Iron supplementation and mortality in incident dialysis patients: an observational study

Abstract

Background: Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting.

Methods: In our observational single-center cohort study (INVOR study) we prospectively studied 235 incident dialysis patients. Time-dependent Cox proportional hazards models using all measured laboratory values for up to 7.6 years were applied to study the association between iron supplementation and all-cause mortality, cardiovascular and sepsis-related mortality. Furthermore, the time-dependent association of ferritin levels with mortality in patients with normal C-reactive protein (CRP) levels (<0.5 mg/dL) and elevated CRP levels (≧0.5 mg/dL) was evaluated by using non-linear P-splines to allow flexible modeling of the association.

Results: One hundred and ninety-one (81.3%) patients received intravenous iron, 13 (5.5%) patients oral iron, whereas 31 (13.2%) patients were never supplemented with iron throughout the observation period. Eighty-two (35%) patients died during a median follow-up of 34 months, 38 patients due to cardiovascular events and 21 patients from sepsis. Baseline CRP levels were not different between patients with and without iron supplementation. However, baseline serum ferritin levels were lower in patients receiving iron during follow up (median 93 vs 251 ng/mL, p<0.001). Iron supplementation was associated with a significantly reduced all-cause mortality [HR (95%CI): 0.22 (0.08-0.58); p = 0.002] and a reduced cardiovascular and sepsis-related mortality [HR (95%CI): 0.31 (0.09-1.04); p = 0.06]. Increasing ferritin concentrations in patients with normal CRP were associated with a decreasing mortality, whereas in patients with elevated CRP values ferritin levels>800 ng/mL were linked with increased mortality.

Conclusions: Iron supplementation is associated with reduced all-cause mortality in incident dialysis patients. While serum ferritin levels up to 800 ng/mL appear to be safe, higher ferritin levels are associated with increased mortality in the setting of concomitant inflammation.

Figure 1. Survival curves for a) all-cause mortality and b) cardiovascular or sepsis-related mortality stratified for iron supplementation.

Adjusted for age, sex, time-dependent type of renal replacement therapy, diabetes, time-dependent C-reactive protein, albumin and hemoglobin. The number of patients at risk for each year of observation is given with the last observation time at 91 months. “% surv” indicates the percentage of survivors for each 12-month interval.

Figure 2. Cox regression results.

P-splines to explore the functional form of the effect of ferritin values (ng/mL) on the log hazard ratio for the risk of all-cause mortality and cardiovascular or sepsis-related mortality in patients with C-reactive protein <0.5 mg/dL and ≥0.5 mg/dL during follow-up, adjusted for age, sex, diabetes mellitus and time-dependent albumin and hemoglobin. Dashed lines are the pointwise 95% CI. The rugplot at the bottom of the figures displays the number of measurements.