Nutrition, Inflammation and Insulin Resistance in End Stage Renal Disease-Aim 2

Study Overview
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Brief Summary
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By 2030 an estimated 2 million people in the US will need dialysis or transplantation for advanced kidney failure. An even more disturbing statistic is that mortality in End Stage Renal Disease (ESRD) is six times higher than in the general Medicare population with adjustment for age, gender and ethnicity. Protein energy wasting is highly prevalent in these patients and is one of the most important determinants of their poor clinical outcome. Despite its well-recognized occurrence, the etiology and the mechanisms leading to protein energy wasting observed in chronic hemodialysis patients cannot be attributed to any single factor. However, irrespective of the specific etiologic mechanisms, it appears that the common pathway for all the metabolic derangements is related to exaggerated protein degradation relative to protein synthesis (47). Two well-recognized and presumably interrelated metabolic abnormalities, insulin resistance and chronic inflammation, may be the major determinants of protein catabolism in coronary heart disease (CHD) patients. There are no studies examining the effects of anti-inflammatory interventions and/or insulin sensitizers on protein homeostasis in CHD. Due to their established anti-inflammatory and other pleiotropic effects, Interleukin-1 receptor antagonist Anakinra and insulin sensitizer peroxisome proliferator-activated receptors (PPAR) agonist Actos represent two such promising interventions. By modulating inflammatory response and insulin signaling through two pharmacological interventions, the investigators will have the unique opportunity to clarify mechanisms contributing of these two particular metabolic derangements in the development of protein energy wasting observed in chronic hemodialysis patients. The overall goal is to elucidate the mechanisms by which chronic inflammation and insulin resistance influence the development of protein energy wasting in hemodialysis patients. Specific Aim: To test the hypothesis that inhibiting inflammatory response by administration of an Interleukin1receptor antagonist (Anakinra) or increasing insulin sensitivity by administration of a PPAR agonist (Actos) will improve net protein metabolism. Hypothesis: The chronic inflammatory component of protein energy wasting (PEW) observed in hemodialysis patients is, at least in part, mediated by insulin resistance. Interim analysis may be performed (no specific plan at this time).

Official Title
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Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease

Conditions
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ESRD

Intervention / Treatment
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* Drug: anakinra
* Drug: actos
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients on CHD undergoing three time a week therapy for more than 6 months; Age 21 years old; Acceptable dialysis adequacy (spKt/V > 1.2); A patent, well-functioning, arterio-venous dialysis access; Ability to give informed consent; Life expectancy greater than 6 months; BMI >=20 and <=45. Exclusion Criteria: Pregnancy; Intolerance or allergy to the study medication (including the metabolic clamp studies); Severe, unstable, active inflammatory disease (active infection, active connective tissue disorder), active cancer or cancer history in the prior 5 years except skin cancer, AIDS-HIV, active or history of liver disease (including hepatitis B virus and hepatitis C virus); Hospitalization or infection within 1 month prior to the study; Patients receiving steroids and/or other immunosuppressive agents (Prednisone > 5 mg/day; excluding inhaled and topical steroids); Diabetes Mellitus on insulin therapy; Previous history of tuberculosis (TB) with or without documented adequate therapy; Patients with recent close exposure to an individual with active TB; Females using oral contraceptives; Patients with New York Heart Association (NYHA) Class III or IV heart failure; Patients with a history of angina, myocardial infarction, transient ischemic attacks, or strokes within the last 6 months.

Ages Eligible for Study
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Minimum Age: 21 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: anakinra<br>100 mg of Anakinra in syringes administered subcutaneously 3 times a week for 3 months and lactose (placebo) in capsules administered orally 1 capsule per day for 3 months | Drug: anakinra<br>* 100 mg in syringes; administered subcutaneously 3 times a week for 12 weeks (3 months)<br>|
| Active Comparator: actos<br>Normal saline (placebo) in syringes administered subcutaneously 3 times a week for 3 months and 30 mg of Actos in capsules administered orally 1 capsule per day for 3 months | Drug: actos<br>* 30 mg capsules; administered orally 1 capsule per day for 12 weeks (3 months)<br>|
| Placebo Comparator: placebo 1 and 2<br>Normal saline (placebo) in syringes administered subcutaneously 3 times a week for 3 months and lactose (placebo) in capsules administered orally 1 capsule per day for 3 months | Other: placebo<br>* placebo capsules and injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Leucine Disposal Rate (LDR) | LDR is a sensitive laboratory assessment of amino acid metabolism | baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Whole-body Net Protein Balance | Whole-body net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the whole body | baseline and 3 months | 
| Change in Skeletal Muscle Net Protein Balance | Skeletal muscle net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the skeletal muscles. | baseline and 3 months |