Sex-specific association of time-varying hemoglobin values with mortality in incident dialysis patients – the INVOR-Study

Background: Previous studies in dialysis patients showed an association between hemoglobin levels and all-cause mortality, however, without addressing sex differences. Methods: We followed 235 incident dialysis patients (61.7±14.0 years, m/f: 146/89) in a prospective single-center cohort study (INVOR-Study – Study of INcident Dialysis Patients in VORarlberg) applying a time-dependent Cox regression analysis using all measured laboratory values for up to more than seven years. In total, 12,242 hemoglobin measurements with a median of 47 (range 3–270) per patient were available to evaluate the impact of hemoglobin levels and their variability on all-cause mortality in a sex-stratified analysis. Nonlinear P-splines were used to allow flexible modeling of the association with mortality. Results: We observed an inverse relationship between increasing hemoglobin values and decreasing risk of mortality. The linear component of the nonlinear spline was highly significant for both, men (p=0.00005) and women (p=0.0000000052). The nonlinear component was also significant but less pronounced than the linear component. The inverse relationship was clear to see up to hemoglobin values of 12–13g/dL in women, which reached a plateau for higher values of hemoglobin. For men an inverse trend was observed but clearly attenuated when compared to women. After adjustment for additional parameters of inflammation and malnutrition as well as diabetes, the linear component was more significant in women (p=0.0018) than in men (p=0.023). Conclusions: This study applied the first time a time-dependent Cox regression analysis over a long-term observation period of several years using all available measurements. Besides the methodological advantages our data indicate a sex-specific linear as well as nonlinear effect of hemoglobin levels on all-cause mortality, which was markedly more pronounced in women.