Markers of Inflammation

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Thirty to fifty percent of patients receiving maintenance dialysis have evidence of an active inflammatory response (15,16). A growing body of evidence suggests that to accurately interpret serum protein status, an understanding of a patient's inflammatory state is critical. Nutritional and inflammatory stresses frequently coexist in people with CKD, and the predictive power of nutritional parameters for clinical outcome is partially or fully attenuated when nutritional parameters are adjusted for the presence of inflammation. Approximately 75% of patients with CKD have evidence of CVD. Proinflammatory cytokines and oxidative stress elicit an inflammatory response, and the presence of inflammation is closely associated with accelerated development of CVD and cardiovascular mortality. In contrast to levels of serum albumin and prealbumin, which generally rise during the first year following initiation of dialysis, circulating levels of inflammatory mediators [e.g., CRP, interleukin-6 (IL-6) and IL-10] do not improve with initiation of dialysis.

Inflammation blunts appetite and increases protein catabolism, lipolysis, and REE. The effect of inflammation on REE is subtle, increasing by approximately 10-15%, but over time, this sustained increase may result in protein-energy deficits, especially when combined with anorexia, which is a common side effect of both CKD and inflammation. Chronic inflammation in CKD patients can be caused by infections, interactions between the blood and dialyzer, contaminants in the dialysate, concomitant conditions, or a combination of these factors. In addition, dialysis itself, even when biocompatible dialysis membranes are used, results in transient inflammatory response that persists for several hours following treatment (17). Thus, an understanding of inflammatory status is increasingly accepted as a key part of biochemical nutritional assessment.

2.2.1. C-Reactive Protein and Proinflammatory Cytokines

A number of positive acute phase proteins can be used to document the presence of acute or chronic inflammation. The most common and consistently used is CRP, a nonspecific marker of inflammation and proinflammatory cytokine activity. CRP has a half-life of approximately 19 hours. Its catabolic rate is not affected by inflammation, while its synthetic rate and release is markedly up-regulated during an acute phase response. Thus, levels of CRP in stressed patients can rapidly rise by several orders of magnitude. Clinically, CRP is not routinely available, but should be considered when inflammation is suspected or when response to nutritional interventions is slower than expected.

Other clinically useful markers are the proinflammatory cytokines— tumor necrosis factor (TNF-a) and IL-6. Up-regulation of TNF-a and IL-6 contributes both to wasting and the high incidence of cardiovascular morbidity and mortality in people with CKD (18,19). Proinflammatory cytokine activity has numerous deleterious effects including the promotion of insulin resistance, anorexia, and oxidative stress. TNF-a stimulates lipolysis and impairs muscle synthesis, whereas IL-6 inhibits insulin growth factor-1 and plays a role in the development of sarcopenia (19).

Serum albumin levels are inversely correlated with CRP (6,20). However, because of its rapid turnover, CRP correlates less well with future albumin levels. In contrast, longer half-life positive acute phase proteins (e.g., ceruloplasmin or a-1 acid glycoprotein) are more predictive of future albumin levels (6). CRP is predictive of hospital-ization and cardiovascular morbidity and mortality, it is a marker for the presence of inflammation and CVD, and an independent predictor of all-cause and cardiovascular mortality in patients with stage 3 and 4CKD. Serum albumin and CRP both were independent predictors of all-cause mortality, suggesting that they either act via different mechanisms (e.g., nutritional vs. inflammatory) or at different points in the inflammatory process (21). CRP increases with declining kidney function prior to dialysis and continues to rise as dialyzed patients become anuric.

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