application) The NIH has funded a multi-year multi-center study to establish the relationship between dialysis dose delivered (KT/V), dialyzer permeability and outcome in a group of hemodialysis patients studied in several centers to identify causes of increased mortality in end stage renal disease (ESRD) patients in the US - the HEMO study. While hypoalbuminemia is the most powerful predictor of death in ESRD, the cause of hypoalbuminemia in these patients is supplements do not increase albumin levels and intravenous amino acids are only partially and inconsistently beneficial. In contrast albumin synthesis and serum albumin increase promptly when patients are fed following starvation, suggesting that malnutrition may not be the primary case of hypoalbuminemia in ESRD. We propose to test an alternative hypothesis, that hypoalbuminemia results from suppressed albumin synthesis as part of the acute phase response rather than from malnutrition. Albumin concentration correlates with alpha2 macroglobulin (alpha2 M), C reactive protein (CRP) and serum amyloid A (SAA) in ESRD patients, and CRP predicts death better than does albumin concentration. Albumin synthesis correlates negatively with alpha2 M and not nutritional status, further supporting the hypothesis. We propose to determine the relative contributions of albumin synthesis, catabolism, redistribution and external albumin loss on baseline albumin levels in patients participating in the HEMO study using kinetic modeling of [125 1] albumin. We will measure albumin homeostasis in an equal number of patients with albumin levels in the lowest quartile and in the upper 3 quartiles in 3 participating centers. We will determine the relative effect of nutritional factors (dietary history, PCRn, anthropometrics) and the acute phase response (measurement of SAA, CRP, alpha2M, fibrinogen, IL-Beta and TNF theta) and albumin losses in establishing baseline albumin levels and synthesis rate using multiple regression models. We will then establish whether changes in nutritional status or inflammation precede changes in albumin concentration measuring nutritional status and acute phase proteins and cytokines monthly and loss of albumin across dialysis membranes bi-weekly. We will repeat kinetic albumin modeling after either a change in albumin concentration of 0.3 g/dL or after 24 months if albumin remains unchanged to identify changes in albumin homeostasis responsible for changes in albumin concentration. We will further establish the effect of KT/V, dialyzer permeability and reuse on changes in albumin, nutritional status and acute phase response.
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