The Role of Urate in Calcium Stone Formation

Introduction

High urine uric acid levels (defined as more than 750 mg in 24 hours for women and more than 800 mg in 24 hours for men) and low urine pH are risk factors for uric acid kidney stones; however, our understanding of the relationship between hyperuricosuria and calcium oxalate stones is obscure. It has long been suggested that urinary uric acid increases the risk of calcium oxalate stones; however, the mechanism is unclear and to date there is only 1 randomized controlled study looking at the role of xanthine oxidase inhibitors (XOI) compared to placebo in the prevention of calcium oxalate stone formation.¹ To discuss the relationship and highlight teaching points (Table 1) between hyperuricosuria and calcium oxalate stones, we utilized a patient case.

Table 1.

Teaching points

•Urine uric acid may lead to calcium oxalate stone formation directly through salting out, reducing stone inhibitors, or epitaxy.

•Urine alkalinization is the mainstay of therapy for uric acid stone formers.

•Insulin resistance leads to impaired ammoniagenesis and low urine pH.

•High purine intake and purine metabolism disorders can lead to high urine uric acid.

•XOI may be considered for calcium oxalate stone prevention beyond modifying traditional risk factors (hypercalciuria, hypocitraturia, hyperoxaluria) if the patient continues to make stones and has hyperuricosuria.

Case Presentation

A 71-year-old male with atrial fibrillation and hypertension presents after his initial kidney stone episode. Two months earlier, he passed a 100% calcium oxalate monohydrate stone. Medications include hydrochlorothiazide 12.5 mg daily, potassium chloride 20 mEq daily, valsartan 160 mg daily, diltiazem 120 mg daily, and systemic anticoagulation. His body mass index was 27 kg/m². Laboratory tests revealed serum potassium 3.7 mEq/l, bicarbonate 27 mEq/l, creatinine of 0.99 mg/dl, and uric acid of 6.4 mg/dl. Two 24-hour urine collections were completed (Table 2). Urine chemistry was notable for relatively low urine pH, moderate uricosuria, and moderate protein intake. On review of systems, he admitted to intermittent first metatarsophalangeal joint redness, swelling, and pain. He has no family history of kidney stones.

Table 2.

Urinary metabolic work up

Collection day	Urine volume (l)	Urine creatinine (mg)	Urine Ca (mg)	Urine Ox (mg)	Urine citrate (mg)	Urine pH	SS UA	Urine UA (g)
1	2.86	1654	80	29	671	5.478	1.3	0.768
2	2.42	1922	137	33	715	5.472	2.1	1.064

Collection day	Urine Na (mEq)	Urine K (mEq)	Urine Mg (mg)	Urine P (g)	Urine NH4 (mEq)	Urine Cl (mEq)	Urine sulfate (mEq)	Urine urea nitrogen (g)	PCR
1	87	87	100	0.825	45	122	43	11.10	1.0
2	158	96	138	1.063	46	181	63	13.71	1.2

Ca, calcium; Cl, chloride; K, potassium; Mg, magnesium; Na, sodium; Ox, oxalate; P, phosphorus; PCR, protein catabolic rate; SS, supersaturation calculated by EQUIL2; UA, uric acid; UUN, urine urea nitrogen.

Discussion

Our patient’s urinary metabolic profile is largely unremarkable; however, it is unknown what his urinary profile was at the time of stone creation. Because he has no prior imaging, it is unclear how long the stone was present before being symptomatic. The patient’s joint complaints are consistent with gout, which raises the question of if his elevated urine uric acid levels, which is noted on day 2 of the paired urine collection, are contributing to stone formation.

There are 3 suggested hypotheses of how uric acid leads to calcium oxalate stone formation (Figure 1). Urine uric acid may directly “salt out” calcium oxalate, whereby uric acid reduces the solubility of calcium oxalate.² Urine uric acid may lower the inhibitory effect of urinary glycosaminoglycans, thereby contributing to calcium stone formation.³ Or a final theory in which uric acid may serve as a nidus for calcium oxalate crystallization (i.e., epitaxy).⁴ In vitro studies show that sodium urate promotes crystallization of calcium oxalate in samples with elevated urinary uric acid even when no uric acid crystals are present.^5,6 This observation makes epitaxy or heterogenous nucleation seem unlikely. Given that uric acid is highly dissolvable at a urine pH of more than 6.0 to 6.5, it is theoretical that urine pH may play a role in calcium oxalate stone formation in individuals with high urine uric acid levels. Equally plausible is that the urinary uric acid does not directly influence calcium stone formation. The impact of urinary uric acid is dependent on the concentration of urine calcium and urine oxalate and is associated with low urine citrate.^2,7, 8, 9 Newer studies utilizing 24-hour urine data indicate that hyperuricosuria may not play a role in stone risk at all, and hyperuricosuria has an inverse relationship with stone risk.^3,S1

Figure 1.

Potential mechanisms that uric acid leads to calcium oxalate stone formation. (a) Urine uric acid reduces the solubility of calcium oxalate, causing them to “salt out” and crystallize. (b) Uric acid binds urinary inhibitors such as glycosaminoglycans, increasing the risk of calcium oxalate stone formation. (c) Uric acid is a nidus for calcium oxalate crystallization (i.e., epitaxy).

In uric acid stone formers, urine alkalinization is the mainstay of therapy. Low urine pH and uric acid stones are associated with metabolic syndrome, diabetes mellitus, and gout. In metabolic syndrome and diabetes mellitus, low urine pH is due to insulin resistance. In vitro studies show that insulin stimulates and increases transcription of sodium-hydrogen exchanger 3 on the renal tubular epithelium, increasing the secretion of hydrogen, thereby trapping ammonia in the urinary space in the form of ammonium. Insulin resistance leads to less sodium-hydrogen exchange, less ammonium formation, and thereby reduces urinary ammonia excretion. Uric acid stone formers exposed to a hyper insulinemic-euglycemic protocol to mimic insulin resistance have lower urine pH, lower urine citrate excretion, and lower ammonium excretion despite higher net acid excretion on 24-hour urine samples compared to healthy individuals.S2 To further demonstrate that insulin resistance can lower urine pH, use of pioglitazone in uric acid stone formers, regardless of presence of diabetes mellitus type 2, led to a significant increase in urine pH and increase in ammonia excretion as a proportion of total net acid excretion in response to an acid load.S3 Patients with gout also have impaired ammoniagenesis in response to an acid load.S4 Although the exact mechanism is unclear, it is likely that obesity and/or metabolic syndrome contribute to the low ammonium excretion in gout.

After alkalinization of the urine, other interventions can be used in uric acid stone formers to further reduce risk. Most cases of elevated urine uric acid are dietary, specifically high purine intake seen in animal protein diets. In our patient on day 2, his protein intake as was uric acid was mildly elevated compared to day 1. Hyperglycemia can also lead to purine production through pentose phosphate pathway. Other conditions associated with elevated urine uric acid include myeloproliferative diseases, tumor lysis syndrome, and metabolic and congenital conditions (Supplementary Table S1). Increasing fluid intake can further increase the capacity to dissolve undissociated uric acid.S1 For example, in the setting of low urine pH, the majority of uric acid will be undissociated. The solubility of undissociated uric acid is 90 mg/l, so a normal dietary load of 500 mg of uric acid requires a urine volume of at least 3.0 l to be kept in solution. In uric acid stone formers, XOI is reserved for patients who have systemic gout, cannot tolerate alkali therapy, cannot adequately increase urine pH because of diarrhea, or continue to form stones despite effective alkalinization.^5, S5

There is no clear consensus of when to utilize XOI in calcium oxalate stone formers; however, there is data showing it may be beneficial. The use of allopurinol in calcium oxalate stone formers and hyperuricemia demonstrated a reduced number of stone recurrences.¹ Notable in this study is that patients with elevated urine calcium more than 300 mg in 24 hours were excluded, so the effect of allopurinol in calcium oxalate stone formers with persistent hypercalciuria is unclear. The suggested mechanism of XOI is by reduction of urinary uric acid. The addition of allopurinol lowered serum and urine uric acid in calcium oxalate stone formers after 3 years compared to dietary intervention alone.S6 However, when allopurinol was compared to indapamide, there was no observable difference identified in urine uric acid levels.S6 Febuxostat lowered urine uric acid in calcium oxalate stone formers compared to both allopurinol and placebo cohorts, though no change in stone symptoms at 6 months was observed.S5 Given the short follow-up, interpreting a symptom-specified outcome was difficult to confirm. Pegloticase and rasburicase have not been evaluated in the context of kidney stone disease. Another suggested mechanism of XOI is by reducing endothelial dysfunction and oxidative stress, which play a role in stone formation.³ Although data supporting XOI for kidney stone prevention for patients with hyperuricosuria is not strong, in a subset population, its use may be effective.

For our patient, we discussed maintaining high fluid intake and low animal protein intake and monitoring for new stone episodes given his unremarkable metabolic profile and single stone episode. We also started allopurinol to address joint symptoms consistent with gout with the thought that it may also prevent calcium oxalate stone formation.

Disclosure

All the authors declared no competing interests.

Patient Consent

The authors declare that they have obtained consent from the patient discussed in the report.

Supplementary Material

Supplementary File (PDF)

Supplementary References. Table S1. Metabolic and congenital conditions associated with hyperuricosuria.