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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050777-05
Application #
6381038
Study Section
Special Emphasis Panel (SRC (01))
Program Officer
Eggers, Paul Wayne
Project Start
1997-08-25
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2003-05-31
Support Year
5
Fiscal Year
2001
Total Cost
$298,429
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Kaysen, George A; Kotanko, Peter; Zhu, Fansan et al. (2009) Relationship between adiposity and cardiovascular risk factors in prevalent hemodialysis patients. J Ren Nutr 19:357-64
Kaysen, George A; Levin, Nathan W; Mitch, William E et al. (2006) Evidence that C-reactive protein or IL-6 are not surrogates for all inflammatory cardiovascular risk factors in hemodialysis patients. Blood Purif 24:508-16
Kaysen, George A (2005) Effects of inflammation on plasma composition and endothelial structure and function. J Ren Nutr 15:94-8
Kaysen, George A (2004) Inflammation: cause of vascular disease and malnutrition in dialysis patients. Semin Nephrol 24:431-6
Don, Burl R; Kaysen, George (2004) Serum albumin: relationship to inflammation and nutrition. Semin Dial 17:432-7
Kaysen, George A; Eiserich, Jason P (2004) The role of oxidative stress-altered lipoprotein structure and function and microinflammation on cardiovascular risk in patients with minor renal dysfunction. J Am Soc Nephrol 15:538-48
Kaysen, George A; Dubin, Joel A; Muller, Hans-Georg et al. (2004) Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. Kidney Int 65:1408-15
Kaysen, George A; Don, Burl R (2003) Factors that affect albumin concentration in dialysis patients and their relationship to vascular disease. Kidney Int Suppl :S94-7
Kaysen, George A; Eiserich, Jason P (2003) Characteristics and effects of inflammation in end-stage renal disease. Semin Dial 16:438-46
Kaysen, George A (2003) Serum albumin concentration in dialysis patients: why does it remain resistant to therapy? Kidney Int Suppl :S92-8

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