
and less calcium is released from the rapidly exchangeable skeletal calcium
pool. Such changes serve to lower the blood ionized calcium concentration
toward baseline values. The rapid onset of these adaptive responses to very
small changes in blood ionized calcium concentration together with the very
steep inverse relationship between extracellular calcium concentrations and
plasma PTH levels provides a robust mechanism for maintaining blood
ionized calcium levels within a narrow physiologic range. With sustained
reductions in plasma PTH levels, renal 1,25-dihdroxyvitamin D production
falls and intestinal calcium absorption decreases, reducing further the
amount of calcium entering extracellular uid (Fig. 2).
Calcium metabolism and bone
Bone is remodeled continuously throughout much of the skeleton by
a tightly regulated sequence of localized cellular events. As such, net skeletal
calcium and phosphorus balance in adults is close to zero. Variations in the
net exchange of calcium between bone and extracellular uid caused by
changes in bone remodeling have little impact on the regulation of serum
calcium levels, which are inuenced predominantly by short-term adjustments in mineral ux between plasma and the rapidly exchangeable
skeletal pool.
Intestinal calcium transport
Calcium transport occurs throughout the gastrointestinal tract. Most
calcium is absorbed in the duodenum and upper portion of the jejunum. In
persons with adequate vitamin D nutrition, approximately 20% of ingested
calcium is absorbed and ultimately enters extracellular uid (Fig. 1).
636
GOODMAN
The transport of calcium by intestinal epithelia occurs by two distinct

mechanisms (Fig. 3). One is an active, energy-dependent process that
regulates the movement of calcium across intestinal epithelial cells. It is
regulated primarily by calcitriol, the most active metabolite of vitamin D.
The other is a passive, energy-independent process occurring by the
paracellular pathway. The passive component of intestinal calcium transport is concentration-dependent and largely unaected by vitamin D.
Passive intestinal calcium transport is largely unregulated. Approximately 15% to 20% of ingested calcium is absorbed by passive mechanisms
across a wide range of dietary calcium intakes. Net calcium absorption by
passive mechanisms is small when the dietary intake of calcium is low but
increases progressively as dietary calcium intake rises, accounting for the
development of hypercalciuria in persons with normal renal function who
ingest large amounts of calcium in the diet. Passive intestinal calcium
transport can contribute to episodes of hypercalcemia in patients with little
or no residual renal function who are treated with large oral doses of
calcium despite the fact that vitamin Ddependent intestinal calcium
absorption is impaired because of reductions in renal calcitriol production.
The active transcellular component of calcium transport in intestinal
epithelia is regulated quite tightly, predominantly by calcitriol. Vitamin
Ddependent calcium transport becomes increasingly important for
maintaining net intestinal calcium absorption as dietary calcium intake is
Fig. 3. An overview of the transepithelial movement of calcium in intestinal and renal tubular
epithelial cells. Calcium entry across the apical membrane is mediated by the epithelial calcium
channels TRPV5 and TRPV6. Calbindin D serves to buer changes in cytosolic calcium
concentration caused by calcium entry across the apical membrane. Calcium extrusion from the
cell is mediated by a sodiumcalcium exchanger (NCX) using energy provided by a calcium
ATPase. The levels of expression of calbindin D, TRPV5, and TRPV6 are aected by vitamin
D. Calcium transport also occurs by diusion through the paracellular pathway.
637
reduced, and it represents a crucial adaptive response to calcium

deprivation. The fractional absorption of calcium may reach 40% to 50%
when dietary intake is in the range of 400 to 500 mg/day. This change is
caused largely by an increase in the active, vitamin Ddependent component
of intestinal calcium transport, which serves to maintain net calcium input
into the extracellular uid at approximately 200 mg/day.
The transcellular movement of calcium in intestinal epithelia involves
calcium entry across the apical membrane through an epithelial calcium
channel; binding of calcium in the cytosol by calbindin D9K, a vitamin
Ddependent protein; and extrusion of calcium across the basolateral
membrane by a sodium-calcium exchanger and an ATP-dependent calcium
ATPase (Fig. 3). Vitamin D aects calcium entry into cells in calciumtransporting epithelia by modifying the expression of two important
members the vanilloid subfamily (TRPV) that is part of the super-family
of transient receptor potential proteins. Two highly homologous proteins,
TRPV5 and TRPV6, are constitutively activated calcium channels that
mediate calcium uptake across the apical membrane of renal tubular and
intestinal epithelial cells, respectively (Fig. 3) [810].
Increases in calcitriol production by the kidney are largely responsible for
the enhanced eciency of intestinal calcium transport during dietary
calcium restriction. Elevated plasma PTH levels and reductions in serum
calcium concentrations both promote renal 1a-hydroxylase activity, and
each contributes to this adaptive response. Modest elevations in serum
calcitriol levels enhance the active vitamin Ddependent component of
intestinal calcium absorption and optimize the eciency of intestinal
calcium transport, whereas modest elevations in plasma PTH levels serve to
mobilize calcium from bone. Such compensatory changes are usually
sucient to maintain serum calcium concentrations during limited periods
of dietary calcium restriction. Serum calcium concentrations decline,
however, if these adaptive responses become inadequate during extended
periods of dietary calcium deprivation.
Calcium transport within the nephron and renal calcium excretion
In adults in whom net skeletal calcium balance is neutral, the amount of
calcium excreted in urine generally reects the amount absorbed from the
gastrointestinal tract (Fig. 1). Net calcium absorption is approximately 200
mg in vitamin Dreplete individuals who ingest diets containing adequate
amounts of calcium. To maintain total body calcium balance, an equivalent
amount of calcium (about 200 mg) is excreted daily in the urine.
Adjustments in renal calcium excretion provide an ongoing mechanism to
maintain constant levels of calcium in plasma despite short-term variations
in the amounts of calcium entering extracellular uid. Changes in the
eciency of renal tubular calcium transport in the distal nephron mediate
this response.
638
GOODMAN
Renal calcium excretion begins at the glomerulus with the formation of

a protein-free ultraltrate of plasma. Calcium that is bound to albumin does
not traverse the ltration barrier of the glomerulus, whereas the ionized
fraction of calcium in blood and soluble complexes of calcium in plasma are
ltered freely. Overall, about 9000 mg of calcium is ltered at the glomerulus
each day. Of this amount, approximately 70% is reabsorbed in the proximal
tubule, 20% in the thick ascending limb of the loop of Henle, and the
remaining 5% to 10% in the distal convoluted tubule and collecting tubule.
Despite the large proportion of calcium that is reclaimed in the proximal
tubule, calcium excretion in the urine is determined primarily by adjustments in calcium transport in the distal nephron.
The transcellular movement of calcium in epithelial cells of the distal
nephron is quite similar to that described previously for intestinal epithelial
cells (Fig. 3). Calcium entry from tubular uid across the apical membrane
is mediated by TRPV5, whereas a calcium ATPase and the sodium-calcium
exchanger account for calcium extrusion across the basolateral membrane.
In kidney, a higher molecular weight form of calbindin D, calbindin D28K, is
expressed predominantly. As in the intestine, calcium transport across renal
tubular epithelia also occurs by the paracellular pathway.
PTH represents the major regulator of calcium transport in the distal
nephron, promoting calcium reabsorption and diminishing calcium
excretion. Other calcium-regulating hormones, such as vitamin D and
calcitonin, have less pronounced eects. The exquisite sensitivity of
parathyroid cells to very small change in blood ionized calcium concentration allows very rapid changes in PTH secretion to modulate distal tubular
calcium transport continuously and to regulate renal calcium excretion in an
ongoing fashion.
The impact of chronic kidney disease on calcium metabolism

Vitamin D metabolism
Serum 1,25-dihydroxyvitamin D levels generally decrease as kidney
function declines [11,12]. Results vary considerably, however, at any
particular level of renal functional impairment. In part, dierences in vitamin
D nutrition may account for such ndings. Plasma 1,25-dihydroxyvitamin D
levels may be normal in some patients, but markedly reduced in others, with
mild to moderate CKD. Values are typically quite low in patients whose renal
function has declined to less than 20% of normal, but they may be only
modestly reduced in others with similar reductions in renal function. The
proportion of patients with subnormal serum calcitriol levels increases,
however, as kidney failure function worsens. Such changes contribute
substantially to decreases in the eciency of intestinal calcium absorption
and to modest decreases in serum calcium levels in many patients with
progressive CKD. Indeed, hypocalciuria is a hallmark of moderate renal
639
insuciency [13]. It is caused not only by diminished intestinal calcium

transport but also by PTH-mediated decreases in renal calcium excretion.
Plasma PTH levels are elevated modestly in many patients with moderate
CKD despite the fact that serum calcium levels remain within the normal
range. Together with evidence that renal calcium excretion is reduced
appropriately as intestinal calcium absorption diminishes, such ndings
indicate that mild secondary hyperparathyroidism is usually sucient to
maintain serum calcium concentrations in patients with moderate CKD.
This is the primary function of the parathyroid glands. Similar biochemical
changes are seen in patients with secondary hyperparathyroidism from other
causes, such as inadequate vitamin D nutrition, and they emphasize the
crucial role of the parathyroid glands in preserving plasma calcium
homeostasis when calcium entry into extracellular uid declines. Although
phosphorus retention and hyperphosphatemia are commonly cited as key
factors in the pathogenesis of secondary hyperparathyroidism in those with
mild to moderate CKD, serum phosphorus levels are normal or reduced, not
elevated, in such patients. Phosphorus concentrations in serum exceed the
upper limit of normal only after 80% or more of kidney function has
been lost.
Other factors that adversely aect renal calcitriol production in patients
with CKD include systemic acidosis and interstitial renal diseases that
disproportionately aect the tubular epithelial cells of the proximal nephron
that are responsible for 1,25-dihydroxyvitamin D synthesis. In some patients
with proteinuria, ongoing losses of vitamin Dbinding protein from plasma
into the urine account for low serum levels of vitamin D metabolites [14]. In
subjects with advanced renal failure, the onset of phosphorus retention and
the development of hyperphosphatemia impair the activity of the renal
1a-hydroxylase responsible for the synthesis of calcitriol.
Apart from reductions in calcitriol production by the kidney, a growing
body of evidence indicates that vitamin D nutrition is marginal or overtly
inadequate in many persons with CKD as documented previously in the
general population, particularly in older adults [15]. Indeed, mild secondary
hyperparathyroidism and modest elevations in plasma PTH levels are not
uncommon in elderly persons among the general population, and repletion
with vitamin D has been shown to lower plasma PTH in such patients. Such
observations serve as the basis for the recent recommendation that
individuals with CKD should be screened for biochemical evidence of
vitamin D deciency and that vitamin D repletion be undertaken if the
disorder is identied. The importance of nutritional vitamin D deciency as
a determinant of secondary hyperparathyroidism in patients with mild to
moderate CKD has yet to be claried fully.
Vitamin D nutrition is best assessed by measuring the plasma levels of
25-dihydroxyvitamin D. Although only limited data are available, values are
often subnormal and may be markedly reduced in patients with CKD [16].
A component of the secondary hyperparathyroidism that emerges as renal
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GOODMAN
function declines in patients with CKD may be caused, at least in part, by

inadequate vitamin D nutrition rather than by impaired renal calcitriol
production.
Parathyroid gland function
Several factors contribute to sustained increases in plasma PTH levels
and, ultimately, to the development of overt secondary hyperparathyroidism in patients with CKD. Among these are hypocalcemia, impaired renal
calcitriol production, skeletal resistance to the biologic actions of PTH,
alterations in the regulation of prepro-PTH gene transcription, reductions
in VDR and CaSR expression in parathyroid tissue, and hyperphosphatemia caused by diminished renal phosphorus excretion [17].
Blood ionized calcium levels represent the most immediate stimulus for
PTH secretion. Disturbances that compromise the maintenance of serum
calcium levels in patients with CKD lead to increases PTH secretion.
Because calcitriol serves to maintain serum calcium levels by promoting
active intestinal calcium absorption, by facilitating calcium release from
bone, and by enhancing renal tubular calcium reabsorption, impairments in
renal 1,25-dihydroxyvitamin D production caused by CKD elicit compensatory increases in PTH secretion to support serum calcium concentrations
[18]. Reductions in VDR expression may attenuate the response of various
target tissues to calcitriol, but it is uncertain whether such changes are
caused by renal failure per se or by down-regulation of the VDR as a result
of low serum calcitriol levels. [19,20].
PTH is synthesized in parathyroid tissue, and it is stored in secretory
granules within parathyroid cells. Gene transcription for PTH is downregulated by 1,25-dihydroxyvitamin D through interactions mediated by the
VDR [21]. Calcium also suppresses PTH gene transcription directly [22]. As
such, decreases in 1,25-dihydroxyvitamin D synthesis, reductions in serum
calcitriol levels, and hypocalcemia, if present, can each independently
promote PTH gene transcription and hormone synthesis in patients with
CKD. Abnormalities in binding of the VDR to vitamin D response elements
within DNA may further interfere with the regulation of pre-pro-PTH gene
transcription in advanced kidney failure [23].
Calcitriol is a potent inhibitor of cell proliferation. Reductions in renal
calcitriol production have traditionally been thought to contribute to the
development of parathyroid hyperplasia in CKD [24]. VDR expression is
markedly reduced in parathyroid tissues that exhibit a nodular pattern of
tissue hyperplasia, whereas lesser reductions occur in glands with diuse chief
cell hyperplasia [25]. Interestingly, the extent of glandular enlargement is
greater in the nodular form of parathyroid gland hyperplasia [26]. The clonal
expansion of subpopulations of parathyroid cells and selected chromosomal
deletions represent additional mechanisms that may contribute to parathyroid
gland enlargement [27].
641
The development of parathyroid gland hyperplasia is a key component of

renal secondary hyperparathyroidism [28]. It is an important determinant of
disease severity and contributes substantially to disease progression. Once
established, parathyroid enlargement is dicult if not impossible to reverse
because the rate of apoptosis in parathyroid tissue is quite low [29]. Clinical
assessments of parathyroid gland function demonstrate that dierences in
functional parathyroid gland size account for wide variations in basal
plasma PTH levels in patients with chronic renal failure [30].
The secretion of PTH from massively enlarged parathyroid glands may
ultimately become uncontrolled in patients with advance secondary
hyperparathyroidism caused by CKD, leading ultimately to hypercalcemia
and progressive bone disease.
Expression of the CaSR is also reduced in hyperplastic parathyroid
tissues [31]. Such changes may render parathyroid cells less sensitive to the
inhibitory eect of calcium on PTH secretion. It is not yet known whether
impairments in renal 1,25-dihydroxyvitamin D synthesis account for such
changes in CKD [32,33].
Phosphorus retention and hyperphosphatemia have been known for
many years to aggravate the severity of secondary hyperparathyroidism.
Phosphorus-mediated decreases in renal 1a-hydroxylase activity and
reductions in renal 1,25-dihydroxyvitamin D synthesis may contribute
[34]. In addition, phosphorus retention has been shown to aggravate
parathyroid gland hyperplasia by altering the expression of several factors
involved in cell cycle regulation and cell proliferation [35].
Phosphorus metabolism
The total body content of phosphorus in adults is approximately 700 g.
Phosphorus, like calcium, is found predominantly in mineralized skeletal
tissues in the form of hydroxyapatite (Fig. 4). Phosphorus-containing
compounds are, however, important intracellular constituents, and approximately 15% of phosphorus is located in soft tissues, particularly in muscle.
Less than 1% of phosphorus is found in extracellular uid (Fig. 4).
The dietary intake of phosphorus in adults typically ranges from 1000 to
1400 mg/day in adults. The major sources are protein and dairy products.
Total body phosphorus balance is generally neutral in healthy persons with
normal renal function. Phosphorus excretion in the urine varies predominantly as a function of the amounts entering the extracellular uid
from two sources: the gastrointestinal tract and bone. The net exchange of
phosphorus between soft tissue and the extracellular uid is close to zero
under basal conditions.
Under basal conditions in adults, phosphorus excretion in the urine
reects the level of dietary phosphorus intake because intestinal phosphorus transport is largely unregulated. Although the capacity to increase
phosphorus excretion is quite large in persons with normal renal function,
642
GOODMAN
(15%)
1000-1200 mg
(85%)
(<1%)
600-800 mg
120-150 mg
400-500 mg
Fig. 4. A depiction of the distribution of phosphorus among bone, soft tissues and extracellular
uid, and the net amounts of phosphorus entering and leaving the extracellular uid each day
from bone and the gastrointestinal tract. Under steady-state conditions in adults, the amount of
phosphorus excreted in the urine each day largely reects net intestinal phosphorus absorption.
phosphorus excretion in the urine becomes inadequate to accommodate the

amounts absorbed daily from the gastrointestinal tract when kidney
function declines to 20% to 25% of normal. As a result, phosphorus
retention develops and serum phosphorus levels rise. Dietary phosphorus
intake must be restricted in patients with moderate to advanced CKD to
prevent hyperphosphatemia from developing. This can be accomplished by
limiting the intake of dietary components that contain large amounts of
phosphorus, primarily dairy products and protein-rich foods. Such
measures are used widely to manage patients with advanced kidney disease
and those who require treatment with dialysis.
In practical terms, the daily intake of phosphorus can be reduced to
approximately 800 mg while maintaining adequate protein nutrition in most
patients with advanced CKD including those undergoing dialysis. More
stringent dietary restriction can lead to inadequate protein nutrition, which
is associated with adverse clinical outcomes. Accordingly, phosphatebinding medications are used commonly to reduce net intestinal phosphorus
absorption further and to limit the amount of phosphorus entering the
extracellular uid each day in patients with advanced CKD.
Phosphorus metabolism and bone
Approximately 125 to 150 mg of phosphorus enters and leaves the
extracellular uid each day as a result of ongoing skeletal remodeling
(Fig. 4). In adults, net skeletal phosphorus balance is close to zero in the
absence of overt metabolic bone disease. Because the capacity of the kidneys
to modify phosphorus excretion in the urine is quite large, variations in the
rate of skeletal remodeling and in the amount of phosphorus exchanged
643
daily between bone and the extracellular uid do not substantially aect
serum phosphorus levels unless renal function is impaired markedly.
Nevertheless, the amounts of phosphorus released from bone are increased
in many patients with secondary hyperparathyroidism caused by CKD.
Such changes can aggravate hyperphosphatemia in those with little or no
residual renal function.
Several factors have been identied recently that play pivotal roles in
regulating phosphorus uptake into bone by osteoblasts and in mediating
skeletal mineralization. These include the phosphate-regulating gene with
homologies to endopeptidase (PHEX), the matrix extracellular phosphoglycoprotein (MEPE), and broblast growth factor 23 (FGF-23). These and
other phosphate-regulating proteins, collectively known as phosphatonins,
may represent discreet components of a hormonal-autocrine-paracrine
network that serves not only to regulate phosphorus metabolism in bone but
also to maintain phosphorus homeostasis systemically [36].
Intestinal phosphorus transport
Between 60% and 70% of dietary phosphorus is absorbed by the
gastrointestinal tract, mostly in the duodenum and jejunum (Fig. 4). Net
phosphorus entry into the extracellular uid from the gastrointestinal tract
is approximately 600 to 800 mg/day. It is this amount of phosphorus that is
excreted in the urine each day to maintain neutral total body balance.
Intestinal phosphorus transport is predominantly a passive, or diusional,
process and occurs primarily through the paracellular pathway. A small
energy-dependent component of intestinal phosphorus transport is caused by
the uptake of sodium and phosphorus across the apical brush-border
membrane of intestinal epithelial cells by a sodium-phosphate cotransporter
using energy provided by a sodium-potassium ATPase. The presence of
certain constituents within the intestinal lumen retards net phosphorus
absorption. A high dietary intake of calcium diminishes intestinal phosphorus
transport by promoting the formation of insoluble complexes of calcium and
phosphorus within the intestinal lumen. Other alkaline metals, such as
aluminum hydroxide, aluminum carbonate, and lanthanum carbonate, also
bind phosphorus in the lumen of the small intestine and diminish its
absorption. These compounds and the calcium-free, phosphate-binding resin
sevelamer are used therapeutically to manage phosphorus retention and to
control hyperphosphatemia in patients with CKD.
Vitamin D sterols promote intestinal phosphorus absorption by increasing
sodium-phosphate cotransport across the apical brush-border membrane.
Because sustained alterations in dietary phosphorus intake aect the level of
activity of the renal 25-hydroxvitamin D, 1a-hydroxylase, changes in renal
calcitriol production may provide some regulatory control over intestinal
phosphorus absorption. The eect of vitamin D to enhance intestinal
phosphorus absorption through sodium-phosphate cotransport-mediated
644
GOODMAN
mechanisms probably explains the increases in serum phosphorus levels that

occur commonly in patients with CKD who are given vitamin D sterols to
treat secondary hyperparathyroidism.
Phosphorus transport within the nephron and renal phosphorus excretion
Most inorganic phosphorus in plasma is in an ultralterable form. It
readily crosses the ltration barrier within the glomerulus and is found in
proximal tubular uid at concentrations similar to those in plasma.
Approximately 60% to 70% of the ltered load of phosphorus is reabsorbed
in the proximal nephron, which serves as the primary site for regulating
phosphorus excretion in the urine. Lesser amounts of phosphorus are
reabsorbed in more distal nephron segments.
The transport of phosphorus, like calcium, across renal tubular epithelia
requires the entry of phosphorus from luminal uid across the apical brushborder membrane, vectorial movement though the cytoplasm, and extrusion
from the cell across the basolateral membrane into peritubular blood.
Phosphorus uptake across the apical membrane of proximal tubular cells is
mediated predominantly by the type 2 sodiumphosphorus cotransporter,
or Na/Pi 2 transporter, which is expressed abundantly in cells of the
proximal nephron. The uptake of phosphorus across the apical brushborder seems to be the rate-limiting step for the transepithelial movement of
phosphorus in renal epithelia.
Dietary phosphorus restriction leads to increases in the level of
expression of the Na/Pi 2 transporter, a change that is associated with
enhanced phosphorus reabsorption in the proximal tubule and decreases in
phosphorus excretion in the urine. Interestingly, phosphorus excretion
changes within only a few hours after the dietary intake of phosphorus is
altered, and this response seems to be independent of PTH. Very short-term
alterations in tracking of the Na/Pi 2 transporter between intracellular
vesicles and the apical membrane may account for this rapid adaptation.
PTH is a potent modier of renal phosphorus excretion and markedly
increases renal phosphorus excretion. It acts primarily in the proximal
nephron to diminish phosphorus reabsorption by altering protein tracking
of the Na/Pi 2 transporter to the apical membrane and by decreasing gene
expression. Changes in the level of expression of the Na/Pi 2 transporter are
thought to be largely responsible for alterations in phosphorus transport in
the proximal nephron that are mediated by PTH and by variations in
dietary phosphorus intake.
The eects of calcitriol on phosphorus handling by the kidney have not
been dened clearly. In contrast, recombinant broblast growth factor 23
has been shown to decrease Na/Pi 2 transporter expression in the proximal
tubule and to diminish 1,25-dihydroxyvitamin D synthesis. Such ndings,
together with observations from clinical studies of patients with selected
hypophosphatemic syndromes and additional assessments of genetically
645
modied mice, indicate that broblast growth factor 23 functions as a key

determinant of phosphorus transport within the nephron.
The impact of chronic kidney disease on phosphorus metabolism
Because the kidney plays such a pivotal role in modulating phosphorus
balance, phosphorus retention and hyperphosphatemia are hallmarks of
advanced CKD. Overt hyperphosphatemia develops when kidney function
declines to approximately 20% of normal. Hyperphosphatemia is almost
always present among patients undergoing dialysis who are nourished
adequately.
Although recognized for many years as a factor that can aggravate soft
tissue calcication, hyperphosphatemia has more recently been associated
with the development of vascular calcication and with adverse clinical
outcomes from cardiovascular causes among patients undergoing long-term
dialysis. Indeed, hyperphosphatemia represents an independent risk factor
for death in patients treated with hemodialysis regularly [37,38]. Eective
control of serum phosphorus levels is a crucial component of clinical
management.
Vitamin D metabolism
High ambient phosphorus levels inhibit renal 1a-hydroxylase activity. As
such, phosphorus retention and hyperphosphatemia can impair 1,25-dihydroxyvitamin D synthesis in advanced CKD. The ability of other factors, such
as calcium and PTH, to up-regulate renal 1a-hydroxylase is maintained to
a certain extent in mild to moderate CKD but declines as kidney disease
progresses. As such, the physiologic regulation of calcitriol synthesis is
disrupted markedly in more advanced kidney failure.
Parathyroid gland function

Phosphorus retention and hyperphosphatemia aggravate the severity of
secondary hyperparathyroidism, at least in part, by promoting parathyroid
gland hyperplasia [35]. The importance of phosphorus retention or
hyperphosphatemia as direct modiers of PTH gene transcription and
PTH secretion is less certain.
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Med Clin N Am 89 (2005) 649687
Drug Dosing in Chronic Kidney Disease

Steven Gabardi, PharmD, BCPSa,b,*,
Stuart Abramson, MDc
a
Department of Pharmacy Services, Brigham and Womens Hospital,

b
Department of Pharmacy Practice, Bouve College of Health Sciences,
Northeastern University, Boston, MA, USA
c
Dialysis Unit, Division of Nephrology and Renal Transplantation, Maine Medical Center,
22 Bramhall Street, Portland, ME 04102, USA
It is a well-known principle that endogenous creatinine clearance correlates well with the renal elimination of most medications [14]. Be that as
it may, it is a common oversight for health care practitioners to fail to take
estimates of creatinine clearance into account before dosing medications
[3,5]. The lack of dose adjustments in patients with renal insuciency is an
often overlooked, yet preventable, cause of drug dosing errors. One study
revealed that greater than 40% of patients with chronic kidney disease
(CKD) stages 3 to 5 received higher than normal medication doses, based
on estimated creatinine clearances [6]. In this analysis the doses were, on
average, 2.5 times higher than the maximum recommended doses based on
the patients calculated glomerular ltration rate. This study emphasizes the
importance of improving the identication of patients with renal insuciency, estimating their glomerular ltration rate, and implementing appropriate dose adjustments according to these estimates [6]. Using estimated
creatinine clearance as the lone measure of medication handling and then
only adjusting those medications that are ltered by the kidney during CKD
is inappropriate, however, because several other factors also play an important role in establishing an appropriate dosing regimen.
CKD inuences drug disposition through changes in several pharmacokinetic parameters. Some of the most common alterations seen in CKD
patients include reduced oral absorption and glomerular ltration; altered
tubular secretion and reabsorption; and changes in intestinal, hepatic, and
* Corresponding author. Department of Pharmacy Services, Brigham and Womens

Hospital, 75 Francis Street, Boston, MA 021156110.
E-mail address: sgabardi@partners.org (S. Gabardi).
doi:10.1016/j.mcna.2004.11.007
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GABARDI & ABRAMSON
renal metabolism [24,79]. CKD-induced variations in medication pharmacokinetics are not easily assessed or understood by most health care
practitioners, because these parameters are both drug- and patient-specic.
Another complicating factor of drug dosing in the CKD population is the
existence of numerous comorbidities, including diabetes, coronary artery
disease, and infection. These patients frequently require multiple pharmaceutical agents to manage both the underlying renal dysfunction and comorbid disease states [2,3,9]. Given the propensity for polypharmacy in this
population, the potential for adverse events and drug-drug interactions is
high. Several studies have established that the incidence of adverse events is
much higher in patients with CKD than in those without renal insuciency
[3,10]. Appropriate drug selection and dosing in CKD patients is imperative
to avoid drug misadventures and to ensure optimal patient outcomes.
General pharmacokinetic principles and terminology

Pharmacokinetics refers to the study of the activity of drugs, with particular emphasis on medication absorption, duration of action, total-body
distribution, metabolism, and eventual excretion [11]. This science is often
used to gain a more complete understanding of how drug handling occurs
in the body. Information collected from this practice can aid in establishing
patient-specic dosing regimens that optimize ecacy and minimize
toxicities. Most drugs follow rst-order elimination pharmacokinetics, including aminoglycosides and digoxin [1,11]. This term refers to the process
by which drug concentrations diminish logarithmically over time. Medication elimination rates are proportional to their total-body concentrations;
a constant fraction of the drug is eliminated per unit of time. The fraction of
the total amount of drug present in the body remains constant and is
independent of the administered dose. This fraction is referred to as the
elimination rate constant. Another important characteristic of rst-order
elimination pharmacokinetics is that, under normal circumstances, volume
of distribution (Vd), elimination half-life, and clearance all remain constant,
regardless of medication dose or plasma concentration [11].
Volume of distribution
A medications Vd is derived by dividing the total amount of drug in the
body by its plasma concentration [11]. It should be noted that this ratio does
not refer to a specic anatomic compartment in the body. The peak
concentration of a medication after a loading dose is determined by its Vd.
This is an important concept, because a proper loading dose may be calculated by knowing the desired serum concentration and the average
medication Vd, which can be calculated or found in the literature. Vd may be
aected by a number of physiologic determinants, including plasma protein
CKD: DRUG DOSING
651
and tissue binding, lipid partitioning, active transport systems, and overall
body composition [11].
Clearance
Clearance is the bodys ability to remove drugs from the blood and is
often expressed as a volume per unit of time (eg, mL/min) [11]. Clearance
is not indicative, however, of how much drug is removed by the body; it
actually represents the theoretical volume of blood that is cleared of the
drug over a given time period. Several factors have been shown to alter
medication clearance, including body weight, body surface area, plasma
protein binding, hepatic and renal function, medication extraction ratio, and
cardiac output [1,11].
Elimination half-life
Elimination half-life is the time needed to reduce medication plasma
concentrations by 50% [11]. After ve half-lives, elimination is 97% complete. Knowledge of elimination half-life is useful because it can be related to
the time required to reach steady-state concentrations and to estimate an
appropriate dosing interval. Typically, a medication reaches steady-state in
approximately four half-lives. In rst-order kinetics, elimination half-life is
completely determined by the variables Vd and clearance [11].
Alterations in pharmacokinetic parameters in the chronic kidney disease
population
It is imperative that health care practitioners have an understanding of
the eects that CKD has on the biochemical and physiologic properties of
medications. To illustrate these points, CKD-induced alterations in medication absorption, distribution, metabolism, and elimination are discussed
in detail.
Absorption
A medications oral bioavailability is dened as the fraction of an
administered dose that reaches the systemic circulation [11]. This pharmacokinetic parameter may be inuenced by numerous physiologic changes in
the gastrointestinal tract, several of which are commonly seen in the CKD
population. It has been suggested that many patients with renal insuciency
suer from gastroparesis, which can result in delayed gastric emptying
[12,13]. Published gastric emptying studies in CKD patients, however, have
yielded conicting results [1418]. It should be noted that delays in gastric
emptying may prolong the time to reach maximum drug concentrations,
but these delays generally do not aect the overall extent of absorption [11].
A prolonged time to reach maximum drug concentrations is an important
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factor when the rapid onset of pharmacologic activity after oral administration is a necessity. Reductions in time to reach maximum drug concentrations are usually insignicant when a drug is continually administered.
The bioavailability of several medications is inuenced by gastric pH.
Increased gastric pH is a common manifestation in CKD and its etiology is
multifactorial. Ammonia formation in the gut, secondary to conversion of
salivary urea by urease enzymes, is one explanation for increased pH [19].
The administration of phosphate binders, liquid antacids, H2-receptor
antagonists, and proton-pump inhibitors in this patient population is
commonplace. These agents alter gastric pH and, to a lesser extent, gastrointestinal motility [7,9,2022]. For medications that are best absorbed in an
acidic environment, drug dissolution and ionization are often reduced
by increased gastric pH, resulting in reduced bioavailability [11,20]. For
example, gastric alkalinization decreases the oral absorption of furosemide
and ferrous sulfate [20,23,24]. Conversely, it has been shown that the
administration of magnesium hydroxide and sodium bicarbonate, commonly used medications in the CKD population, can enhance the absorption of some weakly acidic molecules (eg, ibuprofen, glipizide, glyburide,
tolbutamide), by increasing their water solubility and subsequent absorption [25]. Also, the ingestion of cation-containing antacids (eg, calcium,
magnesium), aluminum hydroxide, sodium polystyrene sulfonate, and
vitamin supplements (eg, iron) may reduce drug absorption because of
chelation with coadministered medications, resulting in the formation of
insoluble compounds [20,21]. The uoroquinolones and tetracyclines are
two medication classes that are highly susceptible to chelate formation in
patients with renal insuciency [20,2628]. Finally, bowel wall edema has
also been cited as a potential cause of diminished oral absorption in CKD
patients [2,3,12].
An often-overlooked component of drug bioavailability is intestinal and
rst-pass metabolism. Once an orally administered medication reaches the
gut wall, it passively diuses or is actively transported across the intestinal
lining [11]. At this point, it may also undergo presystemic metabolism inside
the enterocytes [7]. CKD-induced reductions in intestinal metabolism and
P-glycoproteinmediated drug transport may result in increased oral
bioavailability of certain medications [29].
The most prevalent drug-metabolizing enzyme in the gut is the
cytochrome P-450 (CYP450) 3A4 isozyme [30]. CYP3A4 accounts for
nearly three quarters of all CYP450 isozymes found in the intestines. Several
medications undergo signicant metabolism in the gastrointestinal tract,
including cyclosporine and tacrolimus [3134]. Renal insuciency is associated with decreased intestinal CYP450 activity, with a greater than 30%
reduction in intestinal CYP450 activity seen in animal studies [35]. This
altered activity is thought to be secondary to diminished CYP450 gene
expression [7,35]. CKD-induced reductions in intestinal CYP450 biotransformation have a profound eect on drug absorption by increasing overall
CKD: DRUG DOSING
653
oral absorption [35]. P-glycoprotein is a transport protein that plays a vital

role in drug-disposition. This protein is found in several areas of the body,
including the intestines, liver, and kidneys [32,36]. P-glycoprotein functions
to protect the body against the accumulation of toxic compounds by
transporting these compounds out of the systemic circulation and into the
intestinal lumen, bile, or urine. Several animal models of CKD have
demonstrated decreased activity of intestinal P-glycoprotein [37,38]. Decreased P-glycoprotein activity results in a greater concentration of
medications remaining in the systemic circulation. Box 1 provides examples
of medications that are substrates, inhibitors, and inducers of the Pglycoprotein transport system.
With the higher quantities of drug entering the portal circulation from
the gut, a larger percentage may undergo rst-pass biotransformation in the
liver [9]. Also, CKD-induced reductions in protein binding may make
hepatically metabolized drugs more susceptible to rst-pass metabolism.
These factors could potentially result in decreased serum concentrations.
Overall, estimation and evaluation of oral absorption is a dicult task in the
CKD population. Protein binding and drug biotransformation are discussed
later.
Distribution
Alterations in protein and tissue binding and body composition can
impact a medications Vd[11]. All of these factors are inuenced by renal
function. Plasma drug concentrations are a representation of both drug
bound to plasma proteins and unbound (free) drug. Only free drug, however, is capable of crossing cellular membranes and exerting its pharmacologic eect [11]. CKD-induced alterations in protein binding are associated
with many clinical implications. Medications that are acidic, such as
penicillins, cephalosporins, phenytoin, furosemide, and salicylates, are most
severely aected by reduced protein binding [12,39,40]. Acidic drugs are
bound to albumin, plasma concentrations of which are often decreased in
uremic patients. Hyperalbuminuria is one reason to explain the reductions
seen in protein binding of acidic drugs in CKD, although there are several
other explanations [7,39]. The competition for binding sites by other drugs,
metabolites, and accumulating endogenous substances may displace medications from plasma protein binding sites [12,39,41]. One such example is
CKD-induced accumulation of hippuric acid with a resultant inhibition
of theophylline protein binding [41,42]. Qualitative changes in albumin
binding sites are commonly seen during renal insuciency, which results
in decreased drug-binding anity [12,39,41]. Conversely, alkaline drugs
(eg, propranolol, morphine, oxazepam, vancomycin) bind primarily to
nonalbumin plasma proteins, such as a1-acid glycoprotein [11]. a1-Acid
glycoprotein is an acute-phase protein whose plasma concentrations
are often elevated in renal dysfunction [7]. For this reason, plasma
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GABARDI & ABRAMSON
Box 1. Examples of common P-glycoprotein substrates,

inhibitors, and inducers
Substrates
Amprenavir
Amitriptyline
Cimetidine
Colchicine
Corticosteroids
Cyclosporine
Digoxin
Diltiazem
Erythromycin
Estrogen
Fentanyl
Fexofenadine
Indinavir
Itraconazole
Ivermectin
Loperamide
Losartan
Methadone
Methotrexate
Morphine
Mycophenolic Acid
Nelfinavir
Nortriptyline
Octreotide
Ondansetron
Phenytoin
Ranitidine
Ritonavir
Saquinavir
Tacrolimus
Tamoxifen
Verapamil
Inhibitors
Amiodarone
Cortisol
Cyclosporine
Diltiazem
Felodipine
Itraconazole
Ketoconazole
Nifedipine
Quinidine
Tamoxifen
Inducers
Rifampin
St. Johns Wort
Data from Refs. [319322].
concentrations of alkaline drugs in CKD patients may be reduced (eg,

propranolol), but more often than not remain unchanged [3,4244].
Attempts to achieve therapeutic drug concentrations in the CKD
population without dose adjustment are often associated with higher free
acidic drug concentrations and potentially drug-related toxicities. Increased
free drug concentrations, however, may also result in an increased fraction
of drug that undergoes biotransformation, decreasing pharmacologic
activity [9]. Based on these factors, it is easy to see that one goal of drug
dosing in CKD is to achieve an appropriate free drug concentration, while
avoiding the use of total serum concentrations as a target. Overall, CKDinduced alterations in protein binding makes it very dicult to predict
CKD: DRUG DOSING
655
whether a given dose will produce an adequate, supertherapeutic or subtherapeutic eect.

Besides reduced plasma protein binding, Vd may also be aected by
altered tissue binding [11]. For most medications, changes in tissue binding
are probably irrelevant [7]. The major exception is digoxin. Digoxins Vd is
reduced by half in patients with stage 5 CKD. This reduction in Vd results in
increased digoxin serum concentrations if the loading dose is not reduced
[12].
CKD-induced changes in body composition, such as increased total-body
water and adipose tissue and decreased muscle mass, can have a profound
eect on hydrophilic drugs (eg, pravastatin, uvastatin, morphine, codeine)
[2,9]. Excessive uid retention, manifesting as increased extracellular uid
volume or ascites is expected to increase the Vd of hydrophilic compounds.
This change in Vd may result in reduced serum concentrations [9]. Contrarily, muscle wasting and increased adipose tissue may reduce Vd and
increase serum concentrations of hydrophilic medications [9].
Metabolism
Drug biotransformation is classied as either a phase I or phase II
reaction. Phase I metabolism, the most common type of biotransformation,
consists of hydrolysis, reduction, and oxidation [11]. CYP450-mediated
oxidation comprises the bulk of phase I metabolic reactions. All of the phase
I reactions increase drug hydrophilicity to facilitate excretion or to prepare
it for phase II metabolism. Phase II conjugation reactions, consisting of
glucuronidation, sulfation, glutathione conjugation, acetylation, and methylation, also serve to enhance hydrophilicity and promote excretion [11].
Much has been written on the eect of CKD on drug metabolism
[1,2,7,9,31,40,4547]. Renal dysfunction signicantly alters biotransformation. In general, phase I hydrolysis and reduction reactions are slowed in
CKD [2,9]. A closer look at oxidative phase I metabolism reveals that
biotransformation through several of the CYP450 isozymes is also altered,
with CYP450 2C9, 2C19, 2D6, and 3A4 activity showing reduced activity in
the CKD population [4856]. CYP450 gene expression in the liver is also
reduced by renal insuciency [46,57]. Table 1 provides common medications that are substrates, inhibitors, and inducers of the CYP450 2C9,
2C19, 2D6, and 3A4 isozymes.
Additionally, phase II metabolic reactions are also aected by renal dysfunction. Acetylation (eg, dapsone, hydralazine, isoniazid, procainamide),
glucuronidation (eg, acetaminophen, morphine, lorazepam, oxazepam,
naproxen), sulfation (eg, acetaminophen, minoxidil, dopamine, albuterol),
and methylation (eg, dobutamine, dopamine, 6-mercaptopurine) are all
slowed in patients with CKD [5862]. Slowed phase I and II metabolic
reactions result in increased serum drug concentrations.
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Table 1
Examples of common medications for the isozymes discussed
Isozymes
Substrates
Inhibitors
Inducers
CYP2C9
Fluvastatin
Ibuprofen
Losartan
Rosiglitazone
Warfarin
Amiodarone
Cimetidine
Cotrimoxazole
Fluconazole
Isoniazid
Barbiturates
Rifampin
CYP2C19
Citalopram
Diazepam
Lansoprazole
Omeprazole
Pantoprazole
Fluconazole
Fluoxetine
Fluvoxamine
Omeprazole
Barbiturates
Rifampin
CYP2D6
Amitriptyline
Codeine
Desipramine
Dextromethorphan
Haloperidol
Imipramine
Metoprolol
Paroxetine
Propafenone
Propranolol
Thioridazine
Timolol
Amiodarone
Fluoxetine
Haloperidol
Paroxetine
Propafenone
Propoxyphene
Quinidine
Thioridazine
Rifampin
CYP3A4
Alprazolam
Atorvastatin
Buspirone
Cyclosporine
Diltiazem
Erythromycin
Felodipine
Indinavir
Lidocaine
Lovastatin
Midazolam
Nifedipine
Quinidine
Ritonavir
Sertraline
Simvastatin
Sirolimus
Tacrolimus
Triazolam
Verapamil
Warfarin
Zolpidem
Amiodarone
Azithromycin
Clarithromycin
Delavirdine
Diltiazem
Erythromycin
Fluconazole
Grapefruit juice
Indinavir
Itraconazole
Ketoconazole
Nefazodone
Ritonavir
Verapamil
Voriconazole
Barbiturates
Corticosteroids
Carbamazepine
Nevirapine
Phenytoin
Rifampin
St. Johns Wort
Data from MICROMEDEX Healthcare Series. Greenwood Village (CO): Thomson

MICROMEDEX; 2004.
CKD: DRUG DOSING
657
A factor of drug biotransformation that cannot be overlooked is the

kidney as a site for drug metabolism. Ordinarily, the kidneys have nearly
15% of the metabolic function of the liver, with most of the metabolic
enzymes located in the renal cortex [63]. Renal metabolism is obviously
reduced during cases of renal insuciency. Box 2 lists medications that are
commonly metabolized by the kidneys [6472].
Understanding the metabolic pathways of all medications administered
to a patient with renal insuciency is a necessity. Whether it is intestinal,
hepatic, or renal metabolism, reduction in the overall metabolic rate results
in increased parent compound concentrations, potentially increasing the
prevalence of adverse events.
Elimination
Renal excretion of medications is dependent on glomerular ltration rate,
renal tubular secretion, and reabsorption. The glomerular elimination
of drugs depends on several factors, including the molecular weight and
protein binding characteristics of the medication [11]. After glomerular
ltration, the ultraltrate contains both soluble drugs and other molecules.
Several small proteins are ltered by the glomerulus. Drugs bound to
albumin are not ltered. In this situation, the ltration rate of these drugs is
directly proportional to their free plasma concentrations (ie, fraction of the
Box 2. Medications that are extensively metabolized by

the kidneys
Acetaminophen
Calcitonin
Cephalothin
Clofibrate
Diflunisal
Imipenem-cilastatin
Insulin
Isoproterenol
Morphine
Meperidine
Morphine
Oxytocin
Salicylic acid
Somatostatin
Sulfisoxazole
Sulindac
Vasopressin
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GABARDI & ABRAMSON
drug that actually gets ltered) [11]. In CKD, medication elimination by

glomerular ltration is decreased, resulting in a prolonged free drug
elimination half-life [24,9].
Although protein binding decreases the glomerular ltration of some
drugs, the renal tubular secretion of these medications may be increased.
Highly protein-bound medications are actively secreted into the proximal
convoluted tubules, ensuring they are excreted [11,73]. In CKD, however,
the secretion of drugs eliminated by this active transport system is reduced
[9,73]. Another factor aecting active tubular secretion of drugs is that this
is a transport-mediated process and, with higher drug levels, the secretion
reaches a limit leading to an increased elimination half-life. Also, competition between drugs for secretion can reduce their excretion [2,9,73]. This
is a common phenomenon seen with the coadministration of penicillin and
probenecid [7476]. Box 3 provides medications that are secreted in the
proximal tubules.
In healthy kidneys, the renal clearance of many drugs is slow because
they are substantially reabsorbed from the distal portion of the nephron,
despite glomerular ltration and active secretion [9,11,73]. This is a passive
process and is aected by several factors, including urine concentrating
activities and pH, medication lipophilicity, and protein binding. As
expected, reductions in medication reabsorption are observed in patients
Box 3. Drugs excreted in the proximal tubules

Acids
Ampicillin
Furosemide
Penicillin G
Phenylbutazone
Probenecid
Salicylic acid
Sulfisoxazole
Bases
Cimetidine
Dopamine
N-methylnicotinamide
Neostigmine
Procainamide
Quinidine
Trimethoprim
Data from Refs. [4,12,22,40,73,323].
CKD: DRUG DOSING
659
with CKD, resulting in increased urinary concentrations of renally

eliminated medications, such as aspirin and lithium [9,73,7779].
One aspect of renal excretion that is often overlooked is the elimination
of drug metabolites. Biologically active or toxic metabolites of parent
compounds may accumulate in patients with CKD [2,4,9,73]. The opioid
analgesic meperidine undergoes biotransformation to normeperidine.
Normeperidine, which is renally eliminated, has little opioid activity. As it
accumulates secondary to renal dysfunction, however, it lowers the seizure
threshold [8084]. Similarly, the active metabolite of midazolam, alphahydroxymidazolam, can accumulate in CKD patients [8587]. Accumulation of this metabolite has resulted in excessive sedation [85]. Additionally,
biologically inactive metabolites may have an indirect eect on drug-plasma
protein binding and receptor anity [4,73]. Table 2 provides drugs and their
metabolites that may accumulate in renal dysfunction.
Dosing theories in the chronic kidney disease population

Loading (initial) dose
The purpose of a loading dose is to produce rapidly a therapeutic plasma
concentration. A common oversight in prescribing medications to patients
with renal insuciency is inherently to reduce the drug doses or prolong the
dosing intervals at the initiation of therapy. Under most circumstances,
a normal loading dose should be administered to CKD patients to achieve
therapeutic drug levels quickly [2,9]. Digoxin is one medication exception to
Table 2
Common medications with biologically-active metabolites that may accumulate in chronic
kidney disease
Parent compound [Ref.]
Metabolite(s)
Acebutolol [145,324]
Allopurinol [82,325]
Clobrate [82]
Cefotaxime [326328]
Cyclophosphamide [53,329]
Meperidine [8084]
Midazolam [8587]
Morphine [81,208,209]
N-acetylacebutolol
Oxypurinol
Chlorphenoxyisobutyrate
Desacetyl cefotaxime
4-Ketocyclophosphamide
Normeperidine
Alpha-hydroxymidazolam
Morphine-3-glucuronide
Morphine-6-glucuronide
1-(5-Hydroxyhexyl)-3,7-dimethylxanthine and
1-(3-carboxypropyl)-3,7-dimethylxanthine
N-acetylprocainamide
Norpropoxyphene
p-Hydroxypropranolol
Acetylsulfadiazine
Pentoxifylline [330]
Procainamide [82,183,331334]
Propoxyphene [81,212,335,336]
Propranolol [337]
Sulfadiazine [338,339]
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GABARDI & ABRAMSON
this general rule [2,9]. There are also certain physiologic determinants, however, that require a change in the loading dose. Patients with excess totalbody water (eg, edema, ascites) may require a higher-than-normal loading
dose to take into account a change in medication Vd. This is especially
common in patients who are critically ill or in acute renal failure [88].
Conversely, in dehydrated patients, smaller loading doses may be
appropriate [9]. Another way to ascertain an appropriate loading dose is
by using the following calculation: Loading dose = Vd IBW Cp; where
Vd is measured in liters per kilogram, IBW is ideal body weight in kilogram,
and Cp is the desired medication plasma concentration in milligrams per liter
[2,9].
Maintenance dose
After the initiation of therapy with a loading dose, a maintenance dose is
required to maintain steady-state plasma concentrations. If immediate
pharmacologic activity is not urgent, a loading dose can be omitted and
steady-state can be achieved gradually by administration of maintenance
doses. In general, two methods can be used for administering maintenance
medications in patients with decreased renal function: expanding the dosing
interval or reducing the dose [2]. These methods can be used alone or
simultaneously.
The expanded interval method generally corresponds well with CKDinduced delays in drug medication excretion, allowing more time for the
drug to be eliminated before redosing. To calculate an extended dosing
interval, one must calculate the patients creatinine clearance and know the
normal dosing interval of the medication to be administered. Using the
following equation, one can now determine the appropriate dosing interval
on a patient-by-patient basis: new expanded dosing interval = (normal
creatinine clearance per the patients calculated creatinine clearance) the
normal dosing interval [2]. This method works well with medications that
have a broad therapeutic window and a long half-life. The expanded interval
method has been associated with reduced medication toxicities, but also
with periods of subtherapeutic plasma concentrations [2].
Alternatively, the dose-reduction method may be used, which involves
reducing each individual dose while retaining normal dosing intervals. This
method is generally associated with achievement of a more constant drug
concentration. Again, to use this equation one must know the normal
medication dose and calculate the patients creatinine clearance: new
reduced dose = (the patients calculated creatinine clearance per normal
creatinine clearance) the normal dose [2]. This method is associated with
a higher risk of adverse events.
When using these two methods, the risks of subtherapeutic serum
concentrations must be weighed against the risks of adverse events. Consequently, combining these two approaches in the CKD population frequently
CKD: DRUG DOSING
661
becomes a necessity to optimize medication ecacy and minimize drug

misadventures.
Drugs that need special attention in chronic kidney disease

Anticoagulants
Warfarin metabolism is not signicantly altered in CKD [89]. Patients
with CKD who are placed on warfarin do have a higher incidence of
hemorrhage likely because of platelet dysfunction and interaction with other
medications taken by the patient [90,91]. For this reason, the health care
professional monitoring anticoagulation with warfarin needs to pay close
attention to the international normalization ratio and the other prescribed
and over-the-counter medications the patient is taking [92].
Low-molecular-weight heparins have grown in popularity following
a number of studies showing ease of use and equal or greater ecacy as
compared with unfractionated heparin [9396]. In most patient populations,
monitoring of anticoagulation with anti-Xa assays is not necessary [93].
Peak anti-Xa levels are drawn 4 hours after the third subcutaneous dose
[93]. The clearance of low-molecular-weight heparin is primarily caused by
renal excretion [9799]. As with warfarin, the risk of hemorrhage seems to
be higher in patients with CKD [100,101]. For these reasons, a number of
authors have argued that patients with a creatinine clearance less than
30 mL/min should have additional monitoring if placed on a low-molecularweight heparin [99]. This recommendation has not been supported by
further kinetics studies because it seems that patients with renal function
better than 30 mL/min may develop bleeding complications caused by
accumulation depending on the heparin used [102]. One study of enoxaparin
in unstable angina reduced the dose to 85% and 65% in patients with
a creatinine clearance 30 to 60 mL/min and less than 30 mL/min, respectively.
With this reduction, they achieved a therapeutic anti-Xa level of 1 IU/mL
[103]. The low-molecular-weight heparin tinzaparin has the smallest increase
in half-life with CKD [102]. At this time, there are very little data to guide
the clinician in dosing low-molecular-weight heparin in CKD and
monitoring of anti-Xa levels and caution are advised. Fondaparinux is
a new factor Xa inhibitor with indications for deep vein thrombosis
prophylaxis. It is cleared by the kidney and should be used with caution in
mild CKD and avoided in patients with stages 3, 4, or 5 CKD [104,105].
Although the risk of developing heparin-induced thrombocytopenia
while on low-molecular-weight heparin is lower than while on unfractionated heparin, both forms of heparin can cause heparin-induced thrombocytopenia [99]. Hirudin is a direct thrombin inhibitor and can be used for
anticoagulation in heparin-induced thrombocytopenia [106]. It is cleared by
the kidney and needs to be dose reduced in CKD [107]. The manufacturer of
lepirudin recommends a maintenance infusion of only 15% of the standard
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GABARDI & ABRAMSON
dose for patients with a creatinine clearance 15 to 29 mL/min with frequent

monitoring of activated partial thromboplastin time. It should be avoided in
patients with a clearance less than 15 mL/min [106]. If possible, hirudin
blood levels should be drawn because activated partial thromboplastin time
can underestimate the degree of anticoagulation. Argatroban is the preferred alternative anticoagulant in renal disease because it is cleared by the
liver and does not need dose adjustment in CKD [108].
Antihypertensive and cardiac medications
Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme (ACE) inhibitors form the mainstay of
therapy for CKD [109112]. As a class, these drugs are generally cleared by
the kidney and need to have their dose reduced in CKD [113115]. The
exception to this rule is fosinopril, which is excreted by the hepatobiliary
pathway and requires no dose adjustment [113,116]. There is good evidence
that patients benet from ACE inhibition even with advanced CKD and
stages 3 or 4 CKD is not a contraindication to their use [117]. A small drop
in glomerular ltration rate is common when these agents are started in
advanced CKD and a drop of less than 20% is not a reason to discontinue
the medication [110,118]. The risks of developing severe hyperkalemia or
acute renal failure are higher in patients with CKD but remain less than 5%
in most populations [119]. Patients with diabetes and a history of hyperkalemia are at the highest risk [120]. It is recommended that patients with
CKD have electrolytes and renal function checked 4 to 7 days after starting
or having the dose of an ACE inhibitor adjusted [111,121]. Caution is
advised in the use of other medications that increase the risk of developing
either acute renal failure or hyperkalemia, such as potassium-sparing diuretics or nonsteroidal anti-inammatory drugs (NSAIDs) [121]. ACE inhibitors may cause a drop in hemoglobin, which is usually minor [122124].
For patients with other causes of anemia, such as CKD, the drop may
become signicant but these patients respond to recombinant erythropoietin
therapy [125,126]. Few patients require discontinuation of the ACE inhibitor
because of refractory anemia [125,126].
Angiotensin receptor blockers
All of the angiotensin receptor blockers (ARBs) are metabolized by the
liver and do not need dose reduction in CKD [127130]. Patients with CKD
do have a higher risk of developing acute renal failure or hyperkalemia when
placed on an ARB and should be monitored as recommended for ACE
inhibitors [131]. There is some evidence that ARBs may have a lower
incidence of hyperkalemia as compared with ACE inhibitors but more
evidence is needed before it can be recommended that patients with hyperkalemia be switched to an ARB [132]. Angiotensin receptor blockade can
CKD: DRUG DOSING
663
cause mild anemia that is responsive to recombinant erythropoietin therapy

[133,134]. The combination of an ACE inhibitor and an ARB seems to be
fairly safe in patients with CKD [131,135].
Miscellaneous antihypertensives
A complete list of antihypertensives and their dosing adjustments in
CKD can be found elsewhere [3,12,136,137]. A few agents should be
mentioned here either because of their frequent use in CKD or because of
the needed dose adjustment. A number of a-adrenergic blockers including
methyldopa, doxazosin, prazosin, and reserpine seem to have active
metabolites that can accumulate in CKD [138140]. In the case of all the
agents except reserpine, the antihypertensive eect may be greater and more
prolonged in CKD and these agents should be started at the lowest dose in
these patients. Reserpine can cause excess sedation because of accumulation
of an active metabolite and it should be avoided in advanced CKD [141].
Patients with CKD often have an indication for b-blockade either for
further control of their blood pressure or as treatment of one of their
comorbidities, such as coronary heart disease [142144]. A few of the
b-blockers in common use need dose reduction in CKD. These include
acebutolol, atenolol, nadolol, and sotalol [145147]. b-Blockers that are
eliminated by hepatic metabolism, such as metoprolol, propranolol, or
timolol, may be preferred in advanced CKD because the changes in the liver
metabolism for these drugs seems to be small [148150]. Propranolol has
increased protein binding in CKD and may have less free drug and
a decreased eectiveness in patients with poor kidney function [151].
None of the commonly used calcium channel blockers are signicantly
cleared by the kidney and their half-life does not change substantially in
CKD. They do not need a dose adjustment in CKD [152154]. Nondihydropyridine calcium channel blockers, such as verapamil or diltiazem,
may be superior to other calcium channels blockers because of their ability
to limit proteinuria [110,112,155,156].
Diuretics
Patients with CKD often need a diuretic as part of their antihypertensive
regimen or as treatment of congestive heart failure (CHF) [110,112,157].
Since the publication of the randomized Aldactone evaluation study
(RALES) showing that the addition of spironolactone to ACE inhibition
decreases mortality in CHF, the use of spironolactone in CHF has increased
signicantly [158]. Patients were excluded from the study if they had
a creatinine greater than 2.5 mg/d or hyperkalemia. There was a 2% incidence of severe hyperkalemia in the treatment group. Since the time of
publication of the RALES study, there have been a number of reports of the
development of life-threatening hyperkalemia in patients treated with
spironolactone for CHF [159163]. The risk of hyperkalemia increases
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GABARDI & ABRAMSON
with age, presence of diabetes, advanced CKD, and worsening left ventricular ejection fraction [159,164]. It is clear that a proportion of patients
with CKD benet from the combination of ACE inhibition and spironolactone but extreme caution should be used in advanced CKD [165].
Amiloride and triamterene lack the indication that is found with spironolactone but share the risk of hyperkalemia and should be avoided in
advanced CKD [10,166]. Acetazolamide needs to be dose reduced in stages
2 and 3 CKD and avoided in stages 4 and 5 because of its potential to cause
acidosis. It is an ineective diuretic in advanced CKD [167].
The clearance of a number of thiazide diuretics is prolonged in CKD
[157,168]. Because thiazide diuretics need to get to the nephron lumen to be
active, however, larger doses are needed for the same natriuretic eect in
CKD [157]. Thiazides have little impact in advanced CKD if used alone
[157,168]. As with thiazide diuretics, the clearance of loop diuretics
decreases in CKD but the dose must be increased because of a decreased
fraction of the drug reaching the nephron lumen [169172]. Resistance to
loop diuretics can occur in CKD because of decreased drug delivery to the
nephron lumen, increased sodium reabsorption between doses, decreased
free drug in the lumen in nephrotic syndrome, and increased distal sodium
reabsorption [170,173]. In many cases, this resistance can be overcome by
increasing the dose, switching to a continuous infusion, or adding a thiazide
diuretic [170,174]. The risk of adverse reactions, such as ototoxicity, is much
higher in CKD because of the decreased clearance and the higher doses
used. This is especially true if the patient is also getting another ototoxic
agent, such as an aminoglycoside antibiotic [175,176].
Miscellaneous cardiac medications
A number of cardiac medications need dosage adjustment in CKD.
Digoxin requires complex dose adjustment in CKD [177]. It has a signicant
decrease in its Vd with loss in kidney function with the Vd dropping to
approximately 50% that of healthy volunteers in stage 5 CKD [178]. The
loading dose needs to be reduced in advanced CKD [179]. The maintenance
dose also has to be reduced by up to 95% in advanced CKD [180]. For these
reasons, digoxin toxicity is more common in patients with CKD [181].
Digoxin-specic Fab antibody can be used in patients with CKD and severe
digoxin toxicity. The risk of digoxin rebound is greater and occurs later as
compared with patients with normal kidney function [182].
The antiarrhythmic procainamide is an example of a drug whose metabolite is active and can accumulate in CKD. About 50% of procainamide
undergoes N-acetylation to N-acetylprocainamide with significant individual variation caused by genetic polymorphism in N-acetyltransferase
2 [183,184]. N-acetylation and the excretion of N-acetylprocainamide are
slowed in CKD. For these reasons, procainamide must be dose reduced in
CKD and levels of both procainamide and N-acetylprocainamide must be
monitored closely [183].
CKD: DRUG DOSING
665
Analgesics
Pain management is complex in patients with CKD. Many of the agents
commonly used to treat pain can accumulate in CKD, worsen kidney
function, or have an increased propensity to cause adverse reactions in
patients with below normal renal function.
Nonsteroidal anti-inammatory drugs
NSAIDs are used by one in ve Americans on a regular basis [185].
NSAID use is generally very safe in the general population with a small risk
of mild complications, such as peripheral edema or an increase in blood
pressure [186]. Patients with CKD, CHF, hypertension, liver disease, or
those who require long-term high doses of NSAIDs are at much higher risk
of developing more serious side eects, such as worsening heart failure,
uncontrolled hypertension, acute renal failure, hyponatremia, or hyperkalemia [187]. Concurrent use of many medications commonly used in
patients with CKD, such as ACE inhibitors, ARBs, and diuretics, also
increases the risk [188]. With the exception of ketorolac, most commonly
used NSAIDs do not accumulate in patients with CKD [89,189]. Because
of their higher risk potential in these patients, however, long-term use of
NSAIDs should be avoided in patients with CKD, CHF, hypertension, or
liver disease [190].
The renal eects of NSAIDs, such as worsening volume status,
hyperkalemia, hyponatremia, and acute renal failure, are caused by inhibition of the cyclooxygenase (COX) enzyme leading to a decrease in
prostaglandin synthesis [191]. The synthesis of prostaglandins is not
essential to maintain renal blood ow in normal circumstances. In CKD,
volume contraction, CHF, liver disease, and nephrotic syndrome, the
inhibition of prostaglandin synthesis can lead to excessive vasoconstriction
and decreased renal blood ow [192,193]. COX exists as two isoforms:
COX-1 and COX-2 [194]. Initially, a number of animal models supported
the hypothesis that the COX-1 isoform produced the prostaglandins that
were important in regulating renal blood ow and sodium, water, and
potassium excretion, whereas the COX-2derived prostaglandins regulated
inammation [195]. This led to the hope that the COX-2 inhibitors would
decrease inammation without producing adverse renal eects. More recent
data suggest that COX-2 is expressed in the kidney and that its expression is
up-regulated in states that are known to have prostaglandin-dependent
maintenance of renal blood ow, such as volume depletion [196].
A number of large trials have been completed that examined the safety of
the COX-2 inhibitors. Two large studies showed that COX-2 inhibitors may
cause less gastrointestinal toxicity as compared with conventional NSAIDs
[197,198]. In these two large studies on patients with normal renal function,
only a small number of patients had an increase in blood pressure,
peripheral edema, or creatinine. In the Celecoxib Long-term Arthritis Safety
666
GABARDI & ABRAMSON
Study, 1% of the patients taking Celecoxib developed acute renal failure

(creatinine [2 mg/dL) and 1.7% and 2.8% developed hypertension and
peripheral edema, respectively [198]. Few studies have been done on patients
with CKD but a study on salt-depleted patients showed that COX-2
inhibitors caused similar decreases in glomerular ltration rate, urinary
output, and sodium excretion as conventional NSAIDs [199,200]. There
have also been a number of case reports of acute renal failure in patients
with CKD who were started on a COX-2 inhibitor [188,201,202]. Until there
are further data to suggest otherwise, it must be assumed that COX-2
inhibitors have similar renal eects as conventional NSAIDs. Caution
should be used in patients with CKD, hyperkalemia, CHF, and hypertension [188,191,195,196,201,203,204].
Narcotic analgesics
A number of narcotic analgesics should be used with caution in CKD
because of their transformation to toxic metabolites that can accumulate in
CKD [205,206]. Meperidine is metabolized to normeperidine, which can
accumulate in CKD leading to seizures [83,84]. Meperidine should be
avoided in patients with advanced CKD [81]. The half-life of morphine is
not signicantly changed in patients with CKD [207]. Two metabolites of
morphine, morphine-3-glucuronide and morphine-6-glucuronide, do accumulate in CKD [208] and can cause prolonged sedation and respiratory
depression [205,209]. Morphine-6-glucuronide is 10 times more potent an
analgesic and respiratory depressant than morphine [208]. Naloxone can be
used to reverse the sedative and respiratory depressive eects of morphine
and its metabolites in CKD. Repeated doses of naloxone may be needed
because its half-life is short and the delayed excretion of morphine6-glucuronide allows it to outlast the antagonistic action of naloxone [210].
Finally, propoxyphene should be used with caution in CKD. It is metabolized
to norpropoxyphene, which accumulates in CKD and can cause sedation,
hypoglycemia, and cardiovascular toxicity [211213].
Hypoglycemic agents
Because diabetes mellitus and diabetic nephropathy are two of the most
common causes of CKD, it comes as no surprise that many patients with
CKD are on oral hypoglycemics or insulin. Although 5% of the United
States population carries the diagnosis of diabetes, 25% of patients with
stages 4 or 5 CKD have diabetes [214]. With advancing CKD, medication
options to control blood sugars become more limited and dosing becomes
more complex [215].
Insulins
All of the insulin preparations require some dose reduction in CKD
[215217]. The newest long-acting insulin, insulin glargine, may have
prolonged action in advanced CKD [218].
CKD: DRUG DOSING
667
Oral hypoglycemics
A number of oral agents form active metabolites that may accumulate in
CKD [206,216]. These include the sulfonylureas: acetohexamide, chlorpropamide, glyburide, and tolazamide [215,219]. Severe and prolonged hypoglycemia can develop in patients with CKD using these agents because of
the hypoglycemic action of their metabolites [215,220,221].
The biguanide metformin is contraindicated in all stages of CKD because
of the risk of lactic acidosis [222224]. A number of studies have demonstrated that the incidence of lactic acidosis in patients taking metformin is
extremely low [222226]. These studies were all done with patients with
normal kidney function and no other contraindication to the use of metformin. A number of case reports show that metformin use in patients with
CKD or acute renal failure can lead to lactic acidosis [225,227229].
Complacency with the metformin contraindications has the potential to lead
to an increased incidence of lactic acidosis in the future.
Antimicrobials
Dosing errors are very common with antimicrobials in patients with
CKD [230232]. These errors include underdosing, overdosing, using an
agent with a contraindication, or using an agent with little ecacy in CKD
[233]. For this reason, it is worth spending some time estimating glomerular
ltration rate, determining the most appropriate antimicrobial, and dening
a dosing scheme. A number of agents should be used with caution or
avoided altogether in CKD because of their increased risk in patients with
decreased kidney function [234]. Others lose their ecacy in some clinical
situations (eg, amoxicillin for the treatment of urinary tract infections)
[10,235]. A loading dose is often required to bring the serum level up above
minimum inhibitory concentration within a reasonable time period [236].
This is true for some antibiotics that normally do not need a loading dose in
patients with normal kidney function. An example of this is levooxacin,
whose half-life prolongs from 6 to over 24 hours in advanced CKD. For this
reason, the maintenance dose must be reduced from 500 mg daily to 250 mg
every other day. With this maintenance dose and without a loading dose, it
can take 3 to 5 days to reach a therapeutic level. A loading dose of 500 mg
avoids this delay [28]. The choice of antimicrobial and the dose used requires
a balance of the need for ecacy and the risk of toxicity. More frequent
dosing generally improves ecacy but increases trough levels and may lead
to adverse eects [237]. A critically ill patient may require a higher risk of
toxicity to ensure antimicrobial eectiveness. Where possible, serum levels
should be determined to maximize ecacy and minimize toxicity [238].
Aminoglycosides
Aminoglycosides remain an important part of the treatment regimen
of patients with severe gram-negative and some gram-positive bacterial
668
GABARDI & ABRAMSON
infections [239,240]. Their use in CKD patients is complicated by increased

Vd; decreased clearance; and increased risk of serious adverse reactions,
such as ototoxicity and nephrotoxicity [176,241,242]. The ecacy of
aminoglycosides is determined by their peak concentration. They exhibit
concentration-dependent bacterial killing and a postantibiotic eect such
that they continue to suppress bacterial growth for a period of hours after
a peak concentration [243]. The toxicity of aminoglycosides is determined by
the trough serum level [244]. For these reasons, the ideal dosing scheme
allows for high peak levels followed by rapid decline and low trough levels
[243]. Patients with CKD have a larger aminoglycoside Vd and a slower
clearance leading to decreased ecacy and increased toxicity [241,245,246].
Other risk factors for aminoglycoside nephrotoxicity include long or
multiple treatments, volume depletion, liver disease, hypokalemia, hypomagnesemia, advanced age, and concurrent use of another nephrotoxin
[242,247251]. Ototoxicity may be of even greater concern because it often
leads to permanent and severe disability [176,252254]. The risk of ototoxicity in CKD patients given an aminoglycoside increases with the total
amount given; duration of therapy; and number of other ototoxic agents
(eg, vancomycin or loop diuretics) given concurrently [234].
There has been a lot of interest in once-daily dosing of aminoglycosides
to capitalize on the postantibiotic eect. There are some data that it may
have increased ecacy with decreased nephrotoxicity in patients with normal kidney function [242,255257]. Currently, the data are lacking regarding
the ecacy and toxicity of once-daily dosing as compared with multiple
daily doses in CKD [257]. There are data to suggest that errors in dosing are
common if once-daily dosing is used for patients with CKD or acute renal
failure [241,252].
Current recommendations are to avoid aminoglycoside use in CKD
patients when possible. When one must be used, always start with an estimate of renal function and watch for changes in function. Try to switch to
another agent when appropriate and minimize other risk factors for toxicity,
such as volume depletion, use of other nephrotoxic agents, and electrolyte
disturbances [242]. A loading dose is needed to ensure the rapid development of bactericidal serum tissue levels and larger than normal loading
doses may be needed in patients with critical illness, sepsis, and volume
overload [258260]. The maintenance dose needs to be reduced in CKD and
monitoring of serum levels is essential [259,261]. Large, infrequent dosing of
aminoglycosides in patients with advanced CKD cannot be recommended at
this time.
Cephalosporins
Many of the commonly used cephalosporins have a prolonged half-life in
CKD and require a reduction in the maintenance dose [262273]. Cephalosporins have a slow continuous bactericidal eect, which is dependent on the
CKD: DRUG DOSING
669
time at which tissue levels are above minimum inhibitory concentration

[235,260]. Unlike aminoglycosides, cephalosporins have little postantibiotic
eect. Finally, most cephalosporins have a much lower risk of causing an
adverse reaction as compared with aminoglycosides [234,236]. For this
reason, the lower clearance that is found with many cephalosporins in CKD
is not necessarily a disadvantage [235,236]. In most cases where the risk of
adverse eects is low, the dose of the cephalosporin should be reduced with
less change in dosing interval to maintain tissue levels above minimum
inhibitory concentration [236]. In critically ill patients, the rst dose should
not be reduced, which allows for rapid development of therapeutic levels
[260]. Antibiotics, such as many cephalosporins that are normally excreted
by the kidney, may have decreased ecacy for the treatment of urinary tract
infections or cyst infections and require higher serum levels for these
indications in CKD [274,275].
Penicillins
Penicillins have a similar bactericidal eect as cephalosporins [235]. They
display time-dependent killing with little postantibiotic eect [235]. Many
penicillins are excreted by the kidney and require a reduction in the maintenance dose in CKD [236,276278]. They are generally very well tolerated
and should be dosed frequently with decreased dose as needed in critically ill
patients with CKD [234,236]. A loading dose is required if the maintenance
dose is going to be signicantly reduced [260]. As with cephalosporins in
patients with CKD, penicillins have decreased ecacy in urinary tract
infections and cyst infections [274,275].
Fluoroquinolones
The uoroquinolones have a broad spectrum including both grampositive and gram-negative bacteria, good tissue penetration, and in most
cases excellent bioavailability [235,279]. Most uoroquinolones, with the
exception of moxioxacin, are cleared by the kidney and need a dose reduction in CKD [28,279283]. To ensure the rapid development of adequate
tissue levels, a loading dose must be given if the maintenance dose is
reduced [236]. The Vd of uoroquinolones does not seem to change in
patients with CKD or critical illness [260,280,281]. One concern is that all of
the uoroquinolones and especially ciprooxacin are chelated by antacids
and phosphate binders leading to decreased bioavailability and subtherapeutic tissue levels when the two medications are taken together
[284,285]. Patients on phosphate binders should be instructed to take the
uoroquinolones at least 2 hours before their binder [284]. Because of their
excellent tissue penetration, most uoroquinolones have superior ecacy in
the treatment of urinary tract infections and cyst infections in CKD
[235,274,275,286].
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GABARDI & ABRAMSON
Vancomycin
Vancomycin is a glycopeptide antibiotic with a broad gram-positive
spectrum. It remains the drug of choice to treat methicillin-resistant
Staphylococcus aureus [235]. Its pharmacokinetics is complex in critically ill
patients with CKD. It is cleared by the kidney with increased half-life in
CKD and has an increased Vd in patients with sepsis, multiorgan failure,
and volume overload [287289]. It requires a loading dose, which may need
to be increased in critically ill patients with CKD [260,290]. The
maintenance dose, however, needs to be reduced in patients with CKD
[260,290]. The most serious adverse reactions are nephrotoxicity and
ototoxicity, which are increased in patients with CKD; high trough levels;
advanced age; critical illness; and concurrent use of other ototoxic or
nephrotoxic agents, such as aminoglycosides and diuretics [291294].
Miscellaneous antimicrobials
A number of agents need to be mentioned because they are either
contraindicated or require extreme caution in patients with advanced CKD.
A toxic metabolite of nitrofurantoin accumulates in CKD and can cause
peripheral neuritis. For this reason, nitrofurantoin should not be used in
patients with stage 3 or greater CKD [82]. The antiviral amantadine is
eliminated by glomerular ltration and tubular secretion. Its half-life is
prolonged 10-fold in advanced CKD. It can accumulate leading to signicant
central nervous system toxicity if it is not dose reduced [295].
The antifungal agent amphotericin B is still required to treat certain
severe systemic fungal infections [296]. The risk of amphotericin Binduced
nephrotoxicity is higher in patients with CKD [234]. It is also increased by
concurrent use of cyclosporin or an aminoglycoside, volume depletion,
obesity, critical illness, and advanced age [297]. The risk of nephrotoxicity
can be reduced with a sodium load before each dose and with the use of lipid
formulations of the drug [298]. These formulations seem to have equal
ecacy with decreased toxicity as compared with conventional amphotericin B [298300]. Amphotericin B has decreased ecacy to treat urinary
track infections in CKD [274]. The antifungal voriconazole should not be
given intravenously to patients with stage 3 or greater CKD because its
carrier (SBECD) can accumulate and cause tubular toxicity [301]. The oral
form of voriconazole has good bioavailability and does not need dose
adjustment in CKD [301,302].
Imipenem is a carbapenem antibiotic with a broad gram-negative and
gram-positive bacterial spectrum. It is ltered and then metabolized by the
renal brush border enzyme dehydropeptidase [235]. It is given with
cilastatin, an inhibitor of dehydropeptidase, to reduce tubular toxicity and
prolong imipenems half-life [303]. Both have a prolonged half-life in CKD
[304]. Accumulation of imipenem in CKD may cause seizures and patients
with advanced CKD and a high risk of seizures should be started on
a dierent carbapenem, such as meropenem [234,305].
CKD: DRUG DOSING
671
Miscellaneous drugs
Anticonvulsants
The protein binding of phenytoin decreases in CKD. Although the
clearance of phenytoin shows great individual variability, its half-life does
not change signicantly in CKD [306]. The decrease in protein binding
seems to have no net impact on metabolism because of two opposing
factors: the increase in free drug for enzymatic change and more rapid
metabolism, which may be oset by a decrease in the activity of the
cytochrome P-450 enzymatic activity and an increase in the Vd [40,184,307].
The increased free fraction of phenytoin in CKD can lead to increased
toxicity in the setting of therapeutic total drug levels [308]. For this
reason, free phenytoin levels should be monitored and many patients require
a subtherapeutic total level to achieve nontoxic free level [308].
Antineoplastic agents
A number of antineoplastic agents require dose adjustment in CKD. The
more commonly used agents include carboplatin, cisplatin, cyclophosphamide, etoposide, udarabine, hydroxyurea, and methotrexate [309312].
Methotrexate, for example, can cause severe bone marrow suppression if its
dose is not signicantly reduced in CKD [313,314]. In some cases of toxicity,
hemodialysis can help lower toxic levels and decrease bone marrow
suppression [315].
Agents for gout
Colchicine is partially cleared by renal excretion and has a prolonged
half-life in CKD [316]. The colchicine dose needs to be reduced in patients
with below normal kidney function to avoid serious toxicity, such as mental
status changes, seizures, and coma [317]. Allopurinol is metabolized to
oxypurinol, which is then excreted in the urine [318]. Oxypurinol suppresses
xanthine oxidase and contributes to the ecacy of allopurinol. Accumulation of oxypurinol in CKD can increase risk of adverse eects, such as bone
marrow suppressions, neuritis, and pancreatitis [82].
Summary
Patients with CKD constitute a population at high-risk for adverse drug
reactions and drug-drug interactions. Drug dosing in these patients often
proves to be a dicult task. Renal dysfunction-induced changes in human
pathophysiology may alter medication pharmacodynamics and handling.
Several pharmacokinetic parameters are adversely aected by CKD,
secondary to a reduced oral absorption and glomerular ltration; altered
tubular secretion; and reabsorption and changes in intestinal, hepatic, and
renal metabolism. In general, drug dosing can be accomplished by multiple
methods; however, the most common recommendations are often to reduce
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GABARDI & ABRAMSON
the dose or expand the dosing interval, or use both methods simultaneously.
Some medications need to be avoided all together in CKD either because of
lack of ecacy or increased risk of toxicity. Nevertheless, specic recommendations are available for dosing of certain medications and are an
important resource, because most are based on clinical or pharmacokinetic
trials.
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Dyslipidemias in Patients Who Have

Kambiz Farbakhsh, MDa,b,*,
Bertram L. Kasiske, MDa,b
a
University of Minnesota, Minneapolis, MN, USA

Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415, USA
The incidence of cardiovascular disease (CVD) is substantially higher in

patients with chronic kidney disease (CKD) compared with the general
population [1]. Data from the United States Renal Data System indicate
that survival of CKD patients remains poor in large part because of CVD
[2]. Lipid abnormalities are extremely common in patients with CKD.
Unfortunately, there are few studies linking dyslipidemias to CVD in
patients with CKD. In fact, studies have shown that hemodialysis patients
with high cholesterol have lower mortality than those with low cholesterol,
and inammation, an ever-present condition in hemodialysis patients, may
confound the relationship between CVD and lipid levels in dialysis patients
[3]. Nevertheless, given the very strong evidence from studies in the general
population that dyslipidemias contribute to CVD, in the absence of evidence
to the contrary, new guidelines recommend treating dyslipidemias in patients with CKD [4]. Dyslipidemias have also been linked to the rate of
decline in kidney function, and it is possible that treatment of dyslipidemias
may slow the rate of CKD progression [5].
As the number of patients with CKD increases, understanding abnormal
lipid metabolism and its management assumes greater importance in clinical
practice. The dyslipidemias associated with early stages of CKD generally
worsen with advancing kidney failure and ultimately aect most patients
treated with maintenance dialysis and kidney transplantation [6,7]. This
article describes the possible mechanisms of dyslipidemia in CKD patients,
discusses the implications of dyslipidemias in diabetic and nondiabetic
patients, and reviews the management of dyslipidemias in CKD.
* Corresponding author. Nephrology Division, Hennepin County Medical Center, 701
Park Avenue South, Minneapolis, MN 55415.
E-mail address: farba002@umn.edu (K. Farbakhsh).
doi:10.1016/j.mcna.2004.11.002
690
FARBAKHSH & KASISKE
Denitions
The most clinically useful denitions of dyslipidemia are those that
set thresholds and targets for treatment, and those that rely on measurements readily available in most clinical laboratories. The National
Cholesterol Education Program Adult Treatment Panel III denitions for
dyslipidemia were recently adopted by the National Kidney Foundation
Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines on
managing dyslipidemias (Table 1).
Prevalence
The prevalence of dyslipidemias in CKD patients is very high, but precise
estimates are dicult to make because studies have used very dierent
thresholds to dene dyslipidemias. In addition, levels of low-density lipoprotein (LDL), triglycerides (TGs), and high-density lipoprotein (HDL) are
dierent in stages 1 to 4 CKD, and in stage 5 CKD treated with hemodialysis
patients, peritoneal dialysis patients, and kidney transplantation recipients
(Table 2).
By denition, 100% of patients with nephrotic syndrome have dyslipidemias, almost always elevated LDL, but often also high TGs. In nonnephrotic
patients with stages 1 to 4 CKD, the prevalence of dyslipidemias varies by the
stage of CKD; as kidney function declines, TGs tend to increase and HDL
declines. Levels of LDL in stages 1 to 4 CKD are usually similar to those
found in the general population. Similarly, in stage 5 CKD patients treated
Table 1
Dyslipidemia denitions
Dyslipidemia
Total cholesterol
Desirable
Borderline high
High
LDL cholesterol
Optimal
Near optimal
Borderline
High
Very high
TGs
Normal
Borderline high
High
Very high
HDL cholesterol
Low
Level (mg/dL)
\ 200
200239
240
\ 100
100129
130159
160189
190
\ 150
150199
200499
500
\ 40
To convert mg/dL to mmol/L, multiply TGs by 0.01129 and cholesterol by 0.02586.
691
DYSLIPIDEMIAS IN CKD
Table 2
Estimated prevalences of dyslipidemias in stage 5 chronic kidney disease
Percentage
Denition
Hemodialysis
Peritoneal dialysis
Transplant
Normal
High LDL cholesterol ([ 100 mg/dL)
High TGs ([ 200 mg/dL) and high
non-HDL cholesterol ([ 130 mg/dL)
49
56
5
21
73
5
10
90
NA
To convert mg/dL to mmol/L, multiply TGs by 0.01129 and cholesterol by 0.02586.

Abbreviation: NA, not applicable.
Data from K/DOQI clinical practice guidelines for management of dyslipidemias in patients
with kidney disease. Am J Kidney Dis 2003;41(4 Suppl 3):I-91.
with hemodialysis, levels of LDL are similar to those found in the general
population, but TGs are often high and HDL is frequently reduced. The
LDL levels are higher in peritoneal dialysis patients compared with
hemodialysis patients. In kidney transplantation recipients, LDL levels are
almost always increased, although TGs also may be elevated.
Pathogenesis
Because of their insolubility in water, lipids are transported in plasma in
lipoproteins. Lipoproteins are composed of TGs, phospholipids, cholesterol
esters, cholesterol, and apolipoproteins. The latter form the functional
specicity of lipoproteins and play a major role in activation of lipolytic
enzymes and recognition sites for cell surface receptors. Apolipoprotein A
(Apo A) predominates in HDL, whereas Apo B is found in very-low-density
lipoprotein (VLDL), LDL, and intermediate-density lipoprotein (IDL).
Data from the general population have provided conclusive evidence that
high levels of LDL cause arteriosclerosis. It is increasingly recognized,
however, that other Apo Bcontaining lipoproteins [eg, VLDL, IDL,
lipoprotein(a), and other remnants of VLDL metabolism] are also
atherogenic. Unfortunately, most clinical laboratories cannot directly
measure these so-called remnant lipoproteins. In patients with high TGs,
however, a large proportion of total cholesterol is carried in these remnant
lipoproteins. It is possible indirectly to measure the levels of remnant
lipoproteins (along with LDL) in patients with high TGs by simply
subtracting the HDL cholesterol level from the total cholesterol. This
non-HDL cholesterol reects the level of atherogenic apolipoprotein B
lipoproteins in patients with high TGs. Indeed, recent data suggest that nonHDL cholesterol may be a better predictor of CVD than LDL [8]. In patients
with normal TGs, non-HDL is mostly made up of LDL cholesterol, which
readily can be measured or calculated using the Friedewald formula [9].
Nephrotic syndrome patients with stages 1 to 4 CKD have increased
production and decreased catabolism of LDL and other Apo Bcontaining
692
FARBAKHSH & KASISKE
lipoproteins. Hypercholesterolemia in nephrotic syndrome has been thought

to be secondary to both increased production and decreased catabolism of
lipoproteins. Although the mechanisms for enhanced hepatic synthesis
of Apo B lipoproteins are still being investigated, it is clear that the degree of
lipoprotein abnormality is roughly proportional to the amount of proteinuria, which is inversely proportion serum albumin. Hypertriglyceridemia
in nephrotic patients, however, has been thought to be secondary to altered
catabolism of TGs. The conversion rate of VLDL to IDL and subsequently
to LDL is slower in patients with nephrotic range proteinuria [10].
Nonnephrotic patients with stages 2 to 4 CKD generally have normal
LDL levels, but TGs may be elevated and HDL may decrease the level of
kidney function declines. This may be caused by reduced lipoprotein
lipase activity. Although the underlying causes of reduced lipoprotein
lipase activity are not well understood, several hypotheses have been
suggested. Among those are chronic exposures to high parathyroid
hormone levels resulting in reductions in both hepatic TG lipase and
lipoprotein lipase [11]. Calcium accumulation in pancreatic islet cells with
subsequent functional impairment of pancreas and glucose intolerance
has also been postulated [12]. Patients with CKD also have elevated Apo
C-III levels that may be associated with reduced lipoprotein lipase
activity.
The same mechanisms operative in stages 2 to 4 CKD may also lead
to lipoprotein abnormalities in hemodialysis patients. In addition, heparin
used in hemodialysis may contribute to decreased lipoprotein lipase
activity and consequently elevated TGs. Why patents treated with
peritoneal dialysis have elevated LDL levels is unclear. Absorption and
metabolism of dextrose in the peritoneal dialysate, however, and loss of
lipoprotein cofactors have been postulated to contribute to abnormal
lipoprotein metabolism in peritoneal dialysis.
The principal lipoprotein abnormality in kidney transplantation
recipients is elevated LDL. Mechanisms leading to high LDL are poorly
understood, but high LDL levels are associated with the use of
corticosteroids, cyclosporine (Neoral and Sandimmune, Novartis, East
Hannover, New Jersey; cyclosporine, USP, Apotex, Weston, Florida;
cyclosporine modied, USP, Eon Labs, Laurelton, New York; cyclosporine modied, USP, PLIVA, East Hannover, New Jersey; cyclosporine,
Geneva Generics, Broomeld, Colorado; Gengraf, Abbott, USA, Abbott
Park, Illinois), and sirolimus (Rapamycin, Wyeth Pharmaceuticals,
Madison, New Jersey) (Table 3).
Observational studies have reported associations between lipoprotein(a)
and CVD in the general population. It is worrisome that elevations in
lipoprotein(a) are particularly common in patients with CKD. Nevertheless, there are no interventional studies in the general population showing
that reducing lipoprotein(a) reduces CVD, and the signicance of
increased lipoprotein(a) in CKD remains to be determined.
693
Table 3
Immunosuppressive medications and dyslipidemias
Agent
Abnormalities
Possible mechanism(s)
Corticosteroids
High total cholesterol, high LDL, Insulin resistance and low ACTH
and high TGs
Cyclosporine A
High total cholesterol, high LDL, Not known
high TGs, and low HDL
Tacrolimus
None
None
Sirolimus
High total cholesterol, high LDL, High insulinstimulated LPL
and high TGs
Azathioprine
None
None
Mycophenolate mofetil None
None
Abbreviations: ACTH, adrenocorticotropic hormone; LPL, lipoprotein lipase.
Consequences of dyslipidemias
Dyslipidemias and cardiovascular disease
Abundant evidence from controlled observational studies and randomized intervention trials in the general population has shown that elevated
LDL cholesterol causes CVD. This evidence has prompted the National
Cholesterol Education Program to develop guidelines targeting LDL
cholesterol treatment in patients at risk for coronary heart disease events
[13]. Patients with CKD have been systematically excluded, however, from
the randomized controlled trials that provide the evidence underpinning
these guidelines.
There are few controlled, observational studies and almost no
randomized, intervention trials examining the relationship between dyslipidemias and CVD in patients with CKD. In hemodialysis patients there
seems to be an inverse relationship between total cholesterol and mortality
[14] and between total cholesterol and coronary artery disease [15]. This
could be caused by study design or confounding from more potent risk
factors, such as inammation and malnutrition, which reduce lipid levels but
increase the risk for CVD. In any case, evidence that dyslipidemias cause or
contribute to CVD in CKD patients treated with dialysis is lacking.
In kidney transplantation patients the relationship between dyslipidemias
and CVD seems to be qualitatively similar as that seen in the general
population [16]. Moreover, a randomized, controlled intervention trial in
kidney transplantation patients was recently completed. The Assessment of
Lescol in Renal Transplantation (ALERT) trial randomly allocated 2102
transplant recipients to placebo or uvastatin [17]. Although the eect of
uvastatin on the primary end point (major CVD events) was not
statistically signicant (P = .139), cardiac death was reduced by 38%
(P = .031) and cardiac death or denite nonfatal myocardial infarctions
were reduced by 35% (P = .005) [17]. The evidence is highly suggestive
that cholesterol contributes to the high incidence of CVD in kidney
transplantation recipients.
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FARBAKHSH & KASISKE
Dyslipidemias and kidney disease progression

A number of observational studies have reported correlations between
dyslipidemias and the level of kidney function in patients with stages 1 to 4
CKD. It is possible, however, that proteinuria and metabolic abnormalities
associated with decreased kidney function are responsible for this
association, and that lipid abnormalities do not directly cause CVD. Only
randomized, controlled intervention trials can determine whether dyslipidemias cause or contribute to kidney disease progression. To date, there
have been several, small randomized controlled trials examining the eects
of lipid-lowering agents on the rate of change in glomerular ltration rate. A
meta-analysis of these trials suggested that lipids indeed contribute to
kidney disease progression, but the total number of patients treated was very
small [18]. Clearly, additional randomized trials are needed to test this
hypothesis.
It has been reported that dyslipidemias may also contribute to kidney
dysfunction in kidney transplant recipients. In the ALERT trial, however,
no eect of treatment on kidney function was detected [19]. Certainly,
additional studies are required to understand better the relationship between
dyslipidemia and graft dysfunction.
Treatment
Given the very strong evidence in the general population that treating high
LDL cholesterol in high-risk individuals reduces CVD, and the evidence the
CKD patients are at very high risk for CVD, the K/DOQI guidelines on
dyslipidemias recommend treating LDL cholesterol levels greater than or
equal to 100 mg/dL (2.59 mmol/L) with therapeutic lifestyle changes (TLC)
and statins (Fig. 1) [4]. Occasional patients may have very-high fasting TGs
(eg, persistently 500 [5.65 mmol/L]), indicating hyperchylomicronemia.
There is some evidence that hyperchylomicronemia can cause pancreatitis.
Treating elevated TGs should take precedence in the small number of
patients with very-high TGs (see Fig. 1). For most others, attention should be
focused on LDL cholesterol. Finally, patients with normal LDL, but fasting TGs 200 to 499 mg/dL (2.265.64 mmol/L), should have non-HDL
cholesterol levels greater than or equal to 130 mg/dL (3.37 mmol/L) treated
with TLC and a statin.
Treatment of marked hypertriglyceridemia
Fasting TGs that are persistently greater than or equal to 500 (5.65 mmol/L)
should generally be treated with TLC, such as weight loss programs, diet, and
exercise. Guidelines recommend low-fat diet, medium-chain TGs, and sh oils
for treatment of hypertriglyceridemias [4]. A lipid-lowering agent can be
added if the response to TLC is not adequate. Fibrates and nicotinic acid are
probably the best choices for treating marked hypertriglyceridemia. The dose
695
TG
500?
No
Yes
TLC and Consider
a Fibrate or Niacin
LDL
100?
No
Yes
No
LDL
100-129?
Yes
LDL
130?
No
Yes
TLC
LDL
100?
Yes
TLC+
Statin
No
TG 200 &
No
Non-HDL Chol.
130?
LDL No
130?
Yes
Consider Bile Acid
Sequestrant
Yes
TLC+
Statin
Continue to
Monitor
Fig. 1. Recommended treatment of dyslipidemias in adults with chronic kidney disease. Units
are in mg/dL. To convert mg/dL to mmol/L, multiply TGs by 0.01129 and LDL or non-HDL
cholesterol by 0.02586. HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG,
triglycerides; TLC, therapeutic lifestyle changes. (From K/DOQI clinical practice guidelines
for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003;
41(4 Suppl 3):I-91; with permission.)
of most brates should be reduced in patients with stage 2 to 4 CKD, and

most should be avoided in stage 5 CKD patients treated with dialysis,
because of high brate levels. Gembrozil levels do not seem to be
increased in patients with reduced kidney function, however, and may not
require dose modication. Fibrates should probably not be used in
combination with a statin in patients with CKD. Statins cause less TG
lowering than brates, and bile acid sequestrants can actually increase
elevated TGs.
Treating high low-density lipoprotein cholesterol
For CKD patients with LDL 100 to 129 mg/dL (2.593.34 mmol/L) it is
reasonable to attempt to lower LDL to less than 100 mg/dL (2.59 mmol/L)
with TLC. If after 3 months this target has not been reached, however,
a statin should be added (see Fig. 1). Patients with LDL greater than or
equal to 130 mg/dL (3.37 mmol/L) are unlikely to reach target with diet
alone, so diet and a statin should generally be started simultaneously.
Statins are safe in patients with CKD, but drug interactions (eg, with
macrolide antibiotics, azole antifungal agents, dihydropyridine calcium
channel blockers, and cyclosporine A) should be avoided or should prompt
a reduction in the dose of the statin. In kidney transplantation recipients
696
FARBAKHSH & KASISKE
taking cyclosporine A, for example, the dose of statins should probably be

half of that used in patients not receiving cyclosporine, and additional
agents that may cause an increase in either the statin or cyclosporine should
be avoided.
Acute and chronic liver disease should be ruled out before initiation of
a statin, but it is not necessary to obtain routine liver enzymes to screen for
hepatotoxicity thereafter. Patients should be told that if they develop
unusual muscle soreness or pain, indicating possible statin-induced myopathy, they should stop the statin and contact their physician. It has been
suggested that a baseline creatine phosphokinase be obtained to help interpret creatine phosphokinase levels when myopathy is suspected. Routine
screening with creatine phosphokinase levels in asymptomatic individuals,
however, is not necessary (Box 1).
In the United States, several statins are currently available. Solid
evidence that one statin has any advantage over another has yet to be
established, except for potency and cost. They vary roughly in their
potency for reducing LDL cholesterol from greatest to least in the following order: rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin,
and uvastatin.
Box 1. Dos and donts of statin therapy in chronic

kidney disease
Do
1. Consider starting therapy after a 3-month trial of TLC
if LDL 100129 mg/dL
2. Consider starting therapy immediately with TLC
if LDL 130 mg/dL
3. Reduce dose by 50% if cyclosporine is used
4. Titrate dose to target LDL < 100 mg/dL
5. Consider adding a bile acid sequestrant if LDL
remains 130 mg/dL
6. Warn patients to stop therapy if there is unusual
muscle pain
Dont
1. Routinely monitor liver enzymes
2. Routinely monitor creatine phosphokinase levels
3. Use with macrolide antibiotics, azole antifungal agents,
fibrates, amiodarone, nefazodone, dihydropyridine calcium
blockers
To convert LDL cholesterol mg/dL to mmol/L, multiply by 0.02586.
697
Combination therapy
For patients with LDL persistently greater than or equal to 130 mg/dL
(3.37 mmol/L) despite diet and maximum statin therapy, consideration
should be given to adding a second agent (the risk of adding a second agent
may exceed the benet for individuals with LDL 100 to 139 mg/dL
[2.593.37 mmol/L]).
There are few options for adding a second agent to statin therapy in
patients with CKD. Fibrates should be avoided. If TGs are not elevated,
then a bile acid sequestrant is an option (including sevelamer, which works
like a bile acid sequestrant). The new cholesterol absorption inhibitor
ezetimibe may have fewer gastrointestinal adverse eects than bile acid
sequestrants, and ezetimibe seems to be safe in patients with CKD,
although there are no published data on its use in transplant recipients
treated with cyclosporine. Nicotinic acid may also be an option, but there
are few data on its use with statins in patients with CKD.
Management of nonhigh-density lipoprotein cholesterol
In patients with LDL greater than or equal to 100 mg/dL (2.59 mmol/
L), the LDL should be the target of therapy. Patients with normal LDL,
but TGs greater than or equal to 200 mg/dL (2.26 mmol/L) and non-HDL
cholesterol greater than or equal to 130 mg/dL (3.37 mmol/L), however,
should also be treated. The target of therapy is the non-HDL cholesterol,
which in patients with high TGs and normal LDL contains atherogenic
lipoproteins. The goal should be to reduce the non-HDL cholesterol to less
than 130 mg/dL (3.37 mmol/L).
Addressing causes of hypertriglyceridemia, such as poorly controlled
diabetes, excessive alcohol consumption, immunosuppressive agents
(corticosteroids, cyclosporine, and sirolimus), and anabolic steroids,
should rst be undertaken. Thereafter, TLC should be attempted.
Whether it is best to use brates or statins in patients who do not
respond adequately to nonpharmacologic management is controversial.
Given the strength of evidence that statins reduce CVD events in
patients from the general population with virtually every lipoprotein
prole, however, treatment with a statin is certainly a compelling
option.
The K/DOQI dyslipidemia guidelines recommend that CKD patients,
who are not already receiving a statin for high LDL, with fasting TGs
greater than or equal to 200 mg/dL and non-HDL cholesterol greater
than or equal to 130 mg/dL (without evidence of liver disease) should
receive a statin along with TLC. If the statin is tolerated, no further
treatment of non-HDL cholesterol is indicated. In the case of intolerance
to statins, even with dose reduction, then initiation of a brate should be
considered.
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FARBAKHSH & KASISKE
Special considerations in kidney transplantation

There is reasonably good evidence that elevated LDL cholesterol causes
CVD in kidney transplantation recipients, and treatment with diet and
a statin is particularly compelling in this population. Unfortunately, blood
levels of statins are uniformly increased in patients who are also receiving
cyclosporine A. Patients receiving cyclosporine A and a statin who are then
treated with yet another agent that can increase statin blood levels (eg,
macrolide antibiotics, azole antifungal agents, brates, amiodarone,
nefazodone, dihydropyridine calcium blockers) are especially vulnerable to
myopathies. As a general rule, the doses of statins recommended for patients
in the general population should probably be reduced by 50% in patients
treated with cyclosporine, and additional agents that may increase statin
blood levels should be avoided. Whether tacrolimus also increases the blood
levels of statins has not been as well studied, but given the similarities in the
metabolism of tacrolimus and cyclosporine A, caution should be exercised
when using a statin in patients treated with tacrolimus.
Much of the high prevalence of dyslipidemias in kidney transplantation
recipients is caused by the use of corticosteroids, cyclosporine A, and
sirolimus. It may be possible to alter the immunosuppressive drug regimen in
patients with increased LDL cholesterol, especially if they are at very high risk
of CVD events. Converting cyclosporine A to tacrolimus, for example, results
in a signicant reduction in LDL cholesterol [20]. Changes in immunosuppressive medications, however, must take into account the risk for rejection.
Summary
Patients with CKD are at high risk for developing CVD. In fact, most
CKD patients have a 10-year risk of coronary heart disease events greater
than or equal to 20%, placing them in the highest risk category according to
the National Cholesterol Education Program Adult Treatment Panel III
guidelines [13]. For this reason, the National Kidney Foundation K/DOQI
guidelines for managing dyslipidemia suggest that CKD patients with LDL
greater than or equal to 100 mg/dL (2.59 mmol/L) should be treated with
diet and a statin. The K/DOQI guidelines also make it clear that the
evidence supporting treatment in CKD populations is lacking, however, and
that additional placebo-controlled trials are needed. In the mean time, the
high incidence of CVD makes intensive monitoring and treatment of
dyslipidemias in patients with CKD a reasonable clinical approach.
References
[1] Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease
in chronic renal disease: what do we know? What do we need to learn? Where do we go from
here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney
Dis 1998;32:853906.
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[2] US Renal Data System. USRDS 2003 annual data report: atlas of end-stage renal disease
in the United States. Bethesda: National Institute of Health, National Institute of Diabetes
and Digestive and Kidney Disease; 2003.
[3] Danesh J, Collins R, Appleby P, et al. Association of brinogen, C-reactive protein,
albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective
studies. JAMA 1998;279:147782.
[4] K/DOQI clinical practice guidelines for management of dyslipidemias in patients with
kidney disease. Am J Kidney Dis 2003;41(4 Suppl. 3):I91.
[5] Diamond JR. Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis. Kidney Int Suppl 1991;31:S2934.
[6] Attman PO, Samuelsson O, Alaupovic P. Lipoprotein metabolism and renal failure. Am J
Kidney Dis 1993;21:57392.
[7] Keane WF. Lipids and the kidney. Kidney Int 1994;46:91020.
[8] Chertow GM, Burke SK, Lazarus JM, et al. Poly[allylamine hydrochloride] (RenaGel):
a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal
failure. Am J Kidney Dis 1997;29:6671.
[9] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density
lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem
1972;18:499502.
[10] Warwick GL, Packard CJ, Demant T, et al. Metabolism of apolipoprotein B-containing
lipoproteins in subjects with nephrotic-range proteinuria. Kidney Int 1991;40:12938.
[11] Nishizawa Y, Shoji T, Kawagishi T, et al. Atherosclerosis in uremia: possible roles of
hyperparathyroidism and intermediate density lipoprotein accumulation. Kidney Int Suppl
1997;62:S902.
[12] Arnadottir M, Nilsson-Ehle P. Has parathyroid hormone any inuence on lipid metabolism
in chronic renal failure? Nephrol Dial Transplant 1995;10:23812.
[13] Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults.
Executive summary of the Third Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults (Adult Treatment Panel III). JAMA 2001;285:248697.
[14] Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly
measured variables and an evaluation of death rate dierences between facilities. Am J
Kidney Dis 1990;15:45882.
[15] Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary artery disease
among new dialysis patients in the United States: a cross-sectional study. J Am Soc Nephrol
2001;12:151623.
[16] Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk
after renal transplantation. J Am Soc Nephrol 2000;11:173543.
[17] Holdaas H, Fellstrom B, Jardine AG, et al. Eect of uvastatin on cardiac outcomes in renal
transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:
202431.
[19] Fellstrom B, Holdass H, Jardine A, et al. Eects of uvastatin on graft losses and renal
function in renal transplantation: experience from the ALERT Trial [abstract]. J Am Soc
Nephrol 2003;14:10A.
[20] MCCune TR, Thacker LR II, Peters TG, et al. Eects of tacrolimus on hyperlipidemia after
successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation 1998;65:8792.
Med Clin N Am 89 (2005) 701709
Executing Change in the Management

of Chronic Kidney Disease:
Perspectives on Guidelines and Practice
Adeera Levin, MD, FRCPCa,b,*,
Lesley A. Stevens, MD, FRCPCc
a
Nephrology Education and Research, St. Pauls Hospital, 1081 Burrard Street,
Room 6010A, Vancouver, BC V6Z 1Y6, Canada
b
Division of Nephrology, Department of Medicine, University of British Columbia,
St. Pauls Hospital, Vancouver, BC, Canada
c
Division of Nephrology, TusNew England Medical Center,
750 Washington Street, Boston, MA 02111, USA
Chronic kidney disease (CKD) is recognized as a worldwide epidemic, as

are other chronic diseases, such as diabetes and heart disease. New guidelines have been developed for the diagnosis, classication, and evaluation of
CKD. The challenge is to ensure that these recent advances in formalization
of the classication system for CKD can be translated into actual changes in
management of patients with CKD. There are multiple challenges that face
the general medical and nephrology communities worldwide that hinder the
ability to change the management of CKD [1]. This article identies those
challenges so that successful strategies to impact the care of this growing
patient group can be identied.
CKD is associated with worse outcomes in many patients; early identication and attention to attendant comorbidity may well improve these
outcomes. Serum creatinine is an insensitive marker for kidney disease. To
identify individuals at earlier stages than currently possible using serum
creatinine alone, and to assess severity of kidney function, the recent Kidney
Disease Outcomes Quality Initiative (K/DOQI) guidelines [2] have suggested the use of estimation equations for glomerular ltration rate (GFR).
Dr. Stevens is a Clinical Research Fellow at Tufts-New England Medical Centre, and
University of British Columbia, funded by the Kidney Foundation of Canada and the
Clinical Investigator Program, University of British Columbia.
* Corresponding author. Nephrology Education and Research, St. Pauls Hospital, 1081
Burrard Street, Room 6010A, Vancouver, BC V6Z 1Y6, Canada.
E-mail address: alevin@providencehealth.bc.ca (A. Levin).
doi:10.1016/j.mcna.2004.11.005
702
LEVIN & STEVENS
This principle has been endorsed by several organizations, such as the

American Society of Nephrology, the National Kidney Foundation, and the
National Institutes of Health [35].
The denition and classication of CKD has been the focus of a recent
K/DOQI Working Group [4]. CKD is dened as present if any of the
following exist for greater than 3 months: structural or functional abnormalities of the kidney, with or without reduced GFR, which over time can
lead to kidney failure, as manifested by either pathologic abnormalities or
markers of kidney damage, including abnormalities of the blood or urine or
imaging tests; and GFR less than 60 mL/min, irrespective of blood pressure
or markers of kidney damage.
Using these denitions, stages of severity of CKD have been dened
(Box 1). High-risk persons include those who are over the age of 60; who
have diabetes or cardiovascular disease, including hypertension; or who are
from specic ethnic groups, such as Asians, Aboriginal peoples, African
Americans, and Pacic Islanders.
The denition based on estimates of GFR improves the interpretation of
the serum creatinine, and the new classication system can be used by clinicians, educators, clinical researchers, and the lay public to identify severity
of kidney disease in individuals and groups. Although the classication
system does not reect etiology or prognosis, it does allow the establishment
of a common nomenclature and severity grading system by all clinicians
who care for patients at risk for kidney disease.
Classication system: simplifying a complex disease
The recent K/DOQI denition and classication system describes a simple
approach to a complex disease [4]. Importantly, this system allows for improved communication with researchers, health care providers, and patients
and improves on previous denitions of CKD, which rested on the insenBox 1. Stages of severity in chronic kidney disease
0 = individuals at increased risk
1 = kidney damage with normal or increased
GFR > 90 mL/m/1.73 m2
2 = mild reduction in GFR 6089 mL/m/1.73 m2
3 = moderate reduction in GFR 3059 mL/m/1.73 m2
4 = severe reduction in GFR 1529 mL/m/1.73 m2
5 = kidney failure GFR < 15 mL/m/1.73 m2 or dialysis
Data from K/DOQI clinical practice guidelines for chronic kidney disease:
evaluation, classification, and stratification. Kidney Disease Outcome Quality
Initiative. Am J Kidney Dis 2002;39(2 Suppl 2):S1246.
CKD MANAGEMENT PERSPECTIVES
703
sitive marker of serum creatinine. The classication system presumes that

the diagnosis of the etiology is made, and that treatment of the primary
disease has been instituted where applicable. Irrespective of the diverse
etiologies, most patients with kidney disease progressively lose kidney
function, or incur morbidity and mortality related to cardiovascular disease.
The nuances and details of the system are beyond the scope of this article,
but the reader is referred to major references [4,6].
The high prevalence of CKD based on a reduction in estimated GFR has
recently been demonstrated from analyses of population health surveys [7].
True estimates of the number who progress to dialysis or to adverse events
related to CKD, however, have not yet been described. The unanswered
questions as to key factors (those that are modiable and those that are not)
that predict progression are fruitful for research endeavors. It is possible,
however, that the increasingly recognized complexity of multiple factor
intervention may inadvertently limit implementation of strategies. This
may be caused by the clinicians amount of uncertainty over an individual
patients risk, the multiplicity of treatment options, and the potential interaction and costs of best strategies.
Nonetheless, a substantial body of evidence substantiates that the
progression of CKD can be attenuated if both proteinuria and blood pressure
are reduced, especially if accomplished by blockade of the renin-angiotensin
system [811]. Most studies have been in well-dened populations (ie, diabetes,
later stages of CKD); furthermore, most clinical trials select best patients from
a population of patients. The strategies evaluated in these studies may not be
as easy to implement in real life situations. Nonetheless, the body of evidence
does support clinical strategies that are accessible to most clinicians.
The challenge facing the clinician is not only to delay the progression of
CKD, but perhaps more importantly also to identify and comanage the
multiplicity of comorbid conditions that occur either as a consequence of, or in
conjunction with, kidney dysfunction. Most specically, the high prevalence
of cardiovascular disease and the likelihood that patients are more likely to die
than reach dialysis is most sobering. It is because of these factors that patients
with CKD require complex, multifaceted treatment strategies with attention
to medical, social, cultural, and psychologic factors. CKD as a chronic disease
requires longitudinal follow-up at earlier stages during which symptoms are
often minimal; the lack of tangible immediate returns for either the patient or
the physician complicates the implementation of these strategies.
Barriers to delivering evidence-based care
To execute change in the management of patients with kidney disease,
physician behavior needs to be modied. This is only accomplished after
both a cognitive and behavioral process has been aected. A number of
discrete steps are necessary. First, the acquisition of new knowledge is
required. Second, there is the need to accept that new behavior based on
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LEVIN & STEVENS
that knowledge is preferable, the need actually to decide to adopt and

implement the new behavior in clinical practice. Finally, the clinician needs
to conrm in their own practice that the new behavior in fact leads to better
outcomes. This process requires time, and many barriers may exist during
the process. The major categories of factors, which may limit the change in
clinical behavior from clinician perspectives, are knowledge, attitude, and
external system factors. It is important to identify these barriers to facilitate
the implementation of evidence-based practice in medicine. To change the
management of patients with CKD, improved understanding of these
barriers is essential.
Knowledge
Lack of knowledge can either be related to a deciency of evidence or to
the lack of awareness or familiarity of physicians with the evidence base.
Although the eld of CKD requires signicantly more investigation for full
understanding, key messages about blood pressure targets, reduction of
proteinuria, and treatment of comorbid conditions have been ubiquitous for
the last 5 to 10 years. These messages should be well known to nephrologists. As the emphasis shifts toward earlier recognition and identication
of CKD, there is an increasing importance of nonnephrologist physicians
(both primary care and specialist physicians) in the overall care for patients
with CKD. The new knowledge transfer rate in this group may well be
slower than to a group of nephrology specialists. Central to the care of
patients with CKD is the information that kidney function is best
determined by using an estimating equation to determine GFR less than
60 mL/min/1.73 m2 (ie, not use serum creatinine alone). The concept that
both GFR and markers of kidney damage (urine assessments or radiology)
are necessary for the diagnosis of CKD is also important. This is a novel,
relatively complex concept and may not be disseminated easily without
explicit instruction. In the last 2 years there have been increasing numbers of
publications concerning CKD in general medical journals and nonnephrology specialist journals. It is well documented, however, that the impact of
written materials on changing behavior is usually minimal. Other methods
for improving physician knowledge and behavior include academic
detailing, audit and feedback, provider reminder systems, incentives, local
opinion leaders, outreach visits, continuous quality improvement, clinical
information systems, and computer decision support systems. Each of these
strategies, however, has met with mixed success [1214]. It is clear that
methods of disseminating knowledge continue to be a limiting factor in the
implementation of the new CKD guidelines.
Attitude
The attitude of physicians, and of other decision-makers, as to the
importance of CKD may also be a barrier to implementing appropriate
705
care. There are attitudes about the signicance of data or published studies;
concern over the lack of data on outcomes deemed important to the
physician, patient, or system; and attitudes of individual practitioners
toward implementing care plans, and the feeling of therapeutic nihilism in
patients with multiple disorders. Even within the nephrology community,
there is reluctance by some nephrologists for widespread adoption of the
current classication system: this further confuses nonnephrology practitioners. The absence of data as to the benets of treatment in earlier stages
of CKD (ie, stages 23 GFR 6090 mL/min/m2 with kidney damage or
GFR less than 60 mL/min/1.73 m2) and the potential consequences of
labeling on patients overall quality of health have fuelled this debate
[15,16]. The inconsistency in attitudes of nephrologists toward referrals for
early CKD may increase the diculty for nonnephrologist physicians to
learn about CKD and its management.
External barriers
The external barriers to implementation include patient-specic factors,
contradictory or noncomplimentary nature of existing guidelines or data,
the economic and human resources and time required for care of chronic
diseases, and the health care system itself.
Patient factors
Patients are not homogenous beings to which treatment strategies can be
applied: they come with their own preferences, cultural and ethnic backgrounds, and socioeconomic resources. These factors impact on physician
abilities to implement treatments. Even within universal health care
programs (such as exist in Canada, United Kingdom, and other European
countries), the variability in treatment strategies is mitigated by patient
belief systems and attitudes, not simply by access to economic resources [17].
Because CKD is an asymptomatic disease, it may be dicult to motivate
individuals to follow complex diet and drug treatment regimens, especially
when these regimens are inconvenient and may have side eects. The impact
of chronic disease on social-familial structure and function diers according
to cultural and socioeconomic background. Family dynamics and roles may
be adversely impacted by the diagnosis and treatment of a chronic disease.
Specic populations: ethnic and racial groups
Certain racial and ethnic groups suer from higher prevalence and most
severe forms of chronic diseases, including CKD [18,19]. African Americans
have an overall death rate that is 1.6 times higher than that of the white
United States population [20]. One in four African Americans who reported
that they had a chronic or serious illness did not have an ambulatory visit in
the preceding year as compared with one in six whites; African Americans
were less likely to be covered by any insurance; and African Americans had
706
LEVIN & STEVENS
higher and increasing hospitalization rates than whites in the period between
1991 through to 1998 for the diagnoses of angina, hypertension, diabetes,
and congestive heart failure [2123]. The increased prevalence of CKD in
African Americans, Native Americans, and other ethnic groups may be
caused in part by genetic factors; however, the poor quality of health care
received in these groups has a signicant impact on the poor outcomes. The
inuence of education and healthy lifestyle during the formative years on
long-term outcomes should not be underestimated.
Rural and geographically-isolated populations
Patients and physicians who reside in geographically isolated areas also
pose signicant challenges in terms of knowledge dissemination, access to
implementation tools, or to resources themselves. The unique problems of
more isolated communities are compounded by lack of critical mass of
patient groups, and physician resources, which limit exposure and
familiarity.
Nonalignment of existing guidelines
Interestingly, most existing guidelines for diabetes mention the need for
serial measurement of hemoglobin A1C and urine protein, but not of kidney
function [24,25]. With recent changes in both, the Canadian and American
Diabetes Associations do mention the need to measure serum creatinine,
however, these publications have only been in print in the last 12 months.
Thus, uptake and incorporation into clinical practice will take a substantial
period of time, as does the adoption of most change into clinical practice.
Interestingly, a recent analysis of NHANES III data showed that
approximately 30% of patients with diabetes and impaired kidney function
had no evidence of albuminuria or retinopathy [26]. Guidelines for
cardiovascular disease, hypertension, and dyslipidemia recognize CKD as
a risk factor for these conditions, but do not recommend serial measurement
or follow-up of kidney function other than as it pertains to complications of
specic medication use [27]. Although CKD groups are clear about the
interlinking of diabetes, cardiovascular disease, and CKD, it is not as
apparent from the cardiovascular and diabetes groups that they view CKD
with similar importance at the current time. Conicting prioritization from
dierent subspecialties may contribute to the confusion at the clinical
implementation level.
Resources
Health care economic and human resources need to be reviewed within
the context of prevention initiatives. It is clear that there is a long-term
benet of preventative strategies in the care of chronic asymptomatic
disease; however, it is perceived to be expensive. Limited time and resources
leads to prioritization of those aspects of care that can be managed easily or
require immediate attention. During times of economic constraint, shifts
707
away from preventive strategies occur to ensure appropriate resources are

available for the treatment of seriously ill patients (ie, those requiring
dialysis). It has been explicitly demonstrated from a business case perspective how much cost savings can be accrued by slowing the progression
of CKD and prevention of end-stage renal disease [28]. It is dicult, however, for insurance companies or governments to appreciate the long-term
gain associated with expensive investment in the infrastructure necessary to
establish such preventative strategies as compared with funding of the lifesaving therapies of dialysis. From a societal perspective, the authors and
others argue that if there are insucient resources at the current time,
without a prevention strategy, the resource shortage will only worsen [28].
Summary
In this era of escalating information, costly technology, and an increasing
prevalence of chronic complex diseases in an aging population, a systematic
approach to execute changes in the care of patients with kidney disease
must be developed. Specically, there is a need to facilitate the translation
of research and clinical guidelines into the delivery of quality clinical care.
At present in nephrology, there is some knowledge of disease processes,
accumulating knowledge about risk factors for progression, and knowledge
about how best to deliver care to those with a chronic disease. The current
health care environment is not suited to either the care of chronic conditions
or to prevention. Information technology should facilitate shared models of
care delivery for chronic conditions and allow opportunities to add new
knowledge and deliver good care to complex patient groups.
To execute change in the management of patients with CKD, medical students, health care professionals, and established physicians need to
be educated about the prevalence and consequences of CKD. These
educational initiatives should be done in the context of cases or specic
patients, especially for established practitioners, and should be simplied to
make analogies to familiar concepts. The concept that CKD is a risk factor
for cardiovascular disease, and needs to be managed (as does diabetes and
dyslipidemia), should be more clearly articulated.
Basic and clinical research in kidney disease has been enhanced by
discoveries in vascular biology, diabetes, and cardiology. Much of the
clinical research has been limited, however, by lack of clear denition of
CKD. The development of the new K/DOQI staging system that denes
and classies the severity of kidney disease may improve the execution of
ongoing robust clinical trials. Incorporating this classication system into
the clinical practice of all physicians by automatic laboratory reporting of
estimates of GFR raises awareness and improves communication between
all medical professionals. Collaborative management of CKD patients
between dierent physicians and multidisciplinary teams, in conjunction
with the ongoing investigation of treatments and treatment strategies by
708
LEVIN & STEVENS
both clinicians and researchers, may well lead to improved outcomes for
patients with CKD.
Executing change in the management of CKD requires an increased
awareness on the part of all clinicians, including nephrologists, regarding
the prevalence and importance of the problem of earlier stages of kidney
disease. The systematic evaluation of all patients and incorporation of
simplied denitions and classication systems should enhance the ability
ultimately to improve the outcomes of patients with kidney disease
irrespective of time of identication.
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Chronic Kidney Disease

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Chronic Kidney Disease

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Med Clin N Am 89 (2005) xvxvi

Chronic Kidney Disease

Ajay K. Singh, MB, MRCP(UK)

disease progression and in disease treatment (pharmacogenomics) remains

Med Clin N Am 89 (2005) 419445

Epidemiology and Risk Factors for

Department of Epidemiology, Rollins School of Public Health,

End-stage renal disease (ESRD) occurs when kidney function is

CKD: EPIDEMIOLOGY & RISK FACTORS

occurrence of ESRD in individual patients and in high-risk populations with

used to avoid misinterpretation of serum creatinine values. An estimated

Kidney damage with normal or

CKD: EPIDEMIOLOGY & RISK FACTORS

extensively used the National Health and Nutrition Survey (NHANES), an

CKD: EPIDEMIOLOGY & RISK FACTORS

High-risk populations for progression of chronic kidney disease to end-stage

patients reported that the risk for developing macroalbuminuria was

CKD: EPIDEMIOLOGY & RISK FACTORS

and participants in clinical trials of atherosclerotic disease are at increased

Atherosclerotic heart disease

Scr > 1.4 mg/dL

GFR \ 63.8 mL/min

second-degree relative with CKD was reported by 26% of prevalent ESRD

CKD: EPIDEMIOLOGY & RISK FACTORS

Risk factors associated with progression of chronic kidney disease

CKD: EPIDEMIOLOGY & RISK FACTORS

Comparable dierences among treated subjects on protein or albumin

Dietary protein consumption

CKD: EPIDEMIOLOGY & RISK FACTORS

renal plasma ow moved toward the values observed in the nonobese

Urine protein excretion

Race and poverty

CKD: EPIDEMIOLOGY & RISK FACTORS

characteristics associated risk of incident ESRD caused by diabetes mellitus

CKD: EPIDEMIOLOGY & RISK FACTORS

with a family history of ESRD, diabetes, hypertension, and cardiovascular

[14] Statistics CMS. Medicare. Available at: http://www.cms.hhs.gov/Review/Supp/. Accessed

CKD: EPIDEMIOLOGY & RISK FACTORS

[52] Maschio G, Alberti D, Janin G, et al. Eect of the angiotensin-converting-enzyme inhibitor

CKD: EPIDEMIOLOGY & RISK FACTORS

CKD: EPIDEMIOLOGY & RISK FACTORS

CKD: EPIDEMIOLOGY & RISK FACTORS

Med Clin N Am 89 (2005) 447456

The Familial Clustering of Renal Disease

This article reviews the familial aggregation of chronic kidney diseases

Nephropathy in systemic disease

SATKO & FREEDMAN

Among African Americans residing in the southeastern United States,

CKD & RELATED PHENOTYPES: FAMILIAL CLUSTERING

Familial clustering of surrogate markers of renal disease

SATKO & FREEDMAN

CKD & RELATED PHENOTYPES: FAMILIAL CLUSTERING

environmental causes of high blood pressure or diabetes mellitus, may exist.

SATKO & FREEDMAN

chronic kidney disease. In 32 white European subjects with type 2 diabetes

CKD & RELATED PHENOTYPES: FAMILIAL CLUSTERING

SATKO & FREEDMAN

genes underlying diabetic nephropathy and determine if the loci identied in

CKD & RELATED PHENOTYPES: FAMILIAL CLUSTERING

SATKO & FREEDMAN

Med Clin N Am 89 (2005) 457473

Measurement of Kidney Function

Accurate estimation of kidney function is central to the detection,