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CHRONIC KIDNEY DISEASE
Definition
Chronic kidney disease (CKD) refers to the myriad problems that follow loss of kidney function. It
results from a large number of diseases that either are systemic and damage the kidney or are
intrinsic to the kidney ( Table 131-1 ). CKD has two characteristics. First, there is chronicity
because the kidney damage of CKD is rarely repaired and loss of function persists, unlike the
course of acute kidney failure. Second, loss of kidney function generates even more kidney
damage so that CKD progressively worsens even if the disorder that caused it becomes inactive.
CKD is the preferred term because another widely used one, chronic renal failure or insufficiency,
is not as easily identifiable by patients as a disorder that affects the kidney. In addition, chronic
renal failure suggests that the kidneys have lost all of their function, whereas CKD covers the
spectrum of clinical problems beginning with abnormalities detectable only by laboratory testing to
a late stage, labeled uremia. Uremia literally means “urine in the blood” and represents the toxic
state principally resulting from accumulation of unexcreted waste products derived from
metabolism of protein. When the kidney fails to perform most of its function, the clinical state is
labeled end-stage renal disease (ESRD), and dialysis or transplantation is required to sustain life.
The progressive and chronic nature of CKD is emphasized because treatment can slow or even
halt the loss of kidney function, and many symptoms of uremia can be ameliorated or eliminated.
TABLE 131-1
-- CAUSES OF CHRONIC RENAL FAILURE
Diabetic glomerulosclerosis[*]
Hypertensive nephrosclerosis
Glomerular disease
Glomerulonephritis
Amyloidosis, light chain disease[*]
[*]
Systemic lupus erythematosus, Wegener's granulomatosis
Tubulointerstitial disease
Reflux nephropathy (chronic pyelonephritis)
Analgesic nephropathy
Obstructive nephropathy (stones, benign prostatic hypertrophy)
Myeloma kidney[*]
Vascular disease
Scleroderma[*]
Vasculitis[*]
Renovascular renal failure (ischemic nephropathy)
Atheroembolic renal disease[*]
Cystic diseases
Autosomal dominant polycystic kidney disease
Medullary cystic kidney disease
*
Systemic disease involving the kidney.
Epidemiology
The increase in the number of patients with ESRD in the United States and other industrialized
countries has features of an epidemic. For example, the number of patients with ESRD in the
United States increased by an average of 5% between 1980 and 1990, and the incidence of ESRD
was 219 per million population in 1991 but grew to 334 per million by 2000. A recent assessment
suggests that the rate of increase of patients with ESRD is falling to an annual increase of 1% or
less, possibly because of the emphasis on earlier detection of CKD and aggressive treatment of
hypertension and especially more widespread treatment with blockers of the
renin-angiotensin-aldosterone system (see later).
Population-based studies such as the National Health and Nutrition Survey, a cross-sectional
survey of U.S. adults, have uncovered the magnitude of the CKD problem ( Table 131-2 ).
Approximately 8 million persons are afflicted with stage 3 or stage 4 CKD and hence are at high
risk of progressive kidney failure. Two disorders account for almost 70% of all new ESRD patients;
in 2003, 44.8% had diabetes mellitus and 27.1% had hypertension-induced kidney damage. The
populations experiencing the highest incidence were the elderly (i.e., >65 years) and African
Americans plus Native and Asian Americans. The reasons for the racial susceptibility to CKD are
unknown. Besides a racial susceptibility, groups that have been identified as being at high risk for
progressing from CKD to ESRD are those with hypertension, diabetes mellitus, or cardiovascular
disease and those with family members who have ESRD. Other epidemiologic factors that have
been identified as increasing the risk of progressive CKD include smoking, albuminuria, obesity,
and hyperlipidemia. The presence of any of these factors should be sought and attempts made to
correct them in treating a patient with CKD.
TABLE 131-2
-- STAGES OF CHRONIC KIDNEY DISEASE (CKD) WITH PROJECTED NUMBERS
OF INDIVIDUALS AND THE FREQUENCY OF COMPLICATIONS
GFR[*]
Stage Description
1
Chronic kidney damage with
(mL/min/1.73 m2)
>90
Projected
Number (×1000) Symptoms or Signs
5900
normal or increased GFR
Anemia 4%
Hypertension 40%
5-year mortality 19%
2
Mild GFR loss
60–89
5300
Anemia 4%
GFR[*]
Stage Description
Projected
2
(mL/min/1.73 m )
Number (×1000) Symptoms or Signs
Hypertension 40%
5-year mortality 19%
3
Moderate GFR loss
30–59
7600
Anemia 7%
Hypertension 55%
5-year mortality 24%
4
Severe GFR loss
15–29
400
Hyperphosphatemia
20%
Anemia 29%
Hypertension 77%
5-year mortality 46%
5
Kidney failure
<15 or dialysis
300
Hyperphosphatemia
50%
Anemia 69%
Hypertension >75%
3-year mortality 14%
Scr = serum creatinine.
*
The formula for estimating the glomerular filtration rate (GFR) of adults with CKD is derived from data
obtained during the National Institutes of Health Mod-ification of Diet in Renal Disease trial. GFR 186 ×
[SCr]-1.154 × [age]-0.203 × [0.742 if patient is female] × [1.212 if patient is black].
Pathophysiology
Physiologic and metabolic functions of the kidney include the regulation of ion concentrations in the
extracellular and intracellular fluids, the regulation of blood pressure, the regulation of several
endocrine functions, and the excretion of waste products ( Table 131-3 ). The breadth of these
functions yields several predictable and some unpredictable consequences of CKD. For example,
it is predictable that limitation of the ability to excrete acid would cause hyperventilation and a
decrease in Pco2, but acidosis also causes less easily predictable losses of muscle mass and bone
disease. Although changes in bone metabolism could be predicted from impaired excretion of
calcium and phosphates, the discovery that the rate of parathyroid hormone (PTH) secretion varies
with activation of calcium-sensitive receptors on parathyroid cells as well as the actions of vitamin
D was not predictable. To understand the complex pathophysiologic process of CKD, certain
principles must be integrated.
TABLE 131-3
-- FUNCTIONS OF THE KIDNEY AND PROBLEMS DUE TO IMPAIRMENT OF
KIDNEY FUNCTIONS IN PATIENTS WITH CHRONIC KIDNEY DISEASE
Kidney Functions
Consequences of Dysfunction
Maintain concentrations and
Hyponatremia, hyperkalemia, low total potassium content,
body contents of electrolytes
hypocalcemia, hyperphosphatemia, decreased tolerance to electrolyte
and fluid volumes
or mineral loading
Regulate blood pressure
Hypertension, cardiovascular disease
Endocrine mediators
Anemia (low erythropoietin), hypertension (renin system activation),
bone disease (secondary hyperparathyroidism), low vitamin D
activation, prolonged half-lives of peptide hormones (e.g., insulin)
Waste product excretion
Anorexia, nausea, soft tissue deposition of oxalates and phosphates,
neurologic dysfunction, loss of muscle protein
Balance and Steady-State Considerations
The first principle, balance, is the condition in which the intake or production of a substance equals
its elimination. For example, a loss of nephrons impairs the ability to excrete sodium, but there is
an adjustment by the remaining nephrons to excrete a greater fraction of the sodium that is filtered
by each glomerulus. Similar phenomena occur with other ions and substances, allowing the patient
with CKD to avoid accumulation of sodium or potassium, for example. The ability to achieve
balance has a limit, however, and when this limit is reached, ions and other molecules destined for
excretion by the kidney will instead accumulate unless the intake or production of the retained ion
or compound is reduced.
A related concept is that of the steady state. A patient is in the steady state when the intake or
processes of production and elimination are not changing. Although a patient in balance is also in
the steady state, the converse is not necessarily true. A patient can be in the steady state but not
be in balance because he or she is gaining or losing an ion or compound at a constant rate. For
example, if nitrogen intake is less than the excretion of nitrogen, a patient will be losing protein
stores. Such a patient would be in the steady state but in negative nitrogen balance.
The Tradeoff Hypothesis
The second important principle, the tradeoff hypothesis, is that a patient with CKD will achieve
balance by activating pathophysiologic responses, but the responses lead to a tradeoff that has the
potential of causing adverse consequences. A classic example is the responses activated in CKD
to achieve sodium balance. CKD initially reduces salt excretion, leading to sodium retention and
expansion of extracellular fluid. The result is high blood pressure. Although a higher blood pressure
is beneficial because it increases the filtration and excretion of sodium, the tradeoff for maintaining
sodium balance is persistent hypertension. There is experimental evidence that another
adjustment that can prevent salt accumulation is an increase in circulating inhibitors of
Na+,K+-ATPase in patients with CKD. These inhibitors increase the sodium concentration in tubular
cells, thereby reducing the ability of the cell to reabsorb filtered sodium. The tradeoff for the ability
to increase sodium excretion is that some patients with CKD will not tolerate an abrupt decrease in
sodium intake, and persistent sodium excretion will lead to a fall in extracellular volume, impaired
perfusion of the kidney, and a decrease in glomerular filtration rate (GFR).
Another CKD tradeoff occurs in response to a decreased ability to excrete potassium. The rise in
serum potassium stimulates adrenal aldosterone production, which stimulates potassium excretion
by both the damaged kidney and the colon. The tradeoff for this adaptation is an increase in blood
pressure caused by aldosterone-mediated sodium retention.
The most intensely studied tradeoff is the adaptation to phosphate retention. When CKD limits the
kidney's ability to excrete phosphates, they accumulate in extracellular and intracellular fluids. For
example, CKD patients given a challenge dose of phosphates develop supranormal blood
phosphorus levels. Accumulated phosphates form calcium-phosphate complexes and decrease
the circulating concentration of ionized calcium. This in turn stimulates the production and release
of PTH, a beneficial response because it suppresses the reabsorption of phosphates by the
proximal tubule. The subsequent increase in phosphate excretion leads to a rise in ionized calcium,
but the tradeoff is that the new steady state is maintained only as long as circulating PTH
concentration is high ( Fig. 131-1 ). The tradeoff is stimulation of osteoclastic activity in bone that
accelerates release of minerals, leading to uremic bone disease ( Chapter 132 ). It follows that
restriction of phosphates in the diet plus the use of phosphate binders to increase gastrointestinal
excretion of phosphates will eliminate the increase in circulating PTH concentration. This has been
demonstrated experimentally and in CKD patients.
FIGURE 131-1 A decrease in glomerular filtration rate (GFR) is followed by
an increase in serum phosphorus and a decrease in serum calcium. An
increase in serum parathyroid hormone (PTH) returns phosphorus and calcium to
normal levels.
Hypertension
Hypertension, like anemia, is almost universal in CKD patients and often is the first sign of CKD.
The coincidence of CKD and high blood pressure is particularly important because hypertension
contributes to the development of cardiovascular disease, the leading cause of morbidity and
mortality in CKD patients. Hypertension in CKD patients is mainly the result of an expanded
extracellular volume from a salt-rich diet and a decreased capacity for excretion of sodium. As
discussed earlier, the normal response to an increase in the extracellular volume is a rise in blood
pressure that stimulates sodium excretion to achieve a balance between sodium intake and the
excretion of salt. In the steady state, however, salt balance can be maintained only as long as
blood pressure is high unless dietary salt is restricted and diuretics are used to increase sodium
excretion. Two practical implications arise from these relationships. First, they reveal why
treatment of hypertensive patients with vasodilating drugs alone is frequently unsuccessful. When
vasodilator drugs reduce blood pressure, the fall in sodium excretion leads to sodium retention and
expansion of extracellular volume that raises blood pressure. Second, they explain why control of
the amount of salt in the diet is required even when diuretics are used to treat hypertension in CKD
patients. A salt-rich diet can cancel the benefits of using diuretics, ultimately leading to expansion
of extracellular volume and reappearance of hypertension.
Another mechanism for hypertension in CKD patients is activation of the
renin-angiotensin-aldosterone (RAA) system and the sympathetic nervous system. Evidence for
activation of the RAA system in CKD patients includes circulating levels of renin and aldosterone
that are too high for individuals who are hypertensive, suggesting that the vasoconstrictive action of
angiotensin II and the salt retention induced by aldosterone contribute to hypertension ( Table
131-4 ). Other evidence includes the beneficial effects of inhibitors of the RAA system in reducing
kidney damage and slowing the loss of kidney function. Evidence for activation of the sympathetic
nervous system includes higher circulating levels of norepinephrine and the detection of increased
sympathetic nerve activity in certain dialysis patients. The sympathetic nervous system not only
causes vasoconstriction but also can suppress nitric oxide production in CKD patients. Finally,
patients with hypertension frequently have serum uric acid values in the upper range of normal or
at supranormal levels. Experimentally, a high uric acid level can cause vascular damage,
suggesting that uric acid could play a role in the genesis of hypertension in CKD. The close
association between CKD and hypertension (see Table 131-2 ) and the damaging effects of
hypertension are the reasons that subjects with persistent hypertension (especially those with
hypertension and diabetes or other systemic diseases) should be examined yearly for evidence of
kidney damage.
TABLE 131-4
[*]
-- ANGIOTENSIN II RESPONSES IN CHRONIC KIDNEY DISEASE
Hemodynamic responses
Systemic hypertension
Vasoconstriction
Salt retention (aldosterone)
Intraglomerular hypertension
Efferent arteriolar vasoconstriction
Nonhemodynamic responses in the kidney
Macrophage infiltration and inflammation
Interstitial matrix accumulation
Increased transforming growth factor-β
Increased plasminogen activator inhibitor type 1
Increased aldosterone
*
The proposed actions of angiotensin II that can contribute to the development of cardiovascular
disease and progressive loss of kidney function.
Endocrine Disorders
The mechanisms causing bone disease in CKD patients include abnormalities in endocrine
responses other than stimulation of PTH secretion. Vitamin D is activated by repeated
hydroxylations of the parent molecule, cholecalciferol or vitamin D3. The initial hydroxylation occurs
in the liver, forming 25-hydroxyvitamin D3. Although 25-hydroxyvitamin D3 can influence the
function of muscle and other organs by poorly defined mechanisms ( Chapter 132 ), it mainly serves
as a substrate for a second hydroxylation at the 1α position to form 1,25-dihydroxyvitamin D3, the
most active form of vitamin D. This critical step is catalyzed by 1α-hydroxylase activity in the
proximal tubule of the kidney, so loss of kidney function results in decreased function of
1,25-dihydroxyvitamin D3, including lower absorption of calcium and phosphorus by the
gastrointestinal tract and reduced suppression of PTH secretion. The decrease in phosphate
absorption plus the persistent stimulation of renal phosphate excretion by the action of PTH
accounts for the low values of serum phosphorus that are measured in blood samples obtained
after an overnight fast. These considerations indicate why vitamin D should not be given to CKD
patients with high serum phosphorus levels. Stimulation of gastrointestinal calcium and phosphate
absorption can cause hypercalcemia and, by stimulating the accumulation of phosphates, will
initiate the mechanisms that raise circulating PTH concentration (see earlier).
Decades ago, it was shown that CKD causes insulin resistance by reducing the ability of insulin to
stimulate glucose uptake by muscle and other organs ( Chapter 248 ). This leads to an increase in
circulating insulin concentration, even in CKD patients without type 2 diabetes. In insulin-resistant
CKD patients, insulin has been shown to interact normally with its receptor, so the failure to
stimulate glucose metabolism is due to a post-receptor defect in cell signaling. The abnormality in
insulin-stimulated cell signaling mechanisms is controversial; one possibility is decreased ability to
activate phosphatidylinositol 3-kinase and its downstream kinase, Akt. Reduced function of these
enzymes in muscle cells impairs the metabolism of both glucose and protein. Clinically, the insulin
resistance of nondiabetic CKD patients is rarely associated with blood glucose levels above 200
mg/dL. In fact, blood glucose concentration is usually normal or only slightly high because insulin
secretion rises to overcome defects in cell signaling.
One possible initiator of insulin resistance is metabolic acidosis, a frequent complication of CKD.
Metabolic acidosis will impair insulin-stimulated glucose uptake in normal adults, and it causes loss
of muscle protein, an insulin-sensitive metabolic function. Metabolic acidosis can contribute to
other CKD-induced endocrine abnormalities; it impairs the ability of growth hormone to stimulate
insulin-like growth factor 1. When this is combined with impaired metabolism of bone minerals, it
contributes to the impaired growth of children with CKD. Metabolic acidosis also impairs thyroid
function by increasing thyroid-stimulating hormone and depressing circulating levels of thyroxine
(T4) and triiodothyronine (T3); similar changes are present in the sick euthyroid syndrome ( Chapter
244 ). Metabolic acidosis should be eliminated because its correction largely eliminates these
abnormalities in CKD patients.
Another impaired kidney function that affects a patient's endocrine status is the ability to degrade
small proteins, including several hormones. For example, diabetic patients treated with their usual
dose of insulin can develop hypoglycemia with progressive loss of kidney function because the
damaged kidney does not remove enough of the injected insulin. This same function also affects
interpretation of circulating PTH concentrations because the damaged kidney leads to
accumulation of different fragments of PTH; it is important to know whether the PTH level being
measured is the active or one of the inactive fractions of PTH.
In patients with advanced CKD, normochromic, normocytic anemia is almost universal, principally
due to another endocrine abnormality, impaired production of erythropoietin by the kidney. Anemia
can often be detected in patients with stage 2 CKD who have lost 50% or more of their GFR and
have serum creatinine values that are just outside of the normal range. Erythropoietin is produced
by interstitial cells in the kidney, and loss of kidney function reduces its production, causing
decreased erythropoiesis. Other factors contributing to anemia are a shortened half-life of
erythrocytes and vitamin deficiencies. Fortunately, administration of the recombinant hormone
erythropoietin eliminates the anemia of CKD. This is therapeutically important because correction
of anemia can suppress the development of left ventricular hypertrophy and other factors that
contribute to the cardiovascular disease that is so prevalent in CKD patients. The major reasons for
an impaired response to erythropoietin are iron deficiency and inflammation, and these should be
corrected to achieve optimal responses to erythropoietin therapy ( Chapter 160 ).
Accumulation of Uremic Toxins
The protein in protein-rich foods is metabolized to amino acids that can be used to build body
protein stores ( Fig. 131-2 ). The other fate of amino acids is the formation of urea and other
potentially toxic products that must be excreted. Besides amino acids, protein-rich foods contain
phosphates, sodium, potassium, acid, and other ions that must be eliminated. The principal
nitrogen-containing waste product derived from protein metabolism is urea. When a patient is in
protein balance, the net production of urea is directly proportional to the amount of protein in the
diet; but if a patient is in negative nitrogen balance, urea and other waste products and ions arise
from the breakdown of the body stores of protein. It follows that treatment should be directed at
maintaining neutral protein balance at the lowest rate of urea production. More than 135 years ago,
it was noted that symptoms of uremia in patients with advanced CKD are ameliorated by reducing
the amount of protein in the diet.
FIGURE 131-2 Breakdown of dietary protein enlarges the pool of
essential and nonessential amino acids that can be used to synthesize
body protein. The amino acids are also used to produce urea, which must be
excreted. Besides nitrogenous waste products, dietary protein catabolism
yields inorganic ions that must be excreted.
The consequences of accumulating ions and uremic toxins include the development of symptoms
and problems that involve several organs, including the nervous system, the gastrointestinal
system, and the skin ( Table 131-5 ). For example, phosphate accumulation leads to secondary
hyperparathyroidism and bone disease (see earlier discussion). Acid accumulation contributes to
the bone disease of CKD but also stimulates the breakdown of muscle protein and contributes to
hypoalbuminemia. Accumulation of peptides, also known as middle molecules, is associated with
disorders that range from anorexia to neurologic abnormalities. Accumulation of indoxyl sulfate, a
product of tryptophan metabolism, has been linked to progressive kidney damage;
guanidine-containing compounds are associated with neurologic damage. Ideally, the levels of
these uremic toxins should be monitored, but measuring the levels of individual products is
complicated and impractical. The production of urea, however, is directly proportional to the
production of other waste products because urea is the principal end product of protein metabolism
(see Fig. 131-2 ). For this reason, the production of all waste products is approximated by the
24-hour excretion of urea nitrogen as long as the patient is in the steady state (i.e., the serum urea
nitrogen [SUN] concentration and body water are stable). The corollary is that the production of
urea should be kept to a minimum that is consistent with maintaining body protein stores (see
later).
TABLE 131-5
-- UREMIA RESULTS FROM THE DYSFUNCTION OF MANY ORGANS
SUGGESTING GENERALIZED TOXICITY
Affected System Cause or Mechanism
Clinical Syndrome
Systemic
Anemia, inflammation
Fatigue, lassitude
Hyperparathyroidism,
Rash, pruritus, metastatic calcification
symptoms
Skin
calcium-phosphate deposition
Cardiovascular
Hypertension, anemia,
disease
homocysteinemia, vascular
Atherosclerosis, heart failure, stroke
calcification
Serositis
Unknown
Pericardial or pleural pain and fluid, peritoneal
fluid
Gastrointestinal
Unknown
Anorexia, nausea, vomiting, diarrhea,
gastrointestinal tract bleeding
Immune system
Leukocyte dysfunction,
Infections
depressed cellular immunity
Endocrine
Neurologic
Hypothalamic-pituitary axis
Amenorrhea, menorrhagia, impotence,
dysfunction
oligospermia, hyperprolactinemia
Unknown
Neuromuscular excitability, cognitive dysfunction
progressing to coma, peripheral neuropathy
(restless leg syndrome or sensory deficits)
Progression of Chronic Kidney Disease
Persistence of diseases affecting the kidney (e.g., diabetes or inflammatory conditions such as
systemic lupus erythematosus) is one factor in the progression of CKD, but other mechanisms
progressively damage the kidney in most CKD patients even when the disease that initially
damaged the kidney is no longer active. Mechanisms that have been associated with progression
of CKD include kidney damage from systemic hypertension, hemodynamic injury to the kidney,
proteinuria, and nephrotoxic injury.
Hypertension is suspected to cause progressive loss of kidney function (i.e., progression of CKD)
for several reasons. First, hypertension alone can damage the kidney; malignant hypertension
damages the endothelial cells of the afferent arteriole and the glomerulus and can even cause
thrombosis in these vessels. Second, chronic hypertension is frequently associated with diffuse
ischemic injury to the glomerulus and can include collapse of glomerular vessels. The presumed
mechanism of progressive kidney damage is direct transmission of the increased blood pressure to
the afferent arteriole and the glomerulus, leading to glomerulosclerosis. The degree of
hypertension has been directly correlated with the rate of loss of kidney function, and in a
multicenter trial, effective treatment of hypertension was associated with slowing of CKD
progression. The important question is whether hypertension is a factor contributing to progression
or the principal mechanism causing kidney damage. The answer to this question is unsettled. For
example, when African American patients with hypertension and kidney disease were studied,
progression of CKD continued despite a lowering of blood pressure. Regardless, the close
association between the presence of hypertension and the development of cardiovascular
diseases mandates control of blood pressure. In multicenter, randomized trials of CKD patients
with type 1 or type 2 diabetes or with nondiabetic nephropathy, the major class of drugs with
proven effectiveness was the inhibitors of the RAA system, including angiotensin-converting
enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). The benefits of ACEi or ARB
on progression of CKD are additive to their blood pressure–lowering effects.
The association between hypertension and progression extends to another proposed mechanism
of progressive glomerular damage (see Table 131-4 ). The mechanism is based on preferential
constriction of the glomerular efferent arteriole to a greater extent than in the afferent arteriole. This
imbalance in arteriolar vasoconstriction increases intracapillary pressure to raise filtration (the
hyperfiltration mechanism), but the tradeoff for the increase in GFR is damage to glomerular
capillaries. Angiotensin II is the mediator of preferential efferent arteriolar constriction, and
experimentally, ACEi or ARB administration can prevent both hyperfiltration and damage to the
kidney.
The benefits of ACEi or ARB involve more than correction of hyperfiltration. For example,
angiotensin II has growth factor properties, and it activates transforming growth factor-β,
plasminogen activator inhibitor type 1, and other cytokines, aggravating interstitial damage to the
kidney (see Table 131-4 ). It is also suspected that another product stimulated by angiotensin II,
aldosterone, contributes to the development of interstitial damage and collagen deposition.
Because ACEi and ARB have been demonstrated to slow the loss of kidney function in patients
with diabetes and other types of CKD, they should be considered a major strategy to treat
progressive CKD.
It has been repeatedly demonstrated that ACEi or ARB will reduce albuminuria, presumably by
decreasing albumin filtration. This is relevant because experimental evidence suggests that
albumin or some component of albumin (e.g., lipids or molecules attached to albumin) is toxic to
kidney cells. In these experiments with cultured kidney cells, application of albumin increased the
expression of cytokines and damage to the cells. In addition, patients with the greatest amounts of
albumin in the urine also have the most rapid loss of kidney function, and when the degree of
albuminuria is reduced, the loss of kidney function generally slows. These observations raise the
possibility that albumin is a major cause of progressive kidney damage. The shortcoming of
focusing on albuminuria as the principal cause of progressive kidney damage is that many kidney
diseases initiate albuminuria, and as the kidney damage increases, the degree of albuminuria rises.
It is possible, therefore, that reducing albuminuria may simply reflect correction or suppression of
the mechanism damaging the kidney rather than blocking the ability of albumin to induce kidney
damage.
Other proposed mechanisms for progression of CKD can be grouped under a general heading of
nephrotoxic damage. It has been known for more than 60 years that animals fed a high-protein diet
have more evidence of hypertension and more severe kidney damage, but why this occurs is
controversial. Ions or molecules suspected of exerting toxic effects include phosphates and
oxalates that lead to deposition of calcium-phosphate or calcium-oxalate salts and toxic responses
in the interstitium of the kidney. Other candidates include indoxyl sulfate, generated during the
metabolism of the amino acid tryptophan. The mechanisms proposed to explain the toxicity of
these ions and compounds include direct damage to kidney cells and stimulation of cytokines (e.g.,
transforming growth factor-β) and inflammatory pathways that result in damage and fibrosis in the
kidney. It has been difficult to assign all of the abnormalities in progressive kidney disease to a
single factor.
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