Introduction

Earlier studies undertaken about four decades ago suggested that hyperuricosuria was an important risk factor for calcium oxalate stone formation [1, 2]. Further evidences from a randomized placebo-controlled trial of allopurinol in individuals with calcium oxalate stone disease and isolated hyperuricosuria showed more than 50 % reduction in the recurrence rate in the allopurinol-treated group [3]. However, subsequent observations have questioned such an effect [4, 5]. In 2008, to examine the independent association between urine uric acid and stone formation, Curhan et al. [6], in a large cohort including 3350 participants, found that even after adjusting for other urinary factors, urinary uric acid had an unexpected significant inverse association with stone formation in men, a marginal inverse association with risk in younger women and no association in older women, confirming previous observations by the same group [7]. Therefore, such findings did not support the prevailing belief that higher urine uric acid excretion increased the risk for calcium oxalate stone formation.

For non-calcium nephrolithiasis, despite typically normal or even low total uric acid excretion, the finding of low urine pH causes titration of urate to the highly insoluble uric acid and subsequent urine supersaturation by uric acid. Uric acid is almost 11 times more soluble at a pH of 6.5 than it is at a pH of 5.0 [8, 9]. In other words, the physicochemical basis for uric acid stones is ruled by the level of urinary pH. When it is below 5.5, the amount of undissociated uric acid increases, precipitates and pure uric acid stones are formed. Conversely, when urinary pH is above 5.5, uric acid dissociates contributing to an increase in saturation of monosodium urate hence predisposing to heterogeneous nucleation and calcium stone formation. Although urinary pH determines the equilibrium between uric acid and urate, the latter, albeit more soluble than uric acid, is not infinitely soluble [10]. Sodium decreases, while potassium increases urate solubility thus explaining the risk of crystallization of calcium salts during sodium alkali therapy but not during potassium alkali therapy [11], as will be further discussed. Monosodium urate is more conducive in causing heterogeneous nucleation than uric acid.

Patients with a history of primary gout, although not exhibiting elevated urinary uric acid excretion [12, 13], are at greater risk of forming uric acid stones [14], as are patients with obesity, diabetes, or the complete metabolic syndrome, due to the excretion of abnormally acidic urine. Besides low urine pH as the most important urine variable in the causation of uric acid stones, a reduced urinary volume is also crucial [15, 16]. Accordingly, uric acid stones could form from dehydration due to excessive sweating or strenuous physical exercise (lactic acidosis), to intestinal alkali loss as in chronic diarrhea, or to an animal protein/purine overload [17, 18]. Rare monogenic enzymatic disorders, causing urinary uric acid levels greater than 1000 mg/day are frequently associated with uric acid stones [10].

However, idiopathic uric acid nephrolithiasis has been also identified in the absence of the above secondary causes, a condition previously known as “gouty diathesis”, for sharing features of primary gout, including gouty arthritis, hyperuricemia and hypertriglyceridemia [17]. In 2001, pioneering observations by the group of Pak et al. [19] suggested a unique biochemical profile for idiopathic uric acid nephrolithiasis patients who presented lower pH and fractional excretion of urate than healthy subjects, and hypothesized that impairments in urinary acidification and urate excretion could be associated with primary gout.

Further investigation on the pathophysiological basis for this normouricosuric uric acid nephrolithiasis by Sakhaee et al. [13], revealed that pure uric acid stone formers had a much higher incidence of either diabetes or glucose intolerance [20], excreted less of their acid as ammonium and even with net acid excretion maintained at the expense of increased titratable acidity, presented an acid urinary pH resulting in uric acid nephrolithiasis [13, 20]. In response to an acid load, these uric acid stone formers further acidified their urine, but the magnitude and level of response differed from normal volunteers or calcium stone formers. These investigators thus suggested the presence of a mild renal acidification or urinary buffering defect in these patients, linked to an insulin-resistant state, that did not lead to acid-basic abnormalities under basal conditions [13]. However, the unduly acidic urine in uric acid stone formers could be amplified by acid challenges. Maalouf et al. [21] have shown that metabolic syndrome (MS) patients exhibited a lower urinary pH and higher urinary sulfate excretion because of a more acidogenic diet. Although the underlying mechanisms for the impaired ammoniogenesis were not fully elucidated, experimental data suggested that renal fat infiltration (renal steatosis) might decrease ammonium secretion in the proximal tubule, in part by reducing the activity of the proximal tubule Na+/H+ exchanger (NHE3) and by impairing the regulation of NHE3 by specific agonists [22].

A large epidemiological study examined the association between metabolic syndrome and history of kidney stones [23]. After adjustment for age and other covariates, the presence of two or more metabolic syndrome traits significantly increased the odds of self-reported kidney stone disease and the presence of four or more traits was associated with an approximate two-fold increase in odds of self-reported kidney stone disease [23].

Furthermore, urinary pH has been shown to possess a strong, graded inverse association with body weight, suggesting that obesity may sometimes cause uric acid nephrolithiasis by producing excessively acid urine due to insulin resistance [24]. Negri et al. [25] have also shown a significant decrease in urine pH in overweight men. More recently, Shavit et al. [26] observed that not only obese but overweight kidney stone formers, exhibit a more acidic urine as well as a metabolic urinary profile that is associated with increased overall risk of stone formation characterized by raised urinary excretion of uric acid and sodium and a higher prevalence of hypercalciuria.

Both type 2 diabetes (T2DM) and obesity are associated with low urinary pH and increased risk for uric acid nephrolithiasis as they have similar changes in urinary pH, net acid excretion, and 24-h urinary ammonium obtained under controlled dietary conditions [27]. Nevertheless, since not all patients with T2DM develop kidney stones, Bobulescu et al. [27] studied the excretory response to an acute acid loading and found that uric acid stone formers, but not patients with T2DM or normal volunteers of similar body size, have a unique defect characterized by blunted renal ammonium excretory response to the acid challenge.

Treatment

Based on all the aforementioned considerations, the main principles of therapy for uric acid nephrolithiasis are aimed at increasing urinary volume, urinary alkalinization through diet modification or pharmacologic agents, and less importantly at the reduction of uric acid excretion.

Diet manipulation

The mainstay of dietary management of uric acid nephrolithiasis is urinary alkalization and weight loss as well. A more vegetarian diet, rich in fruits and vegetables, leading to an increase in urine citrate content and pH [28–30], is expected to help with the prevention of uric acid stones. The reduction in animal protein intake would not only lead to urinary alkalization, but also to a reduction in purine ingestion and uric acid excretion, a useful manipulation but ineffective if alkalization does not occur. Although the exact daily amount of fluids needed by uric acid stone-formers remains uncertain, patients should be encouraged to drink fluids to produce at least 30 mL/kg of body weight per day of urine [30]. Achieving 2.5–3 L/day may be optimal. Numerous short-term studies of urinary chemistry measures have demonstrated the impact of citrus juices (grapefruit, orange juice, lemonade and limeade) on urinary pH and citrate levels in nephrolithiasis patients [31–34], with conflicting results but none of them aimed to treat uric acid stone formers. Citrate in orange and grapefruit juices is complexed mainly by potassium, whereas citrate in lemon juice, with high citric acid content, is accompanied by protons, hence not conferring the alkalinizing load that orange juice may provide [32]. Thus, only orange juice was shown to decrease undissociated (insoluble) uric acid excretion [32, 35]. An additional benefit of citrus juice compared with tablet citrate supplements is the requisite increase in overall fluid consumption, thus increasing daily urine volume and reducing urine supersaturation. However, the significant caloric load that accompanies the ingestion of large volumes of orange juice is a major concern and diminishes its appeal as a major stone preventive therapy. Interestingly, in a more recent short-term metabolic study, Baia et al. [29] have shown that melon, a noncitrus source of potassium, citrate, and malate, less caloric than orange, yielded an increase in urinary citrate excretion and urinary pH equivalent to that provided by orange, hence representing an alternative dietary approach for either hypocitraturic or uric acid stone-formers. Concerning other beverages, very few lemonade-flavored soft-drinks present a high concentration of citrate [36]. In addition, consumption of diet orange soda to provide 60 mEq of citrate would have to be in excess of 2 L/day or more than 9 8-oz glasses per day [37]. Mineral water with high amounts of bicarbonate (>1000 mg/L) have also shown to present beneficial effects on citraturia and urine pH in calcium stone-forming patients, but this issue has not been evaluated in uric acid stone formers [38, 39]. Goodman et al. [40] evaluated the effect of two sports drinks and demonstrated that ingestion of Performance® but not Gatorade® led to a significant increase in mean urinary citrate excretion and pH compared to water since the former contained more citrate and a higher pH than the latter, which is ultimately an important determinant of alkali load in beverages containing organic anions such as citrate. However, like juices, sports drinks have significant carbohydrate content, and may contain too many calories and fructose to be considered useful beverages for stone prevention and especially for uric acid stone formers. Moreover, fructose intake (in the form of table sugar or high-fructose corn syrup) is independently associated with an increased risk of incident kidney stones [41]. Notwithstanding such negative effects of fructose on urinary stone risk, fructose-induced hyperuricemia may have a pathogenic role per se in metabolic syndrome as well. Nakagawa et al. [42] have shown that fructose but not dextrose in a pair-feeding study in rats produced features of MS (hyperinsulinemia, hypertriglyceridemia and hyperuricemia) and the reduction of serum uric acid obtained with either allopurinol (a xanthine oxidase inhibitor) or benzobromarone (a uricosuric agent) was able to prevent or reverse some characteristics of MS. In a more recent cross-sectional study by Taylor and associates [43], conducted in a large cohort of 3426 persons with or without nephrolithiasis, showed the benefits of the alkali content of the Dietary Approach to Stop Hypertension (DASH)-style diet (rich in fruits and vegetables), translated by a 16 % greater citraturia and higher urine pH and potassium in the group of patients belonging to the highest quintile of DASH scores [43, 44]. Potassium deficiency stimulates proximal tubular citrate reabsorption so that potassium intake per se might reduce stone risk regardless of the accompanying anion. Martini and colleagues [45] have observed a significant correlation between urinary potassium and citrate. Although non-pharmacological, dietary alternative diets represent an appealing therapy, that may decrease supersaturation for uric acid [28], alkalization may fail in uric acid stone formers as they appear to have increased net acid excretion and lower urine pH at any level of urine sulfate excretion, a surrogate of animal protein intake, compared to non-uric acid stone formers [46]. Finally, weight loss with prevention of the metabolic syndrome, although difficult to achieve, may be a more important dietary manipulation. Of note, a low calorie DASH diet, Weight Watchers® or more balanced plans but not the Atkins diet, which is high in animal protein, should be recommended [30].

Drug therapy

Citrate supplementation: drug-induced urinary alkalinization can be achieved with variable doses of 20–80 mEq/day of potassium citrate (KCit) [15]. In an early study addressing the effects of versus sodium citrate (NaCit) therapies in five patients with uric acid lithiasis, it has been observed that both alkali treatments significantly increased urinary pH and citrate [11], but urinary calcium significantly declined only after KCit. The urinary environment became supersaturated with respect to brushite (calcium phosphate) and monosodium urate. The authors suggested that albeit both alkali therapies have been equally effective in preventing uric acid stone formation because of their ability to increase urinary pH, KCit would be preferable for it could prevent the complication of calcium nephrolithiasis in patients with uric acid stones, whereas sodium citrate would not. Sakhaee et al. [11, 47] have compared the effects of KCit to other salts, such as sodium citrate, potassium bicarbonate, or even potassium chloride on renal citrate excretion. These investigators observed that citrate clearance increased with both KCit and bicarbonate but not with potassium chloride, showing that potassium itself had a negligible effect on renal citrate handling and that the citraturic action of potassium was largely accountable by provision of the alkali load. Patients with heart disease or hypertensive may not tolerate the sodium loads but hypertension, hypervolemia and pulmonary congestion are observed less often with bicarbonate salts than with sodium chloride indiscretions [15]. On the other hand, patients with decreased glomerular filtration rates or taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers may not tolerate the potassium load. A durable alkalization and citraturic response was shown to be achieved with long-term studies with potassium citrate [48] or potassium–magnesium supplementation [49], thus reducing the risk of uric acid based calculi. However, compliance with potassium citrate preparations can be difficult, especially for older people, because of gastrointestinal intolerance. Alkaline salts have an unpleasant taste and can cause symptoms of gastritis or esophagitis. These effects are worse with potassium salts than with sodium salts but may occur with both. Potassium salts tend to increase diarrhea more than do sodium salts [50]. As reviewed by Mattle and Hess [51], up to 48 % of alkali citrate treated patients have left the studies prematurely, because of adverse gastrointestinal effects (nausea, vomiting, constipation, diarrhea, eructation, abdominal bloating, and stomach pain). Besides, potassium citrate therapy is expensive [52].

Bicarbonate supplementation: sodium bicarbonate (NaBic) may also be associated with some gastrointestinal complaints but usually fewer than KCit and its cost is about 4–30 times less than the latter. To avoid the side effects related to potassium salts, and considering the lower cost of NaBic, a randomized double-blind crossover study was conducted by our group, aiming to compare the effects of NaBic and KCit (60 mEq/d capsules of either NaBic or KCit (20 mEq capsules taken t.i.d. for a period of 3 days) [53]. Compared with baseline, either NaBic and KCit citrate led to equivalent and significant increases in urinary citrate and urinary pH. Only 1 out of the 16 patients reported gastrointestinal symptoms (bloating and constipation) after KCit supplementation and none in the NaBic group. NaBic led to a significant increase in sodium excretion without increasing urinary calcium excretion compared with baseline since the calciuretic effect is known to depend on the accompanying anion, being mitigated by an alkali such bicarbonate [54]. On the other hand, KCit induced a significant increase in potassium excretion coupled with a significant reduction in urinary calcium hence reducing calcium oxalate supersaturation (CaOxSS) in a more effective way than NaBic [53]. Uric acid supersaturation (UASS) was nonsignificantly reduced whereas sodium urate supersaturation (NaUSS) was significantly higher after both agents [53], given that sodium urate is highly soluble in alkaline urine. Therefore, this short-term study showed that although NaBic represents an effective alternative for the treatment of hypocitraturic calcium oxalate stone formers who cannot tolerate or afford the cost of KCit. However, uric acid stone-forming patients might be less suited for treatment with NaBic.

The most appropriate timing and dosing of alkaline salts have been a matter of debate, given the evidences that uric acid stone formation ordinarily is prevented by increases in the urinary pH after meals and it seems that the postprandial alkaline tide is lost in patients who make such calculi [55]. According to some investigators [50, 55], in contrast to multiple dose daily regimens (usually three times a day), a single dose once a day (a pulse between 30 and 75 mEq) to achieve a urine pH up to 7.0 (not higher) or alternate day administration of an alkaline potassium salt would increase urinary pH and simulate this normal physiological mechanism, being sufficient to prevent stones and avoid deposition of apatite salts on the stone. Moreover, this mode of base administration would be better tolerated and easier to follow and less likely to cause systemic alkalosis, but an important part of the regimen is patient self-monitoring to verify that the urinary pH increases to greater than 6.8, 1.5–2 h after the medication is taken [55]. On the other hand, in the clinical practice, the adequacy of response to alkali therapy (diet or drug-induced) is often monitored with 24 h urine pH measurement, to prevent excessively high levels favoring calcium phosphate precipitation. More recently, Cameron et al. [56] observed that during treatment of uric acid nephrolithiasis with alkali, excessive nocturnal and early morning urinary acidity can persist despite apparent alkalinization of pooled 24-h urine. These investigators further investigated the 24-h pattern of urinary pH in uric acid stone formers using precise metabolic balance techniques [57] and found that with the exception of two time points, they maintained a mean urine pH of 5.6 throughout the day. Besides, their uric acid excretion rate and concentration were much higher throughout the entire 24-h period. Uric acid stone formers had more acidic urine at each time point compared to normal volunteers, and their circadian pattern of acid excretion (albeit similar to that found in normal participants) led to a lower urine pH in the late afternoon and evening, probably reflecting higher protein intake/dietary acid load at lunch and dinner. Therefore, uric acid stone formers that do not respond alkali therapy may require an increased morning or mid-day dose of alkali to compensate for the fall in urinary pH that occurs in the late afternoon and evening [52]. Other authors also recommend nightly citrate administration for prevention, in addition to round-the-clock alkalinization, checked by the patients by inexpensive test papers at home once a day at varying times for a few weeks [15]. Having patients check their urinary pH is especially critical when there is some urgency to dissolve a stone and not simply preventing new ones. The proton pump inhibitors (PPIs) effects upon the gastric acid secretion and possible modulation of urinary pH have been tested in uric acid stone formers and healthy volunteers [57], but diurnal trends in urinary acidification patterns were not affected by PPIs in any of them.

Carbonic anhydrase inhibitors: acetazolamide (a carbonic anhydrase inhibitor) could also be potentially used to raise urinary pH [58]. The drug was effective in increasing the urinary pH in uric acid stone formers who were already taking potassium citrate, but caution must be taken when prescribing acetazolamide, because of poor tolerance and the risk of inducing calcium phosphate stones [58].

Xanthine oxidase inhibitors: both allopurinol and febuxostat significantly decrease hyperuricemia and hyperuricosuria [59], but their use for uric acid stone formers should be initiated after abnormally low urinary pH is corrected and limited to patients with primary gout or high urinary uric acid levels and calcium stones [60]. Another issue to be considered is the increase in the pool of uric acid to be excreted in conditions associated with increased cell turnover/purine states, such as myelo/lymphoproliferative or hemolytic disorders and other malignancies with or without chemotherapy [61]. Allopurinol prophylaxis should be routinely given when the tumor lysis syndrome is anticipated to prevent the risk of urate nephropathy and uric acid stones in patients treated for lymphoma/leukemia. Finally, uricosuric drugs such as probenecid, the angiotensin 1 receptor blocker (BRA) losartan [62], high-dose salicylates and radiocontrast agents should be avoided in uric acid stone formers whenever possible [61]. The uricosuric effect of losartan, attributed to competitive inhibition of uric acid reabsorption in the renal proximal tubule seems to be unique to this parent compound but not to its active metabolite or other ARB.

In conclusion, uric acid nephrolithiasis and unduly acidic urinary pH are both considered today a renal manifestation of insulin resistance but the underlying mechanisms for the development of low urinary pH and the propensity for UA stone formation due to the conversion of urate salt into undissociated UA are not completely elucidated. Nevertheless, excessive dietary acid intake, increased endogenous acid production and/or defective NH4+ excretion do exist, among other factors [63], such as a lack of some unknown urinary inhibitor of uric acid crystal precipitation. Further studies are warranted to explore whether treatment with insulin sensitizers will help to lower the incidence of uric acid stones in patients with metabolic syndrome.