Metabolic syndrome and uric acid nephrolithiasis

The metabolic syndrome describes a cluster of metabolic features that increases the risk for type 2 diabetes mellitus and cardiovascular disease. The prevalence of uric acid nephrolithiasis is higher among stone-forming patients with features of the metabolic syndrome such as obesity and/or type 2 diabetes mellitus. The major determinant in the development of idiopathic uric acid stones is an abnormally low urinary pH. The unduly urinary acidity in uric acid stone formers increasingly is recognized to be one of the features observed in the metabolic syndrome. Two major abnormalities have been implicated to explain this overly acidic urine: (1) increased net acid excretion, and (2) impaired buffering caused by defective urinary ammonium excretion, with the combination resulting in abnormally acidic urine. New information is emerging linking these defects to changes in insulin signaling in the kidney. This article reviews the epidemiologic and metabolic studies linking uric acid nephrolithiasis with the metabolic syndrome, and examines the potential mechanisms underlying the unduly acidic urine in these conditions.     

Biochemical profile of idiopathic uric acid nephrolithiasis

BACKGROUND: The objective of this study was to elucidate a biochemical profile of patients with idiopathic uric acid nephrolithiasis, without secondary causes (such as dehydration or diarrhea). Study subjects comprised 56 patients with idiopathic uric acid nephrolithiasis (UA stone group) who underwent a full outpatient evaluation. The control group was composed of 54 with absorptive hypercalciuria and 2 normal subjects, matched with the UA stone group according to age, body mass index, and gender. METHODS: Urinary pH and ammonium and serum and urinary uric acid were measured. The fractional excretion of urate was calculated. RESULTS: Compared with the control group, the UA stone group had a significantly higher serum uric acid and significantly lower urinary uric acid, pH (5.34 +/- 0.23 vs. 6.17 +/- 0.36, P < 0.001), and fractional excretion of urate (0.052 +/- 0.028 vs. 0.080 +/- 0.029, P < 0.001), but individual values overlapped considerably between the two groups. Discriminant analysis of the relationship between urinary pH and fractional excretion of urate yielded a "discriminant score," which provided a much better separation between the two groups, with a correct classification in 95.5% of subjects. In contrast, urinary ammonium, citrate, sulfate, and potassium did not differ between two groups. CONCLUSIONS: In idiopathic uric acid nephrolithiasis, urinary pH and fractional excretion of urate are significantly lower than in control subjects, suggestive of defects in urinary acidification and urate excretion. Since these impairments are believed to be associated with primary gout, the underlying disturbance in idiopathic uric acid nephrolithiasis may be primary gout.     

Prevention of recurrences in uric acid nephrolithiasis

Prophylactic treatment of uric nephrolithiasis was carried out in 28 cases for periods of 1 to 4 years without any recurrences.     

Novel insights into the pathogenesis of uric acid nephrolithiasis

PURPOSE OF REVIEW: The factors involved in the pathogenesis of uric acid nephrolithiasis are well known. A low urinary pH is the most significant element in the generation of stones, with hyperuricosuria being a less common finding. The underlying mechanism(s) responsible for these disturbances remain poorly characterized. This review summarizes previous knowledge and highlights some recent developments in the pathophysiology of low urine pH and hyperuricosuria. RECENT FINDINGS: Epidemiological and metabolic studies have indicated an association between uric acid nephrolithiasis and insulin resistance. Some potential mechanisms include impaired ammoniagenesis caused by resistance to insulin action in the renal proximal tubule, or substrate competition by free fatty acids. The evaluation of a large Sicilian kindred recently revealed a putative genetic locus linked to uric acid stone disease. The identification of novel complementary DNA has provided an interesting insight into the renal handling of uric acid, including one genetic cause of renal uric acid wasting. SUMMARY: The recognition of metabolic, molecular, and genetic factors that influence urinary pH, and uric acid metabolism and excretion, will provide novel insights into the pathogenesis of uric acid stones, and open the way for new therapeutic strategies.     

Successful management of uric acid nephrolithiasis with potassium citrate

Eighteen patients with uric acid nephrolithiasis (six with uric acid stones alone and 12 with both uric acid and calcium stones) underwent long-term treatment (1 to 5.33 years, mean of 2.78 years) with potassium citrate (30 to 80 mEq/day, usually 60 mEq/day). Urinary pH increased from low (5.30 +/- 0.31 SD) to normal (6.19 to 6.46) during treatment. Urinary content of undissociated uric acid, which was high to begin with at 204 +/- 82 mg/day, decreased to the normal range (64 to 108 mg/day) following treatment. Urinary citrate rose from 503 +/- 225 mg/day to 852 to 998 mg/day. Urinary saturation of calcium oxalate significantly declined with potassium citrate treatment. New stone formation rate declined from 1.20 +/- 1.68 stones/year to 0.01 +/- 0.04 stones/year (P less than 0.001 by chi square). Remission was experienced in 94.4% of patients, and the group stone formation rate declined by 99.2%. Detailed case reports were obtained in five patients showing different responses between sodium alkali and potassium alkali treatment. All five patients had persistently low urinary pH (typically less than 5.5) and normouricosuria, and four had hyperuricemia. Before treatment, they had stones surgically removed or spontaneously passed, which were pure uric acid in composition. When sodium alkali was give (as bicarbonate or citrate, 60 to 118 mEq/day), new stone formation continued in four patients, and a radiolucent (uric acid) calculus become "calcified" in the remaining patient. The stone analysis disclosed calcium oxalate in five patients and calcium phosphate in three patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis

Type 2 diabetes is a risk factor for nephrolithiasis in general and has been associated with uric acid stones in particular. The purpose of this study was to identify the metabolic features that place patients with type 2 diabetes at increased risk for uric acid nephrolithiasis. Three groups of individuals were recruited for this outpatient study: patients who have type 2 diabetes and are not stone formers (n = 24), patients who do not have diabetes and are uric acid stone formers (UASF; n = 8), and normal volunteers (NV; n = 59). Participants provided a fasting blood sample and a single 24-h urine collection for stone risk analysis. Twenty-four-hour urine volume and total uric acid did not differ among the three groups. Patients with type 2 diabetes and UASF had lower 24-h urine pH than NV. Urine pH inversely correlated with both body weight and 24-h urine sulfate in all groups. Urine pH remained significantly lower in patients with type 2 diabetes and UASF than NV after adjustment for weight and urine sulfate (P < 0.01). For a given urine sulfate, urine net acid excretion tended to be higher in patients with type 2 diabetes versus NV. With increasing urine sulfate, NV and patients with type 2 diabetes had a similar rise in urine ammonium, whereas in UASF, ammonium excretion remained unchanged. The main risk factor for uric acid nephrolithiasis in patients with type 2 diabetes is a low urine pH. Higher body mass and increased acid intake can contribute to but cannot entirely account for the lower urine pH in patients with type 2 diabetes.     

Uric acid nephrolithiasis

Uric acid nephrolithiasis may be the final manifestation of various pathophysiological processes. Recent advances in renal urate transport have elucidated mechanisms by which hyperuricosuria occurs. However, in most uric acid stone formers the primary pathophysiologic defect is an excessively acidic urine pH rather than hyperuricosuria. Insulin resistance may contribute to the development of acidic urine by augmenting endogenous acid production and decreasing renal ammonium excretion. Medical management strategies focus primarily on alkali treatment or decreasing hyperuricosuria.     

The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance

BACKGROUND: Uric acid nephrolithiasis primarily results from low urinary pH, which increases the concentration of the insoluble undissociated uric acid, causing formation of both uric acid and mixed uric acid/calcium oxalate stones. These patients have recently been described as exhibiting features of insulin resistance. This study was designed to evaluate if insulin resistance is associated with excessively low urinary pH in overtly healthy volunteers (non-stone formers) and if insulin resistance may explain the excessively low urinary pH in patients with uric acid nephrolithiasis. METHODS: Fifty-five healthy volunteers (non stone-formers) with a large range of body mass index and 13 patients with recurrent uric acid nephrolithiasis underwent hyperinsulinemic euglycemic clamp, 24-hour urinary studies, and anthropometric measurements of adiposity. A subgroup of 35 non-stone formers had 2-hour timed urinary collection before and during the hyperinsulinemic phase of the clamp studies. RESULTS: For the non-stone former population, low insulin sensitivity measured as glucose disposal rate significantly correlated with low 24-hour urinary pH (r= 0. 35; P= 0.01). In addition to the previously described acidic urine pH and hypouricosuria, patients with recurrent uric acid nephrolithiasis were found to be severely insulin resistant (glucose disposal rate: uric acid stone-formers vs. normals; 4.1 +/- 1.3 vs. 6.9 +/- 2.1 mg/min/kg of lean body mass, P= 0.008). Acute hyperinsulinemia was associated with higher urinary pH (6.1 +/- 0.7 at baseline to 6.8 +/- 0.7 during hyperinsulinemia; P < 0.0001), urinary ammonia excretion (2.7 +/- 1.6 mEq/2 hr at baseline and 4.0 +/- 2.6 mEq/2 hr P= 0.002) and urinary citrate excretion (48 +/- 33 mg/2 hr at baseline and 113 +/- 68 mg/2 hr P < 0.0001). CONCLUSION: We conclude that one renal manifestation of insulin resistance may be low urinary ammonium and pH. This defect can result in increased risk of uric acid precipitation despite normouricosuria.     

Shock wave lithotripsy for uric acid stones

OBJECTIVE: To report our experience of extracorporeal shock wave lithotripsy (SWL) for patients with uric acid stones. METHODS: From December 1987 to December 2003, a total of 443 patients with uric acid stones in the kidney or ureter accepted SWL using ultrasound-guided lithotripters together with alkali therapy. Among them, 168 patients with an average stone burden of 9.1 mm were treated using an EDAP LT-01 piezoelectric lithotripter. The other patients, with an average stone burden of 9.6 mm, were treated using a Dornier Compact S electromagnetic lithotripter. RESULTS: The average duration of treatment using the EDAP LT-01 device was 52.1 minutes with a pulse frequency of 1.25-2.5 shocks per second at 100% power. The average treatment parameters on the Dornier Compact S device were 3,196 shocks at 14.8 kV. For the EDAP LT-01, the 3-month stone-free rate was 86.4%, with a retreatment rate of 24.2%. For the Dornier Compact S, the 3-month stone-free rate was 90.3%, with a retreatment rate of 29.0%. Auxiliary therapy with the push-back technique was needed in 0.45% of patients with upper ureteral stones that could not be localized using ultrasound. The treatment results were best for stones smaller than 20 mm. No anaesthesia was required for any patient. CONCLUSION: SWL with ultrasound localization for uric acid stones is safe and effective. The combination of SWL with urine alkalization may further improve the stone-free rate.     

Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis.

A total of 15 patients with unilateral nephrostomy tubes after extracorporeal shock wave lithotripsy received either 0 (placebo), 100, 500, 1,000 or 2,000 mg. ascorbic acid on days 2 and 3 postoperatively. Before and after administration, successive 6-hour urine specimens were collected from the nephrostomy tube and from the contralateral kidney directly into a preservative to stabilize ascorbic acid and oxalate. In 1 patient in each group preservative was omitted from the collection pouch. Urinary oxalate was then measured enzymatically after removal of ascorbic acid with sodium nitrite. Preservatives proved necessary for full recovery of analyte. At doses of 500 mg. or more of ascorbic acid there was a statistically significant increase in urinary oxalate equivalent to 1.2 to 1.8% of the millimoles of ascorbate administered. This represented an increase in urinary oxalate excretion of 6 to 13 mg. per day per 1,000 mg. ascorbic acid supplement. This amount would increase the risk of calcium oxalate urolithiasis.