Uric Acid Nephropathy

(Gouty Nephropathy)
 Uric Acid Nephropathy is a rapidly worsening (decreasing) kidney function
(renal insufficiency) that is caused by high levels of uric acid in
the urine (hyperuricosuria).
 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 into 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, the product of the xanthine oxidase–catalyzed conversion of xanthine and
hypoxanthine, is the final metabolite of endogenous and dietary purine nucleotide
metabolism. It is a weak acid, with a p Ka of 5.75; at a physiologic pH of 7.40 in the
extracellular compartment, 98% of uric acid is 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; 6-10% is secreted, ultimately appearing 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,
the 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 with decreases in glomerular filtration
result from 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, with the pH becoming
progressively more acidic, uric acid precipitation and obstruction in the tubules,
collecting ducts, and even pelves and ureters may result. In animal models of uric
acid nephropathy, the precipitation of uric acid and urate occurs primarily in the
collecting duct system and, to some extent, in the vasa recta.
Crystal deposition causes increased tubular pressure, increased intrarenal pressure,
and extrinsic compression of the small-diameter renal venous network. This causes
an increase in renal vascular resistance and a fall in renal blood flow. The elevated
tubular pressure and decreased renal blood flow cause a decline in glomerular
filtration and can result in acute renal failure.