Peroxisome Proliferator-Activated Receptor-Gamma Activation in Peritoneal Dialysis Patients

Study Overview
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Brief Summary
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To study whether peroxisome proliferator-activated receptor-gamma activation in peritoneal dialysis patients will reduce inflammation, atherosclerosis, calcification and improve survival of peritoneal dialysis patients

Detailed Description
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Peritoneal dialysis patients are at increased risk of cardiovascular morbidity and mortality and are related to the presence of accelerated atherosclerosis. Other than the traditional cardiovascular risk factors, there is increasing evidence that inflammation is associated with the development of atherosclerosis and cardiovascular events in both the general and dialysis population. C-reactive protein is predictive of higher all-cause mortality and cardiovascular mortality, independent of other cardiovascular risk factors and atherosclerotic vascular disease. As a considerable proportion of peritoneal dialysis patients showed elevated C-reactive protein, it raises an important question as to whether lowering C-reactive protein will have any cardiovascular and survival benefit in these patients. On the other hand, insulin resistance with associated hyperinsulinemia is frequently observed in chronic renal failure and dialysis patients. Although the exact mechanism of insulin resistance needs further evaluation, studies indicated that insulin resistance is an important cardiovascular risk factor and outcome predictor in the general and dialysis population. Moreover, recent evidence indicates an association between chronic inflammation and insulin resistance although the exact interrelationship remains unclear. The peroxisome proliferator-activated receptor-gamma (PPAR-g) is a member of the nuclear receptor family of ligand-dependent transcription factors. PPAR-g is highly expressed in adipose tissue and clinical study has confirmed efficacy of the specific ligands for PPAR-gamma, namely thiazolidinediones (TZD), in improving insulin sensitivity. Recent experimental and clinical studies demonstrated that TZD has anti-inflammatory and anti-atherosclerotic properties other than insulin sensitizing effect in type 2 diabetics. We hypothesize that modulation of the PPAR-g activity may be a novel therapeutic strategy for reducing inflammation and improving insulin sensitivity and may retard the progression of atherosclerosis and possibly reduce mortality of our peritoneal dialysis patients.

Official Title
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Targeting Peroxisome Proliferator-Activated Receptor-Gamma in Peritoneal Dialysis Patients - Will it Reduce Inflammation, Atherosclerosis, Calcification and Improve Survival of Peritoneal Dialysis Patients? (PROOF Trial)

Conditions
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End-stage Renal Disease

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Both prevalent patients or patients newly started on continuous peritoneal dialysis, with or without diabetes mellitus will be considered eligible for study entry. For patients newly started on chronic peritoneal dialysis, they will be suitable for recruitment into the study after one month on peritoneal dialysis. Patients who provide informed consent for the study Exclusion Criteria: Patients with underlying active malignancy Patients with chronic liver disease or liver cirrhosis Patients with active infections Patients with other chronic active inflammatory disease such as systemic lupus erythematosus, rheumatoid arthritis Patients who refuse study participation Patients with underlying congenital heart disease or rheumatic heart disease Patients with poor general condition Patients with plans for living related kidney transplant within 2 years Female patients with pregnancy Patients with history of recurrent hypoglycemia Patients with Class III and IV congestive heart failure Patients already receiving glitazones treatment at the screening visit

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind randomized placebo-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active intervention arm<br>Peroxisome proliferator activator receptor gamma treatment, Pioglitazone | Drug: Pioglitazone<br>* pioglitazone 15mg daily for 12 weeks, then 30mg daily for 84 weeks<br>* Other names: Actos;|
| Placebo Comparator: placebo pill<br>placebo comparator | Drug: placebo comparator<br>* 1 capsule daily, 96 weeks.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in carotid intima-media thickness | Change in carotid intima-media thickness | over 48 weeks | 
| change in flow mediated dilatation (marker of endothelial function) | change in flow mediated dilatation (marker of endothelial function) | over 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in aortic pulse wave velocity | change in aortic pulse wave velocity | over 96 weeks | 
| change in augmentation index-heart rate adjusted | change in augmentation index-heart rate adjusted | over 96 weeks | 
| change in nitroglycerin-mediated dilatation | change in nitroglycerin-mediated dilatation | over 48 weeks | 
| change in coronary artery calcium score | change in coronary artery calcium score | over 96 weeks | 
| change in heart valves calcium score | change in heart valves calcium score | over 96 weeks | 
| change in carotid artery calcium score | change in carotid artery calcium score | over 96 weeks | 
| change in abdominal visceral fat | change in abdominal visceral fat | over 96 weeks | 
| change in subcutaneous fat | change in subcutaneous fat | over 96 weeks | 
| change in blood pressure | change in blood pressure | over 96 weeks | 
| change in C-reactive protein | change in C-reactive protein | over 96 weeks | 
| change in residual kidney function | change in residual kidney function | over 96 weeks | 
| change in HOMA index (among those not on insulin) | Change in insulin resistance index | over 96 weeks | 
| change in D/P creatinine ratio | Change in peritoneal solute transport parameter | over 96 weeks | 
| change in peritoneal ultrafiltration with 2.5% during PET | Change in peritoneal ultrafiltration volume | over 96 weeks | 
| change in handgrip strength | change in handgrip strength | over 96 weeks | 
| Change in cardiac biomarkers | change in cardiac biomarkers | over 96 weeks | 
| change in insulin dose (among those on insulin) | change in insulin dose | over 96 weeks | 
| change in endothelial progenitor cells | change in endothelial progenitor cells | over 96 weeks | 
| change in central systolic blood pressure | change in central systolic blood pressure | over 96 weeks | 
| Change in central diastolic blood pressure | change in central diastolic blood pressure | over 96 weeks | 
| change in glycemic control (fasting glucose, and glycosylated hemoglobin) | change in glycemic control | over 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peritoneal dialysis, cardiovascular, PPAR-gamma