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

• ClinicalTrials.gov Identifier: NCT04370093
• Recruitment Status: Recruiting
• First Posted: April 30, 2020
• Last Update Posted: May 23, 2022
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Khashayar Sakhaee, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Nephrolithiasis, Uric Acid	Drug: Pioglitazone 45 mg; Behavioral: Weight Loss; Other: Pioglitazone + Weight Loss	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: Pathogenesis of Uric Acid Nephrolithiasis: Role of Pioglitazone/Weight Loss
• Actual Study Start Date: October 17, 2019
• Estimated Primary Completion Date: January 2024
• Estimated Study Completion Date: January 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pioglitazone Drug (including Placebo); 45 mg/day- one pioglitazone tablet once daily throughout the 24 weeks of the study	Drug: Pioglitazone 45 mg; 45 mg/day- one pioglitazone tablet once daily throughout the 24 weeks of the study
Experimental: Weight Loss, Behavioral; Weight loss following the Group Lifestyle Balance Program based on the Diabetes Prevention Program that utilizes cognitive behavioral strategies (goal setting, problem solving, self-monitoring, stimulus control),and provides written education materials to support health and nutrition behavior changes for weight management and disease prevention.	Behavioral: Weight Loss; Weight loss following the Group Lifestyle Balance Program based on the Diabetes Prevention Program that utilizes cognitive behavioral strategies (goal setting, problem solving, self-monitoring, stimulus control),and provides written education materials to support health and nutrition behavior changes for weight management and disease prevention.
Pioglitazone + Weight Loss; Pioglitazone 45 mg/day + Weight Loss following the Group Lifestyle Balance Program based on the Diabetes Prevention Program that utilizes cognitive behavioral strategies (goal setting, problem solving, self-monitoring, stimulus control),and provides written education materials to support health and nutrition behavior changes for weight management and disease prevention.	Other: Pioglitazone + Weight Loss; Pioglitazone + Weight loss following the Group Lifestyle Balance Program based on the Diabetes Prevention Program that utilizes cognitive behavioral strategies (goal setting, problem solving, self-monitoring, stimulus control),and provides written education materials to support health and nutrition behavior changes for weight management and disease prevention.

Outcome Measures

Primary Outcome Measures :

1. Urine pH [ Time Frame: 24 weeks ]
   24-hour urine pH is the main determinant of uric acid stone formation and recurrence.

Secondary Outcome Measures :

1. Urine Ammonium/Net Acid Excretion [ Time Frame: 24 weeks ]
   The ratio of urine ammonium to net acid excretion (NH4+/NAE) is a key pathophysiologic risk factor to uric acid stone formation. This is calculated from 24 hr urine ammonium and 24 hr urine net acid excretion.
2. Urine Net Acid Excretion/Sulphate [ Time Frame: 24 weeks ]
   Urine Net Acid Excretion to Sulphate ratio represents the diet-independent fraction of acid excreted. This is calculated from 24 hr urine net acid excretion and 24 hr urine sulphate.
3. Supersaturation Index of Uric Acid [ Time Frame: 24 weeks ]
   Supersaturation Index of Uric Acid is a calculated parameters that indicates the degree of urinary saturation with respect to uric acid.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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%

Contacts and Locations

Contacts

Contact: Khashayar Sakhaee, MD; 214-648-0324; Khashayar.Sakhaee@UTSouthwestern.edu

Contact: Miranda King, MPH; 214-648-2117; Miranda.King@utsouthwestern.edu

Locations

United States, Texas

University of Texas Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390-9107

Contact: Miranda King, MPH 214-648-2117 Miranda.King@utsouthwestern.edu

Contact: Sudeepa Bhattacharya, MPA 214-648-0395 Sudeepa.Bhattacharya@UTSouthwestern.edu

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Khashayar Sakhaee, MD; UTSW

More Information

• Responsible Party: Khashayar Sakhaee, Professor of Medicine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT04370093
• Other Study ID Numbers: STU-2019-0907
• First Posted: April 30, 2020
• Last Update Posted: May 23, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Khashayar Sakhaee, University of Texas Southwestern Medical Center:

Biomedical Sciences

Additional relevant MeSH terms:

Nephrolithiasis; Kidney Calculi; Weight Loss; Body Weight Changes; Body Weight; Kidney Diseases; Urologic Diseases; Urolithiasis; Urinary Calculi; Calculi; Pathological Conditions, Anatomical; Pioglitazone; Hypoglycemic Agents; Physiological Effects of Drugs