Increased production and reduced urinary buffering of acid in uric acid stone formers is ameliorated by pioglitazone

Abstract

Idiopathic uric acid nephrolithiasis is characterized by an overly acidic urine pH caused by the combination of increased acid production and inadequate buffering of urinary protons by ammonia. A large proportion of uric acid stone formers exhibit features of the metabolic syndrome. We previously demonstrated that thiazolidinediones improved the urinary biochemical profile in an animal model of the metabolic syndrome. In this proof-of-concept study, we examined whether the thiazolidinedione pioglitazone can also ameliorate the overly acidic urine in uric acid stone formers. Thirty-six adults with idiopathic uric acid nephrolithiasis were randomized to pioglitazone 30 mg/day or matching placebo for 24 weeks. At baseline and study end, participants underwent collection of blood and 24-hour urine in an inpatient research unit while consuming a fixed metabolic diet, followed by assessment of the ammoniagenic response to an acute oral acid load. Twenty-eight participants completed the study. Pioglitazone treatment improved features of the metabolic syndrome. Pioglitazone also reduced net acid excretion and increased urine pH (5.37 to 5.59), the proportion of net acid excreted as ammonium, and ammonium excretion in response to an acute acid load, whereas these parameters were unchanged with placebo. Treatment of patients with idiopathic uric acid nephrolithiasis with pioglitazone for 24 weeks led to a reduction in the acid load presented to the kidney and a more robust ammoniagenesis and ammonium excretion, resulting in significantly higher urine pH. Future studies should consider the impact of this targeted therapy on uric acid stone formation.

Keywords: insulin resistance; metabolic syndrome; nephrolithiasis; pioglitazone; thiazolidinedione; uric acid.

Figure 1.. Glucose and lipid metabolism.

Data shown as Least Square Means or ^ageometric means ± 95% confidence intervals. P values indicate difference between Baseline and 24 Weeks, * indicates the treatment and visit interaction P value for comparison between placebo and pioglitazone.

Figure 2.. Uric acid metabolism and excretion.

Data shown as Least Square Means ± 95% confidence intervals. P values indicate difference between Baseline and 24 Weeks, * indicates the treatment and visit interaction P value for comparison between placebo and pioglitazone.

Figure 3.. Acid-base profile.

Data shown as Least Square Means ± 95% confidence intervals. P values indicate difference between Baseline and 24 Weeks, * indicates the treatment and visit interaction P value for comparison between placebo and pioglitazone. Figure 3A-3E refer to 24hr urine studies. Figure 3F refers to acute response to an NH₄Cl load.