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Iron Administration and Clinical Outcomes in Hemodialysis Patients

Harold I. Feldman^*, Jill Santanna^*, Wensheng Guo^*, Howard Furst, Eunice Franklin^*, Marshall Joffe^*, Sue Marcus^* and Gerald Faich

*Center for Clinical Epidemiology and Biostatistics and the Department of Biostatistics and Epidemiology, Renal Electrolyte and Hypertension Division of the Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania; Pharmaceutical Safety Assessments, Inc., Narberth, Pennsylvania.

Correspondence to: Dr. Harold I. Feldman, Associate Professor of Medicine and Epidemiology, University of Pennsylvania Medical Center, 423 Service Drive, 720 Blockley Hall, Philadelphia, PA 19104-6021. Phone: 215-898-0901; Fax: 215-898-0643; E-mail: hfeldman{at}cceb.med.upenn.edu

	Abstract

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ABSTRACT. To evaluate the impact of parenteral iron administration on the survival and rate of hospitalization of US hemodialysis patients, a nonconcurrent cohort study of 10,169 hemodialysis patients in the United States in 1994 was conducted. The main outcome measures were patient survival and rate of hospitalization. After adjusting for 23 demographic and comorbidity characteristics among 5833 patients included in multivariable analysis, bills for 10 vials of iron over 6 mo showed no adverse effect on survival (adjusted relative risk [RR] = 0.93; 95% confidence interval [CI], 0.84 to 1.02; P = 0.14) when compared with none, but bills for >10 vials showed a statistically significant elevated rate of death (adjusted RR = 1.11; 95% CI, 1.00 to 1.24; P = 0.05). Bills for 10 vials of iron over 6 mo also showed no significant association with hospitalization (adjusted RR = 0.92; 95% CI, 0.83 to 1.03; P = 0.15), but bills for >10 vials showed statistically significant elevated risk (adjusted RR = 1.12; 95% CI, 1.01 to 1.25; P = 0.03). Prescribing iron in quantities of 10 vials over 6 mo had no association with an elevated risk of death or rate of hospitalization. More intensive dosing was associated with diminished survival and higher rates of hospitalization, even after extensive adjustment for baseline comorbidity. Although these potential risks may be offset by the known elevations in morbidity and mortality associated with anemia, these findings indicate that caution is warranted when prescribing >10 vials (1000 mg) of iron dextran over a period of 6 mo.

	Introduction

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Patients with end-stage renal disease (ESRD) almost invariably develop anemia due to decreased production of erythropoietin by the kidneys. Chronic blood loss to the dialysis circuit worsens anemia in hemodialysis patients. The introduction of recombinant erythropoietin more than a decade ago revolutionized the treatment of the anemia of ESRD, having led to a marked reduction in the need for transfusion and its attendant complications.

Despite the widespread use of erythropoietin, as of 1996 approximately 84% of patients in the United States still had hematocrit levels below the target level of 33% (1). Resistance to erythropoietin may occur for several reasons, including inflammation, infection, hyperparathyroidism, and most commonly, iron deficiency (2,3). Many patients develop iron deficiency during the initial phase of administration of erythropoietin due to depletion of iron stores as the result of the increase in red blood cell mass. After achievement of target hemoglobin levels, patients continue to require maintenance iron administration to replete the ongoing losses that result from residual blood discarded in the dialyzer and tubing after each dialysis session. Furthermore, ongoing administration of parenteral iron preserves levels of hemoglobin and reduces the requirement for administration of erythropoietin (4–9). Given the relative costs of iron and erythropoietin, it is clear that an appropriate use of iron can have substantial cost savings.

Recently, concern has arisen that administration of large doses of parenteral iron may be associated with morbidity and mortality, in particular from infection. These concerns arise, in part, from the known role of iron as a growth factor for bacteria (10,11), its suspected inhibition of neutrophil function (12–17), and clinical studies relating iron overload to infectious morbidity (18–23). More recently, large doses of administered iron have also been associated with elevated rates of hospitalization and mortality (24–28). Although these latter studies may indicate toxicity from high doses of parenteral iron, another explanation for the observed associations between iron administration and elevated morbidity is the nature of the patients treated. In particular, the clinical indication for iron administration, anemia poorly responsive to erythropoietin is itself likely to be associated with higher rates of morbidity and mortality. We hypothesized that administration of high doses of parenteral iron is an indicator of greater morbidity at baseline and subsequent susceptibility to morbid and fatal events, accounting, in part, for the observed association between iron administration of poor clinical outcomes. The purpose of this study was to examine this hypothesis by prospectively studying a large representative sample of US hemodialysis patients for whom extensive baseline information on comorbidity was available.

	Materials and Methods

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Sources of Data
Information on demographics, comorbidity, survival, hospitalization, and iron dosing was obtained from the United States Renal Disease System (USRDS). Data were used from patients enrolled in waves 1, 3, and 4 of the USRDS Dialysis Morbidity and Mortality Studies (DMMS), representing 16,736 hemodialysis patients alive at the end of 1993. The DMMS was a cross-sectional study of a quasi-random sample of US dialysis patients. Because the DMMS collected only limited information on iron dosing, these data were obtained separately from Medicare data files available in the USRDS Standard Analytical File and Physician/Supplier Claims and linked to the DMMS files.

Study Population
Among the 16,736 patients included in waves 1, 3 and 4 of the DMMS, 1753 patients could not be linked to the Medicare data files because of missing identification numbers. In addition to these, we excluded 414 patients because of duplicate identification numbers or missing or nonsensical data on timing of first dialysis.

Because we chose to characterize iron administration during a 6-mo baseline period spanning from January 1, 1994 to June 30, 1994 and observed its association with subsequent mortality, we excluded patients who did not survive until July 1, 1994. To assure the availability of Medicare data on iron and erythropoietin dosing during the baseline period, we also excluded patients based on two other conditions. First, we excluded 1674 patients who were not entitled to Medicare insurance until after December 31, 1993 because of the 3-mo waiting period for Medicare insurance after the onset of ESRD. Second, we excluded 1392 patients who had evidence of a primary payer other than Medicare at any time during the first 6 mo of 1994. Iron dosing that is paid for by payers other than Medicare is not represented in either the USRDS or the Medicare data files. After all exclusions, 10,169 DMMS patients were potentially available for analysis. As outlined in our presentation of results, some data elements were missing for about 4500 of these patients, and they were, therefore, excluded from multivariate analyses. Owing to concerns about potential resultant selection bias, we explored for differences in the relationship of iron and survival in the groups of subjects with and without missing data on comorbidity. We examined this potential interaction between iron’s effect and missing data using proportional hazard models unadjusted for comorbidity.

Study Data
Exposure to Parenteral Iron.
We defined exposure to parenteral iron as the number of 100-mg vials of iron billed for in the Medicare data between January 1, 1994 and June 30, 1994 for each patient. Iron exposure was categorized first as a dichotomous indicator of whether or not the patient ever had bills for iron and then in ordered categories of the number of iron vials billed, including no bills for iron as a reference category.

Potential Confounding Variables.
Potential confounders included demographic and comorbidity data from the DMMS data set. Demographic variables included age, gender, and race. To characterize baseline comorbidity, we reduced the raw USRDS comorbidity data into a set of discrete, clinically coherent comorbidity variables. These variables were coronary artery disease, cerebrovascular disease, peripheral vascular disease, heart failure, pericarditis, diabetes, lung disease, neoplasms, AIDS, and HIV. Additional comorbidity variables included independent transfer, independent eating, smoking status, undernourished, prior transplant, living in a nursing home, duration of ESRD, body mass index, and type of angioaccess. Laboratory measures included serum creatinine, albumin, hemoglobin, cholesterol, hematocrit, bicarbonate, and phosphorous. We also controlled for profit status of dialysis providers, use of erythropoietin, and iron administration in the baseline period.

Statistical Analyses
Survival Analyses.
We performed a descriptive analysis of baseline characteristics, including comorbidity and pertinent laboratory values, and of iron and erythropoietin dosing during follow-up. We also examined frequency distributions of study variables. We used the Kaplan Meier product limit estimator to characterize the unadjusted survival distribution of subgroups of patients defined by comorbid conditions and iron administration. We compared Kaplan Meier curves describing different subgroups of patients using the log rank test (29). We also characterized the unadjusted relationship between iron and survival using bivariate Cox proportional hazards models (30).

We also used Cox proportional hazards regression analysis to examine the adjusted relationship between iron administration and survival. Adherence to the assumption of proportional hazards was confirmed graphically using Ln(-Ln) plots (30). Proportional hazards models are well suited to accommodate baseline representations of iron administration and other potential confounders. To develop multivariable models relating iron dosing to patient mortality adjusted for underlying comorbidity, we initially examined the adjusted relationship between comorbid conditions and study outcomes without iron parameters in the models. Variable selection was guided by unadjusted survival analyses relating comorbidity characteristics to survival. We used a stepwise algorithm to fit a multivariable model of baseline comorbidity measures that were independent predictors of patient survival. We used these sets of comorbidity measures to adjust analyses relating iron dosing to these outcomes by adding iron parameters to these models. We used robust estimators of variance to account for the clustered nature of the data (31,32).

Hospitalization Analyses.
We initially described the rate of hospitalization among study subjects overall and among subgroups on the basis of levels of iron administration. We characterized the unadjusted relationship between iron administration and hospitalization by using bivariate Poisson regression (33). We also based the analysis of the adjusted relationship between iron administration and the rate of hospitalization on Poisson regression. These models assume that the rate of hospitalization remains constant for the entire period of observation. We fit multivariable models by using a strategy parallel to that used for the proportional hazards analysis. Some subjects could have multiple events; the period at risk for a hospitalization was the total time a subject was followed and not in the hospital. To account for nonindependence of events within clusters, we used generalized estimating equations (GEE) to fit the models and estimate the standard errors (34).

	Results

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Descriptive Analyses
Data were available for a total of 34 comorbidity variables, laboratory values, and other patient characteristics among all patients who were potentially eligible for analysis. Table 1 summarizes demographic characteristics of the 10,169 patients who were eligible for analysis. Of these patients, half (50.7%) were men, 52% were white, and 43% were African American.

Table 2 describes the iron dosing for the baseline study period, between January 1, 1994 and June 30, 1994. The majority of subjects (63.0%) had no bills for any iron, 19.8% had bills for a total of 10 or fewer 100-mg vials, and 17.3% had bills for more than 10 vials.

Hospitalization Analysis
The overall rate of hospitalization was 1.35/patient-year at risk (95% CI, 1.34 to 1.37). The analogous rates for patients billed for none, 10 or fewer vials, and greater than 10 vials of iron were 1.31/patient-year (95% CI, 1.29 to 1.33), 1.36/patient-year (95% CI, 1.32 to 1.39), and 1.51/patient-year (95% CI, 1.47 to 1.56), respectively. displays the results of the unadjusted and adjusted Poisson regression analyses. Again, because of missing data, 5434 of 9426 subjects were included in our final model. Compared with none, bills for 10 or fewer vials of iron had no significant association with hospitalization rates (RR = 1.01; 95% CI, 0.90 to 1.14; P = 0.83), but bills for greater than 10 vials were associated with a 25% elevated rate of hospitalization (RR = 1.25; 95% CI,1.11 to 1.41; P < 0.001). After adjusting for demographic and comorbidity variables, the relationship between iron and morbidity was attenuated. Bills for 10 or fewer vials of iron continued to have no significant association with hospitalization (adjusted RR = 0.92; 95% CI, 0.83 to 1.03; P = 0.15), and bills for greater than 10 vials showed a reduced but still statistically significant 12% elevated risk (adjusted RR = 1.12; 95% CI, 1.01 to 1.25; P = 0.03).

	Discussion

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Several mechanisms have been postulated to explain a potential etiological link between parenteral iron administration and morbidity. First, it has been shown that the availability of iron increases the virulence of certain microorganisms (10,11,35). However, few data are available to indicate an increased risk of septicemia from iron with common gram-positive and gram-negative bacteria. Thus, it would appear unlikely that our findings are an indication of increased virulence of the pathogens typical in dialysis patients.

Second, conditions of iron overload among hemodialysis patients have been linked with impaired white cell function and an elevated risk of infection (12–17,22). For example, Patruta et al. (18) demonstrated impaired neutrophil function among patients treated with parenteral iron even in the absence of overt iron overload. Although an iron-induced defect in cellular immunity may potentially lead to a greater risk of bacteremia, the clinical significance of this finding is unknown. Furthermore, reduction of iron stores with desferrioxamine and erythropoietin can improve impaired phagocytosis associated with iron overload (15,16,22.)

Third, it has been speculated that the transient presence of free iron as it transits from its bound form to the reticuloendothelial system may lead to increased oxidative stress, the production of reactive oxygen species, and subsequent atheromatous changes (36). Lim et al. (36) recently reported that hemodialysis patients demonstrated a greater decrease in the plasma levels of the antioxidant enzyme superoxide dismutase and a greater increase in lipid peroxides compared with normal controls after administration of 100 mg of intravenous ferric saccharate (37). Nonetheless, clinical studies relating iron metabolism with cardiovascular disease outside of the dialysis setting have not consistently demonstrated a relationship (38,39).

A number of clinical studies have been reported relating iron stores or administered iron with subsequent morbidity. Hoen et al. (23) prospectively followed adult patients in French dialysis units for 6 mo from late 1989 through early 1990, examining the correlates of bacterial infection. Although these investigators did not study parenteral iron, serum ferritin was included as a potential risk factor for infection. At the end of follow-up, 118 of 607 patients had at least one bacterial infection. Thirty of these infections were associated with at least one positive blood culture. Multiple logistic regression analysis identified three significant risk factors for bacterial infection: a history of bacterial infection, use of a catheter angioaccess device, and an elevated level of serum ferritin. In a subsequent report, however, Hoen et al. (40) examined the relationship between practice patterns and bacteremia. Forty-four of 865 patients developed bacteremia with four significant risk factors being identified in multivariable analysis: use of a catheter, two or more previous episodes of bacteremia, current immunosuppressive treatment, and lower hemoglobin. Neither serum ferritin nor any iron administration in the prior 6 mo was a significant risk factor for bacteremia.

Our findings are consistent with several earlier studies of the relationship between administered iron and morbidity in dialysis patients (25–28). In an analysis of iron dosing patterns and mortality, Collins, et al. (24–27) studied prevalent hemodialysis patients using data from the USRDS and Medicare. Four cohorts of patients were each followed for 1 yr during which the prescription of more than 17 vials of iron over a period of 3 to 6 mo was associated with an increased risk of death from any cause and from infection after adjustment for prior comorbidity requiring hospitalization. These investigators also reported that prescriptions for more than 17 vials of iron over 5 to 6 mo were associated with a 13% increased risk of hospitalization for bacteremia (25). Owing to limitations of their data, these investigations were unable to adjust for multiple measures of morbidity such as serum albumin, body mass index, and functional status among others, all of which were available to us from the DMMS data.

Nurko et al. (28) published an abstract describing their study of the relationship between parenteral iron use and 2-yr mortality among the 2662 nationally representative hemodialysis patients alive in 1993. Although no association between iron use and 2-yr mortality was detected overall, they observed a significant relationship between iron use and 2-yr mortality from infection. Death from infection was not associated with ferritin levels or transferrin saturation.

Our study has several notable limitations. First, we did not have any data on changes in comorbidity or iron dosing over the period of follow-up. Since 1994, when we measured iron administration, its use has risen substantially. This changing pattern of iron use raises the possibility that the patients we studied who were administered parenteral iron differ with respect to characteristics such as the level of comorbidity compared with similarly treated patients today. The generalizability of our findings to current day practice depends on the extent to which we were successful in measuring and adjusting for comorbidity. Despite extensive clinical data on our study subjects, we did not have access to all potentially important information on comorbidity, including changes in patients’ health status over time. Although often observed in causal relationships, the absence of a gradient effect in our findings may suggest a threshold over which iron dosing is associated with lower survival. Second, our sample size was constrained by the large number of subjects in the USRDS database missing data on one or more comorbidity variables. Nonetheless, we were able to detect an association between iron prescriptions for greater than 10 vials over 6 mo and reduced survival. Furthermore, the prescription of 10 or fewer vials was not associated with an elevated risk of death; this is unlikely to change even with a larger study, because the upper bound of the confidence interval was very close to 1.0. However, because of our limited sample size, we were not able to explore subanalyses of death from infection or cardiovascular disease. Third, it is conceivable that the exclusion of a large number of subjects from our multivariable analysis because of missing data may have led to selection bias. Despite this possibility, our finding that the unadjusted iron dosing/survival relationship did not differ across subgroups with and without missing data suggests that selection bias played little role in our study. Fourth, we obtained our measure of iron exposure from Medicare billing data and could not be certain that study subjects received the quantity of iron for which their dialysis providers submitted bills to Medicare. Fifth, although we had extensive data on comorbidity, as noted earlier, we cannot rule out residual confounding from unmeasured or incompletely specified clinical characteristics. Finally, although we studied patients during a time when iron dextran was the only parenteral preparation available in North America, other parenteral preparations are now marketed and increasing in usage. Although we know of no theoretical basis for not generalizing our findings to these other preparations, additional studies would be needed to confirm our study results for these iron preparations.

Prescribing iron in quantities of 10 or fewer vials over 6 mo, a dosing scheme well within the guidelines established by the National Kidney Foundation’s Dialysis Outcomes Quality Initiative (41), had no association with an elevated risk of death or rate of hospitalization and may be associated with a small reduction. Although intensive dosing regimens were associated with diminished adjusted survival and higher adjusted rates of hospitalization, these potential risks need to be balanced against the known elevations in morbidity and mortality associated with anemia. Hemoglobin levels less than 10 g/dl have been associated with an elevated risk of death (41). Furthermore, it is now widely appreciated that most hemodialysis patients require parenteral iron to achieve a hemoglobin target of 11 g/dl (42).

Although we cannot eliminate the possibility that our findings regarding dosing of more than 10 vials (1000 mg) of iron dextran are a result of residual confounding from incomplete measurement of comorbidity, caution is warranted when prescribing this amount of parenteral iron over a period of 6 mo, especially if adequate iron stores and hemoglobin levels can be achieved with lower doses. Additional studies of the relationship between iron administration and patient outcomes should include measures of the changing pattern of comorbidity, iron dosing, and erythropoietin dosing over time and evaluation of preparations of iron in addition to iron dextran.

	References

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1. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin, DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin [see comments]. New Engl J Med 339: 584–590, 1998[Abstract/Free Full Text]
2. MacDougall IC, Hutton RD, Cavill I, Coles GA, Williams, JD: Poor response to treatment of renal anaemia with erythropoietin corrected by iron given intravenously [see comments]. BMJ 299: 57–158, 1989
3. Sakiewicz P, Paganini E: The use of iron in patients on chronic dialysis: mistake and misconceptions. J Nephrol 11: 5–15, 1998[Medline]
4. Sunder-Plassman G, Horl WH: Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant 10: 2070–2076, 1995[Abstract/Free Full Text]
5. MacDougall IC, Tucker B, Thompson J, Baker LRI, Raine AEG: A randomised controlled study of iron supplementation in patients treated with erythropoietin [abstract]. J Am Soc Nephrol 4: 428, 1993
6. Fishbane S, Frei GL, Maesaka J: Reduction of recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26: 41–46, 1995[Medline]
7. Senger JM, Weiss RJ: Hematologic and erythropoietin responses to iron dextran in the hemodialysis environment. ANNA J 3: 319–323, 1996
8. Taylor JE, Peat N, Porter C, Morgan AG: Regular low dose intravenous iron therapy improves response to erythropoietin in hemodialysis patients. Nephrol Dial Transplant 11: 1079–1083, 1996[Abstract/Free Full Text]
9. Sepandj F, Jindal K, West M, Hirsch D: Economic appraisal of maintenance parenteral iron administration in treatment of the anemia in chronic haemodialysis patients. Nephrol Dial Transplant 10: 319–322, 1996
10. Williams P, Griffiths E: Bacterial transferrin receptors—Structure, function and contribution to virulence. Med Microbiol Immunol 181: 301–322, 1992[Medline]
11. Payne SM: Iron and virulence in the family Enterobacteriaceae. Crit Rev Microbiol 16: 81–111, 1988[Medline]
12. Waterlot Y, Cantinieaux B, Hariga-Muller CDE, Maertelaere-Laurent E, Vanherweghem JL, Fondu P: Impaired phagocytic activity of neutrophils in patients receiving haemodialysis: the critical role of iron overload. Br Med J (Clinical Research Ed) 291: 501–504, 1985
13. Flament J, Goldman M, Waterlot Y, Dupont E, Wybran J, Vanherweghem JL: Impairment of phagocyte oxidative metabolism in hemodialyzed patients with iron overload. Clin Nephrol 25: 27–30, 1986
14. Cantinieaux B, Boelaert J, Hariga C, Fondu P: Impaired neutrophil defense against Yersinia enterocolitica in patients with iron overload who are undergoing dialysis. J Lab Clin Med 111: 524–528, 1988[Medline]
15. Boelaert JR, Cantinieaux BF, Hariga CF, Fondu PG: Recombinant erythropoietin reverses polymorphonuclear granulocyte dysfunction in iron-overloaded dialysis patients. Nephrol Dial Transplant 5: 504–517, 1990
16. Veys N, Vanholder R, Ringoir S: Correction of deficient phagocytosis during erythropoietin treatment in maintenance hemodialysis patients. Am J Kidney Dis 19: 58–63, 1992
17. Patruta SI, Edlinger R, Sunder-Plassmann G, Horl WH: Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency. J Am Soc Nephrol 9: 655–63, 1998[Abstract]
18. Mossey RT, Sondheimer J: Listeriosis in patients with long-term hemodialysis and transfusional iron overload. Am J Med 79: 397–400, 1985[CrossRef][Medline]
19. Seifert A, von Herrath D, Schaefer K: Iron overload, but not treatment with desferrioxamine favours the development of septicemia in patients on maintenance hemodialysis. QJM 65: 1015–1024, 1987[Abstract/Free Full Text]
20. Boelaert J, Daneels R, Schurgers M: Bacteraemia by Yersinia and other microorganisms in haemodialysis patients: A role for the iron-overload. Third European Congress of Clinical Microbiology. Den Haag, 1987: Abstract 531
21. 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
22. Tielemans CL, Lenclud CM, Wens R, Collart FE, Dratwa M: Critical role of iron overload in the increased susceptibility of haemodialysis patients to bacterial infections: Beneficial effects of desferrioxamine. Nephrol Dial Transplant 4: 883–887, 1989[Abstract/Free Full Text]
23. Hoen B, Kessler M, Hestin D, Mayeux D: Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey. Nephrol Dial Transplant 10: 377–381, 1995[Abstract/Free Full Text]
24. Collins A, Ebben J, Ma, J: Frequent iron dosing is associated with higher infectious deaths [abstract]. J Am Soc Nephrol 8: 190, 1997
25. Collins A, Ma J, Xia H, Ebben J: Intravenous iron dosing patterns and hospitalization [abstract]. J Am Soc Nephrol 9: 204A, 1998
26. Collins A, Ebben J, Ma J, Xia H: Intravenous iron dosing patterns and mortality [abstract]. J Am Soc Nephrol 9: 205A, 1998
27. Collins A, Ebben J, Ma J: Infectious hospitalization risk in IV iron-treated patients [abstract]. J Am Soc Nephrol 10: 238A–239A, 1999
28. Nurko S, Young E, Port FK: Parenteral iron and infection mortality risk in hemodialysis patients [abstract]. J Am Soc Nephrol 10: 252A, 1999
29. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958[CrossRef]
30. Cox DB: Regression models and life tables. Roy Stat Soc 34: 187–220, 1972
31. Huber PJ: The behavior of maximum likelihood estimates under non-standard conditions.In: Proceedings of the Fifth Berkeley Symposium in Mathematical Statistics and Probability., Berkeley, University of California Press, 1967,pp 221–233
32. White H: A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica 48: 817–830, 1980[CrossRef]
33. Breslow NE, Day NE: Statistical Methods in Cancer Research. Vol. II, The design and analysis of cohort studies [review]. Lyon, France, IARC Scientific Publications, 1987,pp 1–406
34. Zeger SL, Liang KY: Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42: 121–130, 1986[CrossRef][Medline]
35. Green NS: Yersinia infections in patients with homozygous beta-thalassemia associated with iron overload and its treatment. Pediatr Hematol Oncol 9: 247–254, 1992[Medline]
36. Lim PS, Wei YH, Yu YL, Kho B: Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy. Nephrol Dial Transplant 14: 2680–2687, 1999[Abstract/Free Full Text]
37. McCord JM: Is iron sufficiency a risk factor in ischemic heart disease? Circulation 83: 1112–1113, 1991[Free Full Text]
38. Stampfer MJ, Grodstein F, Rosenberg L, Willett W, Hennekins C: A prospective study of plasma ferritin and risk of myocardial infarction in US physicians [abstract]. Circulation 87: 688, 1992
39. Ascherio A, Willett WC, Rimm EB, Giovannucci EI, Stampfer MJ: Dietary iron intake and risk of coronary heart disease among men. Circulation 89: 969–974, 1994[Abstract/Free Full Text]
40. Hoen B, Paul-Dauphin A, Hestin D, Kessler M: EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 9: 869–876, 1998[Abstract]
41. Ma JZ, Ebben J, Xia H, Collins AJ: Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 10: 610–619, 1999[Abstract/Free Full Text]
42. National Kidney Foundation: NKF-DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure. New York, National Kidney Foundation, 1997

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