Nutrition, Inflammation and Insulin Resistance in End Stage Renal Disease-Aim 2
Condition: ESRD
MeSH terms: Kidney Failure, Chronic; Insulin Resistance; Inflammation
Intervention: anakinra; actos; placebo
Intervention description: 100 mg in syringes; administered subcutaneously 3 times a week for 12 weeks (3 months); 30 mg capsules; administered orally 1 capsule per day for 12 weeks (3 months); placebo capsules and injection
Intervention MeSH terms: Interleukin 1 Receptor Antagonist Protein
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 33.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No

Summary:

      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).
    

Eligibility criteria:

        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.