Kidney stones in adults: Uric acid nephrolithiasis

INTRODUCTION — Uric acid stones account for 5 to 10 percent of urinary tract stones in the United States and Europe. By contrast, they comprise 40 percent or more of stones in areas with hot, arid climates in which the tendency to a low urine volume and acid urine pH promote uric acid precipitation. The risk of both uric acid and calcium oxalate stones is increased in patients with gout. (See 'Gout' below and "Clinical manifestations and diagnosis of gout", section on 'Renal complications of hyperuricemia and urate crystal deposition' and "Kidney stones in adults: Epidemiology and risk factors", section on 'Medical conditions'.)

Issues related to uric acid stone disease will be reviewed here. The general approach to the patient with nephrolithiasis and other management issues related to hyperuricemia and gout are discussed separately:

●(See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

●(See "Kidney stones in adults: Evaluation of the patient with established stone disease".)

●(See "Clinical manifestations and diagnosis of gout".)

●(See "Asymptomatic hyperuricemia".)

PATHOGENESIS — The two major factors that promote uric acid precipitation are a high urine uric acid concentration and an acid urine pH, which drives the following reaction toward the right, converting the relatively soluble urate salt into insoluble uric acid [1,2].

A persistently low urine pH is the more clinically relevant of these two biochemical risk factors for the development of uric acid nephrolithiasis [3-9]. Uric acid solubility in the urine falls from approximately 200 mg/dL (1.2 mmol/L) at a urine pH of 7 (a setting in which 95 percent of uric acid is present as the more soluble urate anion) to 15 mg/dL (0.09 mmol/L) at a urine pH of 5 (a setting in which most of the uric acid is the less soluble, undissociated acid) (figure 1) [1,10,11].

The importance of a low urine pH was illustrated by the biochemical characterization of 341 uric acid stone formers from four studies. The mean urine pH in patients with uric acid nephrolithiasis was 5.4, and virtually all patients had a urine pH less than 6 [4-7]. By comparison, the mean urine pH among calcium stone formers was 6.1. Hyperuricosuria, which has been traditionally, although arbitrarily, defined as a 24-hour urine uric acid excretion of more than 750 mg (4.5 mmol) in women or more than 800 mg (4.8 mmol) in men, was uncommon in the patients with uric acid stones. Uric acid excretion was higher in patients who formed calcium stones, but the role of hyperuricosuria in calcium stone formation is unproven. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine uric acid'.)

A low urine pH and/or high urine uric acid concentration can also explain the association between other disorders and uric acid stone formation. Examples include chronically increased uric acid production, as in myeloproliferative diseases such as polycythemia vera (table 1), and when the urine pH is acid and the urine volume is relatively low, as with chronic diarrhea [1,12]. (See 'Predisposing clinical conditions' below.)

PREDISPOSING CLINICAL CONDITIONS — Uric acid nephrolithiasis primarily occurs in patients with no obvious abnormality in uric acid metabolism. Patients who form uric acid stones often possess a combination of biochemical features that are similar to those seen in patients with primary gout who underexcrete uric acid (see "Urate balance", section on 'Hyperuricemia'). However, there are a number of conditions other than gout that increase the risk of uric acid stone formation.

Gout — Uric acid stone disease can occur at any time in the course of gout, antedating gouty arthritis in up to 40 percent of patients with primary gout. (See "Clinical manifestations and diagnosis of gout", section on 'Renal complications of hyperuricemia and urate crystal deposition'.)

In patients with gout and clinical stone disease, as in other uric acid stone formers, the primary predisposing factor is a persistently acid urine (urine pH of 5 to 5.5), which appears to reflect a relative impairment in ammonium excretion in favor of titratable acid [8,9,13]. The low urine pH creates an environment in which uric acid is more likely to precipitate, even though total 24-hour excretion of uric acid may be within the reference range [1]. A low urine pH is also seen in patients with gout who overproduce uric acid and therefore have hyperuricosuria; the combination of an acid urine and a high urine uric acid concentration leads to an increased risk of uric acid nephrolithiasis observed in this group. However, calcium oxalate stones are the most common type of stone formed by individuals with gout as they are in individuals without gout [14]. (See 'Pathogenesis' above.)

The prevalence of clinical stone disease of any type (ie, not limited to uric acid stones) in patients with gout was evaluated in two large cohort studies: a retrospective study from the National Health and Nutrition Examination Survey III (NHANES III), and a prospective report from the Health Professionals' Follow-Up Study [15,16]. The overall prevalence of stone disease in those with a history of gout was 14 and 15 percent, respectively, with an odds ratio after multivariable adjustment of 1.5 and 1.9, respectively. When examined prospectively, the multivariable adjusted relative risk of incident stone formation in men with a history of gout compared with those without a history of gout was 2.1 [16].

Increased fractional excretion of uric acid — Uricosuric drugs used in the prevention of recurrent gout produce only a transient increase in urinary uric acid excretion since the ensuing fall in the serum uric acid concentration results in the reestablishment of a new steady state in which uric acid production and excretion are equivalent (see "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'The steady state'). Thus, it is unlikely that uricosuric drugs increase the risk of uric acid stones. If there is a transient increase in risk after the initiation of therapy, there is no long-term increase in risk.

The fractional excretion of uric acid is also increased in certain rare genetic mutations in renal urate transporters. However, several features of these disorders distinguish them from uricosuric drugs. In severe cases, the serum uric acid may fall close to zero, indicating a much more severe defect than seen with uricosuric drugs. Furthermore, some patients with these mutations have chronic hyperuricosuria. The reasons for this are not fully known, but it is possible that urate which is normally eliminated in the stool is diverted and eliminated in the urine (ie, less gastrointestinal clearance of the daily uric acid load in favor or more urinary clearance) [17]. These patients may have a persistent increase in uric acid stone formation in contrast to the transient increase with uricosuric drugs. (See "Hypouricemia: Causes and clinical significance", section on 'Familial renal hypouricemia' and "Hypouricemia: Causes and clinical significance", section on 'Uric acid stone formation'.)

Uric acid overproduction — Uric acid stones can form in conditions associated with chronically increased uric acid production other than gout (table 1).

Chronic diarrhea — Uric acid stones can be seen in patients with chronic diarrheal states in which bicarbonate loss in the stool and volume depletion lead to a concentrated, acid urine [14]. This is particularly true in patients who have undergone colonic resection [18]. The risk of calcium oxalate stones is also increased in patients with chronic diarrhea due to lower urine volume and lower urine citrate. (Calcium oxalate stones are pH insensitive.)

Diabetes mellitus and metabolic syndrome — Type 2 diabetes mellitus and the metabolic syndrome are associated with an increased incidence of uric acid stones, possibly related to reduced ammoniagenesis and decreased urinary pH [19-25]. Why this occurs is not clear, but both diabetes and the metabolic syndrome are characterized by higher body weight, which is associated with both a more acid urine pH and higher urinary uric acid excretion and supersaturation in proportion to the body mass index [26,27].

DIAGNOSIS — Patients with uric acid nephrolithiasis usually present with the acute onset of flank pain, and often a history of a predisposing underlying condition such as gout or diabetes. Non–contrast-enhanced computerized tomography (CT) scan is the preferred radiologic test to establish the presence of a stone but may be negative if a stone has passed. Plain radiography is not helpful, since pure uric acid stones are radiolucent, but uric acid stones are seen by CT even without contrast [28,29]. Digital tomosynthesis offers comparable sensitivity of identifying uric acid stones in the kidney as noncontrast CT at a lower cost and reduced radiation exposure [30]. Uric acid stone formers may also report frequent passage of "sand" or "gravel" in the urine. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Diagnostic imaging'.)

Distinguishing the chemical composition of the stone is important in guiding treatment (see "Kidney stones in adults: Evaluation of the patient with established stone disease", section on 'Stone analysis'). The type of stone is best determined by chemical analysis of a stone that has passed. There is increasing evidence suggesting that dual-energy CT scan or helical CT can distinguish among different types of stones, including differentiating uric acid from calcium stones, with uric acid stones having lower Hounsfield units [31,32].

As noted above, 24-hour urine collection, which is a standard test in the evaluation of nephrolithiasis, does not typically reveal hyperuricosuria in patients with uric acid stones. A persistently acid urine pH is the primary risk factor. (See 'Pathogenesis' above.)

Most commercial laboratories offer testing of 24-hour urine samples to evaluate kidney stone risk. These laboratories will calculate the urinary supersaturation of uric acid, which is a helpful parameter to follow during treatment since it integrates urine volume, uric acid excretion, and pH.

TREATMENT

Overview of approach — Because alkalinization of the urine with medical therapy can lead to dissolution of nonobstructing pure uric acid stones in the kidney or ureter, more invasive procedures (such as endoscopic stone removal) are usually not required.

The three treatments options to prevent recurrent uric acid nephrolithiasis include [3]:

●Alkalinization of the urine

●Increased fluid intake

●Reduction of uric acid production with reduced purine intake and xanthine oxidase inhibitors

Urinary alkalinization and increased fluid intake should be prescribed to almost all patients with uric acid stones. The indications for xanthine oxidase inhibitors to reduce uric acid production depend upon whether uric acid stones are recurrent despite alkalinization or when alkalinization cannot be used and also upon the presence or absence of gout:

●Recurrent uric acid stones – Xanthine oxidase inhibitors are usually reserved for patients who continue to have stones despite urinary alkalinization and a prescribed higher fluid intake. Recurrent uric acid stone formation despite urinary alkalinization and increased hydration usually occurs in patients with high urinary uric acid excretion (exceeding 1000 mg/day [6 mmol/day]). However, xanthine oxidase inhibitor therapy is warranted in recurrent uric acid stone formers even if urinary uric acid excretion is in the reference range.

●Patients with gout – Patients with uric acid stones who also have recurrent or tophaceous gouty arthritis should be treated with a xanthine oxidase inhibitor for long-term control of gouty manifestations; the primary indication in such patients is gout and not necessarily the prevention of kidney stones (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout"). Serum urate-lowering therapy for gout with uricosuric agents is not indicated as first-line therapy in gouty stone formers to prevent stone recurrence, as this will not lead to a long-term change in the amount of uric acid in the urine (which is dependent upon uric acid generation).

In a patient with a history of uric acid stones and gout but ≤1 flare of gouty arthritis per year, there may be no specific indication for xanthine oxidase inhibitor therapy. Rather, urinary alkalinization and increased hydration are the initial treatment option in such patients for stone prevention. If, however, the patient prefers a single medication that could reduce both gout flare frequency and recurrence of uric acid stones, we would agree to prescribe treatment with a xanthine oxidase inhibitor (along with increased hydration but not necessarily urinary alkalinization).

Urinary alkalinization — The effect of increasing the urine pH on uric acid solubility can be appreciated from the Henderson-Hasselbalch equation for the relationship between soluble urate and insoluble uric acid, where 5.35 is functionally the pKa for this reaction under conditions existing in urine [33]:

At a urine pH of 6.75, more than 90 percent of the total urinary uric acid will be the more soluble urate salt, thereby minimizing the risk of uric acid precipitation.

There are no randomized trials that have evaluated the efficacy of urinary alkalinization on recurrence or dissolution of uric acid stones. However, alkalinization is associated with a remarkable reduction in recurrent stone episodes in observational studies [34]. As an example, the mean rate of recurrent uric acid stones among 18 patients was reduced from 1.2 to 0.01 stones per patient per year with long-term treatment with potassium citrate [35]. Alkalinization can also dissolve existing uric acid calculi, as demonstrated in eight patients with recurrent uric acid stones who underwent serial ultrasound examinations after initiating potassium citrate or potassium bicarbonate [36].

Alkalinization therapy should target a urine pH between 6.5 and 7. Achieving a urine pH higher than 7 will provide little if any further benefit on uric acid stone formation and may increase the risk of calcium phosphate stone formation (figure 1). An alkaline urine pH may not need to be maintained at all times since raising the urine pH to at least 6.5 once per day or every other day may prevent uric acid stone formation [37].

Either potassium bicarbonate or potassium citrate can be given, with the typical dose being 40 to 80 mEq/day (table 2) [3,35]. This regimen can dissolve preexisting pure uric acid stones and prevent the formation of new stones. Some evidence suggests that potassium or sodium bicarbonate offers similar alkalization for those patients unable to tolerate potassium citrate [38]. Alkalinization with potassium salts is preferable since the sodium load with sodium citrate or sodium bicarbonate may increase calcium excretion and promote the formation of calcium stones in some patients [35]. Patients should be instructed to check their urine pH at home; this will help guide the amount of alkali required. Initially, because the urine pH can vary substantially throughout the day, the urine pH should be checked and recorded several times per day for one week. We recommend using pH paper that has 0.5 pH unit increments. If the urine pH is below the target range, then the dose of supplemental alkali should be increased and the urine pH recorded again for another week. Once the desired pH range is obtained, we ask patients to check their urine pH a few times per week for a few weeks. If the urine pH remains in range, the patients do not need to continue checking their urine pH.

Increased fluid intake — Patients with uric acid stones (as with other types of stones) should be encouraged to drink enough fluids to achieve a 24-hour urine volume of at least two liters. Although there are no studies in uric acid stone formers, the potential importance of increasing fluid intake was shown in a randomized trial of 199 patients with calcium stones [39]. During five years of follow-up, the rate of recurrent stones was significantly lower in the patients who were counseled to increase their urine volume to at least two liters per day (12 versus 27 percent).

Efficacy of xanthine oxidase inhibitors — As discussed above, chronic administration of a xanthine oxidase inhibitor to lower uric acid production and excretion is generally reserved for patients (most often with hyperuricosuria) who continue to form uric acid stones despite alkali therapy and increased fluid intake [3].

There are, however, no randomized trials that have evaluated the effect of allopurinol or febuxostat (a newer xanthine oxidase inhibitor [40]) on the risk of forming uric acid stones in patients with hyperuricosuria [41]. The only randomized trials testing xanthine oxidase inhibitors in patients with nephrolithiasis have studied patients with calcium (not uric acid) stones and hyperuricosuria (which was defined either as a 24-hour uric acid excretion of 800 mg or more in men and 750 mg or more in women [42] or as "higher" uric acid excretion [43]). As examples:

●In a placebo-controlled trial of 60 patients with calcium oxalate stones, allopurinol (100 mg three times daily) significantly reduced the three-year incidence of stone-related events (31 versus 58 percent) [42].

●By contrast, a six-month trial comparing febuxostat (80 mg daily) or allopurinol (300 mg daily) with placebo in 86 patients with calcium stones and "higher" urinary uric acid excretion found no benefit from xanthine oxidase inhibitors, despite a reduction in urinary uric acid excretion [43]. However, the follow-up may have been too short, and sample size too small, to detect a benefit.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney stones".)

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●Beyond the Basics topic (see "Patient education: Kidney stones in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Uric acid stones account for 5 to 10 percent of all kidney stones in the United States and Europe; however, they comprise 40 percent or more of stones in areas with hot, arid climates. (See 'Introduction' above.)

●Pathogenesis – The most important biochemical risk factor for uric acid nephrolithiasis is a persistently low urine pH. Hyperuricosuria is not always present in patients with pure uric acid stones. Low urine volume (with a high urine concentration of uric acid) and an acid urine pH drive the conversion of the relatively soluble urate salt into insoluble uric acid. (See 'Pathogenesis' above.)

●Predisposing clinical conditions – Common clinical conditions that increase the risk of uric acid stone formation include gout, chronic diarrhea, diabetes, and the metabolic syndrome. (See 'Predisposing clinical conditions' above.)

●Diagnosis – Patients with uric acid nephrolithiasis usually present with the acute onset of flank pain, often in the setting of a known predisposing condition (such as gout). Non–contrast-enhanced computerized tomography (CT) typically reveals the presence of a stone. Confirmation of the diagnosis is best made by chemical analysis of a stone that has been passed. (See 'Diagnosis' above.)

●Treatment – Invasive treatments may be needed for large and acutely symptomatic stones. However, for asymptomatic kidney stones, noninvasive treatments should be attempted first since hydration and urinary alkalinization can lead to dissolution of pure uric acid stones. (See 'Overview of approach' above.)

•For patients with uric acid nephrolithiasis, we recommend urinary alkalinization and an increased fluid intake for prevention (Grade 1B).

-Alkalinization is generally performed with potassium citrate or potassium bicarbonate and should target a urine pH between 6.5 and 7. (See 'Urinary alkalinization' above.)

-Patients with uric acid stones should be encouraged to drink enough fluids to achieve a 24-hour urine volume of at least two liters. (See 'Increased fluid intake' above.)

•For patients who continue to form uric acid stones despite urinary alkalinization (or who cannot tolerate supplemental alkali) and a higher fluid intake, we recommend treatment with a xanthine oxidase inhibitor (Grade 1B). Such patients usually have hyperuricosuria (greater than 1000 mg/day [6 mmol/day]), but xanthine oxidase inhibitors are warranted even in patients with recurrent uric acid stones and lower levels of urinary uric acid excretion. (See 'Efficacy of xanthine oxidase inhibitors' above.)

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