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End-stage renal disease (ESRD) is the irreversible loss of renal function, resulting in the accumulation of toxins and the loss of internal homeostasis. Uremia, the clinical syndrome resulting from ESRD, is universally fatal without some form of renal replacement therapy. At present, renal replacement therapy consists of two basic modalities: renal transplant and dialytic therapy, either hemodialysis or peritoneal dialysis (PD).

Hemodialysis is the initial therapy in the vast majority of new cases of adult ESRD, with a few starting PD and an even smaller number receiving predialytic renal transplants. The proportions are reversed in children, with most children receiving transplants. More than 90,000 Americans await a renal transplant, with a median time of 2.6 years on a transplant wait list.

Approximately half of hemodialysis and PD patients will be alive 3 years after starting therapy, with cardiac causes accounting for about half of all deaths. Infections trigger death in up to a quarter of patients, with cerebrovascular events and malignancy being other causes.


Uremia, contamination of the blood with urine, differs from azotemia, the buildup of nitrogen in the blood. Renal failure assumes many forms, often co-existing.

Excretory failure leads to elevated levels of >70 chemicals in uremic plasma, which gives rise to the hypothesis that these toxins, individually or in combination, cause uremic organ dysfunction and produce the symptoms of uremia. Urea is not the major toxin, and potential uremic toxins include cyanate, guanidine, polyamines, and β2-microglobulin.1 If uremia were simply a toxidrome, then dialysis would reverse all its untoward effects; however, it does not, in part because many toxins are highly protein bound and nondialyzable.2 Because many uremia-related organ dysfunctions persist after dialysis, other processes are clearly important.

Biosynthetic failure refers to the aspects of uremia caused by loss of the renal hormones 1,25(OH)2-vitamin D3 and erythropoietin. The kidneys are primarily responsible for the secretion of erythropoietin and 1α-hydroxylase, which is necessary to produce the active form of vitamin D3. Because 85% of erythropoietin is produced in the kidneys, ESRD patients have depressed levels of erythropoietin, which contributes to anemia. Vitamin D3 deficiency results in decreased GI calcium absorption, inducing secondary hyperparathyroidism, leading to renal bone disease.

Regulatory failure results in an oversecretion of hormones, leading to uremia by disruption of normal feedback mechanisms. The uremic state produces excess free oxygen radicals, which react with carbohydrates, lipids, and amino acids to create advanced glycation end products, linked to atherosclerosis and amyloidosis in ESRD patients.3 This may explain the progressive nature of the atherosclerosis and amyloidosis seen in ESRD patients.4


Uremia is a clinical syndrome, and no single symptom, sign, or laboratory test result reflects all aspects of uremia. Although a ...

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