H.

PATHOPHYSIOLOGY
Etiology

PRECIPITATING PRESENT JUSTIFICATION

FACTORS
Diabetes mellitus is the leading cause of
Diabetes Mellitus chronic kidney disease (CKD) and a major
public health issue worldwide.
Approximately 20–30% of patients with
type 2 diabetes mellitus (T2DM) have renal
impairment, classified as moderate-to-
severe CKD (glomerular filtration rate
(GFR) <60 mL/min/1.73 m2).
(Glucose lowering therapeutic strategies
for type 2 diabetic patients with chronic
kidney disease in primary care setting in
france: a cross-sectional study. Int J
Endocrinol. 2013)
Hypertension is one of the leading causes
Hypertension of CKD due to the deleterious effects that
increased BP has on kidney vasculature.
Long-term, uncontrolled, high BP leads to
high intraglomerular pressure, impairing
glomerular filtration.
(American Heart Association 2013)
Sedentary Lifestyle Chronic renal disease is accompanied by
(smoking, alcohol, diet characteristic abnormalities of lipid
and physical inactivity) metabolism, which appear as a
consequence of nephrotic syndrome or
renal insufficiency and are reflected in an
altered apolipoprotein profile as well as
elevated plasma lipid levels.
(Acta paul, enferm. São Paulo Mar/Apr.
2014)
 PREDISPOSING PRESENT JUSTIFICATION
FACTOR
Age (older 45 for men The most powerful independent predictor
and 55 for women) for the development of ACS, including
presentation with myocardial infarction, is
age.
(Keith A A Fox, 2014)
Gender Well documented that the incidence of
acute coronary syndrome is higher in men
approximately in age up to 45 years old
than women
(Falcone and Chong, 2017
Family History A family history of heart disease is
associated with a higher risk of acute
coronary syndrome, especially if a close
relative developed heart disease at an
early age. Your risk is highest if your father
or a brother was diagnosed with heart
disease before age 55 or if your mother or
a sister developed it before age 65.
(Hoseini K, et al. Monaldi Arch Chest Dis.
2013)

Symptomatology
SYMPTOMS PRESENT JUSTIFICATION
Edema Kidney damage. Damage to the tiny,
filtering blood vessels in your kidneys can
result in nephrotic syndrome. In nephrotic
syndrome, declining levels of protein
(albumin) in your blood can lead to fluid
accumulation and edema.
(American Heart Association)
Shortness of Breath Fatigue or weakness — a build-
up of wastes or a shortage of red blood
cells (anemia) can cause these problems
when the kidneys begin to fail. Shortness
of breath — kidney failure is sometimes
confused with asthma or heart failure,
because fluid can build up in the lungs.
(Porth 2017)
 Increased glucose Insulin is a hormone that helps regulate
level sugar (glucose) in the blood. When blood
sugar levels get too high, the condition is
called hyperglycemia. If your diabetes is
not controlled, it can lead to increased loss
of kidney function, cardiovascular disease,
vision loss and other complications.
(Patrick Gallagher, 2013)
Slurred speech Dysarthria often is characterized
by slurred or slow speech that can be
difficult to understand. Common causes of
dysarthria include nervous system
(neurological) disorders such as stroke,
brain injury, brain tumors, and conditions
that cause facial paralysis or tongue or
throat muscle weakness.
(Porth 2017). 3
Metabolic Acidosis As a result, CKD leads to retention of
hydrogen ions. The retained acid is
buffered by bicarbonate in the extracellular
fluid, by tissue buffers, and by bone. With
worsening renal function, however,
progressive metabolic acidosis can
develop.
(Sethi SS, et al. Curr Diab Rep. 2013
Increased urine output Diuresis is determined not only by residual
GFR, but also by the rate of tubular
reabsorption . The equilibrium between
GFR and tubular reabsorption is lost in
advanced uremia, sometimes in earlier
stages, depending on the concomitant
complications as hypertension or/ and the
primary renal diseases.
(Association between extracellular water,
left ventricular mass and hypertension in
haemodialysis patients. Nephrol Dial
Transplant. 2003)
NARRATIVE

The pathogenesis of essential hypertension is multifactorial and highly complex. The

kidney is both the contributing and the target organ of the hypertensive processes,and
the disease involves the interaction of multiple organ systems and numerous
mechanisms of independent or interdependent pathways. Factors that play an important
role in the pathogenesis of hypertension include genetics, activation of neurohormonal
systems such as the sympathetic nervous system and renin-angiotensin-aldosterone
system, obesity, and increased dietary salt intake.

Arterial hypertension is the condition of persistent elevation of systemic blood pressure

(BP). BP is the product of cardiac output and total peripheral vascular resistance.

Multiple factors are involved in short-term and long-term regulation of BP for adequate
tissue perfusion; these include the following:
 Cardiac output and circulatory blood volume
 Vascular caliber, elasticity, and reactivity
 Humoral mediators
 Neural stimulation

Over the course of its natural history, essential hypertension progresses from
occasional to established hypertension. After a long, invariable, asymptomatic period,
persistent hypertension develops into complicated hypertension, in which target organ
damage to the aorta and small arteries, heart, kidneys, retina, and central nervous
system is evident.

The progression of essential hypertension begins with prehypertension in persons aged

10-30 years (by increased cardiac output); then advances to early hypertension in
persons aged 20-40 years (in which increased peripheral resistance is prominent); then
progresses to established hypertension in persons aged 30-50 years; and finally
advances to complicated hypertension in persons aged 40-60 years.

Acute ischemic strokes result from vascular occlusion secondary to thromboembolic

disease . Ischemia causes cell hypoxia and depletion of cellular adenosine triphosphate
(ATP). Without ATP, there is no longer the energy to maintain ionic gradients across the
cell membrane and cell depolarization. Influx of sodium and calcium ions and passive
inflow of water into the cell lead to cytotoxic edema.
Ischemic core and penumbra
An acute vascular occlusion produces heterogeneous regions of ischemia in the
affected vascular territory. Local blood flow is limited to any residual flow in the major
arterial source plus the collateral supply, if any.
Affected regions with cerebral blood flow of lower than 10 mL/100 g of tissue/min are
referred to collectively as the core. These cells are presumed to die within minutes of
stroke onset.
Zones of decreased or marginal perfusion (cerebral blood flow < 25 mL/100g of
tissue/min) are collectively called the ischemic penumbra. Tissue in the penumbra can
remain viable for several hours because of marginal tissue perfusion.
Ischemic cascade
On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and
membrane ion-transport systems fail. Disruption of cellular metabolism also impairs
normal sodium-potassium plasma membrane pumps, producing an intracellular
increase in sodium, which in turns increases intracellular water content. This cellular
swelling is referred to as cytotoxic edema and occurs very early in cerebral ischemia.

Cerebral ischemia impairs the normal sodium-calcium exchange protein also found on
cell plasma membranes. The resulting influx of calcium leads to the release of a number
of neurotransmitters, including large quantities of glutamate, which in turn activates N -
methyl-D-aspartate (NMDA) and other excitatory receptors on other neurons.

These neurons then become depolarized, causing further calcium influx, further
glutamate release, and local amplification of the initial ischemic insult. This massive
calcium influx also activates various degradative enzymes, leading to the destruction of
the cell membrane and other essential neuronal structures. [11] Free radicals, arachidonic
acid, and nitric oxide are generated by this process, which leads to further neuronal
damage.

Ischemia also directly results in dysfunction of the cerebral vasculature, with breakdown
of the blood-brain barrier occurring within 4-6 hours after infarction. Following the
barrier’s breakdown, proteins and water flood into the extracellular space, leading to
vasogenic edema. This produces greater levels of brain swelling and mass effect that
peak at 3-5 days and resolve over the next several weeks with resorption of water and
proteins.

Within hours to days after a stroke, specific genes are activated, leading to the
formation of cytokines and other factors that, in turn, cause further inflammation and
microcirculatory compromise. [ Ultimately, the ischemic penumbra is consumed by these
progressive insults, coalescing with the infarcted core, often within hours of the onset of
the stroke.

Infarction results in the death of astrocytes, as well as the supporting oligodendroglial

and microglial cells. The infarcted tissue eventually undergoes liquefaction necrosis and
is removed by macrophages, with the development of parenchymal volume loss. A well-
circumscribed region of cerebrospinal fluid–like low density, resulting from
encephalomalacia and cystic change, is eventually seen. The evolution of these chronic
changes may be seen in the weeks to months following the infarction.

A normal kidney contains approximately 1 million nephrons, each of which contributes to

the total glomerular filtration rate (GFR). In the face of renal injury (regardless of the
etiology), the kidney has an innate ability to maintain GFR, despite progressive
destruction of nephrons, as the remaining healthy nephrons manifest hyperfiltration and
compensatory hypertrophy. This nephron adaptability allows for continued normal
clearance of plasma solutes. Plasma levels of substances such as urea and creatinine
start to show measurable increases only after total GFR has decreased to 50%.

The plasma creatinine value will approximately double with a 50% reduction in GFR.
For example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2
mg/dL in a patient, although still within the adult reference range, actually represents a
loss of 50% of functioning nephron mass.

The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the
reasons noted, has been hypothesized to represent a major cause of progressive renal
dysfunction. The increased glomerular capillary pressure may damage the capillaries,
leading initially to secondary focal and segmental glomerulosclerosis (FSGS) and
eventually to global glomerulosclerosis. This hypothesis is supported by studies of five-
sixths nephrectomized rats, which develop lesions identical to those observed in
humans with chronic kidney disease (CKD).

Factors other than the underlying disease process and glomerular hypertension that
may cause progressive renal injury include the following:
 Systemic hypertension
 Nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], intravenous
contrast media)
 Decreased perfusion (eg, from severe dehydration or episodes of shock)
 Proteinuria (in addition to being a marker of CKD)
 Hyperlipidemia
 Hyperphosphatemia with calcium phosphate deposition
 Smoking
 Uncontrolled diabetes

Thaker et al found a strong association between episodes of acute kidney injury (AKI)
and cumulative risk for the development of advanced CKD in multiple hospitalized
patients with diabetes mellitus. Any AKI versus no AKI was a risk factor for stage 4
CKD, and each additional AKI episode doubled that risk.

Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective

observational cohort, suggest that inflammation and hemostasis are antecedent
pathways for CKD. [7] This study used data from 1787 cases of CKD that developed
between 1987 and 2004.
Childhood renal function and CKD in children
In children, the GFR increases with age and is calculated with specific equations that
are different than those for adults. Adjusted for body surface area, the GFR reaches
adult levels by age 2-3 years.
Aspects of pediatric kidney function and the measure of creatinine are informative not
only for children but also for adults. For example, it is important to realize that creatinine
is derived from muscle and, therefore, that children and smaller individuals have lower
creatinine levels independent of the GFR. Consequently, laboratory reports that do not
supply appropriate pediatric normal ranges are misleading. The same is true for
individuals who have low muscle mass for other reasons, such as malnutrition,
cachexia, or amputation.

Another important note for childhood CKD is that physicians caring for children must be
aware of normal blood pressure levels by age, sex, and height. Prompt recognition of
hypertension at any age is important, because it may be caused by primary renal
disease.

Fortunately, CKD during childhood is rare and is usually the result of congenital defects,
such as posterior urethral valves or dysplastic kidney malformations. Another common
cause is FSGS. Genetic kidney diseases are also frequently manifested in childhood
CKD. Advances in pediatric nephrology have enabled great leaps in survival for
pediatric CKD and end-stage renal disease (ESRD), including for children who need
dialysis or transplantation.
Aging and renal function
The biologic process of aging initiates various structural and functional changes within
the kidney. Renal mass progressively declines with advancing age, and
glomerulosclerosis leads to a decrease in renal weight. Histologic examination is
notable for a decrease in glomerular number of as much as 30-50% by age 70 years.

The GFR peaks during the third decade of life at approximately 120 mL/min/1.73 m 2; it
then undergoes an annual mean decline of approximately 1 mL/min/y/1.73 m 2, reaching
a mean value of 70 mL/min/1.73 m2 at age 70 years.

Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the

renal medulla. Juxtamedullary glomeruli see a shunting of blood from afferent to efferent
arterioles, resulting in redistribution of blood flow favoring the renal medulla. These
anatomic and functional changes in renal vasculature appear to contribute to an age-
related decrease in renal blood flow.

Renal hemodynamic measurements in aged humans and animals suggest that altered
functional response of the renal vasculature may be an underlying factor in diminished
renal blood flow and increased filtration noted with progressive renal aging. The
vasodilatory response is blunted in the elderly when compared to younger patients.

However, the vasoconstrictor response to intrarenal angiotensin is identical in young

and older human subjects. A blunted vasodilatory capacity with appropriate
vasoconstrictor response may indicate that the aged kidney is in a state of
vasodilatation to compensate for the underlying sclerotic damage.
Given the histologic evidence for nephronal senescence with age, a decline in the GFR
is expected. However, a wide variation in the rate of GFR decline is reported because of
measurement methods, race, gender, genetic variance, and other risk factors for renal
dysfunction.
Genetics
Most cases of CKD are acquired rather than inherited, although CKD in a child is more
likely to have a genetic or inherited cause. Well-described genetic syndromes
associated with CKD include autosomal dominant polycystic kidney disease(ADPKD)
and Alport syndrome. Other examples of specific single-gene or few-gene mutations
associated with CKD include Dent disease, nephronophthisis, and atypical hemolytic
uremic syndrome (HUS).

APOL1 gene

More recently, researchers have begun to identify genetic contributions to increased risk
for development or progression of CKD. Friedman et al found that more than 3 million
black persons with genetic variants in both copies of apolipoprotein L1 (APOL1) are at
higher risk for hypertension-attributable ESRD and FSGS. In contrast, black individuals
without the risk genotype and European Americans appear to have similar risk for
developing nondiabetic CKD.

FGF-23 gene

Circulating levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-

23) are affected by variants in the FGF23 gene. Isakova et al reported that elevated
FGF-23 levels are an independent risk factor for ESRD in patients who have fairly well-
preserved kidney function (stages 2-4) and for mortality across the scope of CKD.

Single-nucleotide polymorphisms

A review of 16 single-nucleotide polymorphisms (SNPs) that had been associated with

variation in GFR found that development of albuminuria was associated mostly with an
SNP in the SHROOM3 gene. Even accounting for this variant, however, there is
evidence that some unknown genetic variant influences the development of albuminuria
in CKD. This study also suggests a separate genetic influence on development of
albuminuria versus reduction in GFR.

A genome-wide association study (GWAS) that included over 130,000 patients found 6
SNPs associated with reduced GFR, located in or
near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. The SNP
in SLC47A1 was associated with decreased GFR in nondiabetic individuals, whereas
SNPs located in the DNAJC16 and CDK12genes were associated with decreased GFR
in individuals younger than 65 years.
Immune-system and RAS genes
A number of genes have been associated with the development of ESRD. Many of
these genes involve aspects of the immune system (eg, CCR3, IL1RN, IL4).

Unsurprisingly, polymorphisms in genes involving the renin-angiotensin system (RAS)

have also been implicated in predisposition to CKD. One study found that patients with
CKD were significantly more likely to have the A2350G polymorphism in the ACE gene,
which encodes the angiotensin-converting enzyme (ACE). They were also more likely to
have the C573T polymorphism in the AGTR1 gene, which encodes the angiotensin II
type 1 receptor.
Hyperkalemia
The ability to maintain potassium excretion at near-normal levels is generally
maintained in CKD, as long as aldosterone secretion and distal flow are maintained.

Another defense against potassium retention in patients with CKD is increased

potassium excretion in the gastrointestinal tract, which also is under control of
aldosterone.

Hyperkalemia usually does not develop until the GFR falls to less than 20-25
mL/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium.
Hyperkalemia can be observed sooner in patients who ingest a potassium-rich diet or
have low serum aldosterone levels. Common sources of low aldosterone levels are
diabetes mellitus and the use of ACE inhibitors, NSAIDs, or beta-blockers.
Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as
occurs in the setting of acidemia or from lack of insulin.

Hypokalemia

Hypokalemia is uncommon but can develop in patients with very poor intake of
potassium, gastrointestinal or urinary loss of potassium, or diarrhea or in patients who
use diuretics.
Metabolic acidosis
Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the
latter is observed generally with stage 5 CKD but with the anion gap generally not
higher than 20 mEq/L. In CKD, the kidneys are unable to produce enough ammonia in
the proximal tubules to excrete the endogenous acid into the urine in the form of
ammonium. In stage 5 CKD, accumulation of phosphates, sulfates, and other organic
anions are the cause of the increase in anion gap.

Metabolic acidosis has been shown to have deleterious effects on protein balance,
leading to the following:
 Negative nitrogen balance
 Increased protein degradation
 Increased essential amino acid oxidation
  Reduced albumin synthesis
 Lack of adaptation to a low-protein diet

Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean

body mass, and muscle weakness. The mechanism for reducing protein may include
effects on adenosine triphosphate (ATP)–dependent ubiquitin proteasomes and
increased activity of branched-chain keto acid dehydrogenases.

Metabolic acidosis also leads to an increase in fibrosis and rapid progression of kidney
disease, by causing an increase in ammoniagenesis to enhance hydrogen excretion.
In addition, metabolic acidosis is a factor in the development of renal osteodystrophy,
because bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis
may interfere with vitamin D metabolism, and patients who are persistently more
acidotic are more likely to have osteomalacia or low-turnover bone disease.
Salt- and water-handling abnormalities
Salt and water handling by the kidney is altered in CKD. Extracellular volume expansion
and total-body volume overload results from failure of sodium and free-water excretion.
This generally becomes clinically manifested when the GFR falls to less than 10-15
mL/min/1.73 m², when compensatory mechanisms have become exhausted.

As kidney function declines further, sodium retention and extracellular volume

expansion lead to peripheral edema and, not uncommonly, pulmonary edema and
hypertension. At a higher GFR, excess sodium and water intake could result in a similar
picture if the ingested amounts of sodium and water exceed the available potential for
compensatory excretion.

Tubulointerstitial renal diseases represent the minority of cases of CKD. However, it is

important to note that such diseases often cause fluid loss rather than overload. Thus,
despite moderate or severe reductions in GFR, tubulointerstitial renal diseases may
manifest first as polyuria and volume depletion, with inability to concentrate the urine.
These symptoms may be subtle and require close attention to be recognized. Volume
overload occurs only when GFR reduction becomes very severe.
Anemia
Normochromic normocytic anemia principally develops from decreased renal synthesis
of erythropoietin, the hormone responsible for bone marrow stimulation for red blood
cell (RBC) production. The anemia starts early in the course of the disease and
becomes more severe as, with the shrinking availability of viable renal mass, the GFR
progressively decreases.

Using data from the National Health and Nutrition Examination Survey (NHANES),
Stauffer and Fan found that anemia was twice as prevalent in people with CKD (15.4%)
as in the general population (7.6%). The prevalence of anemia increased with stage of
CKD, from 8.4% at stage 1 to 53.4% at stage 5.
No reticulocyte response occurs. RBC survival is decreased, and bleeding tendency is
increased from the uremia-induced platelet dysfunction. Other causes of anemia in CKD
include the following:
 Chronic blood loss: Uremia-induced platelet dysfunction enhances bleeding
tendency
 Secondary hyperparathyroidism
 Inflammation
 Nutritional deficiency
 Accumulation of inhibitors of erythropoiesis
Bone disease
Renal bone disease is a common complication of CKD. It results in skeletal
complications (eg, abnormality of bone turnover, mineralization, linear growth) and
extraskeletal complications (eg, vascular or soft-tissue calcification).

Different types of bone disease occur with CKD, as follows:

 High-turnover bone disease from high parathyroid hormone (PTH) levels
 Low-turnover bone disease (adynamic bone disease)
 Defective mineralization (osteomalacia)
 Mixed disease
 Beta-2-microglobulin–associated bone disease

Bone disease in children is similar but occurs during growth. Therefore, children with
CKD are at risk for short stature, bone curvature, and poor mineralization (“renal rickets”
is the equivalent term for adult osteomalacia).

CKD–mineral and bone disorder (CKD-MBD) involves biochemical abnormalities related

to bone metabolism. CKD-MBD may result from alteration in levels of serum
phosphorus, PTH, vitamin D, and alkaline phosphatase.

Secondary hyperparathyroidism develops in CKD because of the following factors:

 Hyperphosphatemia
 Hypocalcemia
 Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-
dihydroxyvitamin D, or calcitriol)
 Intrinsic alteration in the parathyroid glands, which gives rise to increased PTH
secretion and increased parathyroid growth
 Skeletal resistance to PTH

Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus

to PTH synthesis and secretion.

Hyperphosphatemia and hypocalcemia

Phosphate retention begins in early CKD; when the GFR falls, less phosphate is filtered
and excreted, but because of increased PTH secretion, which increases renal excretion,
serum levels do not rise initially. As the GFR falls toward CKD stages 4-5,
hyperphosphatemia develops from the inability of the kidneys to excrete the excess
dietary intake.

Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D

to calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73
m². Increased phosphate concentration also effects PTH concentration by its direct
effect on the parathyroid glands (posttranscriptional effect).

Hypocalcemia develops primarily from decreased intestinal calcium absorption because

of low plasma calcitriol levels. It also possibly results from increased calcium-phosphate
binding, caused by elevated serum phosphate levels.

Increased PTH secretion

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been
demonstrated to independently trigger PTH synthesis and secretion. As these stimuli
persist in CKD, particularly in the more advanced stages, PTH secretion becomes
maladaptive, and the parathyroid glands, which initially hypertrophy, become
hyperplastic. The persistently elevated PTH levels exacerbate hyperphosphatemia from
bone resorption of phosphate.

Skeletal manifestations

If serum levels of PTH remain elevated, a high ̶ bone turnover lesion, known as osteitis
fibrosa, develops. This is one of several bone lesions, which as a group are commonly
known as renal osteodystrophy and which develop in patients with severe CKD. Osteitis
fibrosa is common in patients with ESRD.

The prevalence of adynamic bone disease in the United States has increased, and it
has been described before the initiation of dialysis in some cases. The pathogenesis of
adynamic bone disease is not well defined, but several factors may contribute, including
high calcium load, use of vitamin D sterols, increasing age, previous corticosteroid
therapy, peritoneal dialysis, and increased level of N-terminally truncated PTH
fragments.

Low-turnover osteomalacia in the setting of CKD is associated with aluminum

accumulation. It is markedly less common than high-turnover bone disease.
Another form of bone disease is dialysis-related amyloidosis, which is now uncommon
in the era of improved dialysis membranes. This condition occurs from beta-2-
microglobulin accumulation in patients who have required chronic dialysis for at least 8-
10 years. It manifests with cysts at the ends of long bones.