Metabolic Effects of Thiazolidinediones in Chronic Kidney Disease

The substantially increased cardiovascular morbidity and mortality rates in chronic kidney disease (CKD) patients cannot be sufficiently explained by traditional coronary risk factors. It is apparent that inflammation of the vessel wall plays an essential role in the pathophysiology of atherosclerosis, and the strong association between elevated inflammatory biomarkers and cardiovascular death further supports this mechanism. Approximately 50% of the mortality in this population of patients is attributable to cardiovascular disease. Insulin resistance is also a common problem in uremic patients. It has been shown that insulin resistance may contribute to atherosclerotic cardiovascular disease. An intriguing observation in CKD patients with advanced uremia is that the metabolic profile of these patients is characterized by persistent low-grade inflammation, a state of insulin resistance, and significantly increased prevalence of atherosclerosis. It is possible that these metabolic derangements can be the inciting factors for development and progression of uremic atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated nuclear transcription factor found in cells of the immune system and the vasculature, where it exerts an overall protective effect on the development of atherosclerosis, in part through modulation of inflammation. The agonists for PPAR-gamma improve not only the insulin resistance, but also have profound beneficial effects on inflammation, oxidative stress, endothelium, and lipid metabolism. In this proposal, the investigators hypothesize that short-term administration of a PPAR-gamma agonist (pioglitazone) will improve the inflammatory state, insulin resistance, and endothelial dysfunction in chronic kidney disease patients with advanced uremia.

Study Overview

• Status: Terminated
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: pioglitazone; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with Stage 3 or 4 chronic kidney disease as measured by a Modification in Diet in Renal Disease Study (MDRD) estimate of between 15 ml/min and 59 ml/min.
2. Age between 18 and 75 years old.
3. Patients without hospitalization for cardiac or infection related morbidity over the previous four weeks (due to the potential confounding effects on baseline study variables).
4. Patients who are able to provide consent to participate in the study.

Exclusion Criteria:

1. Patients with prior documented diagnosis of diabetes mellitus.
2. Patients with fasting blood glucose > 110mg/dL.
3. Prisoners, patients will significant mental illness, pregnant women, and other vulnerable populations.
4. Patients with active hepatic disease and/or ALT > 2.5 times upper limit of normal.
5. Patients with history of congestive heart failure and NYHA Class III-IV symptoms at any time.
6. Patients for whom living donor renal transplantation is already scheduled or in the process of being evaluated, as these patients will be unlikely to complete study protocols before transplantation.
7. Patients with severe co-morbid conditions (eg, symptomatic hepatic cirrhosis, metastatic cancer, HIV infection with AIDS).
8. Patient with active inflammatory process (eg., SLE, rheumatoid arthritis, gout) for which they are currently receiving immune modulating medications.
9. Patients who are on corticosteroid therapy.
10. Patients who do not consent to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2	Drug: placebo; 1 pill once a day for 12 weeks
Active Comparator: 1	Drug: pioglitazone; 30 mg once a day for 12 weeks; Other Names: ACTOS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
A decrease in C-reactive protein (CRP) levels	14 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Improved insulin resistance	14 weeks
Improved endothelium-dependent vasodilation	14 weeks

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: Alp Ikizler, MD, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): September 1, 2007
• Study Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: August 23, 2006
• First Submitted That Met QC Criteria: August 23, 2006
• First Posted (Estimate): August 24, 2006

Study Record Updates

• Last Update Posted (Estimate): November 3, 2010
• Last Update Submitted That Met QC Criteria: November 1, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 060042