Pathophysiology of Uric Acid Nephrolithiasis

NCT ID: NCT00904046

Last Updated: 2024-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 172 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-01-15
• Study Completion Date: 2017-11-16

Brief 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.

Detailed 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.

Conditions

Uric Acid Kidney Stone Disease

Keywords

Uric acid; Nephrolithiasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Pioglitazone

For 60 Aim 2 Subjects Only - Pioglitazone (Actos)

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

30 mg orally daily for 6 months

Placebo

For 60 Subjects in Aim 2 Only - Placebo for Pioglitazone

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo taken orally once a day for 6 months.

Interventions

Pioglitazone

30 mg orally daily for 6 months

Intervention Type: DRUG

Placebo

Placebo taken orally once a day for 6 months.

Intervention Type: DRUG

Other Intervention Names

Thiazolidinedione

Eligibility Criteria

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Takeda Pharmaceuticals North America, Inc.

INDUSTRY

Sponsor Role: collaborator

University of Texas Southwestern Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Khashayar Sakhaee

Professor of Internal Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Khashayar Sakhaee, MD

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern

Locations

UT Southwestern Medical Center - Center for Mineral Metabolism

Dallas, Texas, United States

Countries

United States

Related Links

https://www.utsouthwestern.edu/education/medical-school/departments/min-metab-center/research.html

Center for Mineral Metabolism Website

Other Identifiers

1R01DK081423

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Study00000125

Identifier Type: -

Identifier Source: org_study_id