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NCT00904046 Clinical Trial

Pathophysiology of Uric Acid Nephrolithiasis

Uric Acid Kidney Stone Disease Clinical Trial

— IUAN  

Official title:
Pathophysiology of Uric Acid Nephrolithiasis

Clinical Trial Details — Status: Recruiting

Administrative data
NCT number NCT00904046
Other study ID # Study00000125
Secondary ID 1R01DK081423
Status Recruiting
Phase N/A
First received
Last updated
Start date September 5, 2019
Est. completion date December 31, 2024

Study information
Verified date December 2023
Source University of Texas Southwestern Medical Center
Contact Ann Heard-Sakhaee, RN
Phone 214-648-4893
Email Ann.Heard-Sakhaee@UTSouthwestern.edu
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This study has two aims: Aim 1: To determine the presence of accumulation of fat within cells and the functional consequences of this in the kidney by correlating kidney fat content with urine test results. Aim 2: The investigators will evaluate the effect of thiazolidinedione (pioglitazone) on excess fatty acid accumulation in kidney tissue and its correlation with uric acid stone formation in subjects with uric acid stones. Pioglitazone is already U.S. Food & Drug Administration (FDA)-approved for the treatment of type 2 diabetes, but is not approved by the FDA for treating or preventing or diagnosing stone risk.

Description:

The study will use a combination of cell culture, animal, and human studies employing some of the latest technologies in magnetic resonance spectroscopy and single-photon emission computed tomography, combined with classical physiology, biochemistry, and molecular biology to test four interrelated hypotheses. There is increased uptake of free fatty acids into the kidney as a result of higher circulating levels as well as preferential transport by the proximal tubule as part of a "conditioning" effect. The increased provision of free fatty acid supplies metabolic substrate for ATP generation hence reducing the consumption of other substrates such as glutamine, which is the principal source of ammoniagenesis by the proximal tubule. This substrate competition, or metabolic switch, can lower the formation of the major urinary buffer ammonia, even in the absence of injury to the proximal tubule. With sustained lipid loading of the proximal tubule that exceeds its oxidative capacity, lipid storage is first activated but with time, toxic lipid metabolites may build up. We have evidence that excess saturated fat, which is prevalent in the Western diet, leads to proximal tubule lipotoxicity manifested as endoplasmic reticulum (ER) leakage/stress, and we propose that defective ammoniagenesis is part of a broader lipotoxic phenotype. We further propose that accumulation of a specific lipid species may be responsible for the toxicity. To test whether proximal tubule steatosis and lipotoxicity in humans have a functional consequence, we will study uric acid stone formers. Having previously shown that thiazolidinediones (TZD) reduce renal steatosis and lipotoxicity and improve ammonium excretion in animals, we have initiated a randomized intervention trial with TZD or placebo in human uric acid stone formers. The interim analysis showed that after 6 months of TZD therapy, stone formers had improved urinary biochemical parameters and reduced propensity for uric acid precipitation. We will continue this trial but add a novel highly sensitive method to non-invasively measure renal fat, testing whether improvement in urinary biochemistry associates with reduction of renal fat. This proposal addresses fundamental concepts of renal tubular lipid biology and lipotoxicity, and clinically will shift the paradigm of uric acid stone therapy from empiric urinary alkalinization to specific reduction in renal fat. We will also introduce cutting-edge human imaging studies for kidney research.

Recruitment information / eligibility
Status Recruiting
Enrollment 60
Est. completion date December 31, 2024
Est. primary completion date November 30, 2024
Accepts healthy volunteers No
Gender All
Age group 21 Years to 99 Years
Eligibility Inclusion Criteria: - Subjects with uric acid kidney stone disease - Age > 21 years Exclusion Criteria: - Body weight> 350 lb - Chronic alcohol use - Chronic liver disease - Chronic renal disease - Anemia - Contraindication to pioglitazone use: - history of congestive heart failure NYHA class III or IV - significant pedal edema - liver failure - not willing to practice an effective contraception for the duration of the study - Thiazolidinedione use in the preceding 18 months

Study Design

Related Conditions & MeSH terms

Intervention

Drug:
• Pioglitazone
30 mg orally daily for 6 months
• Placebo
Placebo taken orally once a day for 6 months.

Locations
Country Name City State
United States UT Southwestern Medical Center - Center for Mineral Metabolism Dallas Texas

Sponsors (3)
Lead Sponsor Collaborator
University of Texas Southwestern Medical Center National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Takeda Pharmaceuticals North America, Inc.

Country where clinical trial is conducted

United States, 

Outcome
Type Measure Description Time frame Safety issue
Primary Reversal of renal lipotoxicity will occur with pioglitazone. 6 months

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