Pathogenesis of Uric Acid Nephrolithiasis: Role of Pioglitazone/Weight Loss
Pathogenesis of Uric Acid Nephrolithiasis: Role of Pioglitazone/Weight Loss
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)