Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Inflammation and Insulin Resistance as Novel Mechanisms of Wasting in Chronic Dialysis Patients

Over the last decade, there have been no proven therapies to lower the mortality and morbidity risk for chronic dialysis patients. One of the most important determinants of this poor clinical outcome is protein energy wasting (PEW), a unique and highly prevalent nutritional and metabolic abnormality primarily characterized by increased protein breakdown in the skeletal muscle compartment. Although the etiology and mechanisms leading to increased protein breakdown in chronic dialysis patients are complex and mostly ill‐defined, two well‐recognized and presumably interrelated metabolic abnormalities, insulin resistance and chronic inflammation, are likely to play a critical role in the pathogenesis of this condition. Multiple studies demonstrate the anabolic effects of insulin that extend beyond simple carbohydrate metabolism. Insulin is a mediator of accelerated protein breakdown in the catabolic condition such as advanced kidney disease. Chronic inflammation, a condition known to cause muscle catabolism in experimental conditions, has a strong association with advanced kidney disease in epidemiologic studies. Chronic inflammation is also known to induce insulin resistance, primarily by the induction of proinflammatory cytokines. The protein catabolic effects of inflammation and insulin resistance involve common cellular pathways. Thus, it is reasonable to speculate that chronic inflammation of advanced kidney disease mediates its protein catabolic effects by inducing insulin resistance of protein metabolism at both the physiologic and cellular levels. Modulating inflammatory response or insulin signaling by pharmacologic interventions could allow us to clarify the mechanisms contributing to the development of PEW in the setting of these particular metabolic derangements.