Urate Nephropathy – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

The water-insoluble nature of uric acid presents a unique problem in the acidic environment of the distal nephron of the kidney. Owing to the lack of the enzyme uricase, which converts uric acid into a more soluble compound, allantoin, the human kidney is more susceptible to the side effects of uric acid crystal deposition.There are three different types of renal diseases induced by uric acid or urate crystal deposition: Acute uric acid nephropathy (UAN)Chronic urate nephropathyUric acid nephrolithiasis

Description

Renal parenchymal damage and dysfunction associated with disordered uric acid metabolismAffects the renal/urologic system; several syndromes may present: Acute UAN: Precipitated by renal tubular obstruction resulting from acute massive elevation of serum uric acid, often owing to cell lysis during induction chemotherapy or radiation; furthermore, crystallization of uric acid or calcium phosphate in renal tubules affects renal function.Uric acid nephrolithiasis: Seen most commonly in patients with underlying hyperuricemia or gout who have abnormally low urine pH owing 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 owing 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; effect of hyperuricemia on development and progression of chronic renal disease in humans is largely unknown. Studies in animals have shown an association between hyperuricemia and intrarenal vascular disease (1).

Epidemiology

Incidence

1 in every 114 patients newly diagnosed with gout develops uric acid stones per year. 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. Uric acid nephrolithiasis has a peak incidence in the 5th decade of life.Predominant age: AdultsPredominant sex: Male > Female (4:1). In the US, the prevalence rate is 4–9% in men and 1.7–4.1% in women.

Prevalence

Gout 1%, hyperuricemia 5–10%, uric acid nephrolithiasis 0.1% in the USuric acid calculi account for 5–10% of all stones in the US.The overall prevalence of uric acid calculi in persons with primary gout is estimated to be 22%.

Risk Factors

Hyperuricemic acute renal failure (2): Chemotherapy of neoplastic disordersSudden increase in uric acid loadVolume depletionPreexisting acute or chronic renal insufficiencyLarge tumor burdenLactate dehydrogenase (LDH) >1,500 IUExtensive bone marrow involvementElevated tumor sensitivity to chemotherapeutic agentsUric acid nephrolithiasis (3): Decreased urine pHDiminished urinary volumeExcessive urinary uric acidAcute diarrheal states and inflammatory bowel diseaseDiabetes mellitusMetabolic syndromeProbenecid and aspirin use

General Prevention

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

Etiology

Hyperuricemic acute renal failure: Endogenous uric acid overproduction: Rapid cell turnover/destruction owing to malignancy or rhabdomyolysis, enzymatic/metabolic abnormalities, inappropriate high dose of uricosuric agent in hyperuricemic individualExogenous uric acid overproduction: Excessive dietary purine ingestionUric acid nephrolithiasis: Idiopathic: SporadicFamilial (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 ISecondary hyperuricemia: Lead intoxicationDiureticsCytotoxic chemotherapy or radiation in leukemia or lymphomaHeat stress and exerciseDiabetic ketoacidosisStarvation ketosisChronic myeloproliferative diseasePsoriasisSecondary 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.It may occur more often in pediatric patients because of the increased incidence of acute lymphoblastic leukemia and Burkitt lymphoma in this population.

Commonly Associated Conditions

Treatment of neoplastic disordersGout (4)HTN (1)Myocardial infarction (1)Stroke (1)IgA nephropathy: Worse prognosis with elevated uric acid levels (1)

 

Diagnosis

Hyperuricemic acute renal failure (2): Precipitated by chemotherapy for leukemia or lymphoma or some solid-tumor malignanciesHyperkalemia: Weakness, paresthesias, muscle cramps, nausea, vomiting, diarrhea, anorexiaHyperphosphatemia: Acute nephrocalcinosisHypocalcemia: Muscle cramps, tetany, cardiac arrhythmia, seizuresOliguriaAnuriaAnorexia, nausea, vomiting, encephalopathy, and other manifestations of uremiaHTNDehydrationUric acid nephrolithiasis: Flank painGroin painMicroscopic or gross hematuriaAnorexiaNausea, vomitingUreteral obstructionUrinary tract infectionDehydrationHyperuricemia of chronic renal failure: Established chronic renal failure with glomerular filtration rate (GFR) <15–20 mL/minSerum uric acid 7–10 mg/dL chronicallyAcute onset of uremic symptoms

History

Nonspecific, but includes nausea, vomiting, and fatigue; predisposing causes help to direct clinical suspicion.

Diagnostic Tests & Interpretation

Lab

Hyperuricemic acute renal failure: Serum uric acid >15–20 mg/dL (0.88–1.18 mmol/L)Rising blood urea nitrogen and creatinineUrinary uric acid/creatinine ratio >1; ratio of 0.6–0.75 suggests another cause of renal failure (2)[C].Uric acid crystals in urineUric acid nephrolithiasis: Urine pH <6 (Nitrazine paper) (3)[A].Uric acid crystals in urine; urate crystals tend to be needle-shaped or flat, square plates; both are strongly birefringent.24-h urinalysis: Urinary uric acid often >4,800 µmol/d in men and >4,400 µmol/d in women or uric acid/creatinine ratio >530 µmol/mmol (hyperuricosuria) (5)[A].Measure serum uric acid, calcium, and creatinine: Serum uric acid is often normal, especially with low urine pH <6.2 (3)[A]HematuriaStone analysis: Uric acid or mixed uric acid with calcium oxalate or calcium phosphateHyperuricemia of chronic renal failure: Serum uric acid usually 7–10 mg/dL and is rarely >10 mg/dL owing to compensatory increase in GI secretion of uric acid (1)[A].Serum uric acid remains normal until GFR <20 mL/min (6)[C].

Imaging

IV pyelography: Filling defects (3)Nonenhanced CT scan: Lower density than calcium stones (3)[A]; CT attenuation values between 300 and 400 HU (7)

Diagnostic Procedures/Surgery

Cystoscopy and retrograde pyelography (3)Renal biopsy

Pathological Findings

Hyperuricemic acute renal failure: Uric acid crystals in collecting ducts, eventually obstructing nephrons (2)Uric acid nephrolithiasis: Radiolucent, often orange or red stones that can occlude ureters or entire renal collecting system (3)Chronic urate nephropathy: Birefringent, needle-like crystals in the tubular lumen or in the interstitium with surrounding inflammatory cells and fibrosis (5)

Differential Diagnosis

Hyperuricemic acute renal failure: Prerenal failure, contrast nephropathy, acute tubular necrosis, tumor infiltration of kidneys, obstructionUric acid nephrolithiasis: Calcium oxalate, calcium phosphate, struvite, cystine stones; 20% of patients with calcium nephrolithiasis have hyperuricemia (3).Chronic urate nephropathy: Other causes of chronic renal failure, including diabetes, atherosclerotic disease, HTN, and glomerular disease, are more likely. Environmental lead poisoning is another consideration in a patient with hypertension, gout, hyperuricemia, and chronic kidney disease (8).

Treatment

Medication

Hyperuricemic acute renal failure: Prevent by pretreating with allopurinol or rasburicase and hydrating patient prior to administration of chemotherapeutic agents for leukemia or lymphoma (2,9)[A]. Begin hydration 2 days prior to and continue for 2 days after induction chemotherapy (2)[A].Allopurinol 200–600 mg/d (adults) (2)[A] and 10 mg/kg q8h (children) (10)[A]Rasburicase 0.2 mg/kg/d IV during initial chemotherapy for pediatric patients with advanced-stage lymphoma or high-tumorburden leukemia (9,10)[B]Promptly correct metabolic abnormalities (2)[A].Dialyze when renal failure fails to resolve with conservative management or when life-threatening electrolyte or volume-overload disorders are present (2)[A].Uric acid nephrolithiasis: Encourage hydration to obtain urine output 1.5–2.0 L (5,7)[A].Alkali to maintain urine pH at 6.0–7.0; give potassium alkali 20–30 mEq b.i.d. to t.i.d. (3,5)[A].If hyperuricosuric and urinary alkalinization is unsuccessful, give allopurinol starting at 100–300 mg/d (5)[B].Hyperuricemia of chronic renal failure: Consider allopurinol only in patients with prior history of gout or nephrolithiasis (6)[C].Asymptomatic hyperuricemia: There is insufficient evidence to indicate treatment of asymptomatic hyperuricemia (1)[A].Precautions: In patients with renal impairment, dosing for allopurinol, which is cleared renally, must be adjusted (2)[A].Avoid abrupt decreases or increases in serum uric acid, which may precipitate acute gouty arthritis.Significant possible interactions of allopurinol: Inhibits metabolism of mercaptopurine and azathioprineEthanol decreases its effects.Increases likelihood of skin rash when used with amoxicillin or ampicillin.Risk of nephrolithiasis with excess vitamin C.

Additional Treatment

General Measures

Hyperuricemic acute renal failure: IV hydrationHemodialysis in severe casesUric acid nephrolithiasis: Hydration to increase urine outputNormalize renal uric acid excretion.Normalize urine pH.Antibiotic treatment of urinary tract infection

Surgery/Other Procedures

Uric acid nephrolithiasis resistant to conservative management: Lithotripsy, cystoscopic stenting, percutaneous nephrostomy (3)[A]

In-Patient Considerations

Initial Stabilization

Outpatient treatment except for complicated nephrolithiasis and hyperuricemic acute renal failure

Ongoing Care

Diet

Moderation of purine intake (5)[C]For nephrolithiasis, ensure that fluid intake is adequate to produce urine output of at least 2 L/d unless urine output is limited by acute or chronic renal failure (5)[A].In renal failure, restrict sodium for HTN and potassium for hyperkalemia.

Prognosis

With effective drug therapy and general management, prognosis is excellent in patients with hyperuricemic acute renal failure (2) and nephrolithiasis (3).Development of progressive renal insufficiency in patients with gout or hyperuricemia is unlikely to occur unless caused by underlying renal disease or associated medical conditions with adverse renal effects (4).

Complications

Gout and asymptomatic hyperuricemia: No renal complications proven in humans (1)Hyperuricemic acute renal failure (2): Irreversible renal failure (ESRD)Residual renal insufficiencyPersistent renal tubular functional defectsUric acid nephrolithiasis (4): Urinary obstructionUrinary tract infection, pyelonephritisRenal insufficiencyHyperuricemia of chronic renal failure: Progression to end-stage renal failure

Geriatric Considerations

Renal insufficiency is more likely because of age and associated medical conditions.

References

1. Kanellis J, Feig DI, Johnson RJ. Does asymptomatic hyperuricaemia contribute to the development of renal and cardiovascular disease? An old controversy renewed. Nephrology (Carlton). 2004;9:394–9.

2. Davidson MB, et al. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004;1116(8):546–54.

3. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest. 2005;115:2598–608.

4. Nakagawa T, Mazzali M, Kang DH, et al. Uric acid–a uremic toxin? Blood Purif. 2006;24:67–70.

5. Reynolds TM. ACP Best Practice No 181: Chemical pathology clinical investigation and management of nephrolithiasis. J Clin Pathol. 2005;58:134–40.

6. Snaith ML. ABC of rheumatology: Gout, hyperuricemia, and crystal arthritis. Br Med J. 1995;310:521–4.

7. Becker G. Uric acid stones. Nephrology (Carlton). 2007;12(Suppl 1):S21–5.

8. Lin JL, Yu CC, Lin-Tan DT, et al. Lead chelation therapy and urate excretion in patients with chronic renal diseases and gout. Kidney Int. 2001;60:266–71.

9. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767–78.

10. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001;97:2998–3003.

Codes

ICD9

274.10 Gouty nephropathy, unspecified274.11 Uric acid nephrolithiasis

Snomed

236495001 urate nephropathy (disorder)190829000 chronic urate nephropathy (disorder)