Excerpt from Nephropathy, Uric Acid

Synonyms, Key Words, and Related Terms: uric acid nephropathy, urate nephropathy, tumor lysis syndrome, TLS, gouty nephropathy, uric acid nephrolithiasis, hyperuricemia, gout nephropathy, kidney disease, renal disease, renal disorder, kidney disorder, renal calculi, renal calculus, kidney stone, chemotherapy reaction, chemotherapy complication, uric acid nephrolithiasis, urate nephrolithiasis, cancer treatment reaction, leukemia treatment reaction, lymphoma treatment reaction, hyperuricemia, dialysis, chemotherapeutic reaction, HGPRT syndrome, HGPRT deficiency, Lesch-Nyhan syndrome

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Background: Uric acid is the relatively water-insoluble end product of purine nucleotide metabolism. It poses a special problem for humans because of its limited solubility, particularly in the acidic environment of the distal nephron of the kidney. It is problematic because humans do not possess the enzyme uricase, which converts uric acid to the more soluble compound allantoin. Three forms of kidney disease have been attributed to excess uric acid: acute uric acid nephropathy, chronic urate nephropathy, and uric acid nephrolithiasis. These disorders share the common element of excess uric acid or urate deposition, although the clinical features vary.

Pathophysiology:

Properties of uric acid

Uric acid is the final metabolite of endogenous and dietary purine nucleotide metabolism. It is the product of xanthine oxidase–catalyzed conversion of xanthine and hypoxanthine. It is a weak acid with a pKa of 5.75, and, at a physiologic pH of 7.40 in the extracellular compartment, 98% of uric acid is thus in the ionized form as urate. In the collecting tubules of the kidneys, where the pH can fall to 5.0, uric acid formation is favored.

The critical physical property of uric acid in the clinical setting is solubility. Uric acid is less soluble than urate; thus, an acidic environment decreases solubility. Plasma at a pH of 7.40 is saturated with urate at a concentration of 7 mg/dL. Because normal plasma levels of urate are 3-7 mg/dL for men and 2-6 mg/dL for women, the solubility limit apparently is approached under physiologic conditions. Of the uric acid produced daily, the biliary and gastrointestinal tracts excrete 30% and the kidney excretes 70%.

Renal handling of urate

Renal excretion of uric acid involves 4 pathways—filtration, reabsorption, secretion, and postsecretory reabsorption. Urate is freely filtered at the glomerulus. An active anion-exchange process in the early proximal convoluted tubule reabsorbs most of it. Most urinary uric acid appears to be derived from tubular secretion, possibly from the S2 segment of the proximal tubule. Overall, 98-100% of filtered urate is reabsorbed and 6-10% is secreted and ultimately appears in the final urine.

Several factors influence the renal handling of urate. Many medications can affect the renal transport of uric acid through effects of proximal tubular absorption and secretion. Extracellular volume expansion or contraction, respectively, enhances or reduces uric acid excretion through the paired movement of sodium; consequently, in cases of extracellular compartment depletion, urate excretion is diminished.

Physiologically, the major factors that affect urate excretion are the tubular fluid pH, tubular fluid flow rate, and renal blood flow. The first 2 factors primarily diminish uric acid and urate precipitation in the collecting ducts, while the third is important in urate secretion. In disorders such as sickle cell disease, hypertension, and eclampsia, hyperuricemia out of proportion to decreases in glomerular filtration are a result of decreased renal blood flow. Organic acids, such as lactic acid and ketoacids, also can impair the proximal secretion of uric acid.

Acute uric acid nephropathy

Overproduction of uric acid occurs primarily when tissue breakdown is accelerated. Acute uric acid nephropathy is the term applied to the development of acute oligoanuric renal failure caused by renal tubular obstruction by urate and uric acid crystals. This is observed almost exclusively in the setting of malignancy, especially leukemia and lymphoma, in which rapid cell turnover or cell lysis occurs from chemotherapeutic agents or radiation therapy.

The release of intracellular nucleotides leads to severe hyperuricemia. When urate is filtered at exceedingly high concentrations from the plasma and is further concentrated through the course of the tubular system wi .....