Hyperuricosuria and Gouty Diathesis 

Hyperuricosuria is defined as urinary excretion of uric acid greater than 800 mg/day in men and greater than 750 mg/day in women. Uric acid, the major end-product of purine metabolism, is relatively insoluble in water. This excess uric acid leads to the formation of uric acid calculi. Such high levels may be due to either excess dietary intake of purine-rich foods or endogenous uric acid overproduction. Hyperuricosuria may be associated with hyperuricemia. In contrast, the term gouty diathesis describes the formation of urinary stones in persons with primary gout. These patients may present with other manifestations of gout (eg, gouty arthritis).

Uric acid–related nephrolithiasis may involve pure calcium stones, uric acid stones, or a combination of both. Furthermore, uric acid stones may develop in persons with normal urinary and serum levels of uric acid. Unlike most other forms of urolithiasis, medical therapy is an integral part of management of uric acid stones. Therefore, an understanding of the pathophysiology of uric acid–related nephrolithiasis is important for a cost-effective treatment approach.

The urinary solubility of uric acid depends on its concentration in urine and the urinary pH. At a pH below 5.5, nearly 100% of uric acid exists in an undissociated form. The 3 mechanisms responsible for uric acid related stone formation include (1) an acidic urinary milieu, (2) dehydration, and (3) hyperuricosuria. One or more of these factors may be found in patients with uric acid–related calculi. However, persistently acidic urine (ie, pH < 5.5) is the most important factor observed in patients with uric acid stones. Patients with gouty diathesis have consistently acidic urine (pH < 5.5) and elevated levels of serum uric acid. Urine uric acid levels in these patients may be elevated or within the reference range.

Although the mechanism of low urinary pH in many patients may not be completely clear and can be multifactorial, recent studies suggest an association between diabetes and insulin resistance in patients with normal urinary uric acid levels and acidic urine.^[1] Therefore, a subset of patients with idiopathic uric acid stones may have a broader systemic disorder of insulin resistance. A manifestation of insulin resistance is a mild defect in ammonium excretion that can result in stone formation. Acidic urine and uric acid stones have been reported as more common in patients with non–insulin-dependent diabetes than in patients with stones who do not have diabetes. The loss of diurnal variation in urinary pH and dietary content are other factors that contribute to acidity of the urine.

Hyperuricosuria is defined as urinary uric acid levels that exceed 800 mg/day in men and 750 mg/day in women. The most common cause of hyperuricosuria is increased dietary purine intake, but many other hereditary or acquired factors (eg, gout) may result in this condition. Individuals with hyperuricosuria may develop uric acid or calcium oxalate stones due to supersaturation of urine with monosodium urate. Monosodium urate may initiate calcium oxalate stone formation by the induction of heterogeneous nucleation or by absorption of certain inhibitors. Patients with calcium oxalate stones have a urinary pH of greater than 5.5.

Finally, all conditions that contribute to low urinary volume may increase uric acid supersaturation in urine and result in uric acid stone formation.

Frequency

United States

Uric acid stones account for 5-10% of urinary stones. Approximately 15-20% of patients with calcium stones have hyperuricosuria. Up to 20% of patients with gout develop uric acid stones.

International

The frequency of uric acid–related stones in other Western countries is similar to that in the United States; however, the incidence varies in other countries, and some geographic differences may exist. In Israel, for example, uric acid stones have been found in approximately 40% of individuals who form stones. Uric acid bladder stones are a common problem in children in rural Southeast Asia.

Mortality/Morbidity

• With appropriate diagnosis and treatment, most patients survive with minimal long-term morbidity. The prognoses of the familial and genetic forms depend on the primary disease and associated abnormalities.

Sex

• Between 80 and 90% of persons with hyperuricosuric calcium nephrolithiasis are men. Similarly, most individuals (70%) with calcium stones who do not have hyperuricosuria are also men.
• Gout is mainly a disorder of men, and only 5% of cases occur in women.
• Uric acid stones are more common in men than in women. Most uric acid stones are not associated with gout. Dehydration and urine acidity predispose patients to uric acid stones.

Age

• Hyperuricosuric calcium nephrolithiasis and gouty diathesis usually manifest in middle-aged individuals. In men, the peak age of onset of clinical gout is approximately 45 years.