Correspondence LETTERS TO THE EDITOR Intravenous Iron, Inflammation, and Ventricular Dysfunction During Hemodialysis To the Editor: Assa et al1 describe an association between circulating inflammatory cytokine concentrations and hemodialysis-induced left ventricular (LV) systolic dysfunction. The authors speculate that inflammation could adversely affect endothelial or myocyte function in the heart. Intravenous (IV) iron preparations cause inflammation, endothelial dysfunction, and oxidative stress, as reviewed by Van Buren et al.2 However, Assa et al1 did not address the possible etiologic contribution of IV iron. The proportion of patients receiving IV iron has increased substantially over the past 15 years, as have iron doses.3 In an international analysis, we recently reported an association between higher doses of IV iron and mortality among hemodialysis patients.4 We encourage the authors to examine whether there is an association (or a trend) between high IV iron doses and intradialytic LV dysfunction. We suggest comparing patients who received doses $ 300 mg/mo versus ,300 mg/mo, based on our mortality findings. It also would be of interest to see whether serum ferritin concentration, a marker of iron burden, correlates with LV dysfunction after adjustment for the other inflammatory markers. However, it is possible that the sample size of only 29 patients with LV dysfunction will prove too small to permit inferences. David A. Goodkin, MD1 George R. Bailie, PharmD, PhD2 1 Arbor Research Collaborative for Health, Ann Arbor, Michigan 2 Albany College of Pharmacy and Health Sciences, Albany, New York

Acknowledgements Financial Disclosure: Dr Goodkin has consulted for Allocure, Alnylam, Baxter, ChemoCentryx, FibroGen, Isis, Pieris, Rakth Therapeutics, Tengion, and Xenon. He also holds Xenon stock options and shares of Cempra Pharmaceuticals. Dr Bailie has received speaker fees from and has served on advisory panels for American Regent, Fresenius Medical Care, Mitsubishi Pharma, and Vifor.

References 1. Assa S, Hummel YM, Voors AA, et al. Hemodialysis-induced regional left ventricular systolic dysfunction and inflammation: a cross-sectional study. Am J Kidney Dis. 2014;64:265-273. 2. Van Buren P, Velez RL, Vaziri ND, Zhou XJ. Iron overdose: a contributor to adverse outcomes in randomized trials of anemia correction in CKD. Int Urol Nephrol. 2012;44:499-507. 3. Bailie GR, Larkina M, Goodkin DA, et al. Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2013;28:2570-2579. 4. Bailie GR, Larkina M, Goodkin DA, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015;87:162-168. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2014.09.030

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In Reply to ‘Intravenous Iron, Inflammation, and Ventricular Dysfunction During Hemodialysis’ To the Editor: We thank Drs Goodkin and Bailie1 for their relevant comments. While intravenous (IV) iron may promote inflammation, endothelial dysfunction, and oxidative stress,2-5 studies of the association between IV iron and cardiovascular outcome have showed divergent results. Bailie et al6 showed that cardiovascular mortality was significantly higher in patients receiving hemodialysis (HD) who were prescribed IV iron doses $ 300 mg/mo; however, IV iron was not associated with a higher incidence of cardiac adverse events in a randomized trial.7 Additionally, in patients with heart failure, IV iron improved functional capacity,8,9 reduced the risk of hospitalization for worsening heart failure,9 and had no adverse effect on survival.8,9 To address the questions of Drs Goodkin and Bailie, we calculated the cumulative IV iron and darbepoetin doses of all patients (n 5 105) in the 4 months preceding inclusion in our study and determined ferritin, iron, and transferrin concentrations in stored (280 C) plasma samples obtained prior to HD sessions.10,11 (Notably, no IV iron was administered during the HD sessions that occurred in our study.) As shown in Table 1, there were no significant differences in IV iron and darbepoetin doses, ferritin and iron levels, and transferrin saturations between patients with and without HD-induced regional left ventricular (LV) systolic dysfunction. There was a trend toward a lower proportion of patients receiving IV iron $ 300 mg/mo among those who developed regional LV systolic dysfunction. Although the relatively small sample size precludes firm conclusions, our findings do not support an association between IV iron and HD-induced regional LV systolic dysfunction.

Table 1. IV Iron and Darbepoetin Doses, Hematocrit, and Iron Parameters HD-Induced Regional LV Dysfunction

IV iron dose (mg/mo)a IV iron dose . 300 mg/mo Darbepoetin (mg/wk)b

All Patients (N 5 105)

Absent (n 5 76)

Present (n 5 29)

P

214 [107-273]

214 [107-309]

196 [107-214]

0.3

23 (22)

20 (26)

3 (10)

0.08

138 [80-226]

134 [76-223]

159 [80-284]

0.6 0.5

35.0 6 3.7

35.1 6 4.0

34.6 6 3.0

Ferritin (mg/L)

271 [126-594]

284 [134-630]

192 [116-466]

0.2

Iron (mmol/L)

8 [6-11]

9 [6-11]

7 [6-12]

0.3

17 [13-25]

17 [14-26]

15 [12-23]

0.2

Hematocrit (%)

Transferrin saturation (%)

Note: Values for continuous variables given as mean 6 standard deviation or median [interquartile range]; values for categorical variable, as number (percentage). The t test was used for normally distributed and Wilcoxon signed rank test for skewed parameters. The proportion of patients with IV iron dose . 300 mg/mo was tested with c2 test. Abbreviations: HD, hemodialysis; IV, intravenous; LV, left ventricular. a Ferricarboxymaltose in 83 patients; iron(III)-hydroxide dextran complex in 14 patients. b In the 13 patients who used epoetin beta, the weekly epoetin beta dose was divided by 200 to achieve darbepoetin equivalence.

Am J Kidney Dis. 2015;65(3):518-523