Nephropathy, Urate


  • Uric acid requires the enzyme uricase to convert it to a more soluble compound (allantoin); in humans, the enzyme is absent, making the kidney more susceptible to the side effects of uric acid crystal deposition.
  • Three different types of renal diseases are induced by uric acid or urate crystal deposition:
    • Acute uric acid nephropathy (UAN)
    • Chronic urate nephropathy
    • Uric acid nephrolithiasis


Renal parenchymal damage and dysfunction associated with disordered uric acid metabolism may manifest as:

  • Acute UAN: due to renal tubular obstruction resulting from acute massive elevation of serum uric acid, often due to cell lysis during induction chemotherapy or radiation
  • Chronic urate nephropathy: renal insufficiency attributed to proinflammatory cascade and intravascular effects of hyperuricemia independent of urate deposition in renal parenchyma. Hyperuricemia is an independent predictor of chronic kidney disease.
    • Hyperuricemia is an early result of chronic renal failure as well due to retention of uric acid resulting from decreased tubular secretion.
  • Uric acid nephrolithiasis: common in underlying hyperuricemia or gout and in patients who have abnormally low urine pH due to low ammonia excretion
    • Frequency of stone formation increases with increasing serum uric acid levels and urinary uric acid excretion rates.
    • ~20% of patients with gout will form uric acid stones.



  • Higher incidence with gout and myeloproliferative diseases and in those treated with cytotoxic drugs
  • 20–60% of people with gout and hyperuricemia will have renal impairment.
  • 25–40% of people with untreated hypertension (HTN) have hyperuricemia.
  • Predominant age: peak incidence in 5th decade of life
  • Predominant sex: male > female (4:1). In the United States, the prevalence rate is 4–9% in men and 1.7–4.1% in women.


  • Gout 1%, hyperuricemia 5–10%, uric acid nephrolithiasis 0.1% in the United States
  • Uric acid calculi account for 5–10% of all stones in the United States.
  • The overall prevalence of uric acid calculi with primary gout is ~22%.

Etiology and Pathophysiology

  • Hyperuricemic acute renal failure
    • Endogenous uric acid overproduction: rapid cell turnover/destruction due to malignancy or rhabdomyolysis, enzymatic/metabolic abnormalities, and inappropriate high dose of uricosuric agent in hyperuricemic individual
    • Exogenous uric acid overproduction: excessive dietary purine ingestion
  • Chronic urate nephropathy
    • Hyperuricemia causes endothelial dysfunction through impaired nitric oxide production and release, platelet activation, increased oxidative stress through xanthine oxidase, vascular smooth muscle cell proliferation, and proinflammatory activity.
  • Uric acid nephrolithiasis
    • Idiopathic: sporadic
    • Familial (primary hyperuricemia)
      • Congenital gout, HTN, and interstitial nephropathy (autosomal dominant; FJHN1, MCKD2, glomerulocystic kidney disease)
      • Congenital hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome, X-linked recessive)
      • Congenital phosphoribosylpyrophosphate overactivity (X-linked recessive)
      • Congenital glycogen storage disease type I
    • Secondary hyperuricemia
      • Lead intoxication
      • Cadmium
      • Diuretics
      • Cytotoxic chemotherapy or radiation in leukemia or lymphoma
      • Heat stress and exercise
      • Diabetic ketoacidosis
      • Starvation ketosis
      • Chronic myeloproliferative disease
      • Psoriasis
    • Secondary hyperuricosuria: primary gout, excessive purine intake, tubular reabsorptive defect, uricosuric drugs (e.g., cyclosporine, ethambutol, probenecid, phenylbutazone, pyrazinamide, salicylates, vitamin A, tacrolimus, radiocontrast materials)
    • Dehydration: GI or skin loss

URAT1 (gene SLC22A12) and GLUT9 (gene SLC2A9) are proximal renal tubule transporters of urate. Polymorphisms in these genes are associated with urine uric acid variations. Additionally, abnormalities of uromodulin (UMOD) gene are associated with multiple genetic renal tubule diseases.

Risk Factors

  • Hyperuricemic acute renal failure
    • Sudden increase in uric acid load (chemotherapy of neoplastic disorder)
    • Volume depletion
    • Acute or chronic renal insufficiency
    • Large tumor burden
    • Lactate dehydrogenase (LDH) >1,500 IU
    • Extensive bone marrow involvement
  • Elevated tumor sensitivity to chemotherapeutic agents
  • Chronic urate nephropathy
    • IgA nephropathy
    • Diabetes mellitus
    • Acute or chronic renal insufficiency
    • Metabolic syndrome
  • Uric acid nephrolithiasis
    • Decreased urine pH (most important)
    • Diminished urinary volume
    • Excessive urinary uric acid
    • Acute diarrheal states (IBD, etc.)
    • Diabetes mellitus
    • Obesity/metabolic syndrome
    • High-protein diet
    • Uricosuric drugs (i.e., probenecid)

General Prevention

  • Appropriate pretreatment prior to chemotherapy for leukemia or lymphoma
  • Avoidance of factors that can cause abrupt or persistent increases in serum uric acid or urinary uric acid excretion

Pediatric Considerations
Gout and uric acid nephrolithiasis may have onset in infancy or childhood with familial causes of hyperuricemia, such as Lesch-Nyhan syndrome, acute lymphoblastic leukemia, and Burkitt lymphoma. Low birth weight has been associated with hyperuricemia in neonate and mother.

Commonly Associated Conditions

  • Treatment of neoplastic disorders
  • Gout
  • HTN
  • Myocardial infarction
  • Stroke
  • Chronic kidney disease

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