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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 : October 8, 2019
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Takeda Pharmaceuticals North America, Inc.
Information provided by (Responsible Party):
Khashayar Sakhaee, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE May 15, 2009
First Posted Date  ICMJE May 19, 2009
Last Update Posted Date October 8, 2019
Actual Study Start Date  ICMJE September 5, 2019
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 18, 2009)
Reversal of renal lipotoxicity will occur with pioglitazone. [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00904046 on Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Pathophysiology of Uric Acid Nephrolithiasis
Official Title  ICMJE Pathophysiology of Uric Acid Nephrolithiasis
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE Uric Acid Kidney Stone Disease
Intervention  ICMJE
  • Drug: Pioglitazone
    30 mg orally daily for 6 months
    Other Name: Thiazolidinedione
  • Drug: Placebo
    Placebo taken orally once a day for 6 months.
Study Arms  ICMJE
  • Experimental: Pioglitazone
    For 60 Aim 2 Subjects Only - Pioglitazone (Actos)
    Intervention: Drug: Pioglitazone
  • Placebo Comparator: Placebo
    For 60 Subjects in Aim 2 Only - Placebo for Pioglitazone
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 18, 2009)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ann Heard-Sakhaee, RN 214-648-4893
Contact: Marsha Roberts, RN 214-648-0399
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00904046
Other Study ID Numbers  ICMJE 00000125 - 856
1R01DK081423 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Khashayar Sakhaee, University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Takeda Pharmaceuticals North America, Inc.
Investigators  ICMJE
Principal Investigator: Khashayar Sakhaee, MD UT Southwestern
PRS Account University of Texas Southwestern Medical Center
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP