Uric Acid Nephropathy

Updated: Jun 20, 2023
  • Author: Mark T Fahlen, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Practice Essentials

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, [1] and 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. [2, 3]



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 kidney 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. [1]

The release of intracellular nucleotides leads to severe hyperuricemia. [4] 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 kidney injury.

Chronic urate nephropathy

A widely accepted belief is that the overproduction of uric acid and the presence of hyperuricemia can cause acute kidney injury; however, whether chronic hyperuricemia independently results in chronic interstitial nephritis and progressive kidney disease is less clear.

In patients with chronic hyperuricemia and gout, early studies revealed microtophi formation in the renal medullary interstitium. These deposits were found to contain monosodium urate monohydrate and to be surrounded by a giant cell reaction. Thus, the theory was that urate deposition triggers a foreign body reaction and leads to chronic inflammation and fibrosis. Chronic kidney disease from this process was termed chronic uric acid nephropathy, or gouty nephropathy, and articles from the 1960s suggested that all patients with long-standing gout had gouty nephropathy. However, the existence of a chronic urate nephropathy has since been questioned.

In a study of 11,408 consecutive autopsies in Switzerland, only 37 revealed urate deposits in the kidney and only 3 of those patients had had otherwise unexplained kidney failure. [5] Investigators also found urate deposition in the kidneys of patients without gout, suggesting that this finding is not specific for gout.

In another study, a long-term follow-up evaluation of 524 subjects with gout, the authors concluded that deterioration of kidney function could not be ascribed to hyperuricemia and gout alone. They found that in general, the decline in kidney function could be attributed to other known causes of chronic kidney disease, such as nephropathy not associated with uric acid, renal stones, aging, or hypertension. In summary, little compelling evidence exists that chronic hyperuricemia leads to chronic urate nephropathy. [6]

There continues to be considerable interest and debate, however, on the relationship between hyperuricemia, hypertension, and progressive kidney failure. [7, 8, 9] In several prospective cohort trials, hyperuricemia was identified in subjects with normal kidney function at baseline as an independent risk factor for development of chronic kidney disease. [10, 11, 12, 13]

A newer hypothesis proposes that hyperuricemia may cause impairment of renal autoregulation, leading to hypertension, microalbuminuria and overt albuminuria, and progressive kidney failure. [14] Moreover, epidemiologic studies in Japan have supported a link between hyperuricemia and progressive kidney disease.

The use of allopurinol [15] to lower uric acid levels has been proposed as a means of retarding the progression of chronic kidney disease and of preventing end-stage renal disease. It has been claimed that at least 1 small, prospective clinical trial demonstrated allopurinol's efficacy for this purpose. However, the routine use of allopurinol in chronic kidney disease and asymptomatic hyperuricemia is not considered to be the standard of care, primarily due to the risk and cost of therapy and the lack of a large, randomized, controlled trial demonstrating the efficacy of uric acid reduction in retarding the progression of chronic kidney disease.

There are 2 other situations in which elevated uric acid levels appears to be linked with chronic kidney disease. First, evidence suggests that environmental lead exposure can result in hyperuricemia, gout, hypertension, and chronic kidney disease. [16] Lead exposure may affect urate excretion by the kidney, leading to chronic hyperuricemia and kidney disease. Whether hyperuricemia is the key mechanism for lead-related nephrotoxicity is not clear, however.

Second, chronic hyperuricemia clearly leads to kidney failure in persons with a congenital absence of hypoxanthine guanine phosphoribosyltransferase (HGPRT), a condition that is also known as Lesch-Nyhan syndrome. In this rare X-linked disorder—which also includes mental retardation, involuntary movement, and self-mutilation—chronic uric acid overproduction causes hyperuricemia and uricosuria. The incidence of chronic kidney disease is high in these individuals, who have intratubular uric acid deposits and interstitial urate deposits.

Uric acid nephrolithiasis

Uric acid stones, which represent 5-10% of all renal calculi in the United States population, also result from uric acid precipitation in the collecting system. Uric acid stones are related to uric acid exceeding its solubility in the urine; thus, patients with hyperuricosuria have an increased risk of uric acid nephrolithiasis. Urine oversaturation with uric acid and subsequent crystal formation is determined largely by urinary pH. Individuals who form uric acid stones tend to excrete less ammonium, which contributes directly to low urinary pH. In addition, persons with gout and those who form stones, in particular, have a reduced postprandial alkaline tide (alkaline urinary pH). [17, 18]



Most cases of acute uric acid nephropathy occur during treatment for leukemia or lymphoma. Uric acid nephropathy is observed more commonly in persons with an acute leukemia than in persons with a chronic form of the disease. It also has been described in association with other malignancies, such as metastatic breast carcinoma, bronchogenic carcinoma, and disseminated adenocarcinoma.

Seizures or ischemic states can lead to extensive release of cell metabolites and consequent hyperuricemia.

Hyperuricemic acute kidney injury has also been reported during pregnancy-related preeclampsia [19]  or eclampsia, as well as in the setting of cyclosporine use and kidney transplantation.

Chronic hyperuricemia and gout are the only causes of chronic urate nephropathy, if it exists as a clinical entity. Uric acid stones develop in 20% of people with gout.

The hereditary enzyme disorder HGRPT deficiency, which leads to overproduction of urate, is an indisputable cause of a chronic urate nephropathy leading to kidney insufficiency. 

Uric acid nephrolithiasis can be caused by any underlying disorder that causes hyperuricosuria. This includes all of the previously mentioned causes of acute uric acid nephropathy, such as malignancy, hypercatabolic states, and the hereditary enzyme deficiencies.

Acute diarrheal states may increase urinary uric acid concentration through excessive water loss and dehydration, leading to stone formation. Urinary pH also tends to decrease with extracellular volume contraction, and gastrointestinal bicarbonate loss may contribute to the acidic urine, thus promoting stone formation. Aspirin and probenecid augment uric acid secretion and may lead to stone formation, especially in people with a purine-rich diet.



The incidence rate of acute uric acid nephropathy is not known. However, some deterioration in renal function secondary to hyperuricemia has been estimated to occur in as many as 10% of patients with leukemia and lymphoma who have undergone intensive chemotherapy and radiation. With prophylactic therapy, however, the occurrence of renal failure requiring dialysis due to acute uric acid nephropathy now appears to be quite rare.

Although chronic urate nephropathy was once thought to be common, studies have indicated that the condition is actually very rare; in fact, its very existence has come into question.

The annual incidence of all renal calculi is 124 cases per 100,000 population. The exact prevalence of uric acid calculi is unknown, but in the United States, the prevalence of all renal calculi in men is 4-9%, and in women is 1.7-4.1%. Uric acid calculi account for 5-10% of all stones in the United States.

Uric acid stones are more common in patients with gout, and the chance of stone formation increases with increasing serum urate levels and urine excretion rates. In one series, 35% of patients with gout who had urinary uric acid levels of 700-1100 mg/d had uric acid calculi; the overall prevalence in persons with primary gout is estimated to be 22%. In a retrospective series, the annual incidence rate of stones in patients with newly diagnosed gout was 1 case per 114 patients.

Reported rates vary widely in other countries. In one report from Israel, 75% of all stones were uric acid calculi.

In the United States, the prevalence rate is 4-9% in men and 1.7-4.1% in women. Uric acid nephrolithiasis occurs most frequently in those with underlying hyperuricemia or gout, which occurs in men more frequently than women by a male-to-female ratio of 4:1 and has a peak incidence in the fifth decade of life. Uric acid nephropathy has been well documented in the pediatric and adult populations. It may occur more often in pediatric patients because of the increased incidence of acute lymphoblastic leukemia and Burkitt lymphoma in this population. 



Prior to the dialysis era, treatment of acute uric acid nephropathy was not very successful, with mortality rates approaching 50%. With the use of modern treatment, including prophylaxis and dialysis, uric acid nephropathy is rare. Additionally, when it does occur, the prognosis for acute kidney failure is excellent.

The morbidity of uric acid nephrolithiasis arises from the manifestations of stones, obstruction, and crystalluria and is often accompanied by dysuria and hematuria. [20]  Secondary bacteriuria and pyelonephritis also can occur. However, life-threatening complications are rare.