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

Emanuel Zitt,Gisela Sturm,Karl Lhotta,Günter Weiss,Ulrich Neyer,Florian Kronenberg,Florian Knoll,Kostas Pantopoulos

doi:10.1371/journal.pone.0114144

Abstract

BackgroundStudies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting.MethodsIn 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.ResultsOne 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.ConclusionsIron 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.

Highlights

Imbalances of iron homeostasis are a frequent finding in dialysis patients
These are due to true iron deficiency caused by gastrointestinal bleeding [1], blood loss with every hemodialysis session [2], decreased duodenal iron absorption [3] and by iron demand from the use of erythropoiesis-stimulating agents (ESA) [4]
Chronic inflammation of multiple causes in these patients results in impaired duodenal iron absorption and stimulates macrophage iron retention through the combined activities of the acute-phase protein hepcidin and cytokines [5]. All these mechanisms lead to iron-restricted erythropoiesis, which aggravates anemia due to the lack of erythropoietin found in association with chronic kidney disease

Summary

Introduction

Imbalances of iron homeostasis are a frequent finding in dialysis patients These are due to true iron deficiency caused by gastrointestinal bleeding [1], blood loss with every hemodialysis session [2], decreased duodenal iron absorption [3] and by iron demand from the use of erythropoiesis-stimulating agents (ESA) [4]. Chronic inflammation of multiple causes in these patients results in impaired duodenal iron absorption and stimulates macrophage iron retention through the combined activities of the acute-phase protein hepcidin and cytokines [5]. All these mechanisms lead to iron-restricted erythropoiesis, which aggravates anemia due to the lack of erythropoietin found in association with chronic kidney disease. Iron supplementation was associated with a significantly reduced all-cause mortality [HR (95%CI): 0.22 (0.08–0.58); p50.002] and a reduced cardiovascular and sepsis-related mortality [HR (95%CI): 0.31

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