The investigators will randomize overweight and obese iuan patients to Pio (45 mg/day, highest approved dose or placebo), WL (10% of body weight, following the established program used in the Diabetes Prevention Program), or Pio+WL. Participants will be evaluated at baseline and after 24 weeks of intervention while on a fixed metabolic diet to exclude the confounding effects of diet and perspiration. The primary endpoint will be change in upH, and multiple additional endpoints (serum, urine, imaging) will be assessed.

In IUAN patients, the investigator will compare 1. PPAR activation; 2. weight loss; or 3. combination; on urine acid-base parameters relevant to UA stone risk. The investigator will assess the effect of these interventions on fat distribution, insulin sensitivity, and serum adiponectin, and correlate these changes with urine chemistry.

Hypothesis: Weight loss + TZD independently result in durable changes in urine chemistry.

Significance: Epidemiology of uric acid nephrolithiasis: Nephrolithiasis is an increasingly prevalent condition that leads to significant pain1, work productivity loss2, reduced quality of life3, urinary tract infection4, chronic kidney disease5,6 and end-stage renal disease7. In the U.S., nephrolithiasis prevalence doubled in the past 30 years to a level similar to diabetes, and is the most expensive non-malignant urologic condition (2006 U.S. annual cost: $10 billion)8. Compared with other stone types, uric acid stones recur at a higher rate9, lead to more CKD10, and comprise a rising fraction of stones11,12 , in part due to the growing prevalence of obesity and diabetes13-18. The single most important pathogenic factor in human IUAN is an overly acidic urine, promoting protonation of urate to the insoluble UA16,19. In previously completed NIH-supported studies, the Investigator identified increased net acid excretion and blunted ammoniagenesis to be the principal metabolic defects underlying aciduria in humans IUAN and in rodent models of IUAN risk16,18,20-23. Treatment has been empirical urinary alkalinization24 which is efficacious but has not changed since 1986. Limitations include frequent dosing25, need for high dose in obese patients26, medication intolerance27, and need for periodic urine collections disliked by patients. Therapy that targets the underlying pathophysiologic defect rather than urinary chemistry is directly needed. The Investigator showed that the thiazolidinedione (TZD) pioglitazone that activates PPAR, improves systemic and urinary abnormalities in IUAN including impaired excessive acid excretion and ammoniagenesis, and results in a rise in UpH. TZD treatment of rodent IUAN model shows similar improvements28. The Investigator may have a therapy targeting the underlying pathobiology.

The translational potential of our regimen is extremely high and immediate. If combined TZD and weight loss (Aim) are efficacious in reducing stone risk, one can move straight to a clinical trial using hard outcomes such as stone events, and stone count by imaging to test this regimen. None of these maneuvers requires FDA approval to initiate. Patients will then have instant control of urinary chemistry with empiric alkali therapy (existing therapy), but also a chance to achieve more lasting improvement with TZD and weight loss, which reverses the pathophysiology. Separately, adiponectin (APN) receptor agonists are being developed as potential pharmacological agents for the management of metabolic syndrome complications including diabetes and dyslipidemia29,30. If approved, such agents could be tested as therapy for aciduria in the metabolic syndrome if adiponectin mediates the impact of TZD on renal ammoniagenesis.

UA nephrolithiasis is the clinically palpable sentinel of some complex underlying systemic pathophysiology; hence the impact of these studies extends beyond UA stones. The Investigator is examining a novel multi-organ paradigm of increased acid production from the gut that escapes hepatic metabolism, and ending up as an acid load imposed on the kidney. When compounded with renal ammoniagenesis defect, this leads to aciduria and UA lithogenesis. The Investigator will address some fundamental pathobiologic mechanisms of the metabolic syndrome. Due to the time and budget limits, the Investigator will concentrate our efforts to yield informative data; hence the renal focus. Our long-term goal is to use this as a portal to study multiple aspects of the gut, hepatic, and adipose pathophysiology of the metabolic syndrome.

Inclusion Criteria:

Idiopathic uric acid nephrolithiasis, with last stone analysis showing that stone has >90% uric acid in composition Age >21 years Any gender, race/ethnicity (from weight loss), but weight <165 Kg (to fit into MR instrument); eGFR>60ml/min/1.73 m2

Exclusion Criteria:

Bariatric surgery, chronic diarrhea, recurrent UTIs current insulin use use of a thiazolidinedione in past 2 years contraindication to thiazolidinedione use (liver dz, pedal edema, CHF NYHA class III/IV, no contraception) Bladder cancer Use of SGLT2-i, GLP-1 analogs, gemfibrozil, topiramate, rifampin Hba1c > 8.5%