Pathophysiology of Uric Acid Nephrolithiasis (IUAN)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Uric Acid Kidney Stone Disease	Drug: Pioglitazone; Drug: Placebo	Not Applicable

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Basic Science
Official Title:	Pathophysiology of Uric Acid Nephrolithiasis
Study Start Date :	May 2009
Estimated Primary Completion Date :	April 2019
Estimated Study Completion Date :	December 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Pioglitazone; For 60 Aim 2 Subjects Only - Pioglitazone (Actos)	Drug: Pioglitazone; 30 mg orally daily for 6 months; Other Name: Thiazolidinedione
Placebo Comparator: Placebo; For 60 Subjects in Aim 2 Only - Placebo for Pioglitazone	Drug: Placebo; Placebo taken orally once a day for 6 months.

Outcome Measures

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Primary Outcome Measures :

1. Reversal of renal lipotoxicity will occur with pioglitazone. [ Time Frame: 6 months ]

Eligibility Criteria

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

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

Contacts and Locations

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Contacts

Contact: Ann Heard-Sakhaee, RN	214-648-4893	Ann.Heard-Sakhaee@UTSouthwestern.edu
Contact: Marsha Roberts, RN	214-648-0399	marsha.roberts@UTSouthwestern.edu

Locations

United States, Texas
UT Southwestern Medical Center - Center for Mineral Metabolism	Recruiting
Dallas, Texas, United States, 75390-8885

Sponsors and Collaborators

University of Texas Southwestern Medical Center

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

Takeda Pharmaceuticals North America, Inc.

Investigators

Principal Investigator:	Khashayar Sakhaee, MD	UT Southwestern

More Information

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Additional Information:

Center for Mineral Metabolism Website 

Responsible Party:	Khashayar Sakhaee, Professor of Internal Medicine, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:	NCT00904046 History of Changes
Other Study ID Numbers:	00000125 - 856; 1R01DK081423 ( U.S. NIH Grant/Contract )
First Posted:	May 19, 2009
Last Update Posted:	October 31, 2016
Last Verified:	October 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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

Uric acid; Nephrolithiasis

Additional relevant MeSH terms:

Kidney Calculi; Nephrolithiasis; Kidney Diseases; Urologic Diseases; Urolithiasis; Urinary Calculi; Calculi; Pathological Conditions, Anatomical	Pioglitazone; Uric Acid; Hypoglycemic Agents; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents