Article
Intravenous Iron Exposure and Mortality in Patients on Hemodialysis Dana C. Miskulin, Navdeep Tangri, Karen Bandeen-Roche, Jing Zhou, Aidan McDermott, Klemens B. Meyer, Patti L. Ephraim, Wieneke M. Michels, Bernard G. Jaar, Deidra C. Crews, Julia J. Scialla, Stephen M. Sozio, Tariq Shafi, Albert W. Wu, Courtney Cook, and L. Ebony Boulware for The Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network Patient Outcomes in End Stage Renal Disease Study Investigators
Abstract Background and objectives Clinical trials assessing effects of larger cumulative iron exposure with outcomes are lacking, and observational studies have been limited by assessment of short-term exposure only and/or failure to assess cause-specific mortality. The associations between short- and long-term iron exposure on all-cause and cause-specific mortality were examined.
Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
Design, setting, participants, & measurements The study included 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rolling windows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazards models that used marginal structural modeling to control for time-dependent confounding.
Correspondence: Dr. Dana C. Miskulin, Tufts Medical Center, Box 391, Division of Nephrology, 800 Washington Street, Boston, MA 02111. Email: dmiskulin@ tuftsmedicalcenter.org
Results Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during which there were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced risk of all-cause mortality with receipt of .150–350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or .350 mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with .0–150 mg over 1 month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infectionrelated mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardiovascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of .1050 mg intravenous iron in 3 months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and .2100 mg in 6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46). Conclusions Among patients on incident dialysis, receipt of #1050 mg intravenous iron in 3 months or 2100 mg in 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However, nonstatistically significant findings suggested the possibility of infection-related mortality with receipt of .1050 mg in 3 months or .2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure to greater cumulative intravenous iron doses. Clin J Am Soc Nephrol 9: 1930–1939, 2014. doi: 10.2215/CJN.03370414
Introduction Intravenous (IV) iron use in the United States hemodialysis (HD) population has increased (1) in recent years after changes in product labeling (2) and bundling of erythropoiesis-stimulating agents (ESAs) into dialysis per-treatment payments (3). The amount of iron that can be safely administered over the short and long term is unknown. In experimental studies, excess iron has been shown to impair phagocytosis and enhance bacterial virulence, increasing risk for infection (4–7). However, the iron concentrations achieved in these experiments greatly exceed the plasma iron levels achieved in clinical practice. Iron, a potent oxidant, may also play a role in atherosclerosis (8–11). Additionally, recent studies show hepatic iron content to be severely elevated in some patients on HD (12–14), although the clinical significance of this finding is unclear. 1930
Copyright © 2014 by the American Society of Nephrology
Clinical trials assessing the safety of more aggressive iron repletion on patient-centered outcomes have not been conducted, and observational studies have yielded inconsistent results (9,15–19). In a prevalent 1997–1998 HD population, receipt of a cumulative iron dose exceeding 1800 mg in 6 months was not associated with mortality (16). A more recent study found an increase in infection-related mortality and hospitalizations with receipt of .200 mg IV iron in 1 month and bolus as opposed to maintenance iron therapy (15). Exposures .1 month were not examined in the first study (16), and cause-specific mortality was not examined in the second study (16). Furthermore, both of these studies were conducted on prevalent populations and therein, may have been subject to survivor bias. Studies examining the association of administering varying doses of IV iron with clinical outcomes assessed www.cjasn.org Vol 9 November, 2014
Clin J Am Soc Nephrol 9: 1930–1939, November, 2014
over differing lengths of time among patients on HD with similar dialysis history could help better elucidate the safety of IV iron administration in clinical practice. Furthermore, it is possible that IV iron administration could decrease ESA requirements, leading to improvements in clinical outcomes, such as mortality. We examined associations of higher versus lower IV iron doses accumulated over 1, 3, and 6 months with all-cause, cardiovascular (CV), and infectionrelated mortality in an entirely incident HD population using analytic methods to account for potential time-varying confounders.
Materials and Methods Study Population The study, described in detail previously (20,21), included patients who initiated HD at dialysis units from a mediumsized national dialysis provider, Dialysis Clinic, Inc. (DCI), between January 1, 2003, and December 31, 2008, and had Medicare as the primary payer. Data Sources The electronic medical information system of DCI was the primary source of information about ESA and IV iron doses and laboratory test results. Data were linked to the US Renal Data System to obtain additional information about IV iron and ESA doses and Medicare claims. Cause of death was on the basis of the National Death Index. The study was conducted with adherence to the Declaration of Helsinki. The Johns Hopkins Medicine Institutional Review Board approved the study. Outcomes The primary outcome was all-cause mortality. We censored patients at the time of the switch from in-center HD to peritoneal or home HD, kidney transplant, transfer to another dialysis unit, loss to follow-up, December 31, 2008, or 4 years of follow-up. For analyses of infection-related and CV mortality, patients were censored for other causes of death. IV Iron Exposure Our primary exposure of interest was cumulative IV iron dose calculated as the sum of IV iron in milligrams (all formulations) administered over 1-, 3-, and 6-month rolling windows. We categorized IV iron doses into four mutually exclusive levels (no iron, low dose, moderate dose, or high dose) on the basis of the distribution of the data, previous analyses, and our clinical experience. Before 2009, IV iron was not administered by a protocol at DCI. Covariates We defined baseline comorbidity from inpatient and outpatient claims and diagnoses entered in the DCI database during the first 90 days after starting dialysis. We scored comorbidity using a previously validated ESRD-specific comorbidity index (22). We converted erythropoietin doses to average daily doses and summed doses across 30-day analytic periods. Then, we created an average weekly dose for the month by dividing by four. We used the percent saturation of transferrin (TSat) and serum ferritin measured closest to but not .90 days before the start of the
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iron exposure window. To replicate decision-making in practice, we considered the joint values of serum ferritin and TSat. We created a five-category variable reflecting the likelihood that iron would be prescribed. We defined vascular access type as the access in use on the first day of the month preceding the iron exposure window. We defined infection as (1) the use of IV antibiotics as recorded in DCI or Medicare claims or (2) a hospitalization with a primary diagnosis of infection within 21 days before the start of the iron exposure window. We defined noninfection-related hospitalizations as hospitalizations with a primary diagnosis other than infection occurring within 21 days before the start of the iron exposure window. Statistical Analyses We used marginal structural modeling (23,24) as our primary methodology for analyzing associations of IV iron dose with mortality, because prescribing decisions are affected by characteristics that reflect past prescribing decisions and also affect risk for death. We calculated monthly inverse probability weights to address timevarying confounding from the inverse of the predicted probability that each subject belonged to the dosing category in which his or her own observed iron dose at each follow-up month fell conditional on their histories of prior treatment and time-varying confounders deemed to affect both treatment choices and subsequent outcomes. Because treatment was defined by four levels of IV iron dose, we fitted multinomial logistic regression models for treatment probabilities. Treatment propensities were modeled before the start of the iron exposure window to avoid prediction of treatment by future information (Figure 1). For each 30-day interval, we calculated the inverse of the probability of receiving the treatment (e.g., treatment weight) and the inverse probability of dropping out of the study (e.g., censoring weight). We calculated final weights as the product of the treatment and censoring weights up to the month preceding the outcome assessment with stabilization using baseline demographic characteristics and comorbidity (23). We fit outcome models (separately) for 1-, 3-, and 6-month rolling window cohorts using iron exposure averaged over a single preceding interval as the primary predictor. They were implemented as discrete time proportional hazards models taking person-months as observations (25). Because we hypothesized that the effect of iron on CV disease death was delayed, although the effect on infection-related death was more immediate, we imposed a 30-day lag between iron exposure and CV mortality, with no lag for all-cause and infection-related mortality in our primary analyses. In sensitivity analyses, we also used similar models without the time lag. In marginal structural modeling analyses, a few people with very unusual treatment patterns may have extremely large weights (corresponding to small probabilities of their occurrence in the sample). Although disproportionate weighting is necessary to give them adequate representation in analyses, these few individuals may then greatly influence the analytic findings—a particularly troubling outcome when one considers that very large weights tend to be imprecisely estimated. A common remedy is to apply truncation—that is, set all weights higher than a specified level to that level. We truncated weights at a level of
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Clinical Journal of the American Society of Nephrology
Figure 1. | Timing of predictor, exposure, and outcome windows. Iron was accumulated during exposure windows of 30, 90, or 180 days. Time-dependent confounders were defined during 90 days before the exposure window, and the outcome was defined during 30 days after the exposure window (with a 30-day lag for the all-cause mortality model). Longitudinal analyses were conducted on the basis of parameters defined in successive 1-month increments of this series of windows from the start to end of follow-up for each individual. Details are in Materials and Methods and Supplemental Appendix.
10 (e.g., any weights.10 were reset to 10), a value selected a priori to conform with commonly invoked truncation thresholds and limit undue influence while not diverging too widely from a percentile-based truncation criterion of 1% of observations (23,24). At a weight truncation of 10, approximately 2%–5% of extreme weights were truncated. We conducted sensitivity analyses and truncated weights at 3, 5, 20, and 100. We accounted for outcome clustering by dialysis facilities using generalized estimating equations (26) and estimated robust SEMs. We performed statistical analyses using SAS 9.2 (SAS Institute Inc., Cary, NC). Detailed methods are provided in the Supplemental Appendix.
Results Characteristics of Study Cohorts Of 21,233 patients who initiated dialysis between January 1, 2003, and December 31, 2008, at DCI, 66.3%, 59.6%, and 51.3% met eligibility criteria (Figure 2) for the 1-, 3-, and 6-month cumulative iron dose analyses, respectively (Table 1). Patients receiving larger cumulative IV iron doses over 1 (Table 2), 3, or 6 months were more likely to be white and have diabetes; they had higher comorbidity index, lower serum albumin, and lower TSat and serum ferritin, and they were less likely to have a hemoglobin.12 g/dl (Supplemental Tables 2 and 3) The vast majority (86%, 85%, and 87%) of patients who received the highest IV iron doses over 1, 3, and 6 months, respectively, had serum ferritin#500 ng/ml. Association of IV Iron with Mortality in Weighted Models One-Month Cohort. In fully adjusted models, receipt of .150–350 mg and .350 mg IV iron were statistically significantly associated with 2% and 21%, respectively, lower hazards of all-cause mortality compared with the reference range (global test P=0.01). Findings for CV- and infection-related mortality were not statistically significant (Table 3). Three-Month Cohort. There was no association of cumulative IV iron dose over 3 months with all-cause or CV mortality. Findings for infection-related mortality were not statistically significant, and point estimates differed in direction (,1.0 and .1.0) for the dose ranges .450–1050 and .1050 mg relative to the reference dose (Table 3).
Six-Month Cohort. There were no associations of cumulative iron doses over 6 months with all-cause or CV mortality. Similar to infection-related mortality in the 3-month model, we observed a higher hazard of infection-related mortality for the highest dose category (.2100 mg for .6 months) but a lower hazard with the moderate dose category (900– 2100 mg) compared with the reference (.0–900 mg), and these associations were not statistically significant (Table 3). Sensitivity Analyses Influence of Imposing Lag on CV Disease Deaths When we eliminated the 30-day lag for ascertainment of CV disease deaths, the categories of .150–350 and .350 mg IV iron were associated with 27% and 26%, respectively, lower hazards of CV mortality (global test P=0.06), which contrasted with the lagged model in which the hazard ratios were close to one and not significant (Supplemental Table 4). Models of 3- and 6-month iron exposure and CV mortality without a lag did not differ from the lagged models. Altering Weight Truncations Results using weight truncations of 3, 5, 10, 20, and 100 in the weighted models were the same for all except two models (Supplemental Tables 7–15). The lower hazards of all-cause mortality with the .150–350 and .350 mg 1-month iron dose ranges that were found at a weight truncation of 10 were no longer statistically significant at a weight truncation of 20 or 100 (Supplemental Table 7). Point estimates were similar at all truncation levels, which may implicate amplified variability accompanying incorporation of extreme weights rather than residual confounding. In the 3-month model of infectionrelated death, the relationship of the .1050-mg IV iron dose range with infection-related mortality at weight truncations ,20 was not significant, but .20, it was significant (Supplemental Table 12). The difference in result may reflect better control for confounding by giving individuals more representative weights.20 or that these rare individuals with unusual treatment patterns are exerting undue influence on the model.
Discussion We assessed the associations of short- and longer-term cumulative IV iron doses with mortality in an incident HD
Clin J Am Soc Nephrol 9: 1930–1939, November, 2014
IV Iron and Mortality in Dialysis Patients, Miskulin et al.
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Figure 2. | Flow diagram of exclusions from the analytic cohorts for the 1-, 3-, and 6- month intravenous iron exposure models. The reasons for exclusions from the 1-, 3-, and 6-month model cohorts are shown. Accounting for the 90-day time window to define time-varying predictors, patients had to survive for a minimum of 120, 180, and 270 days to contribute to the 1-, 3-, and 6-month models of iron exposure, respectively. DCI, Dialysis Clinic, Inc.
Table 1. Study population size and number of events for the 1-, 3-, and 6-month iron exposure cohorts
Study Population and Event Rates
1-Month Iron Exposure Window
3-Month Iron Exposure Window
6-Month Iron Exposure Window
Study population, n Median (IQR) follow-up time, mo All-cause deaths, n (%) CVD deaths, n (%) Infection-related deaths, n (%)
14,078 19 (10–34) 3889 (27.6) 1896 (13.5) 424 (3.0)
12,646 22 (13–36) 3609 (28.6) 1778 (14.7) 388 (3.0)
10,899 25 (16–39) 2810 (25.8) 1404 (12.9) 293 (2.7)
IQR, interquartile range; CVD, cardiovascular disease.
population. We observed no evidence of increased all-cause or cause-specific mortality with administration of larger iron doses .1 month. Larger IV iron dose accumulations over 3 and 6 months were also not associated with all-cause or CV mortality, but there was a nonsignificant trend toward an increase in infection-related mortality. Results of this study would suggest that dose accumulations #1050 mg IV iron in 3 months and #2100 mg in 6 months are not associated with all-cause, CV, or infection-related mortality. However, findings suggest higher IV iron doses may increase infectionrelated mortality. Previous studies have produced conflicting results regarding the association of IV iron dose with clinical outcomes.
Studies with no or minimal adjustment for time-dependent confounding have shown increased mortality with cumulative IV iron doses .1000 mg in 6 months (17), .840 mg in 6 months (9), or .400 mg in 13 weeks (18). In a subsequent study, receipt of .1800 mg in 6 months at baseline was also associated with mortality, but the association was no longer significant after adjustment for time-dependent confounders (15). Our findings are consistent with that study. Our results for infection-related mortality are also consistent with a recent study that examined 1-month exposure in a mostly prevalent population and showed an increase in infectionrelated deaths and hospitalizations with higher short-term IV iron exposures (.200 mg IV iron per month) as well as
n Demographics Age, yr (median) Sex (%) Women Race (%) White Black Other Ethnicity (%) Hispanic Non-Hispanic Cause of ESRD (%) Diabetes Hypertension GN Other Baseline comorbidities Indexb Congestive heart failure (%) Diabetes (%) Hemoglobinopathyc (%) Ferritin (ng/ml) and TSat (%) combination Ferritin#500 and TSat#20 Ferritin#500 and TSat=21–30 Ferritin=501–800 and TSat#20 Ferritin.800 regardless of TSat Other Ferritin,500 ng/ml and TSat.30% Ferritin.501–800 ng/ml and TSat=20% Hemoglobin, g/dl (%) #10 10.1–11 11.1–12 .12 Mean weekly epogen dose, units/wk (%) #5000 5001–12,000 12,001–25,000 .25,000
Patient Characteristics 4193 64.0 45.4 59.3 36.2 4.4 6.5 93.5 46.1 26.7 9.6 17.7 4.0 (1.0–6.0) 40.8 58.8 4.8 33.1 19.2 4.3 21.0 22.4 11.3 11.1 9.4 12.4 23.2 54.9 24.7 19.9 27.9 27.5
64.0 44.9 60.2 35.6 4.3 5.6 94.5 47.7 27.7 9.1 15.5 4.0 (1.0–6.0) 40.5 61.4 3.6 46.7 20.8 5.7 8.6 18.2 8.7 9.5 7.8 11.3 24.1 56.7 18.3 18.7 30.2 32.8
None 14,078
Total Cohort
Table 2. Patient characteristics according to 1-month intravenous iron dose
24.7 22.5 27.7 25.1
6.3 10.0 22.8 61.0
37.4 21.8 7.1 6.2 27.5 11.9 15.6
3.0 (1.0–6.0) 38.2 58.9 2.6
44.8 29.2 9.6 16.4
5.1 94.9
59.2 36.2 4.6
44.5
63.0
1784
.0–150
18.8 20.1 31.1 30.0
6.1 8.9 24.5 60.6
44.4 25.8 6.5 3.0 20.2 9.4 10.8
3.0 (1.0–6.0) 39.5 63.1 3.2
48.7 28.9 9.3 13.1
4.7 95.3
60.4 35.1 4.5
44.6
64.0
3114
.150–350
Intravenous Iron Dose (mg)
10.4 15.3 32.5 41.8
8.6 12.3 25.0 54.1
62.9 18.4 5.9 2.7 10.1 4.8 5.3
4.0 (1.0–7.0) 41.9 63.4 3.1
49.5 27.3 8.3 14.8
5.4 94.6
61.1 35.0 3.9
44.9
63.0
4903
.350
,0.001
,0.001
0.11 0.03 ,0.001 ,0.001 ,0.001
,0.001
,0.01
0.47
0.47 0.88
P Valuea
1934 Clinical Journal of the American Society of Nephrology
IV Iron and Mortality in Dialysis Patients, Miskulin et al.
TSat, saturation of transferrin. a Comparison across subgroups of 1-month cumulative intravenous iron dose. b Median and interquartile range. c Includes sickle cell, hereditary spherocytosis, myelodysplasia, multiple myeloma, and other anemia not caused by erythropoietin or iron deficiency; mean serum albumin findings are rounded. Values were 3.55, 3.55, 3.58, and 3.57 for intravenous iron doses of none, .0–150 mg, .150–350 mg, and .350 mg, respectively.
0.04 0.72 ,0.001 0.14 0.52 ,0.001 18.4 8.7 72.9 3.6 (3.3–3.9) 6.1 (4.6–8.1) 27.9 (23.5–33.5) 18.3 6.5 1250 (800–1700) 18.5 9.8 71.6 3.6 (3.3–3.9) 6.1 (4.6–8.0) 27.2 (23.4–32.7) 18.8 6.3 1200 (650–1600) 17.9 8.5 73.6 3.6 (3.3–3.9) 6.2 (4.5–8.2) 26.6 (22.8–32.0) 19.0 6.1 1100 (500–1500) 17.7 9.4 72.9 3.6 (3.3–3.9) 6.1 (4.6–8.1) 27.2 (23.1–32.6) 19.1 6.5 1000 (300–1600)
Vascular access (%) Arteriovenous fistula Arteriovenous graft Central venous catheter Serum albumin (g/dl)b Serum creatinine (g/dl)b Body mass index (kg/m2)b Infection in past 21 d (%) Noninfection-related hospitalization in past 21 d (%) Iron (mg) over the past 3 mob
16.1 10.3 73.6 3.6 (3.3–3.9) 6.1 (4.6–8.1) 26.6 (22.8–31.7) 20.2 7.0 0 (0–150)
.150–350 .0–150 Total Cohort Patient Characteristics
Table 2. (Continued)
None
Intravenous Iron Dose (mg)
.350
,0.01
P Valuea
Clin J Am Soc Nephrol 9: 1930–1939, November, 2014
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bolus ($100 mg for two or more consecutive treatments in 1 month) versus maintenance therapy (15). Although two studies, including our study, suggest a relation between IV iron and greater risk of infection-related outcomes, inconsistencies in findings should be considered. The discordance in our findings for infection-related mortality and all-cause mortality, wherein we found an increase in infection-related deaths with higher cumulative IV iron dose but no effect on all-cause mortality, is counterintuitive. If iron truly increased infections, we would have expected an increase in all-cause mortality, considering that this population is an older, frail population (50% of patients had diabetes). A prior study linking higher shortterm iron exposure to infection-related outcomes in patients on HD (15) did not report on all-cause mortality. A recent meta-analysis examining outcomes associated with administering IV iron versus oral iron or no iron in various clinical trials involving iron-deficient (including HD) populations (27), also found an increased risk of infections but no effect on mortality. Discordance in findings regarding infection-related mortality and all-cause mortality could reflect bias caused by unmeasured confounders or, possibly, that IV iron increases infection-related deaths while decreasing noninfection-related deaths. We found no doseresponse relationship of IV iron with infection-related mortality, calling into question the validity of a possible causal relation between IV iron and infection-related mortality. The increased risk for infection-related death was only seen among the highest dose category of the 3- and 6-month exposure models, whereas the hazard ratios of the next highest dose categories in both models are ,1. Additionally, the prior study reported a modest 5% increased hazard of infection-related deaths and hospitalizations with the administration of bolus or high-dose IV iron compared with nonbolus or lower-dose IV iron (28). It is possible that the association that we observed between higher-dose IV iron may only indicate that patients who survived long enough to incur these higher doses were actually more ill, because they required more iron because of ineffective use or some other reason. Considering that blood is lost with each HD treatment (29), iron is used in ESA-stimulated erythropoiesis, and iron absorption is impaired (30), most patients on HD would be expected to be deficient in iron if iron were not repleted. Indeed, studies consistently show that administering IV iron increases hemoglobin and reduces ESA doses (31–36), even among patients with serum ferritin=500–1200 ng/ml (37,38). Given the range of documented and speculated toxicities of ESAs (39–41), it is possible that avoiding higher ESA doses by giving more IV iron may be of net benefit to patients, even if there were a modest increase in the risk of infection. Beyond its role in erythropoiesis, administering iron may increase or improve the function of other heme-containing proteins, specifically the cytochromes (42,43), which are integral to energy production and many metabolic processes. It has been speculated that iron deficiency itself may induce cardiomyopathies and CV-related deaths. Studies have shown left ventricular dilation and mitochondrial swelling as well as normal sarcomere structure in rats fed an iron-deficient diet for 12 weeks (44). Randomized control trials of administering IV iron in heart failure populations have shown reductions in inflammatory
34.32 20.16 23.96 21.56 19.17 25.59 34.48 20.77 9.19 31.14 47.10 12.57
45,247 60,407 81,396 49,038
18,555 62,845 95,058 25,375
Percent
90,178 53,302 63,327 56,993
n (patient-mo)
1.24 (0.92 to 1.69) Reference 0.98 (0.80 to 1.21) 1.12 (0.81 to 1.57)
1.19 (0.90 to 1.57) Reference 0.99 (0.81 to 1.20) 1.09 (0.84 to 1.42)
0.98 (0.79 to 1.22) Reference 0.78 (0.64 to 0.95) 0.79 (0.62 to 0.99)
HR (95% CI)
0.31
0.41
0.01
P Valueb
All-Cause Mortality
1.46 (0.98 to 2.16) Reference 1.15 (0.85 to 1.56) 1.17 (0.76 to 1.79)
1.06 (0.72 to 1.54) Reference 0.87 (0.67 to 1.14) 1.02 (0.74 to 1.41)
1.11 (0.84 to 1.48) Reference 1.08 (0.80 to 1.44) 0.95 (0.70 to 1.29)
HR (95% CI)
0.28
0.49
0.66
P Valueb
Cardiovascular Mortality
0.75 (0.29 to 1.95) Reference 0.98 (0.53 to 1.81) 1.59 (0.73 to 3.46)
0.86 (0.38 to 1.96) Reference 0.99 (0.56 to 1.74) 1.69 (0.87 to 3.28)
0.92 (0.54 to 1.57) Reference 0.77 (0.47 to 1.26) 1.26 (0.75 to 2.12)
HR (95% CI)
0.48
0.24
0.43
P Valueb
Infection-Related Mortalitya
The weighting on cumulative iron doses received was on the basis of iron history, age, sex, race, ethnicity, baseline comorbidity at 90 days, baseline body mass index, cause of ESRD, year of starting dialysis, baseline iron doses, hemoglobinopathies, saturation of transferrin (TSat)/ferritin categories, hemoglobin categories, weekly erythropoietin (EPO) doses categories, change in EPO, interaction of TSat/ferritin categories and hemoglobin categories, albumin, creatinine, predialysis systolic BP, body weight, change in weight, vascular access type, noninfection-related hospitalization, and infection. Demographics and baseline comorbidity were included in the outcome models. HR, hazard ratio; 95% CI, 95% confidence interval. a Models were adjusted for all covariates included in all-cause and cardiovascular morality models, except recent infection. b Global tests of iron exposure.
One-month iron exposure None .0–150 .150–350 .350 Three-month iron exposure None .0–450 .450–1050 .1050 Six-month iron exposure None .0–900 .900–2100 .2100
Doses (mg)
Table 3. Association of intravenous iron dose with time to all-cause, cardiovascular, and infection-related death
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Clin J Am Soc Nephrol 9: 1930–1939, November, 2014
markers and improvements in functional classification, exercise capacity, and quality of life, regardless of the continued presence of anemia (45,46), which may suggest a role for iron independent of effects on hemoglobin. A recent study found increased CV events and reduced survival associated with a TSat,20% relative to TSat=20%–40%, independent of hemoglobin level (47). A reduction in platelets is another postulated mechanism for a reduction in CV events with IV iron replacement (48). There are several unique strengths of our study. To date, this study is the only observational study relating IV iron dose to outcomes that has (1) been conducted on an entirely incident population, (2) assessed both short- and long-term exposures to IV iron, (3) examined effects on all-cause, infection-related, and CV deaths, and (4) examined iron doses and outcomes as early as 120 days after dialysis initiation, a time period during which larger doses of IV iron tend to be given (49) and the potential for harm may be greater because of greater central venous catheter use. Our study also had limitations. Although we adjusted for many potential confounders and used marginal structural modeling to attempt to control for time-dependent confounding, the potential for residual confounding remains. This concern may be particularly relevant to our analyses on infection-related mortality, for which our power to detect subtle associations was limited. The timing of adverse events relative to iron exposure is uncertain, and the difference between lagged and unlagged models for 1-month iron exposure and CV mortality further highlights the need for a prospective trial, in which adverse events are measured immediately after and over a longer period after iron exposure. Our study ended on December 31, 2008. Since that time, larger cumulative iron doses have been more frequently prescribed, potentially limiting the generalizability of our findings to current practice. The safety of administering higher doses of IV iron in patients with serum ferritin.500 ng/ml also may not have been assessed adequately, because it was an infrequent practice during the time course of this study. Our study was not designed to explore the influence of the pattern of iron administration on outcomes, which may be important, in addition to cumulative dose. It is possible that risk may be on the basis of iron preparations, which were not analyzed separately in this study. Nonetheless, our study represents one of the first studies to rigorously explore the potential association of cumulative IV iron use over shorter and longer periods and cause-specific mortality. In conclusion, we did not observe consistent findings of an association between higher cumulative IV iron doses over 1, 3, or 6 months with all-cause mortality or CV mortality, but there was a nonsignificant increase in infectionrelated mortality with receipt of .1050 mg IV iron in 3 months or .2100 mg in 6 months. Associations on the basis of observational data may be biased. Because a majority of patients on HD receives IV iron therapy, rigorously conducted and adequately powered clinical trials studying iron administration patterns reflective of presentday practice are greatly needed to provide definitive evidence about the safety of exposure to greater cumulative IV iron doses in patients on HD.
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Acknowledgments The authors express their gratitude to the staff and patients of Dialysis Clinic Inc. The Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network Patient Outcomes in ESRD Study was supported by Agency for Healthcare Research and Quality Contract HHSA290200500341I (Task Order 6). W.M.M. was supported by Dutch Kidney Foundation (Nierstichting) Postdoctoral Full Fellowship Abroad Grant (KFB 11.005). D.C.C. was supported by the Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation. J.J.S. was supported by National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) Grant K23DK095949. T.S. was supported by NIDDK Grant K23-DK083514. Parts of this manuscript were previously presented as a poster at the Annual American Society of Nephrology Meeting in San Diego, CA (October 30 to November 4, 2012). Identifiable information, on which this report, presentation, or other form of disclosure is based, is confidential and protected by federal law: Section 903(c) of the Public Health Service Act, 42 USC 299a-1(c). Any identifiable information that is knowingly disclosed is disclosed solely for the purpose for which it has been supplied. No identifiable information about any individual supplying the information or described in it will be knowingly disclosed except with the prior consent of that individual. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government. The DEcIDE Network Patient Outcomes in ESRD Study Team consists of members from Johns Hopkins University (K.B.-R., J.Z., A. M., P.L.E., W.M.M., B.G.J., D.C.C., S.M.S., T.S., A.W.W., C.C., L.E.B., Josef Coresh, Jeonyong Kim, Yang Liu, Jason Luly, and Paul Scheel), University of California, San Francisco (Neil Powe), Chronic Disease Research Group (Allan Collins, Robert Foley, David Gilbertson, Haifeng Guo, Brooke Heubner, Charles Herzog, Jiannong Liu, and Wendy St. Peter), Cleveland Clinic Foundation (Joseph Nally, Susana Arrigain, Stacey Jolly, Vicky Konig, Xiaobo Liu, Sankar Navaneethan, and Jesse Schold), University of New Mexico (Philip Zager), Tufts University (D.C.M. and K.B.M.), University of Miami (J.J.S.), University of Manitoba (N.T.), and Academic Medical Center (W.M.M.). Disclosures None. References 1. Fuller DS, Pisoni RL, Bieber BA, Gillespie BW, Robinson BM: The DOPPS Practice Monitor for US dialysis care: Trends through December 2011. Am J Kidney Dis 61: 342–346, 2013 2. FDA Drug Safety Communication: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease. Available at: http://www. fda.gov/Drugs/DrugSafety/ucm259639.htm. Accessed July 2, 2012 3. The Federal Register 42 CFR Parts 410, 413 and 414 Medicare Program; End-Stage Renal Disease Prospective Payment System; Final Rule and Proposed Rule. Available at: http://www.gpo. gov/fdsys/pkg/FR-2010-08-12/pdf/2010-18466.pdf. Accessed July 2, 2013 4. Boelaert JR, Daneels RF, Schurgers ML, Matthys EG, Gordts BZ, Van Landuyt HW: Iron overload in haemodialysis patients increases the risk of bacteraemia: A prospective study. Nephrol Dial Transplant 5: 130–134, 1990 5. Payne SM: Iron and virulence in the family Enterobacteriaceae. Crit Rev Microbiol 16: 81–111, 1988
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6. Seifert A, von Herrath D, Schaefer K: Iron overload, but not treatment with desferrioxamine favours the development of septicemia in patients on maintenance hemodialysis. Q J Med 65: 1015–1024, 1987 7. Sunder-Plassmann G, Patruta SI, Ho¨rl WH: Pathobiology of the role of iron in infection. Am J Kidney Dis 34[Suppl 2]: S25–S29, 1999 8. Dru¨eke T, Witko-Sarsat V, Massy Z, Descamps-Latscha B, Guerin AP, Marchais SJ, Gausson V, London GM: Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation 106: 2212– 2217, 2002 9. Kuo K-L, Hung S-C, Lin Y-P, Tang C-F, Lee T-S, Lin C-P, Tarng DC: Intravenous ferric chloride hexahydrate supplementation induced endothelial dysfunction and increased cardiovascular risk among hemodialysis patients. PLoS ONE 7: e50295, 2012 10. Reis KA, Guz G, Ozdemir H, Erten Y, Atalay V, Bicik Z, Ozkurt ZN, Bali M, Sindel S: Intravenous iron therapy as a possible risk factor for atherosclerosis in end-stage renal disease. Int Heart J 46: 255–264, 2005 11. Rooyakkers TM, Stroes ES, Kooistra MP, van Faassen EE, Hider RC, Rabelink TJ, Marx JJ: Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo. Eur J Clin Invest 32[Suppl 1]: 9–16, 2002 12. Ferrari P, Kulkarni H, Dheda S, Betti S, Harrison C, St Pierre TG, Olynyk JK: Serum iron markers are inadequate for guiding iron repletion in chronic kidney disease. Clin J Am Soc Nephrol 6: 77–83, 2011 13. Rostoker G, Griuncelli M, Loridon C, Couprie R, Benmaadi A, Bounhiol C, Roy M, Machado G, Janklewicz P, Drahi G, Dahan H, Cohen Y: Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: A MRI study. Am J Med 125: 991–999, 2012 14. Canavese C, Bergamo D, Ciccone G, Longo F, Fop F, Thea A, Martina G, Piga A: Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney Int 65: 1091–1098, 2004 15. Brookhart MA, Freburger JK, Ellis AR, Wang L, Winkelmayer WC, Kshirsagar AV: Infection risk with bolus versus maintenance iron supplementation in hemodialysis patients. J Am Soc Nephrol 24: 1151–1158, 2013 16. Feldman HI, Joffe M, Robinson B, Knauss J, Cizman B, Guo W, Franklin-Becker E, Faich G: Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 15: 1623–1632, 2004 17. Feldman HI, Santanna J, Guo W, Furst H, Franklin E, Joffe M, Marcus S, Faich G: Iron administration and clinical outcomes in hemodialysis patients. J Am Soc Nephrol 13: 734–744, 2002 18. Kalantar-Zadeh K, Regidor DL, McAllister CJ, Michael B, Warnock DG: Time-dependent associations between iron and mortality in hemodialysis patients. J Am Soc Nephrol 16: 3070– 3080, 2005 19. Kshirsagar AV, Freburger JK, Ellis AR, Wang L, Winkelmayer WC, Brookhart MA: Intravenous iron supplementation practices and short-term risk of cardiovascular events in hemodialysis patients. PLoS ONE 8: e78930, 2013 20. Boulware LE, Tangri N, Ephraim PL, Scialla JJ, Sozio SM, Crews DC, Shafi T, Miskulin DC, Liu J, St Peter W, Jaar BG, Wu AW, Powe NR, Navaneethan SD, Bandeen-Roche K; DEcIDE ESRD Patient Outcomes in Renal Disease Study Investigators: Comparative effectiveness studies to improve clinical outcomes in end stage renal disease: The DEcIDE patient outcomes in end stage renal disease study. BMC Nephrol 13: 167–177, 2012 21. Miskulin DC, Zhou J, Tangri N, Bandeen-Roche K, Cook C, Ephraim PL, Crews DC, Scialla JJ, Sozio SM, Shafi T, Jaar BG, Boulware LE; DEcIDE Network Patient Outcomes in End Stage Renal Disease Study Investigators: Trends in anemia management in US hemodialysis patients 2004-2010. BMC Nephrol 14: 264, 2013 22. Liu J, Huang Z, Gilbertson DT, Foley RN, Collins AJ: An improved comorbidity index for outcome analyses among dialysis patients. Kidney Int 77: 141–151, 2010 23. Herna´n MA, Brumback B, Robins JM: Marginal structural models to estimate the causal effect of zidovudine on the survival of HIVpositive men. Epidemiology 11: 561–570, 2000
24. Robins JM, Herna´n MA, Brumback B: Marginal structural models and causal inference in epidemiology. Epidemiology 11: 550– 560, 2000 25. Prentice RL, Gloeckler LA: Regression analysis of grouped survival data with application to breast cancer data. Biometrics 34: 57–67, 1978 26. Liang K-Y, Zeger SL: Longitudinal data analysis using generalized linear models. Biometrika 73: 13–22, 1986 27. Litton E, Xiao J, Ho KM: Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: Systematic review and meta-analysis of randomised clinical trials. BMJ 347: f4822, 2013 28. Monson R: Occupational Epidemiology, 2nd Ed., Boca Raton, FL, CRC Press Inc., 1990 29. Sargent JA, Acchiardo SR: Iron requirements in hemodialysis. Blood Purif 22: 112–123, 2004 30. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group: KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl 2: 295–296, 2012 31. Besarab A, Kaiser JW, Frinak S: A study of parenteral iron regimens in hemodialysis patients. Am J Kidney Dis 34: 21–28, 1999 32. Chang CH, Chang CC, Chiang SS: Reduction in erythropoietin doses by the use of chronic intravenous iron supplementation in iron-replete hemodialysis patients. Clin Nephrol 57: 136–141, 2002 33. DeVita MV, Frumkin D, Mittal S, Kamran A, Fishbane S, Michelis MF: Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients. Clin Nephrol 60: 335–340, 2003 34. Fishbane S, Frei GL, Maesaka J: Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26: 41–46, 1995 35. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE: A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 50: 1694– 1699, 1996 36. Sunder-Plassmann G, Ho¨rl WH: Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant 10: 2070–2076, 1995 37. Coyne DW, Kapoian T, Suki W, Singh AK, Moran JE, Dahl NV, Rizkala AR; DRIVE Study Group: Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: Results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 18: 975–984, 2007 38. Kapoian T, O’Mara NB, Singh AK, Moran J, Rizkala AR, Geronemus R, Kopelman RC, Dahl NV, Coyne DW: Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol 19: 372–379, 2008 39. Injection Epogen (Recombinant Epoetin Alpha) Prescribing Information. Available at: http://www.epogen.com/. Accessed July 11, 2014 40. Unger EF, Thompson AM, Blank MJ, Temple R: Erythropoiesisstimulating agents—time for a reevaluation. N Engl J Med 362: 189–192, 2010 41. Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK: Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 74: 791–798, 2008 42. Dallman PR: Biochemical basis for the manifestations of iron deficiency. Annu Rev Nutr 6: 13–40, 1986 43. Dallman PR, Schwartz HC: Myoglobin and cytochrome response during repair of iron deficiency in the rat. J Clin Invest 44: 1631– 1638, 1965 44. Dong F, Zhang X, Culver B, Chew HG Jr., Kelley RO, Ren J: Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: Involvement of nitric oxide synthase and protein tyrosine nitration. Clin Sci (Lond) 109: 277–286, 2005 45. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lu¨scher TF, Bart B, Banasiak W, Niegowska J, Kirwan B-A, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P; FAIR-HF Trial Investigators: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 361: 2436–2448, 2009
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46. Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Lu¨scher TF, Mori C, Willenheimer R, Ponikowski P, Anker SD: The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: A subanalysis of the FAIR-HF study. Eur Heart J 34: 30–38, 2013 47. Koo HM, Kim CH, Doh FM, Lee MJ, Kim EJ, Han JH, Han JS, Oh HJ, Park JT, Han SH, Yoo T-H, Kang S-W: The relationship of initial transferrin saturation to cardiovascular parameters and outcomes in patients initiating dialysis. PLoS ONE 9: e87231, 2014 48. Streja E, Kovesdy CP, Greenland S, Kopple JD, McAllister CJ, Nissenson AR, Kalantar-Zadeh K: Erythropoietin, iron depletion, and relative thrombocytosis: A possible explanation for hemoglobin-survival paradox in hemodialysis. Am J Kidney Dis 52: 727–736, 2008 49. USRDS: Assessment of the new bundled dialysis payment system and overview of the ESRD program. Presented at the Annual
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Meeting of the American Society of Nephrology, San Diego, CA, October 30-November 4, 2012 Received: April 2, 2014 Accepted: July 18, 2014 Published online ahead of print. Publication date available at www. cjasn.org. This article contains supplemental material online at http://cjasn. asnjournals.org/lookup/suppl/doi:10.2215/CJN.03370414/-/ DCSupplemental. See related editorial, “Intravenous Iron Exposure and Outcomes in Patients on Hemodialysis,” on pages 1837–1839.
Intravenous Iron Exposure and Mortality in Patients on Hemodialysis Dana C. Miskulin, Navdeep Tangri, Karen Bandeen-Roche, Jing Zhou, Aidan McDermott, Klemens B. Meyer, Patti L. Ephraim, Wieneke M. Michels, Bernard G. Jaar, Deidra C. Crews, Julia J. Scialla, Stephen M. Sozio, Tariq Shafi, Albert W. Wu, Courtney Cook, and L. Ebony Boulware for The Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network Patient Outcomes in End Stage Renal Disease Study Investigators
Abstract Background and objectives Clinical trials assessing effects of larger cumulative iron exposure with outcomes are lacking, and observational studies have been limited by assessment of short-term exposure only and/or failure to assess cause-specific mortality. The associations between short- and long-term iron exposure on all-cause and cause-specific mortality were examined.
Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
Design, setting, participants, & measurements The study included 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rolling windows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazards models that used marginal structural modeling to control for time-dependent confounding.
Correspondence: Dr. Dana C. Miskulin, Tufts Medical Center, Box 391, Division of Nephrology, 800 Washington Street, Boston, MA 02111. Email: dmiskulin@ tuftsmedicalcenter.org
Results Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during which there were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced risk of all-cause mortality with receipt of .150–350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or .350 mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with .0–150 mg over 1 month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infectionrelated mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardiovascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of .1050 mg intravenous iron in 3 months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and .2100 mg in 6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46). Conclusions Among patients on incident dialysis, receipt of #1050 mg intravenous iron in 3 months or 2100 mg in 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However, nonstatistically significant findings suggested the possibility of infection-related mortality with receipt of .1050 mg in 3 months or .2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure to greater cumulative intravenous iron doses. Clin J Am Soc Nephrol 9: 1930–1939, 2014. doi: 10.2215/CJN.03370414
Introduction Intravenous (IV) iron use in the United States hemodialysis (HD) population has increased (1) in recent years after changes in product labeling (2) and bundling of erythropoiesis-stimulating agents (ESAs) into dialysis per-treatment payments (3). The amount of iron that can be safely administered over the short and long term is unknown. In experimental studies, excess iron has been shown to impair phagocytosis and enhance bacterial virulence, increasing risk for infection (4–7). However, the iron concentrations achieved in these experiments greatly exceed the plasma iron levels achieved in clinical practice. Iron, a potent oxidant, may also play a role in atherosclerosis (8–11). Additionally, recent studies show hepatic iron content to be severely elevated in some patients on HD (12–14), although the clinical significance of this finding is unclear. 1930
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Clinical trials assessing the safety of more aggressive iron repletion on patient-centered outcomes have not been conducted, and observational studies have yielded inconsistent results (9,15–19). In a prevalent 1997–1998 HD population, receipt of a cumulative iron dose exceeding 1800 mg in 6 months was not associated with mortality (16). A more recent study found an increase in infection-related mortality and hospitalizations with receipt of .200 mg IV iron in 1 month and bolus as opposed to maintenance iron therapy (15). Exposures .1 month were not examined in the first study (16), and cause-specific mortality was not examined in the second study (16). Furthermore, both of these studies were conducted on prevalent populations and therein, may have been subject to survivor bias. Studies examining the association of administering varying doses of IV iron with clinical outcomes assessed www.cjasn.org Vol 9 November, 2014
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over differing lengths of time among patients on HD with similar dialysis history could help better elucidate the safety of IV iron administration in clinical practice. Furthermore, it is possible that IV iron administration could decrease ESA requirements, leading to improvements in clinical outcomes, such as mortality. We examined associations of higher versus lower IV iron doses accumulated over 1, 3, and 6 months with all-cause, cardiovascular (CV), and infectionrelated mortality in an entirely incident HD population using analytic methods to account for potential time-varying confounders.
Materials and Methods Study Population The study, described in detail previously (20,21), included patients who initiated HD at dialysis units from a mediumsized national dialysis provider, Dialysis Clinic, Inc. (DCI), between January 1, 2003, and December 31, 2008, and had Medicare as the primary payer. Data Sources The electronic medical information system of DCI was the primary source of information about ESA and IV iron doses and laboratory test results. Data were linked to the US Renal Data System to obtain additional information about IV iron and ESA doses and Medicare claims. Cause of death was on the basis of the National Death Index. The study was conducted with adherence to the Declaration of Helsinki. The Johns Hopkins Medicine Institutional Review Board approved the study. Outcomes The primary outcome was all-cause mortality. We censored patients at the time of the switch from in-center HD to peritoneal or home HD, kidney transplant, transfer to another dialysis unit, loss to follow-up, December 31, 2008, or 4 years of follow-up. For analyses of infection-related and CV mortality, patients were censored for other causes of death. IV Iron Exposure Our primary exposure of interest was cumulative IV iron dose calculated as the sum of IV iron in milligrams (all formulations) administered over 1-, 3-, and 6-month rolling windows. We categorized IV iron doses into four mutually exclusive levels (no iron, low dose, moderate dose, or high dose) on the basis of the distribution of the data, previous analyses, and our clinical experience. Before 2009, IV iron was not administered by a protocol at DCI. Covariates We defined baseline comorbidity from inpatient and outpatient claims and diagnoses entered in the DCI database during the first 90 days after starting dialysis. We scored comorbidity using a previously validated ESRD-specific comorbidity index (22). We converted erythropoietin doses to average daily doses and summed doses across 30-day analytic periods. Then, we created an average weekly dose for the month by dividing by four. We used the percent saturation of transferrin (TSat) and serum ferritin measured closest to but not .90 days before the start of the
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iron exposure window. To replicate decision-making in practice, we considered the joint values of serum ferritin and TSat. We created a five-category variable reflecting the likelihood that iron would be prescribed. We defined vascular access type as the access in use on the first day of the month preceding the iron exposure window. We defined infection as (1) the use of IV antibiotics as recorded in DCI or Medicare claims or (2) a hospitalization with a primary diagnosis of infection within 21 days before the start of the iron exposure window. We defined noninfection-related hospitalizations as hospitalizations with a primary diagnosis other than infection occurring within 21 days before the start of the iron exposure window. Statistical Analyses We used marginal structural modeling (23,24) as our primary methodology for analyzing associations of IV iron dose with mortality, because prescribing decisions are affected by characteristics that reflect past prescribing decisions and also affect risk for death. We calculated monthly inverse probability weights to address timevarying confounding from the inverse of the predicted probability that each subject belonged to the dosing category in which his or her own observed iron dose at each follow-up month fell conditional on their histories of prior treatment and time-varying confounders deemed to affect both treatment choices and subsequent outcomes. Because treatment was defined by four levels of IV iron dose, we fitted multinomial logistic regression models for treatment probabilities. Treatment propensities were modeled before the start of the iron exposure window to avoid prediction of treatment by future information (Figure 1). For each 30-day interval, we calculated the inverse of the probability of receiving the treatment (e.g., treatment weight) and the inverse probability of dropping out of the study (e.g., censoring weight). We calculated final weights as the product of the treatment and censoring weights up to the month preceding the outcome assessment with stabilization using baseline demographic characteristics and comorbidity (23). We fit outcome models (separately) for 1-, 3-, and 6-month rolling window cohorts using iron exposure averaged over a single preceding interval as the primary predictor. They were implemented as discrete time proportional hazards models taking person-months as observations (25). Because we hypothesized that the effect of iron on CV disease death was delayed, although the effect on infection-related death was more immediate, we imposed a 30-day lag between iron exposure and CV mortality, with no lag for all-cause and infection-related mortality in our primary analyses. In sensitivity analyses, we also used similar models without the time lag. In marginal structural modeling analyses, a few people with very unusual treatment patterns may have extremely large weights (corresponding to small probabilities of their occurrence in the sample). Although disproportionate weighting is necessary to give them adequate representation in analyses, these few individuals may then greatly influence the analytic findings—a particularly troubling outcome when one considers that very large weights tend to be imprecisely estimated. A common remedy is to apply truncation—that is, set all weights higher than a specified level to that level. We truncated weights at a level of
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Figure 1. | Timing of predictor, exposure, and outcome windows. Iron was accumulated during exposure windows of 30, 90, or 180 days. Time-dependent confounders were defined during 90 days before the exposure window, and the outcome was defined during 30 days after the exposure window (with a 30-day lag for the all-cause mortality model). Longitudinal analyses were conducted on the basis of parameters defined in successive 1-month increments of this series of windows from the start to end of follow-up for each individual. Details are in Materials and Methods and Supplemental Appendix.
10 (e.g., any weights.10 were reset to 10), a value selected a priori to conform with commonly invoked truncation thresholds and limit undue influence while not diverging too widely from a percentile-based truncation criterion of 1% of observations (23,24). At a weight truncation of 10, approximately 2%–5% of extreme weights were truncated. We conducted sensitivity analyses and truncated weights at 3, 5, 20, and 100. We accounted for outcome clustering by dialysis facilities using generalized estimating equations (26) and estimated robust SEMs. We performed statistical analyses using SAS 9.2 (SAS Institute Inc., Cary, NC). Detailed methods are provided in the Supplemental Appendix.
Results Characteristics of Study Cohorts Of 21,233 patients who initiated dialysis between January 1, 2003, and December 31, 2008, at DCI, 66.3%, 59.6%, and 51.3% met eligibility criteria (Figure 2) for the 1-, 3-, and 6-month cumulative iron dose analyses, respectively (Table 1). Patients receiving larger cumulative IV iron doses over 1 (Table 2), 3, or 6 months were more likely to be white and have diabetes; they had higher comorbidity index, lower serum albumin, and lower TSat and serum ferritin, and they were less likely to have a hemoglobin.12 g/dl (Supplemental Tables 2 and 3) The vast majority (86%, 85%, and 87%) of patients who received the highest IV iron doses over 1, 3, and 6 months, respectively, had serum ferritin#500 ng/ml. Association of IV Iron with Mortality in Weighted Models One-Month Cohort. In fully adjusted models, receipt of .150–350 mg and .350 mg IV iron were statistically significantly associated with 2% and 21%, respectively, lower hazards of all-cause mortality compared with the reference range (global test P=0.01). Findings for CV- and infection-related mortality were not statistically significant (Table 3). Three-Month Cohort. There was no association of cumulative IV iron dose over 3 months with all-cause or CV mortality. Findings for infection-related mortality were not statistically significant, and point estimates differed in direction (,1.0 and .1.0) for the dose ranges .450–1050 and .1050 mg relative to the reference dose (Table 3).
Six-Month Cohort. There were no associations of cumulative iron doses over 6 months with all-cause or CV mortality. Similar to infection-related mortality in the 3-month model, we observed a higher hazard of infection-related mortality for the highest dose category (.2100 mg for .6 months) but a lower hazard with the moderate dose category (900– 2100 mg) compared with the reference (.0–900 mg), and these associations were not statistically significant (Table 3). Sensitivity Analyses Influence of Imposing Lag on CV Disease Deaths When we eliminated the 30-day lag for ascertainment of CV disease deaths, the categories of .150–350 and .350 mg IV iron were associated with 27% and 26%, respectively, lower hazards of CV mortality (global test P=0.06), which contrasted with the lagged model in which the hazard ratios were close to one and not significant (Supplemental Table 4). Models of 3- and 6-month iron exposure and CV mortality without a lag did not differ from the lagged models. Altering Weight Truncations Results using weight truncations of 3, 5, 10, 20, and 100 in the weighted models were the same for all except two models (Supplemental Tables 7–15). The lower hazards of all-cause mortality with the .150–350 and .350 mg 1-month iron dose ranges that were found at a weight truncation of 10 were no longer statistically significant at a weight truncation of 20 or 100 (Supplemental Table 7). Point estimates were similar at all truncation levels, which may implicate amplified variability accompanying incorporation of extreme weights rather than residual confounding. In the 3-month model of infectionrelated death, the relationship of the .1050-mg IV iron dose range with infection-related mortality at weight truncations ,20 was not significant, but .20, it was significant (Supplemental Table 12). The difference in result may reflect better control for confounding by giving individuals more representative weights.20 or that these rare individuals with unusual treatment patterns are exerting undue influence on the model.
Discussion We assessed the associations of short- and longer-term cumulative IV iron doses with mortality in an incident HD
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Figure 2. | Flow diagram of exclusions from the analytic cohorts for the 1-, 3-, and 6- month intravenous iron exposure models. The reasons for exclusions from the 1-, 3-, and 6-month model cohorts are shown. Accounting for the 90-day time window to define time-varying predictors, patients had to survive for a minimum of 120, 180, and 270 days to contribute to the 1-, 3-, and 6-month models of iron exposure, respectively. DCI, Dialysis Clinic, Inc.
Table 1. Study population size and number of events for the 1-, 3-, and 6-month iron exposure cohorts
Study Population and Event Rates
1-Month Iron Exposure Window
3-Month Iron Exposure Window
6-Month Iron Exposure Window
Study population, n Median (IQR) follow-up time, mo All-cause deaths, n (%) CVD deaths, n (%) Infection-related deaths, n (%)
14,078 19 (10–34) 3889 (27.6) 1896 (13.5) 424 (3.0)
12,646 22 (13–36) 3609 (28.6) 1778 (14.7) 388 (3.0)
10,899 25 (16–39) 2810 (25.8) 1404 (12.9) 293 (2.7)
IQR, interquartile range; CVD, cardiovascular disease.
population. We observed no evidence of increased all-cause or cause-specific mortality with administration of larger iron doses .1 month. Larger IV iron dose accumulations over 3 and 6 months were also not associated with all-cause or CV mortality, but there was a nonsignificant trend toward an increase in infection-related mortality. Results of this study would suggest that dose accumulations #1050 mg IV iron in 3 months and #2100 mg in 6 months are not associated with all-cause, CV, or infection-related mortality. However, findings suggest higher IV iron doses may increase infectionrelated mortality. Previous studies have produced conflicting results regarding the association of IV iron dose with clinical outcomes.
Studies with no or minimal adjustment for time-dependent confounding have shown increased mortality with cumulative IV iron doses .1000 mg in 6 months (17), .840 mg in 6 months (9), or .400 mg in 13 weeks (18). In a subsequent study, receipt of .1800 mg in 6 months at baseline was also associated with mortality, but the association was no longer significant after adjustment for time-dependent confounders (15). Our findings are consistent with that study. Our results for infection-related mortality are also consistent with a recent study that examined 1-month exposure in a mostly prevalent population and showed an increase in infectionrelated deaths and hospitalizations with higher short-term IV iron exposures (.200 mg IV iron per month) as well as
n Demographics Age, yr (median) Sex (%) Women Race (%) White Black Other Ethnicity (%) Hispanic Non-Hispanic Cause of ESRD (%) Diabetes Hypertension GN Other Baseline comorbidities Indexb Congestive heart failure (%) Diabetes (%) Hemoglobinopathyc (%) Ferritin (ng/ml) and TSat (%) combination Ferritin#500 and TSat#20 Ferritin#500 and TSat=21–30 Ferritin=501–800 and TSat#20 Ferritin.800 regardless of TSat Other Ferritin,500 ng/ml and TSat.30% Ferritin.501–800 ng/ml and TSat=20% Hemoglobin, g/dl (%) #10 10.1–11 11.1–12 .12 Mean weekly epogen dose, units/wk (%) #5000 5001–12,000 12,001–25,000 .25,000
Patient Characteristics 4193 64.0 45.4 59.3 36.2 4.4 6.5 93.5 46.1 26.7 9.6 17.7 4.0 (1.0–6.0) 40.8 58.8 4.8 33.1 19.2 4.3 21.0 22.4 11.3 11.1 9.4 12.4 23.2 54.9 24.7 19.9 27.9 27.5
64.0 44.9 60.2 35.6 4.3 5.6 94.5 47.7 27.7 9.1 15.5 4.0 (1.0–6.0) 40.5 61.4 3.6 46.7 20.8 5.7 8.6 18.2 8.7 9.5 7.8 11.3 24.1 56.7 18.3 18.7 30.2 32.8
None 14,078
Total Cohort
Table 2. Patient characteristics according to 1-month intravenous iron dose
24.7 22.5 27.7 25.1
6.3 10.0 22.8 61.0
37.4 21.8 7.1 6.2 27.5 11.9 15.6
3.0 (1.0–6.0) 38.2 58.9 2.6
44.8 29.2 9.6 16.4
5.1 94.9
59.2 36.2 4.6
44.5
63.0
1784
.0–150
18.8 20.1 31.1 30.0
6.1 8.9 24.5 60.6
44.4 25.8 6.5 3.0 20.2 9.4 10.8
3.0 (1.0–6.0) 39.5 63.1 3.2
48.7 28.9 9.3 13.1
4.7 95.3
60.4 35.1 4.5
44.6
64.0
3114
.150–350
Intravenous Iron Dose (mg)
10.4 15.3 32.5 41.8
8.6 12.3 25.0 54.1
62.9 18.4 5.9 2.7 10.1 4.8 5.3
4.0 (1.0–7.0) 41.9 63.4 3.1
49.5 27.3 8.3 14.8
5.4 94.6
61.1 35.0 3.9
44.9
63.0
4903
.350
,0.001
,0.001
0.11 0.03 ,0.001 ,0.001 ,0.001
,0.001
,0.01
0.47
0.47 0.88
P Valuea
1934 Clinical Journal of the American Society of Nephrology
IV Iron and Mortality in Dialysis Patients, Miskulin et al.
TSat, saturation of transferrin. a Comparison across subgroups of 1-month cumulative intravenous iron dose. b Median and interquartile range. c Includes sickle cell, hereditary spherocytosis, myelodysplasia, multiple myeloma, and other anemia not caused by erythropoietin or iron deficiency; mean serum albumin findings are rounded. Values were 3.55, 3.55, 3.58, and 3.57 for intravenous iron doses of none, .0–150 mg, .150–350 mg, and .350 mg, respectively.
0.04 0.72 ,0.001 0.14 0.52 ,0.001 18.4 8.7 72.9 3.6 (3.3–3.9) 6.1 (4.6–8.1) 27.9 (23.5–33.5) 18.3 6.5 1250 (800–1700) 18.5 9.8 71.6 3.6 (3.3–3.9) 6.1 (4.6–8.0) 27.2 (23.4–32.7) 18.8 6.3 1200 (650–1600) 17.9 8.5 73.6 3.6 (3.3–3.9) 6.2 (4.5–8.2) 26.6 (22.8–32.0) 19.0 6.1 1100 (500–1500) 17.7 9.4 72.9 3.6 (3.3–3.9) 6.1 (4.6–8.1) 27.2 (23.1–32.6) 19.1 6.5 1000 (300–1600)
Vascular access (%) Arteriovenous fistula Arteriovenous graft Central venous catheter Serum albumin (g/dl)b Serum creatinine (g/dl)b Body mass index (kg/m2)b Infection in past 21 d (%) Noninfection-related hospitalization in past 21 d (%) Iron (mg) over the past 3 mob
16.1 10.3 73.6 3.6 (3.3–3.9) 6.1 (4.6–8.1) 26.6 (22.8–31.7) 20.2 7.0 0 (0–150)
.150–350 .0–150 Total Cohort Patient Characteristics
Table 2. (Continued)
None
Intravenous Iron Dose (mg)
.350
,0.01
P Valuea
Clin J Am Soc Nephrol 9: 1930–1939, November, 2014
1935
bolus ($100 mg for two or more consecutive treatments in 1 month) versus maintenance therapy (15). Although two studies, including our study, suggest a relation between IV iron and greater risk of infection-related outcomes, inconsistencies in findings should be considered. The discordance in our findings for infection-related mortality and all-cause mortality, wherein we found an increase in infection-related deaths with higher cumulative IV iron dose but no effect on all-cause mortality, is counterintuitive. If iron truly increased infections, we would have expected an increase in all-cause mortality, considering that this population is an older, frail population (50% of patients had diabetes). A prior study linking higher shortterm iron exposure to infection-related outcomes in patients on HD (15) did not report on all-cause mortality. A recent meta-analysis examining outcomes associated with administering IV iron versus oral iron or no iron in various clinical trials involving iron-deficient (including HD) populations (27), also found an increased risk of infections but no effect on mortality. Discordance in findings regarding infection-related mortality and all-cause mortality could reflect bias caused by unmeasured confounders or, possibly, that IV iron increases infection-related deaths while decreasing noninfection-related deaths. We found no doseresponse relationship of IV iron with infection-related mortality, calling into question the validity of a possible causal relation between IV iron and infection-related mortality. The increased risk for infection-related death was only seen among the highest dose category of the 3- and 6-month exposure models, whereas the hazard ratios of the next highest dose categories in both models are ,1. Additionally, the prior study reported a modest 5% increased hazard of infection-related deaths and hospitalizations with the administration of bolus or high-dose IV iron compared with nonbolus or lower-dose IV iron (28). It is possible that the association that we observed between higher-dose IV iron may only indicate that patients who survived long enough to incur these higher doses were actually more ill, because they required more iron because of ineffective use or some other reason. Considering that blood is lost with each HD treatment (29), iron is used in ESA-stimulated erythropoiesis, and iron absorption is impaired (30), most patients on HD would be expected to be deficient in iron if iron were not repleted. Indeed, studies consistently show that administering IV iron increases hemoglobin and reduces ESA doses (31–36), even among patients with serum ferritin=500–1200 ng/ml (37,38). Given the range of documented and speculated toxicities of ESAs (39–41), it is possible that avoiding higher ESA doses by giving more IV iron may be of net benefit to patients, even if there were a modest increase in the risk of infection. Beyond its role in erythropoiesis, administering iron may increase or improve the function of other heme-containing proteins, specifically the cytochromes (42,43), which are integral to energy production and many metabolic processes. It has been speculated that iron deficiency itself may induce cardiomyopathies and CV-related deaths. Studies have shown left ventricular dilation and mitochondrial swelling as well as normal sarcomere structure in rats fed an iron-deficient diet for 12 weeks (44). Randomized control trials of administering IV iron in heart failure populations have shown reductions in inflammatory
34.32 20.16 23.96 21.56 19.17 25.59 34.48 20.77 9.19 31.14 47.10 12.57
45,247 60,407 81,396 49,038
18,555 62,845 95,058 25,375
Percent
90,178 53,302 63,327 56,993
n (patient-mo)
1.24 (0.92 to 1.69) Reference 0.98 (0.80 to 1.21) 1.12 (0.81 to 1.57)
1.19 (0.90 to 1.57) Reference 0.99 (0.81 to 1.20) 1.09 (0.84 to 1.42)
0.98 (0.79 to 1.22) Reference 0.78 (0.64 to 0.95) 0.79 (0.62 to 0.99)
HR (95% CI)
0.31
0.41
0.01
P Valueb
All-Cause Mortality
1.46 (0.98 to 2.16) Reference 1.15 (0.85 to 1.56) 1.17 (0.76 to 1.79)
1.06 (0.72 to 1.54) Reference 0.87 (0.67 to 1.14) 1.02 (0.74 to 1.41)
1.11 (0.84 to 1.48) Reference 1.08 (0.80 to 1.44) 0.95 (0.70 to 1.29)
HR (95% CI)
0.28
0.49
0.66
P Valueb
Cardiovascular Mortality
0.75 (0.29 to 1.95) Reference 0.98 (0.53 to 1.81) 1.59 (0.73 to 3.46)
0.86 (0.38 to 1.96) Reference 0.99 (0.56 to 1.74) 1.69 (0.87 to 3.28)
0.92 (0.54 to 1.57) Reference 0.77 (0.47 to 1.26) 1.26 (0.75 to 2.12)
HR (95% CI)
0.48
0.24
0.43
P Valueb
Infection-Related Mortalitya
The weighting on cumulative iron doses received was on the basis of iron history, age, sex, race, ethnicity, baseline comorbidity at 90 days, baseline body mass index, cause of ESRD, year of starting dialysis, baseline iron doses, hemoglobinopathies, saturation of transferrin (TSat)/ferritin categories, hemoglobin categories, weekly erythropoietin (EPO) doses categories, change in EPO, interaction of TSat/ferritin categories and hemoglobin categories, albumin, creatinine, predialysis systolic BP, body weight, change in weight, vascular access type, noninfection-related hospitalization, and infection. Demographics and baseline comorbidity were included in the outcome models. HR, hazard ratio; 95% CI, 95% confidence interval. a Models were adjusted for all covariates included in all-cause and cardiovascular morality models, except recent infection. b Global tests of iron exposure.
One-month iron exposure None .0–150 .150–350 .350 Three-month iron exposure None .0–450 .450–1050 .1050 Six-month iron exposure None .0–900 .900–2100 .2100
Doses (mg)
Table 3. Association of intravenous iron dose with time to all-cause, cardiovascular, and infection-related death
1936 Clinical Journal of the American Society of Nephrology
Clin J Am Soc Nephrol 9: 1930–1939, November, 2014
markers and improvements in functional classification, exercise capacity, and quality of life, regardless of the continued presence of anemia (45,46), which may suggest a role for iron independent of effects on hemoglobin. A recent study found increased CV events and reduced survival associated with a TSat,20% relative to TSat=20%–40%, independent of hemoglobin level (47). A reduction in platelets is another postulated mechanism for a reduction in CV events with IV iron replacement (48). There are several unique strengths of our study. To date, this study is the only observational study relating IV iron dose to outcomes that has (1) been conducted on an entirely incident population, (2) assessed both short- and long-term exposures to IV iron, (3) examined effects on all-cause, infection-related, and CV deaths, and (4) examined iron doses and outcomes as early as 120 days after dialysis initiation, a time period during which larger doses of IV iron tend to be given (49) and the potential for harm may be greater because of greater central venous catheter use. Our study also had limitations. Although we adjusted for many potential confounders and used marginal structural modeling to attempt to control for time-dependent confounding, the potential for residual confounding remains. This concern may be particularly relevant to our analyses on infection-related mortality, for which our power to detect subtle associations was limited. The timing of adverse events relative to iron exposure is uncertain, and the difference between lagged and unlagged models for 1-month iron exposure and CV mortality further highlights the need for a prospective trial, in which adverse events are measured immediately after and over a longer period after iron exposure. Our study ended on December 31, 2008. Since that time, larger cumulative iron doses have been more frequently prescribed, potentially limiting the generalizability of our findings to current practice. The safety of administering higher doses of IV iron in patients with serum ferritin.500 ng/ml also may not have been assessed adequately, because it was an infrequent practice during the time course of this study. Our study was not designed to explore the influence of the pattern of iron administration on outcomes, which may be important, in addition to cumulative dose. It is possible that risk may be on the basis of iron preparations, which were not analyzed separately in this study. Nonetheless, our study represents one of the first studies to rigorously explore the potential association of cumulative IV iron use over shorter and longer periods and cause-specific mortality. In conclusion, we did not observe consistent findings of an association between higher cumulative IV iron doses over 1, 3, or 6 months with all-cause mortality or CV mortality, but there was a nonsignificant increase in infectionrelated mortality with receipt of .1050 mg IV iron in 3 months or .2100 mg in 6 months. Associations on the basis of observational data may be biased. Because a majority of patients on HD receives IV iron therapy, rigorously conducted and adequately powered clinical trials studying iron administration patterns reflective of presentday practice are greatly needed to provide definitive evidence about the safety of exposure to greater cumulative IV iron doses in patients on HD.
IV Iron and Mortality in Dialysis Patients, Miskulin et al.
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Acknowledgments The authors express their gratitude to the staff and patients of Dialysis Clinic Inc. The Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network Patient Outcomes in ESRD Study was supported by Agency for Healthcare Research and Quality Contract HHSA290200500341I (Task Order 6). W.M.M. was supported by Dutch Kidney Foundation (Nierstichting) Postdoctoral Full Fellowship Abroad Grant (KFB 11.005). D.C.C. was supported by the Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation. J.J.S. was supported by National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) Grant K23DK095949. T.S. was supported by NIDDK Grant K23-DK083514. Parts of this manuscript were previously presented as a poster at the Annual American Society of Nephrology Meeting in San Diego, CA (October 30 to November 4, 2012). Identifiable information, on which this report, presentation, or other form of disclosure is based, is confidential and protected by federal law: Section 903(c) of the Public Health Service Act, 42 USC 299a-1(c). Any identifiable information that is knowingly disclosed is disclosed solely for the purpose for which it has been supplied. No identifiable information about any individual supplying the information or described in it will be knowingly disclosed except with the prior consent of that individual. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government. The DEcIDE Network Patient Outcomes in ESRD Study Team consists of members from Johns Hopkins University (K.B.-R., J.Z., A. M., P.L.E., W.M.M., B.G.J., D.C.C., S.M.S., T.S., A.W.W., C.C., L.E.B., Josef Coresh, Jeonyong Kim, Yang Liu, Jason Luly, and Paul Scheel), University of California, San Francisco (Neil Powe), Chronic Disease Research Group (Allan Collins, Robert Foley, David Gilbertson, Haifeng Guo, Brooke Heubner, Charles Herzog, Jiannong Liu, and Wendy St. Peter), Cleveland Clinic Foundation (Joseph Nally, Susana Arrigain, Stacey Jolly, Vicky Konig, Xiaobo Liu, Sankar Navaneethan, and Jesse Schold), University of New Mexico (Philip Zager), Tufts University (D.C.M. and K.B.M.), University of Miami (J.J.S.), University of Manitoba (N.T.), and Academic Medical Center (W.M.M.). Disclosures None. References 1. Fuller DS, Pisoni RL, Bieber BA, Gillespie BW, Robinson BM: The DOPPS Practice Monitor for US dialysis care: Trends through December 2011. Am J Kidney Dis 61: 342–346, 2013 2. FDA Drug Safety Communication: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease. Available at: http://www. fda.gov/Drugs/DrugSafety/ucm259639.htm. Accessed July 2, 2012 3. The Federal Register 42 CFR Parts 410, 413 and 414 Medicare Program; End-Stage Renal Disease Prospective Payment System; Final Rule and Proposed Rule. Available at: http://www.gpo. gov/fdsys/pkg/FR-2010-08-12/pdf/2010-18466.pdf. Accessed July 2, 2013 4. Boelaert JR, Daneels RF, Schurgers ML, Matthys EG, Gordts BZ, Van Landuyt HW: Iron overload in haemodialysis patients increases the risk of bacteraemia: A prospective study. Nephrol Dial Transplant 5: 130–134, 1990 5. Payne SM: Iron and virulence in the family Enterobacteriaceae. Crit Rev Microbiol 16: 81–111, 1988
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IV Iron and Mortality in Dialysis Patients, Miskulin et al.
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Meeting of the American Society of Nephrology, San Diego, CA, October 30-November 4, 2012 Received: April 2, 2014 Accepted: July 18, 2014 Published online ahead of print. Publication date available at www. cjasn.org. This article contains supplemental material online at http://cjasn. asnjournals.org/lookup/suppl/doi:10.2215/CJN.03370414/-/ DCSupplemental. See related editorial, “Intravenous Iron Exposure and Outcomes in Patients on Hemodialysis,” on pages 1837–1839.
