Uric acid kidney diseases

INTRODUCTION — There are three different types of kidney disease induced by uric acid or urate crystal deposition: acute uric acid nephropathy, chronic urate nephropathy, and uric acid nephrolithiasis [1]. The first two disorders will be reviewed here, while uric acid nephrolithiasis is discussed separately. (See "Kidney stones in adults: Uric acid nephrolithiasis".)

Uric acid is a weak organic acid and exists in one of two forms in biological systems, depending upon the prevailing pH (see "Kidney stones in adults: Uric acid nephrolithiasis"): the sparingly soluble undissociated uric acid form (the most highly represented form when the pH is less than 5.5, which can occur in the urine), and the substantially more soluble urate anion form (the most highly represented form [98 percent] at the physiologic, systemic pH of 7.4). For the purposes of this discussion, we use the term "uric acid" to denote the poorly soluble undissociated form and the term "urate" to denote the soluble dissociated urate anion.

ACUTE URIC ACID NEPHROPATHY — Acute uric acid nephropathy (UAN) is characterized by acute oliguric or anuric kidney failure due at least in part to uric acid precipitation within the distal tubules and collecting ducts [1,2]. However, in UAN caused by tumor lysis, other mechanisms may contribute, such as the release of substances from malignant cells that injure the endothelium [3].

UAN most often results from overproduction and overexcretion of uric acid in patients with rapid malignant cell turnover such as in lymphoma, leukemia, or a myeloproliferative disease (eg, polycythemia vera). It typically occurs after chemotherapy or radiation has induced rapid cell lysis as the nucleic acids released during cell lysis are converted to uric acid. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Acute myeloid leukemia: Overview of complications".)

Less frequent causes of UAN include tissue catabolism due to seizures or treatment of solid tumors, primary overproduction of uric acid due to hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome) or hyperuricosuria due to decreased urate reabsorption in the proximal tubule, as can occur with an acute Fanconi-like syndrome [1,2,4,5] or with exercise in patients with familial renal hypouricemia due to an inherited deficiency in the activity of the urate-anion transporter URAT1. (See "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome' and "Hypouricemia: Causes and clinical significance", section on 'Familial renal hypouricemia' and "Hypouricemia: Causes and clinical significance", section on 'Acute kidney injury'.)

Clinical manifestations — UAN is typically associated with no symptoms referable to the urinary tract, although flank pain can occur if there is renal pelvic or ureteral obstruction. The diagnosis should be suspected when acute kidney injury develops in any of the above settings in association with marked hyperuricemia (plasma or serum urate concentration generally above 15 mg/dL or 893 µmol/L). This is in contrast to most other forms of acute kidney injury in which the serum urate concentration usually is less than 12 mg/dL (714 µmol/L), except for prerenal disease in which there is an increase in proximal sodium and urate reabsorption [6].

The urinalysis in UAN may show many uric acid crystals (picture 1A-B), but can be unremarkable due to no output from the obstructed nephrons. Overexcretion of uric acid can be documented in many patients by a uric acid-to-creatinine ratio (mg/mg) above 1 on a random urine specimen; in comparison, the value is below 0.60 to 0.75 in most other forms of acute kidney injury [7].

Release of other intracellular constituents also occurs when there is marked tissue breakdown (as in the tumor lysis syndrome), possibly leading to hyperkalemia, hyperphosphatemia, and hypocalcemia [8,9]. Hyperphosphatemia may result in acute kidney injury, independent of uric acid precipitation [8]. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Prevention and treatment — Strategies to prevent UAN in patients at high risk (eg, high-grade lymphoma and some leukemias, tumor lysis syndrome) are important and consist of intensive intravenous volume expansion and use of a recombinant urate oxidase (rasburicase) to convert urate to the much more water-soluble end product, allantoin, and/or a xanthine oxidase inhibitor (allopurinol or febuxostat) to reduce uric acid production. These issues are discussed in detail elsewhere. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Therapy after the onset of acute kidney injury consists of allopurinol, febuxostat, or rasburicase and an attempt to "wash out" the uric acid crystals by increasing urine output with intravenous fluids and a loop diuretic. Sodium bicarbonate should not be given at this time, particularly if the patient does not have a metabolic acidosis, since it has not been proven effective and may increase the risk of calcium phosphate precipitation [10]. Hemodialysis can remove excess circulating urate in patients with persistent oliguria or anuria, and is useful in managing the volume status and other complications of acute kidney injury. The prognosis for complete recovery is excellent if treatment is initiated rapidly.

CHRONIC URATE NEPHROPATHY — Chronic urate nephropathy is a form of chronic kidney disease induced by the deposition of urate crystals in the medullary interstitium. The crystals induce a chronic inflammatory response, similar to that seen with tophus formation elsewhere in the body, potentially leading to interstitial fibrosis and chronic kidney disease [11]. Although urate crystals in the renal medulla may be demonstrable on biopsy, the clinical features of chronic urate nephropathy are nonspecific: kidney function impairment, bland urinary sediment, mild proteinuria, and serum urate concentrations often higher than expected for the degree of impaired kidney function. Thus, it is difficult to separate this disorder from the multiple other causes of kidney function impairment that can occur in patients with hyperuricemia, such as hypertension, diabetes mellitus, and obesity [12].

In the 1980s, many patients thought to have chronic urate nephropathy had lead nephropathy [13,14]. However, the applicability of this association to current practice in developed countries is uncertain in view of the reductions in population lead exposure (although excessive lead exposure does still occur in some regions). (See "Lead nephropathy and lead-related nephrotoxicity".)

Chronic urate nephropathy was primarily seen in the past in people with tophaceous gout [15]. However, it is currently thought to be uncommon and some feel that the diagnosis cannot be made on clinical grounds in the absence of kidney biopsy [16,17].

Others feel that chronic urate nephropathy can be considered in patients who have chronic kidney disease, the above nonspecific clinical features, and hyperuricemia out of proportion to the degree of kidney function impairment [18]. However, there is no universally accepted definition for "out of proportion," and previous studies used serum creatinine alone.

There are at least two potential problems with defining hyperuricemia as being out of proportion to the degree of kidney function impairment:

●The serum creatinine concentration is not an accurate estimate of glomerular filtration rate (GFR) since it is also determined by muscle mass. As an example, older adult or chronically ill patients may have a marked impairment in GFR with serum creatinine concentrations that are only modestly elevated. Estimation equations have been devised to account for this, but these equations have not been used to define serum urate concentrations higher than expected. (See "Assessment of kidney function".)

●Patients with chronic kidney disease often have hypertension treated at least in part with diuretic therapy. The ensuing volume depletion can raise the serum urate concentration and, potentially, the serum creatinine concentration. Treatment of hypertension with angiotensin inhibition, particularly losartan, may lower both the blood pressure and serum urate concentration. These issues are discussed in detail elsewhere. (See "Diuretic-induced hyperuricemia and gout".)

The relatively modest hyperuricemia in chronic kidney disease not due to urate nephropathy may reflect mechanisms that partially compensate for the reduced efficiency of renal excretion, such as enhanced intestinal uric acid excretion [19-21].

The role of hyperuricemia in the progression of chronic kidney disease, and the role of urate-lowering therapy in preventing chronic kidney disease progression, is controversial [12]. These issues are discussed in detail elsewhere. (See "Secondary factors and progression of chronic kidney disease", section on 'Hyperuricemia'.)

UROMODULIN KIDNEY DISEASE — Uromodulin kidney disease, previously known as familial juvenile hyperuricemic nephropathy (FJHN) or familial juvenile gouty nephropathy, is an autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by a mutation of the uromodulin (UMOD) gene.

It is characterized by hyperuricemia and gout early in the course of the disease and by progressive kidney function impairment. The available evidence suggests that urate crystal deposition in the kidney is not a primary pathogenetic mechanism for the chronic kidney disease in this disorder. Issues related to this disease are discussed in detail elsewhere. (See "Autosomal dominant tubulointerstitial kidney disease", section on 'ADTKD due to UMOD pathogenic variants'.)

SUMMARY

●Definition – Acute uric acid nephropathy and chronic urate nephropathy are uncommon kidney diseases related to the deposition, respectively, of crystals of undissociated uric acid in renal tubules and crystals of sodium urate in the kidney interstitium. (See 'Introduction' above.)

●Acute uric acid nephropathy

•Clinical manifestations – Acute uric acid nephropathy is characterized by acute oliguric or anuric kidney failure due to uric acid precipitation within the tubules. This disorder is usually due to overproduction and accompanying excessive renal excretion of uric acid in patients with lymphoma, leukemia, or a myeloproliferative disease, particularly after chemotherapy or radiation has induced rapid cell lysis. (See 'Acute uric acid nephropathy' above.)

•Diagnosis – The diagnosis of acute uric acid nephropathy should be suspected when acute kidney injury develops in an appropriate clinical setting and in association with marked hyperuricemia (plasma or serum urate concentrations generally above 15 mg/dL or 893 micromol/L). The urinalysis in acute uric acid nephropathy may show many uric acid crystals (picture 1A-B), but can be relatively normal. Many patients have a uric acid-to-creatinine ratio (mg/mg) above 1 on a random urine specimen; in comparison, the value is below 0.60 to 0.75 in most other forms of acute kidney injury. (See 'Clinical manifestations' above.)

•Prevention – Prevention of acute uric acid nephropathy consists of intravenous hydration and the use of rasburicase or a xanthine oxidase inhibitor (ie, allopurinol or febuxostat). Prevention of acute uric acid nephropathy in high-risk clinical scenarios is discussed in detail elsewhere. (See 'Prevention and treatment' above and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)

•Management – Therapy of acute uric acid nephropathy consists of allopurinol, febuxostat, or rasburicase, an attempt to "wash out" the obstructing uric acid crystals by increasing the urine output with intravenous fluids and a loop diuretic, and, if required, hemodialysis. Sodium bicarbonate should not be given at this time, particularly if the patient does not have metabolic acidosis, since it has not been proven effective and may increase the risk of calcium phosphate precipitation. These issues are discussed in detail elsewhere. (See 'Prevention and treatment' above and "Tumor lysis syndrome: Prevention and treatment", section on 'Treatment of established tumor lysis syndrome'.)

●Chronic urate nephropathy – Chronic urate nephropathy is a form of chronic kidney disease induced by the deposition of sodium urate crystals in the medullary interstitium. The clinical features of this disorder are nonspecific: kidney function impairment, bland urinary sediment, mild proteinuria, and serum urate concentrations often higher than expected for the degree of impaired kidney function. Thus, chronic urate nephropathy is difficult to separate from the multiple other causes of kidney function impairment in people with gout, such as hypertension and diabetes mellitus. It is thought to be uncommon, and some feel that the diagnosis cannot be made on clinical grounds in the absence of kidney biopsy. (See 'Chronic urate nephropathy' above.)

●Uromodulin kidney disease – Uromodulin kidney disease, previously known as familial juvenile hyperuricemic nephropathy (FJHN) or familial juvenile gouty nephropathy, is an autosomal dominant disorder characterized by hyperuricemia, gout early in the course of the disease, and by progressive kidney function impairment. (See 'Uromodulin kidney disease' above and "Autosomal dominant tubulointerstitial kidney disease".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael A Becker, MD, who contributed to an earlier version of this topic review.