Iron Supplementation and Mortality in Incident Dialysis Patients: An Observational Study

<div><p>Background</p><p>Studies on the association between iron supplementation and mortality in dialysis patients are rare and conflicting.</p><p>Methods</p><p>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.</p><p>Results</p><p>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 <i>vs</i> 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.</p><p>Conclusions</p><p>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.</p></div

The association of time-dependent HbA_1c with all-cause mortality, CVD events and the combination of CVD and PAD events using multiple Cox-proportional hazards models.

<p>For each model, estimated HRs are shown for the linear component of the non-linear P-spline as well as HRs for HbA_1c measurements per 1% increase.</p><p>*Adjusted for age, sex, time-dependent systolic blood pressure, diastolic blood pressure, albumin, CRP, hemoglobin and previous CVD <b>**</b>.</p><p>**<b>Cardiovascular disease events</b>: myocardial infarction, percutaneous transluminal coronary angioplasty, aortocoronary bypass, angiographically-proven coronary stenosis ≥50%, ischemic or hemorrhagic cerebral infarction, transient ischemic attack, carotid stenosis and carotid endarterectomy.</p><p>***<b>Cardiovascular and peripheral arterial disease events</b>: CVD events or significant ultrasound- or angiographically-proven vascular stenosis, percutaneous transluminal angioplasty, peripheral bypass, amputation.</p

Association between iron supplementation and all-cause mortality in patients with diabetes mellitus and without diabetes mellitus using time-dependent Cox proportional hazards models^*.

<p><b>*</b> Adjusted for age, sex and the time-dependent variables type of renal replacement therapy, C-reactive protein, albumin and hemoglobin.</p><p>Association between iron supplementation and all-cause mortality in patients with diabetes mellitus and without diabetes mellitus using time-dependent Cox proportional hazards models^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114144#nt113" target="_blank">*</a>}.</p

Cox regression results: P-splines to explore the functional form of the effect of HbA_1c values on the log hazard ratio for the risk of a) all-cause mortality and of b) cardiovascular disease events, adjusted for age, sex, time-dependent systolic blood pressure, diastolic blood pressure, albumin, CRP, hemoglobin and previous CVD.

<p>Dashed lines are the pointwise 95% CI. The rugplot at the bottom of the figures displays the number of measurements.</p

Studies in dialysis patients with diabetes mellitus which found an association between HbA_1c and different clinical outcomes.

<p>CV, cardiovascular; CVD cardiovascular disease; MI myocardial infarction; HD hemodialysis.</p><p>*exact numbers of events are not available.</p

Association between time-dependent ferritin and 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 using time-dependent Cox proportional hazards models.

<p>Shown for each model are estimated HRs for the linear component of the non-linear P-spline and HRs for ferritin measurements per 100 ng/mL increase.</p><p><b>*</b> Adjusted for age, sex, diabetes mellitus and time-dependent albumin and hemoglobin.</p><p>** <b>Cardiovascular or sepsis mortality</b>: myocardial infarction (MI), heart failure, sudden death, ischemic stroke, hemorrhagic stroke, sepsis.</p><p>Association between time-dependent ferritin and 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 using time-dependent Cox proportional hazards models.</p

Cox regression results.

<p>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.</p

Association between iron supplementation and all-cause mortality and cardiovascular or sepsis-related mortality using time-dependent Cox proportional hazards models^*.

<p><b>*</b> Adjusted for age, sex, diabetes mellitus and the time-dependent variables type of renal replacement therapy, C-reactive protein, albumin and hemoglobin.</p><p>** <b>Cardiovascular or sepsis mortality</b>: myocardial infarction (MI), heart failure, sudden death, ischemic stroke, hemorrhagic stroke, sepsis.</p><p>Association between iron supplementation and all-cause mortality and cardiovascular or sepsis-related mortality using time-dependent Cox proportional hazards models^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114144#nt111" target="_blank">*</a>}.</p

Causes of death stratified by HbA_1c <7% vs. ≥7% at baseline.

<p>Causes of death stratified by HbA_1c <7% vs. ≥7% at baseline.</p

Clinical characteristics of patients at baseline and during follow-up stratified for iron supplementation during follow-up.

<p>Mean ±SD [25^th, 50^th and 75^th percentile for cases of non-normal distribution] or number (%).</p>a<p>p<0.05;</p>b<p>p<0.01;</p>c<p>p<0.005;</p>d<p>p<0.001, comparison between patients who ever received iron supplementation and patients who never received iron supplementation during the observation period.</p><p>* <b>Coronary artery disease (CAD)</b>: myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), aortocoronary bypass (ACBP).</p><p>** <b>Cardiovascular disease (CVD)</b>: myocardial infarction (MI), percutaneous transluminal coronary angioplasty (PTCA), aortocoronary bypass (ACBP), coronary artery stenosis ≥50%, ischemic cerebral infarction, transient ischemic attack (TIA)/PRIND.</p><p>*** <b>Peripheral arterial disease (PAD)</b>: vascular stenosis, percutaneous transluminal angioplasty (PTA), peripheral bypass, amputation.</p>‡<p>Follow-up time was calculated as the time from the start of dialysis until the patient died or the end of the observation period was reached.</p>#<p><b>Cardiovascular mortality</b>: myocardial infarction (MI), heart failure, sudden death, ischemic stroke, hemorrhagic stroke.</p><p>Clinical characteristics of patients at baseline and during follow-up stratified for iron supplementation during follow-up.</p