Description

• Renal parenchymal damage and dysfunction associated with disordered uric acid metabolism
• Affects the renal/urologic system; several syndromes may present:
  • 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; additionally, crystallization of uric acid or calcium phosphate in renal tubules affects renal function
  • Uric acid nephrolithiasis: Common in underlying hyperuricemia or gout, 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.
  • Hyperuricemia of chronic renal failure: An early result of chronic renal failure due to retention of uric acid resulting from decreased tubular secretion or altered postsecretory reabsorption or both; secondary gout occurs in <1% of all patients.
• Chronic urate nephropathy: Renal insufficiency attributed to parenchymal damage secondary to medullary urate deposition. Studies in animals have shown an association between hyperuricemia and intrarenal vascular disease.

Epidemiology

• Higher incidence with gout, myeloproliferative diseases, and those treated with cytotoxic drugs. 1:114 patients diagnosed with gout develops uric acid stones per year (1).
• The chance of urate nephrolithiasis increases with increasing urine uric acid concentration and decreased solubility because of low urine pH. Most patients with uric acid calculi do not have hyperuricemia (1).
• Predominant age: Peak incidence in 5th decade of life
• Predominant sex: Male > Female (4:1). In the US, 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 US
• Uric acid calculi account for 5–10% of all stones in the US.
• The overall prevalence of uric acid calculi with primary gout is ~ 22%.

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
• Uric acid nephrolithiasis (1):
  • 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)

Genetics
URAT1 and GLUT9 transporters have been identified as facilitators of urate reabsorption.

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

Pathophysiology

• Chronic urate nephropathy (2):
  • Hyperuricemia causes endothelial dysfunction, activation of local renin-angiotensin system, increased oxidative stress, and proinflammatory and proliferative actions.
• Uric acid nephrolithiasis (1):
  • The solubility of undissociated uric acid is 90 mg/L. At pH <5.35, more than 1/2 the uric acid is in undissociated form.
  • Therefore, a normal daily uric acid excretion of 500 mg cannot be kept in solution with urine volume of <3 L and urine pH of <5.35.

Etiology

• Hyperuricemic acute renal failure:
  • Endogenous uric acid overproduction: Rapid cell turnover/destruction due to malignancy or rhabdomyolysis, enzymatic/metabolic abnormalities, inappropriate high dose of uricosuric agent in hyperuricemic individual
  • Exogenous uric acid overproduction: Excessive dietary purine ingestion
• Uric acid nephrolithiasis:
  • Idiopathic: Sporadic
  • Familial (primary hyperuricemia):
    • Congenital gout, hypertension (HTN), and hyperuricemia (autosomal dominant)
    • Congenital hypoxanthine–guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome, X-linked recessive)
    • Congenital phosphoribosyl pyrophosphate overactivity (X-linked recessive)
    • Congenital glycogen storage disease type I
  • Secondary hyperuricemia:
    • Lead intoxication
    • 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

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.

Commonly Associated Conditions

• Treatment of neoplastic disorders
• Gout
• HTN
• Myocardial infarction
• Stroke
• IgA nephropathy: Worse prognosis with elevated uric acid levels