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Pathophysiology of Uric Acid Nephrolithiasis (IUAN)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2016 by University of Texas Southwestern Medical Center
Sponsor:
Collaborators:
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
ClinicalTrials.gov Identifier:
NCT00904046
First received: May 15, 2009
Last updated: October 27, 2016
Last verified: October 2016
  Purpose

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 Intervention
Uric Acid Kidney Stone Disease
Drug: Pioglitazone
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Pathophysiology of Uric Acid Nephrolithiasis

Resource links provided by NLM:


Further study details as provided by University of Texas Southwestern Medical Center:

Primary Outcome Measures:
  • Reversal of renal lipotoxicity will occur with pioglitazone. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: May 2009
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: April 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.
  Eligibility

Ages Eligible for Study:   21 Years to 99 Years   (Adult, Senior)
Genders Eligible for Study:   Both
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00904046

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

Additional Information:
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 
Study First Received: May 15, 2009
Last Updated: October 27, 2016
Health Authority: United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by University of Texas Southwestern Medical Center:
Uric acid
Nephrolithiasis

Additional relevant MeSH terms:
Nephrolithiasis
Kidney Calculi
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

ClinicalTrials.gov processed this record on December 02, 2016