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Beta-2-microglobulin (β2M), a multifunctional protein involved in immune function, is a filtration marker that has been reported to predict renal failure, cancer, cardiovascular disease (CVD), and all-cause mortality. Previous studies of β2M and mortality were limited to select study samples (elderly or patient-based) lacking information on cancer or kidney function. We examined plasma β2M as a predictor of all-cause and cause-specific mortality in those with and without chronic kidney disease (CKD). The study sample consisted of Framingham Heart Study participants from the 2nd (n=3196) and 3rd (n=3911) generations who attended an on-site examination (2001-2007). Plasma β2M concentration was measured using a Luminex bead-based immunoassay. Mortality events were adjudicated by a physician committee. Proportional hazard models were conducted based on standardized values of β2M, adjusted for CVD risk factors, prevalent CVD, cancer, and family structure. We additionally analyzed subgroups stratified for CKD (defined as GFRckdepi < 60 mL/min/1.73 m2). The study sample included 7107 individuals [mean age 50 years, 54% female, 4% with prevalent CKD, mean length of follow-up: 13 years]. In the overall sample, β2M concentrations were associated with increased risk of CVD death (HR=1.42 [CI=1.17-1.72]), cancer death (HR=1.27 [CI=1.07-1.5]), and all-cause mortality (HR=1.27 [CI=1.16-1.4]). β2M performed better in participants with prevalent CKD than in those free of CKD. Adjusting for cystatin C, a filtration biomarker, did not affect the results. For all-cause mortality, including plasma β2M yielded a relative integrated discrimination improvement of 3% (p-value 0.03) beyond the covariate-only model. The net reclassification improvements (NRI) for all-cause mortality was 4% that was not statistically significant (p-value 0.26). We conclude that among middle-aged adults, plasma β2M is a predictor of all-cause and cause-specific mortality. Much of the risk associated with β2M is concentrated in those with CKD.