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review article
current concepts
A
cute renal failure is defined as a rapid decrease in the glomer- From the Division of Kidney Disease and
ular filtration rate, occurring over a period of minutes to days. Because the Hypertension, Department of Medicine,
Rhode Island Hospital and the Warren
rate of production of metabolic waste exceeds the rate of renal excretion in Alpert Medical School of Brown Univer-
this circumstance, serum concentrations of markers of renal function, such as urea sity, Providence, RI. Address reprint re-
and creatinine, rise. The causes of acute renal failure are classically divided into quests to Dr. Abuelo at the Division of
Kidney Disease and Hypertension, Rhode
three categories: prerenal, postrenal (or obstructive), and intrinsic. Prerenal azotemia Island Hospital, 593 Eddy St., Providence,
is considered a functional response to renal hypoperfusion, in which renal structure RI 02903, or at jgabuelo@lifespan.org.
and microstructure are preserved. Postrenal azotemia obstruction of the urinary
N Engl J Med 2007;357:797-805.
tract is initially accompanied by few microscopical changes (early hydronephrosis, Copyright 2007 Massachusetts Medical Society.
with enlargement of the pelvic cavity and minimal distention or blunting of the
renal papilla) or none. In contrast, intrinsic renal azotemia is due to parenchymal
injury of the blood vessels, glomeruli, tubules, or interstitium. In prerenal and
postrenal azotemia, complete recovery may be seen 1 to 2 days after relief of the
offending lesion, provided that normal perfusion or urinary outflow is reestablished
before structural changes occur.
A research focus group organized by the American Society of Nephrology recent
ly recommended that the term acute kidney injury replace the term acute renal
failure.1 However, the group left the actual definition of acute kidney injury to be
determined in the future. Thus, whether acute kidney injury refers only to acute
tubular necrosis or includes prerenal and postrenal azotemia and parenchymal dis
eases such as acute glomerulonephritis remains unclear. Most clinicians still use
the term acute renal failure as defined above.
The two forms of ischemic acute renal failure, prerenal azotemia and acute
tubular necrosis, account for more than half the cases of renal failure seen in
hospitalized patients and are familiar to most clinicians.2-4 Yet in many patients
with acute renal failure, the contribution of ischemia is initially unrecognized.
Patients with ischemic acute renal failure typically have low systemic perfusion,
sometimes caused by volume depletion, although their blood pressure may not fall
dramatically but instead may remain within the normal range (in an adult, systolic
blood pressure >90 to 100 mm Hg). In such cases, in the absence of frank hypo
tension, the clinician may speculate that an unobserved drop in blood pressure must
have caused the renal failure. Although this scenario cannot be ruled out, other
causative mechanisms can usually be identified. This type of ischemic acute renal
failure (termed normotensive, because the patients blood pressure is at least
temporarily within the normal range) can occur as a result of several processes,
most of which involve increased renal susceptibility to modest reductions in perfu
sion pressure. Fortunately, the factors that lead to ischemic renal failure in patients
with apparently normal blood pressure are discernible in most instances. Recogni
tion of these factors allows the physician to make an early diagnosis and facilitates
the interventions that can help to reestablish normal renal hemodynamics.
The importance of addressing even mild renal failure is illustrated by a recent
study showing that hospitalized patients with a modest increase in the serum
Afferent Efferent
arteriole arteriole
Increased Increased
vasodilatory angiotensin II
prostaglandins
Glomerulus
Tubule
C Decreased perfusion pressure in the presence of NSAIDs D Decreased perfusion pressure in the presence of ACEI or ARB
Figure 2. Intrarenal Mechanisms for Autoregulation of the Glomerular Filtration Rate under Decreased Perfusion Pressure and Reduction
of the Glomerular Filtration Rate by Drugs.
Panel A shows normal conditions and a normal glomerular filtration rate (GFR). Panel B shows reduced perfusion pressure within the
COLOR FIGURE
autoregulatory range. Normal glomerular capillary pressure is maintained by afferent vasodilatation and efferent vasoconstriction.
Draft 3 Panel C
08/03/07
shows reduced perfusion pressure with a nonsteroidal antiinflammatory drug (NSAID). Loss of vasodilatory prostaglandins
Author increases affer-
Abuelo
ent resistance; this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease.
Fig #Panel 2D shows reduced
Title GFR regulation
perfusion pressure with an angiotensin-convertingenzyme inhibitor (ACEI) or an angiotensin-receptor blocker (ARB). Loss of angiotensin II
ME
action reduces efferent resistance; this causes the glomerular capillary pressure to drop below normal values DEand the Ingelfinger
GFR to decrease.
Artist KMK
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Leukocyte Polymerizing of
infiltration TammHorsfall
protein
Peritubular
capillaries
Collecting
Release of
duct
cytokines, enzymes,
Increase in
and reactive oxygen
adhesion
species
molecules
Denuded tubular walls
Thick
Cytoskeletal disruption ascending
limb
Backleak
of fluid Loss of microvilli
Necrotic cell
Increased
vasoconstrictors Decreased
Mislocation renal function
Decreased of integrins
vasodilators
Apoptotic Mislocation of Na+/K+ATPase
cell
Congestion
Hypoperfusion
Tubular injury is a direct consequence of metabolic pathways activated by ischemia but is potentiated by inflammation
Draftand
6 microvascular 08/07/07
compromise. The inset shows shedding of epithelial cells and denudation of the basement membrane in the proximal
Author tubule,
Abuelo with back-
Fig # 3
leak of filtrate (inset, left) and obstruction by sloughed cells in the distal tubule (inset, right).
Title Acute tubular necrosis
ME Perkins
DE Ingelfinger
Artist KMK
structural narrowing of the arterioles.7,9,15
In dal antiinflammatory drugs (NSAIDs)
AUTHOR PLEASE NOTE: or cyclo
Figure has been redrawn and type has been reset
creased susceptibility to renal ischemia may also oxygenase-2 (COX-2) inhibitors, which reduce the
Please check carefully
date 08/23/07
occur in malignant hypertension because of inti synthesis of vasodilatory Issue
prostaglandins in the
mal thickening and fibrinoid necrosis of the small kidneys (Fig. 2C). 16,18-20 When this occurs, angio
arteries and arterioles.16 In addition, in chronic tensin II, norepinephrine, and other vasoconstric
kidney disease, afferent arterioles in the function tors released in low-perfusion states may act on
ing glomeruli become dilated, which increases the afferent arterioles unopposed, further decreas
their filtration rate (hyperfiltration). Although an ing glomerular capillary pressure. In other situ
increased glomerular filtration rate per nephron ations, sepsis,21,22 hypercalcemia,23,24 severe liver
compensates for the loss of nephrons, the inabil failure,25,26 calcineurin inhibitors,27 and radiocon
ity to vasodilate further markedly impairs the kid trast agents28 can act through various vasocon
neys ability to autoregulate the glomerular filtra strictor mediators to increase afferent arteriolar
tion rate in low-perfusion states.17 resistance. In addition, sepsis and contrast agents
Failure of afferent resistance to decrease can may have direct toxic effects on the tubules.21,28
also occur when a patient is receiving nonsteroi Decreased renal perfusion may also cause an ex
but is accompanied by hypertension from hyper patients usually have one or more of the follow
volemia or renin release into the circulation. ing signs or symptoms: hypothermia, confusion,
Small-vessel disease in malignant hypertension cool extremities, leukocytosis, bandemia (an
similarly leads to renal ischemia with increased elevated level of band forms of white cells), leuko
renin secretion, which worsens the hypertension. penia, or unexplained lactic acidosis. Especially
in patients with relative hypotension and acute
renal failure, any of these clinical pictures should
Di agnosis of Nor mo tensi v e
Is che mic Acu te R ena l Fa ilur e lead the clinician to search for an occult infec
tion, using physical examination, imaging, and
Common conditions in which normotensive is microbiologic studies.
chemic acute renal failure may develop include Alternatively, a patient in stable condition who
hypertension, chronic kidney disease, and old age, is receiving diuretics for hypertension or conges
all of which are associated with narrowing and tive heart failure may have anorexia and stop eat
blunted vasodilatory capacity of renal vessels. ing for some reason or may otherwise have de
Other conditions include cirrhosis, infection, myo creased salt intake. Progressive negative sodium
cardial infarction, and congestive heart failure, balance results in volume depletion and a down
as well as decreased intake of food, which can ward drift in blood pressure. Patients may not be
reduce renal perfusion. In addition, diuretics re aware of decreases in oral intake or may not
duce extracellular volume, which can compromise volunteer the information spontaneously. Thus,
cardiac output, and medications such as ACE in the clinician needs to question the patient, family,
hibitors and NSAIDs interfere with autoregula and caregivers about recent weight loss or changes
tion. In classic ischemic acute renal failure, when in diet.
a patient goes into shock, the physician should In addition to watching for low-perfusion
be vigilant in looking for a decrease in urinary states, clinicians should try to identify suscepti
output and an increase in the serum creatinine bility factors for renal ischemia (Table 1). Be
concentration. In the normotensive variant, when cause normotensive renal failure is multifactorial,
the urinary output decreases or the creatinine several low-perfusion states and susceptibility fac
concentration increases, the clinician should look tors may be present. It is important to ask about
for the presence of a low-perfusion state that may the patients use of over-the-counter NSAIDs that
not have been readily apparent. On the first day might change renal perfusion and to obtain a
during which the creatinine concentration in measurement of the serum calcium concentra
creases, the blood pressure is usually noted to be tion, corrected for any degree of hypoalbumin
below its usual level. In persons who have under emia that is present. Sepsis, hypercalcemia, and
lying hypertension, blood pressure decreases from the hepatorenal syndrome may all cause both low-
high to normal (e.g., a drop in systolic blood pres perfusion states and increased afferent arteriolar
sure from 160 to 118 mm Hg). Since patients are resistance.21-26
normotensive when renal failure occurs, the de Susceptibility factors may sometimes result in
crease in blood pressure may be overlooked. Fre ischemic acute renal failure in the absence of a
quently the patients usual blood pressure is not low-perfusion state. In these cases, the factors
recorded alongside current blood pressures; the result in severe enough renal vasoconstriction to
usual blood pressure must be ascertained from cause a critical reduction in renal perfusion. Ex
medical records and compared with the blood amples are radiocontrast agents given to patients
pressures when the serum creatinine concentra with chronic renal failure28 and cyclosporine, ta
tion began to rise. In patients with hypovolemia, crolimus,27 NSAIDs,35 or COX-2 inhibitors36 given
blood pressure must often be measured in the up in high or supratherapeutic doses.
right position to confirm the degree and ortho Patients with malignant hypertension, renal-
static nature of the decline in blood pressure. artery stenosis in a solitary kidney, or bilateral
The cause of the decline in blood pressure may renal-artery stenosis have severe hypertension on
not be apparent. The following two scenarios are presentation but also have compromised renal
not uncommon. In the first, a patient has what perfusion. As high blood pressure is controlled,
turns out to be early sepsis but at the onset does renal function may worsen because of a critical
not have fever or any localizing symptoms. Such drop in glomerular capillary pressure.16,30-32
Once low-perfusion states and susceptibility mixed findings for example, a ratio of blood
factors are recognized, a tentative diagnosis of urea nitrogen to creatinine of 25:1 and urinary
normotensive renal failure can be made, supported sodium excretion of 15 mmol per liter, suggesting
by laboratory findings and a response to therapy. prerenal azotemia, but with renal tubular epi
thelial cells in the urinary sediment, a finding
L a bor at or y Findings that is consistent with acute tubular necrosis.
monitored. Fluid, electrolyte, and acidbase bal toms, volume overload, hyperkalemia, and meta
ance must be maintained, and volume overload bolic acidosis that cannot be managed by conser
and hyperkalemia avoided. In certain cases, sodi vative means. How severe these problems need to
um bicarbonate intravenous solutions (150 mmol be before treatment is initiated is controversial.
of sodium bicarbonate added to 1 liter of a 5% Arguments in favor of starting renal-replacement
dextrose solution in water) can be used for vol therapy early may be based on the desire to avoid
ume resuscitation, rather than sodium chloride, the dangerous metabolic, fluid, and electrolyte
to mitigate acidosis from uremia or diarrhea. derangements of uremia47; arguments in favor
Furosemide and low-dose dopamine have long of withholding renal-replacement therapy until
been used to treat acute renal failure, but there definite indications are present are based on the
is no evidence of their effectiveness.41,43,44 Simi risk of hemorrhage during vascular access, hypo
larly, atrial natriuretic peptide and mannitol do tension and arrhythmia during dialysis, and pos
not appear to ameliorate acute renal failure.41 sible dialysis-induced recurrent renal injury or
Adequate nutrition should be provided; mal delayed renal recovery.48 Existing data on the tim
nutrition is associated with increased complica ing of renal-replacement therapy are inadequate
tions and death in patients with acute renal fail to provide clear guidance.47,49 Unfortunately, many
ure.41,45 Such patients frequently have accelerated patients with normotensive renal failure have
protein breakdown and increased caloric needs, important complicating factors, such as old age,
especially if they are critically ill or receiving sepsis, and heart disease, and progression to
renal-replacement therapy (hemodialysis). In gen frank shock and death is not unusual.
eral, daily intake should include 25 to 30 kcal per
kilogram of body weight; catabolic patients should C onclusions
receive up to 1.5 g of protein per kilogram daily.
Enteral nutrition with food or formula designed An acute increase in the serum creatinine con
for renal failure is preferred over parenteral nu centration is usually due to renal ischemia. If the
trition, when possible, because it maintains the patient does not have frank hypotension, normo
integrity of the gut, requires less fluid intake, tensive ischemic acute renal failure must be con
and is less expensive.41,45,46 Advice from a dieti sidered. A drop in systolic blood pressure to the
tian or a nutrition consultant may be helpful. low-normal range (100 to 115 mm Hg) must not
Although intake of potassium and phosphate is be overlooked. Many cases can be treated quickly
typically restricted because of impaired renal ex by replacing volume, treating infection, or stop
cretion, hypokalemia and hypophosphatemia due ping medications such as NSAIDs, diuretics, and
to cell uptake or external losses can occur, and antihypertensive agents, especially ACE inhibitors
supplements may be required. or angiotensin-receptor blockers.
Indications for intermittent or continuous No potential conflict of interest relevant to this article was
renal-replacement therapy are florid uremic symp reported.
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