Article

Intravenous Iron Exposure and Mortality in Patients onHemodialysis

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 aboutEffectiveness (DEcIDE) Network Patient Outcomes in End Stage Renal Disease Study Investigators

AbstractBackground and objectives Clinical trials assessing effects of larger cumulative iron exposure with outcomes arelacking, and observational studies have been limited by assessment of short-term exposure only and/or failure toassess cause-specific mortality. The associations between short- and long-term iron exposure on all-cause andcause-specific mortality were examined.

Design, setting, participants, & measurements The study included 14,078 United States patients on dialysisinitiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rollingwindows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazardsmodels that used marginal structural modeling to control for time-dependent confounding.

Results Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during whichthere were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced riskof all-cause mortality with receipt of.150–350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or.350mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with.0–150 mg over 1month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infection-related mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardio-vascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of.1050mg intravenous iron in 3months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and.2100mg in6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46).

ConclusionsAmong patients on incident dialysis, receipt of#1050 mg intravenous iron in 3 months or 2100 mgin 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However,nonstatistically significant findings suggested the possibility of infection-relatedmortalitywith receipt of.1050mgin 3 months or.2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure togreater cumulative intravenous iron doses.

Clin J Am Soc Nephrol 9: ccc–ccc, 2014. doi: 10.2215/CJN.03370414

IntroductionIntravenous (IV) iron use in the United States hemo-dialysis (HD) population has increased (1) in recentyears after changes in product labeling (2) and bun-dling of erythropoiesis-stimulating agents (ESAs) intodialysis per-treatment payments (3). The amount ofiron that can be safely administered over the shortand long term is unknown. In experimental studies, ex-cess iron has been shown to impair phagocytosis andenhance bacterial virulence, increasing risk for infection(4–7). However, the iron concentrations achieved inthese experiments greatly exceed the plasma iron levelsachieved in clinical practice. Iron, a potent oxidant,may also play a role in atherosclerosis (8–11). Addition-ally, recent studies show hepatic iron content to be se-verely elevated in some patients on HD (12–14), althoughthe clinical significance of this finding is unclear.

Clinical trials assessing the safety of more aggressiveiron repletion on patient-centered outcomes have notbeen conducted, and observational studies have yieldedinconsistent results (9,15–19). In a prevalent 1997–1998HD population, receipt of a cumulative iron dose ex-ceeding 1800 mg in 6 months was not associated withmortality (16). A more recent study found an increasein infection-related mortality and hospitalizations withreceipt of .200 mg IV iron in 1 month and bolus asopposed to maintenance iron therapy (15). Exposures.1 month were not examined in the first study (16),and cause-specific mortality was not examined in thesecond study (16). Furthermore, both of these studieswere conducted on prevalent populations and therein,may have been subject to survivor bias.Studies examining the association of administering

varying doses of IV ironwith clinical outcomes assessed

Due to the number ofcontributing authors,the affiliations areprovided in theSupplementalMaterial.

Correspondence:Dr. Dana C. Miskulin,Tufts Medical Center,Box 391, Division ofNephrology, 800Washington Street,Boston, MA 02111.Email: dmiskulin@tuftsmedicalcenter.org

www.cjasn.org Vol 9 November, 2014 Copyright © 2014 by the American Society of Nephrology 1

. Published on October 15, 2014 as doi: 10.2215/CJN.03370414CJASN ePress

over differing lengths of time among patients on HD withsimilar dialysis history could help better elucidate the safetyof IV iron administration in clinical practice. Furthermore, itis possible that IV iron administration could decrease ESArequirements, leading to improvements in clinical outcomes,such as mortality. We examined associations of higherversus lower IV iron doses accumulated over 1, 3, and 6months with all-cause, cardiovascular (CV), and infection-related mortality in an entirely incident HD population us-ing analytic methods to account for potential time-varyingconfounders.

Materials and MethodsStudy PopulationThe study, described in detail previously (20,21), included

patients who initiated HD at dialysis units from a medium-sized national dialysis provider, Dialysis Clinic, Inc. (DCI),between January 1, 2003, and December 31, 2008, and hadMedicare as the primary payer.

Data SourcesThe electronic medical information system of DCI was

the primary source of information about ESA and IV irondoses and laboratory test results. Data were linked to theUS Renal Data System to obtain additional informationabout IV iron and ESA doses andMedicare claims. Cause ofdeath was on the basis of the National Death Index. Thestudy was conducted with adherence to the Declaration ofHelsinki. The Johns Hopkins Medicine Institutional ReviewBoard approved the study.

OutcomesThe primary outcome was all-cause mortality. We cen-

sored patients at the time of the switch from in-center HDto peritoneal or home HD, kidney transplant, transfer to an-other dialysis unit, loss to follow-up, December 31, 2008, or 4years of follow-up. For analyses of infection-related and CVmortality, patients were censored for other causes of death.

IV Iron ExposureOur primary exposure of interest was cumulative IV iron

dose calculated as the sum of IV iron in milligrams (allformulations) administered over 1-, 3-, and 6-month rollingwindows. We categorized IV iron doses into four mutuallyexclusive levels (no iron, low dose, moderate dose, or highdose) on the basis of the distribution of the data, previousanalyses, and our clinical experience. Before 2009, IV ironwas not administered by a protocol at DCI.

CovariatesWe defined baseline comorbidity from inpatient and out-

patient claims and diagnoses entered in the DCI databaseduring the first 90 days after starting dialysis. We scoredcomorbidity using a previously validated ESRD-specific co-morbidity index (22). We converted erythropoietin dosesto average daily doses and summed doses across 30-dayanalytic periods. Then, we created an average weekly dosefor the month by dividing by four. We used the percentsaturation of transferrin (TSat) and serum ferritin mea-sured closest to but not .90 days before the start of the

iron exposure window. To replicate decision-making inpractice, we considered the joint values of serum ferritinand TSat. We created a five-category variable reflecting thelikelihood that iron would be prescribed. We defined vas-cular access type as the access in use on the first day of themonth preceding the iron exposure window. We definedinfection as (1) the use of IV antibiotics as recorded in DCIor Medicare claims or (2) a hospitalization with a primarydiagnosis of infection within 21 days before the start of theiron exposure window. We defined noninfection-relatedhospitalizations as hospitalizations with a primary diag-nosis other than infection occurring within 21 days beforethe start of the iron exposure window.

Statistical AnalysesWe used marginal structural modeling (23,24) as our

primary methodology for analyzing associations of IViron dose with mortality, because prescribing decisionsare affected by characteristics that reflect past prescribingdecisions and also affect risk for death. We calculatedmonthly inverse probability weights to address time-varying confounding from the inverse of the predictedprobability that each subject belonged to the dosing cate-gory in which his or her own observed iron dose at eachfollow-up month fell conditional on their histories of priortreatment and time-varying confounders deemed to affectboth treatment choices and subsequent outcomes. Becausetreatment was defined by four levels of IV iron dose, wefitted multinomial logistic regression models for treatmentprobabilities. Treatment propensities were modeled beforethe start of the iron exposure window to avoid prediction oftreatment by future information (Figure 1). For each 30-dayinterval, we calculated the inverse of the probability of re-ceiving the treatment (e.g., treatment weight) and the inverseprobability of dropping out of the study (e.g., censoringweight). We calculated final weights as the product of thetreatment and censoring weights up to the month preced-ing the outcome assessment with stabilization using base-line demographic characteristics and comorbidity (23).We fit outcome models (separately) for 1-, 3-, and 6-month

rolling window cohorts using iron exposure averaged over asingle preceding interval as the primary predictor. Theywereimplemented as discrete time proportional hazards modelstaking person-months as observations (25). Because we hy-pothesized that the effect of iron on CV disease death wasdelayed, although the effect on infection-related death wasmore immediate, we imposed a 30-day lag between ironexposure and CV mortality, with no lag for all-cause andinfection-related mortality in our primary analyses. In sen-sitivity analyses, we also used similar models without thetime lag.In marginal structural modeling analyses, a few people

with very unusual treatment patterns may have extremelylarge weights (corresponding to small probabilities of theiroccurrence in the sample). Although disproportionateweighting is necessary to give them adequate representa-tion in analyses, these few individuals may then greatlyinfluence the analytic findings—a particularly troublingoutcome when one considers that very large weights tendto be imprecisely estimated. A common remedy is to applytruncation—that is, set all weights higher than a specifiedlevel to that level. We truncated weights at a level of

2 Clinical Journal of the American Society of Nephrology

10 (e.g., any weights.10 were reset to 10), a value selecteda priori to conform with commonly invoked truncation thresh-olds and limit undue influence while not diverging too widelyfrom a percentile-based truncation criterion of 1% of observa-tions (23,24). At a weight truncation of 10, approximately2%–5% of extreme weights were truncated. We conductedsensitivity analyses and truncated weights at 3, 5, 20, and 100.We accounted for outcome clustering by dialysis facilities

using generalized estimating equations (26) and estimatedrobust SEMs. We performed statistical analyses using SAS9.2 (SAS Institute Inc., Cary, NC). Detailed methods are pro-vided in the Supplemental Appendix.

ResultsCharacteristics of Study CohortsOf 21,233 patients who initiated dialysis between January

1, 2003, and December 31, 2008, at DCI, 66.3%, 59.6%, and51.3% met eligibility criteria (Figure 2) for the 1-, 3-, and6-month cumulative iron dose analyses, respectively (Table1). Patients receiving larger cumulative IV iron doses over 1(Table 2), 3, or 6 months were more likely to be white andhave diabetes; they had higher comorbidity index, lowerserum albumin, and lower TSat and serum ferritin, and theywere less likely to have a hemoglobin.12 g/dl (Supplemen-tal Tables 2 and 3) The vast majority (86%, 85%, and 87%) ofpatients 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 ModelsOne-Month Cohort. In fully adjusted models, receipt of

.150–350 mg and .350 mg IV iron were statistically sig-nificantly associated with 2% and 21%, respectively, lowerhazards of all-cause mortality compared with the refer-ence range (global test P=0.01). Findings for CV- andinfection-related mortality were not statistically signifi-cant (Table 3).Three-Month Cohort. There was no association of cu-

mulative IV iron dose over 3 months with all-cause or CVmortality. Findings for infection-related mortality were notstatistically significant, and point estimates differed in di-rection (,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 cumu-lative iron doses over 6 months with all-cause or CV mor-tality. Similar to infection-related mortality in the 3-monthmodel, we observed a higher hazard of infection-related mor-tality 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), andthese associations were not statistically significant (Table 3).

Sensitivity AnalysesInfluence of Imposing Lag on CV Disease Deaths

When we eliminated the 30-day lag for ascertainment ofCV disease deaths, the categories of .150–350 and .350mg IV iron were associated with 27% and 26%, respectively,lower hazards of CV mortality (global test P=0.06), whichcontrasted with the lagged model in which the hazard ratioswere close to one and not significant (Supplemental Table 4).Models of 3- and 6-month iron exposure and CV mortalitywithout a lag did not differ from the lagged models.AlteringWeight Truncations Results using weight trun-

cations of 3, 5, 10, 20, and 100 in the weighted models werethe same for all except two models (Supplemental Tables7–15). The lower hazards of all-cause mortality with the.150–350 and .350 mg 1-month iron dose ranges thatwere found at a weight truncation of 10 were no longerstatistically significant at a weight truncation of 20 or 100(Supplemental Table 7). Point estimates were similar at alltruncation levels, which may implicate amplified variabilityaccompanying incorporation of extreme weights rather thanresidual confounding. In the 3-month model of infection-related death, the relationship of the .1050-mg IV irondose range with infection-related mortality at weight trun-cations ,20 was not significant, but .20, it was significant(Supplemental Table 12). The difference in result may re-flect better control for confounding by giving individualsmore representative weights.20 or that these rare individ-uals with unusual treatment patterns are exerting undueinfluence on the model.

DiscussionWe assessed the associations of short- and longer-term

cumulative IV iron doses with mortality in an incident HD

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 outcomewas defined during 30 days after theexposure window (with a 30-day lag for the all-cause mortality model). Longitudinal analyses were conducted on the basis of parametersdefined in successive 1-month increments of this series of windows from the start to end of follow-up for each individual. Details are inMaterials and Methods and Supplemental Appendix.

Clin J Am Soc Nephrol 9: ccc–ccc, November, 2014 IV Iron and Mortality in Dialysis Patients, Miskulin et al. 3

population. We observed no evidence of increased all-causeor cause-specific mortality with administration of larger irondoses .1 month. Larger IV iron dose accumulations over 3and 6 months were also not associated with all-cause or CVmortality, but there was a nonsignificant trend toward anincrease in infection-related mortality. Results of this studywould suggest that dose accumulations#1050 mg IV iron in3 months and#2100 mg in 6 months are not associated withall-cause, CV, or infection-related mortality. However, find-ings suggest higher IV iron doses may increase infection-related mortality.Previous studies have produced conflicting results regard-

ing the association of IV iron dose with clinical outcomes.

Studies with no or minimal adjustment for time-dependentconfounding have shown increased mortality with cumula-tive IV iron doses .1000 mg in 6 months (17), .840 mg in 6months (9), or .400 mg in 13 weeks (18). In a subsequentstudy, receipt of .1800 mg in 6 months at baseline was alsoassociated with mortality, but the association was no longersignificant after adjustment for time-dependent confounders(15). Our findings are consistent with that study. Our resultsfor infection-related mortality are also consistent with a re-cent study that examined 1-month exposure in a mostlyprevalent population and showed an increase in infection-related deaths and hospitalizations with higher short-termIV iron exposures (.200 mg IV iron per month) as well as

Figure 2. | Flow diagram of exclusions from the analytic cohorts for the 1-, 3-, and 6- month intravenous iron exposure models. The reasonsfor exclusions from the 1-, 3-, and 6-monthmodel cohorts are shown. Accounting for the 90-day timewindow todefine 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 andEvent Rates

1-Month Iron ExposureWindow

3-Month Iron ExposureWindow

6-Month Iron ExposureWindow

Study population, n 14,078 12,646 10,899Median (IQR) follow-up time, mo 19 (10–34) 22 (13–36) 25 (16–39)All-cause deaths, n (%) 3889 (27.6) 3609 (28.6) 2810 (25.8)CVD deaths, n (%) 1896 (13.5) 1778 (14.7) 1404 (12.9)Infection-related deaths, n (%) 424 (3.0) 388 (3.0) 293 (2.7)

IQR, interquartile range; CVD, cardiovascular disease.

4 Clinical Journal of the American Society of Nephrology

Tab

le2.

Patientch

arac

teristicsac

cordingto

1-m

onth

intrav

enousirondose

Patien

tCha

racteristics

Total

Coh

ort

Intrav

enou

sIron

Dose(m

g)PValue

a

Non

e.0–

150

.15

0–35

0.35

0

n14

,078

4193

1784

3114

4903

Dem

ographics

Age

,yr(m

edian)

64.0

64.0

63.0

64.0

63.0

0.47

Sex

(%)

0.88

Wom

en44

.945

.444

.544

.644

.9Race(%

)0.47

White

60.2

59.3

59.2

60.4

61.1

Black

35.6

36.2

36.2

35.1

35.0

Other

4.3

4.4

4.6

4.5

3.9

Ethnicity(%

),0.01

Hispa

nic

5.6

6.5

5.1

4.7

5.4

Non

-Hispan

ic94

.593

.594

.995

.394

.6Cau

seof

ESRD

(%)

,0.00

1Diabe

tes

47.7

46.1

44.8

48.7

49.5

Hyp

ertens

ion

27.7

26.7

29.2

28.9

27.3

GN

9.1

9.6

9.6

9.3

8.3

Other

15.5

17.7

16.4

13.1

14.8

Baselinecomorbidities

Index

b4.0(1.0–6.0)

4.0(1.0–6.0)

3.0(1.0–6.0)

3.0(1.0–6.0)

4.0(1.0–7.0)

0.11

Con

gestivehe

artfailu

re(%

)40

.540

.838

.239

.541

.90.03

Diabe

tes(%

)61

.458

.858

.963

.163

.4,0.00

1Hem

oglobino

pathyc

(%)

3.6

4.8

2.6

3.2

3.1

,0.00

1Fe

rritin

(ng/ml)an

dTSat

(%)co

mbination

,0.00

1Fe

rritin#50

0an

dTSa

t#20

46.7

33.1

37.4

44.4

62.9

Ferritin#50

0an

dTSa

t=21

–30

20.8

19.2

21.8

25.8

18.4

Ferritin=50

1–80

0an

dTSa

t#20

5.7

4.3

7.1

6.5

5.9

Ferritin.80

0rega

rdless

ofTSa

t8.6

21.0

6.2

3.0

2.7

Other

18.2

22.4

27.5

20.2

10.1

Ferritin,50

0ng

/mla

ndTSa

t.30

%8.7

11.3

11.9

9.4

4.8

Ferritin.50

1–80

0ng

/mla

ndTSa

t=20

%9.5

11.1

15.6

10.8

5.3

Hem

oglobin,g

/dl(%)

,0.00

1#10

7.8

9.4

6.3

6.1

8.6

10.1–11

11.3

12.4

10.0

8.9

12.3

11.1–12

24.1

23.2

22.8

24.5

25.0

.12

56.7

54.9

61.0

60.6

54.1

Mea

nwee

kly

epog

endos

e,units/wk(%

),0.00

1#50

0018

.324

.724

.718

.810

.450

01–12

,000

18.7

19.9

22.5

20.1

15.3

12,001

–25

,000

30.2

27.9

27.7

31.1

32.5

.25

,000

32.8

27.5

25.1

30.0

41.8

Clin J Am Soc Nephrol 9: ccc–ccc, November, 2014 IV Iron and Mortality in Dialysis Patients, Miskulin et al. 5

bolus ($100 mg for two or more consecutive treatments in1 month) versus maintenance therapy (15).Although two studies, including our study, suggest a re-

lation between IV iron and greater risk of infection-relatedoutcomes, inconsistencies in findings should be considered.The discordance in our findings for infection-related mor-tality and all-cause mortality, wherein we found an in-crease in infection-related deaths with higher cumulativeIV iron dose but no effect on all-cause mortality, is coun-terintuitive. If iron truly increased infections, we wouldhave expected an increase in all-cause mortality, consider-ing that this population is an older, frail population (50% ofpatients had diabetes). A prior study linking higher short-term iron exposure to infection-related outcomes in pa-tients on HD (15) did not report on all-cause mortality. Arecent meta-analysis examining outcomes associated withadministering IV iron versus oral iron or no iron in variousclinical trials involving iron-deficient (including HD) pop-ulations (27), also found an increased risk of infections butno effect on mortality. Discordance in findings regardinginfection-related mortality and all-cause mortality couldreflect bias caused by unmeasured confounders or, possi-bly, that IV iron increases infection-related deaths whiledecreasing noninfection-related deaths. We found no dose-response relationship of IV iron with infection-related mor-tality, calling into question the validity of a possible causalrelation between IV iron and infection-related mortality. Theincreased risk for infection-related death was only seenamong the highest dose category of the 3- and 6-month ex-posure models, whereas the hazard ratios of the next highestdose categories in both models are ,1. Additionally, theprior study reported a modest 5% increased hazard ofinfection-related deaths and hospitalizations with the ad-ministration of bolus or high-dose IV iron compared withnonbolus or lower-dose IV iron (28). It is possible that theassociation that we observed between higher-dose IV ironmay only indicate that patients who survived long enoughto incur these higher doses were actually more ill, becausethey required more iron because of ineffective use or someother reason.Considering that blood is lost with each HD treatment

(29), iron is used in ESA-stimulated erythropoiesis, andiron absorption is impaired (30), most patients on HDwould be expected to be deficient in iron if iron were notrepleted. Indeed, studies consistently show that administer-ing IV iron increases hemoglobin and reduces ESA doses(31–36), even among patients with serum ferritin=500–1200ng/ml (37,38). Given the range of documented and specu-lated toxicities of ESAs (39–41), it is possible that avoidinghigher ESA doses by giving more IV iron may be of netbenefit to patients, even if there were a modest increase inthe risk of infection. Beyond its role in erythropoiesis, ad-ministering iron may increase or improve the function ofother heme-containing proteins, specifically the cytochromes(42,43), which are integral to energy production and manymetabolic processes. It has been speculated that iron defi-ciency itself may induce cardiomyopathies and CV-relateddeaths. Studies have shown left ventricular dilation and mi-tochondrial swelling as well as normal sarcomere structurein rats fed an iron-deficient diet for 12 weeks (44). Random-ized control trials of administering IV iron in heart failurepopulations have shown reductions in inflammatory

Tab

le2.(Continued

)

Patien

tCha

racteristics

Total

Coh

ort

Intrav

enou

sIron

Dose(m

g)PValue

a

Non

e.0–

150

.15

0–35

0.35

0

Vascu

laraccess

(%)

,0.01

Arteriove

nousfistula

17.7

16.1

17.9

18.5

18.4

Arteriove

nousgraft

9.4

10.3

8.5

9.8

8.7

Cen

tral

veno

uscatheter

72.9

73.6

73.6

71.6

72.9

Serum

albu

min

(g/dl)b

3.6(3.3–3.9)

3.6(3.3–3.9)

3.6(3.3–3.9)

3.6(3.3–3.9)

3.6(3.3–3.9)

0.04

Serum

creatinine

(g/dl)b

6.1(4.6–8.1)

6.1(4.6–8.1)

6.2(4.5–8.2)

6.1(4.6–8.0)

6.1(4.6–8.1)

0.72

Bod

ymassindex

(kg/

m2 )b

27.2

(23.1–

32.6)

26.6

(22.8–

31.7)

26.6

(22.8–

32.0)

27.2

(23.4–

32.7)

27.9

(23.5–

33.5)

,0.00

1Infectionin

past

21d(%

)19

.120

.219

.018

.818

.30.14

Non

infection-relatedho

spitalizationin

past21

d(%

)6.5

7.0

6.1

6.3

6.5

0.52

Iron

(mg)

over

thepa

st3mob

1000

(300

–16

00)

0(0–15

0)11

00(500

–15

00)

1200

(650

–16

00)

1250

(800

–17

00)

,0.00

1

TSa

t,saturation

oftran

sferrin.

a Com

parisonacross

subg

roups

of1-mon

thcu

mulativeintrav

enou

siron

dose.

bMed

ianan

dinterqua

rtile

rang

e.c Inc

ludes

sick

lecell,

hereditarysp

herocy

tosis,mye

lodysplasia,multiplemye

loma,an

dothe

rane

miano

tcau

sedby

erythrop

oietin

oriron

defi

cien

cy;m

eanserum

albu

min

find

ings

areroun

ded

.Value

swere3.55

,3.55,

3.58

,and

3.57

forintrav

enou

siron

doses

ofno

ne,.

0–15

0mg,

.15

0–35

0mg,

and.35

0mg,

resp

ective

ly.

6 Clinical Journal of the American Society of Nephrology

Tab

le3.

Associationofintrav

enousirondose

withtimeto

all-ca

use,ca

rdiovascular,an

dinfection-related

death

Doses

(mg)

n(patient-m

o)Pe

rcen

tAll-Cau

seMortality

Cardiova

scular

Mortality

Infection-Related

Mortalitya

HR(95%

CI)

PValue

bHR(95%

CI)

PValue

bHR(95%

CI)

PValue

b

One-mon

thiron

exposure

Non

e90

,178

34.32

0.98

(0.79to

1.22

)0.01

1.11

(0.84to

1.48

)0.66

0.92

(0.54to

1.57

)0.43

.0–

150

53,302

20.16

Referen

ceReferen

ceReferen

ce.15

0–35

063

,327

23.96

0.78

(0.64to

0.95

)1.08

(0.80to

1.44

)0.77

(0.47to

1.26

).35

056

,993

21.56

0.79

(0.62to

0.99

)0.95

(0.70to

1.29

)1.26

(0.75to

2.12

)Three-mon

thiron

exposure

Non

e45

,247

19.17

1.19

(0.90to

1.57

)0.41

1.06

(0.72to

1.54

)0.49

0.86

(0.38to

1.96

)0.24

.0–

450

60,407

25.59

Referen

ceReferen

ceReferen

ce.45

0–10

5081

,396

34.48

0.99

(0.81to

1.20

)0.87

(0.67to

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Clin J Am Soc Nephrol 9: ccc–ccc, November, 2014 IV Iron and Mortality in Dialysis Patients, Miskulin et al. 7

markers and improvements in functional classification, exer-cise capacity, and quality of life, regardless of the continuedpresence of anemia (45,46), which may suggest a role foriron independent of effects on hemoglobin. A recent studyfound increased CV events and reduced survival associatedwith a TSat,20% relative to TSat=20%–40%, independent ofhemoglobin level (47). A reduction in platelets is anotherpostulated mechanism for a reduction in CV events withIV iron replacement (48).There are several unique strengths of our study. To date,

this study is the only observational study relating IV irondose to outcomes that has (1) been conducted on an en-tirely incident population, (2) assessed both short- andlong-term exposures to IV iron, (3) examined effects onall-cause, infection-related, and CV deaths, and (4) exam-ined iron doses and outcomes as early as 120 days afterdialysis initiation, a time period during which larger dosesof IV iron tend to be given (49) and the potential for harmmay be greater because of greater central venous catheteruse.Our study also had limitations. Althoughwe adjusted for

many potential confounders and used marginal structuralmodeling to attempt to control for time-dependent con-founding, the potential for residual confounding remains.This concern may be particularly relevant to our analyseson infection-related mortality, for which our power to de-tect subtle associations was limited. The timing of adverseevents relative to iron exposure is uncertain, and the dif-ference between lagged and unlagged models for 1-monthiron exposure and CV mortality further highlights the needfor a prospective trial, in which adverse events are mea-sured immediately after and over a longer period after ironexposure. Our study ended on December 31, 2008. Sincethat time, larger cumulative iron doses have been morefrequently prescribed, potentially limiting the generaliz-ability of our findings to current practice. The safety ofadministering higher doses of IV iron in patients with se-rum ferritin.500 ng/ml also may not have been assessedadequately, because it was an infrequent practice duringthe time course of this study. Our study was not designedto explore the influence of the pattern of iron administra-tion on outcomes, which may be important, in addition tocumulative dose. It is possible that risk may be on the basisof iron preparations, which were not analyzed separatelyin this study. Nonetheless, our study represents one of thefirst studies to rigorously explore the potential associationof cumulative IV iron use over shorter and longer periodsand cause-specific mortality.In conclusion, we did not observe consistent findings of

an association between higher cumulative IV iron dosesover 1, 3, or 6 months with all-cause mortality or CV mor-tality, but there was a nonsignificant increase in infection-related mortality with receipt of .1050 mg IV iron in 3months or .2100 mg in 6 months. Associations on thebasis of observational data may be biased. Because a ma-jority of patients on HD receives IV iron therapy, rigor-ously conducted and adequately powered clinical trialsstudying iron administration patterns reflective of present-day practice are greatly needed to provide definitive evi-dence about the safety of exposure to greater cumulativeIV iron doses in patients on HD.

AcknowledgmentsThe authors express their gratitude to the staff and patients of

Dialysis Clinic Inc.The Developing Evidence to Inform Decisions about Effective-

ness (DEcIDE) Network Patient Outcomes in ESRD Study was sup-ported by Agency for Healthcare Research and Quality ContractHHSA290200500341I (Task Order 6). W.M.M. was supported byDutch Kidney Foundation (Nierstichting) Postdoctoral Full Fel-lowship Abroad Grant (KFB 11.005). D.C.C. was supported by theAmos Medical Faculty Development Program of the Robert WoodJohnson Foundation. J.J.S. was supported by National Institute forDiabetes, Digestive and Kidney Diseases (NIDDK) Grant K23-DK095949. 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 NephrologyMeeting 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 byfederal law: Section 903(c) of the Public Health Service Act, 42 USC299a-1(c). Any identifiable information that is knowingly disclosedis disclosed solely for the purpose forwhich it has been supplied.Noidentifiable information about any individual supplying the in-formation or described in it will be knowingly disclosed exceptwiththe prior consent of that individual. The data reported here havebeen supplied by the US Renal Data System. The interpretation andreporting of these data are the responsibility of the author(s) and innoway shouldbe seen as anofficial policy or interpretation of theUSGovernment.The DEcIDE Network Patient Outcomes in ESRD Study Team

consists ofmembers from JohnsHopkinsUniversity (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, JeonyongKim, Yang Liu, Jason Luly, andPaul Scheel),UniversityofCalifornia, SanFrancisco (Neil Powe),ChronicDiseaseResearch 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, SankarNavaneethan, and Jesse Schold), University of NewMexico (PhilipZager), Tufts University (D.C.M. and K.B.M.), University of Miami(J.J.S.),University ofManitoba (N.T.), andAcademicMedicalCenter(W.M.M.).

DisclosuresNone.

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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.

10 Clinical Journal of the American Society of Nephrology