Inflammation, proteolysis and IL-1beta receptor inhibition in CHD patients

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DESCRIPTION (provided by applicant): / Abstract Chronic hemodialysis (CHD) patients display multiple metabolic abnormalities related to advanced uremia. Despite vigorous attempts to prevent these abnormalities and their consequences, most CHD patients suffer from a unique form of nutritional derangement, which can be termed as "uremic wasting". Several studies have demonstrated that the presence of uremic wasting, especially the degree of loss of muscle mass, sharply increases mortality and hospitalization rate in CHD patients. Several factors have been thought to be associated with uremic wasting, including hormonal derangement, anorexia, physical inactivity, and concurrent illnesses. Chronic inflammation, also highly prevalent in these patients, causes muscle catabolism in animal models and certain clinical conditions. Epidemiological studies show an association between chronic inflammation and uremic wasting in hemodialysis patients indicating a possible causal relationship. The cause for the activated inflammatory state in CHD patients is believed to be multi-factorial. Nevertheless, it is certainly important for the host to limit its biological activity by eliciting a stronger anti-inflammatory response, for example through the production of naturally occurring receptor antagonist. Interleukin 1 beta, one of the major pro-inflammatory cytokines has been shown to be associated with protein catabolism in several chronic disease states, including advanced uremia. A balance between interleukin 1 beta (agonist) and its naturally occurring receptor antagonist IL-1ra may play a pivotal role in controlling the inflammatory response and its consequences in this population. The overall goal of this particular grant application is to examine the short-term effects of the administration of the recombinant form of IL-1ra on 1) protein homeostasis in chronically inflamed CHD patients and in2) the chronic inflammatory state . We hypothesize that in chronically inflamed CHD patients, the administration of IL-1ra over 4 weeks will decrease their muscle protein breakdown leading to a net protein anabolic state and improve their inflammatory state. We will test this hypothesis through a prospective, randomized trial of IL-1ra administration over 4weeks designed to examine its effects on: 1) Muscle protein turnover rate (as assesed by stable isotope kinetic studies), and 2) Chronic inflammatory state (as measured by serum CRP concentration). If successful, the proposed studies will provide strong rationale for more detailed and potentially longer-term studies assessing the effects on more readily available nutritional parameters as well as morbidity and mortality. Ultimately, the administration of an anti-inflammatory agent may represent a new effective pathway for the treatment of uremic wasting in CHD patients Patients on dialysis suffer a high death rate. One of the most important factors responsible for this is a form of malnutrition termed as "uremic wasting". A manifestation of uremic wasting is progressive loss of muscle mass. Chronic inflammation is commonly seen in dialysis patients and has been linked to uremic wasting. We want to test if reducing inflammation with an anti-inflammatory treatment will reduce muscle loss in dialysis patients.