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Pathophysiology of Uric Acid Nephrolithiasis (IUAN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00904046
Recruitment Status : Recruiting
First Posted : May 19, 2009
Last Update Posted : May 19, 2020
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Takeda Pharmaceuticals North America, Inc.
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

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.

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.

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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
Actual Study Start Date : September 5, 2019
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Stones

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.

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00904046

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Contact: Ann Heard-Sakhaee, RN 214-648-4893
Contact: Marsha Roberts, RN 214-648-0399

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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.
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Principal Investigator: Khashayar Sakhaee, MD UT Southwestern
Additional Information:
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Responsible Party: University of Texas Southwestern Medical Center Identifier: NCT00904046    
Other Study ID Numbers: Study00000125
1R01DK081423 ( U.S. NIH Grant/Contract )
First Posted: May 19, 2009    Key Record Dates
Last Update Posted: May 19, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Texas Southwestern Medical Center:
Uric acid
Additional relevant MeSH terms:
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Kidney Calculi
Kidney Diseases
Urologic Diseases
Pathological Conditions, Anatomical
Urinary Calculi
Hypoglycemic Agents
Physiological Effects of Drugs