The Importance of Iron in Long-Term Survival of Maintenance Hemodialysis Patients Treated With Epoetin-Alpha and Intravenous Iron: Analysis of 9.5 Years of Prospectively Collected Data

Victor E. Pollak; Jonathan A. Lorch; Rakesh Shukla; Supriya Satwah

Disclosures

BMC Nephrology 

In This Article

Methods

Patients

A total of 1790 patients was available who were treated by maintenance in-center HD in 3 dialysis units managed by The Rogosin Institute (New York, NY), affiliated with New York Presbyterian Hospital and Weill Medical College of Cornell University; 1774 were included in the present study. Because they had hemolytic anemias and persistently high serum ferritin levels in association with the primary disease, 15 patients with sickle cell anemia and sickle cell trait were excluded, as well as one with acute myeloid leukemia who had recently received a bone marrow transplant and total body irradiation. The patient characteristics were described in detail previously.[17] All started the in-center HD course between January 1, 1998 and December 31, 2006. The present study includes survival follow up until June 30, 2007.

EPO, IV iron, and other medications were prescribed by attending nephrologists using an approach guided, with assistance of an anemia management team, by then current NKF DOQI guidelines available in 2002[14] and 2006.[15] EPO was administered IV. Three IV iron preparations were used: iron dextran (InFed®), iron sucrose (Venofer®), and sodium ferric gluconate (Ferrlecit®). Clinical practice was also influenced by changing mandates from the Center for Medicare and Medicaid Services (CMS) and by publications suggesting adverse effects of high serum ferritin levels.[13]

A comprehensive patient-centric, computerized record system (Disease Manager Plus™, MIQS, Inc., Boulder CO), in which data are stored in coded, extractable, form was used in patient care. Described in detail elsewhere, it enabled patient management and the present analyses.[17] Variables abstracted for analysis included:

  • Demographic: age at treatment start, race; gender; primary renal disease leading to ESRD

  • Co-morbid diseases present at or before treatment start: arteriosclerotic heart disease (ICD9-CM 410–414, 36.06, 36.07, 36.1), cerebrovascular disease (ICD 430–438), peripheral vascular disease (ICD 440, 441, 443, 785.4, V49.7, 84.1), malignancy (ICD 149–208), diabetes mellitus Types I (ICD 250.x1) and II (ICD 250.x0), AIDS (ICD 042), peptic ulcer disease (ICD 531–533).

  • Drugs: EPO and IV iron recorded as administered during HD treatments on 430,077 and 135,595 occasions respectively. During the course of the study there were three double blind dose equivalence studies, comparing then new ESAs with EPO. In all, these involved 3,531 (0.82%) of all ESA administrations. Data from these double blind studies have been included using the appropriate dose of EPO and its assumed equivalent.

  • Laboratory test results: Hb, red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), serum iron, transferrin saturation (TSAT), total iron binding capacity (TIBC), serum calcium, serum phosphorus, calcium × phosphorus product, serum intact parathyroid hormone (iPTH), Kt/V, and serum albumin were obtained on admission and monthly thereafter. Serum ferritin was measured 3-monthly. Approximately 58,980 measurements of each set of laboratory tests were analyzed.

Patients who continued in-center HD without interruption were followed until death or study termination on June 30, 2007. Save for the 29 who returned to in-center HD within 3 months of the last in-center HD treatment, those treated subsequently in another dialysis unit, or by kidney transplantation, home HD, or peritoneal dialysis were censored at the time of their last in-center HD treatments.

Statistical Analysis

Survival was defined from the date of the first in-center HD during the study period to death or termination of the follow-up (June 30, 2007), at which time patients still alive were treated as censored for survival analyses. Patients were also censored at the last in-center HD treatment before kidney transplantation, start of home HD, peritoneal dialysis, or transfer to another dialysis unit for in-center maintenance HD treatment.

Since each patient had numerous administered doses of EPO and IV iron, we obtained each patient's EPO dose as units per week, and IV iron dose as mg per month. This single characterization for each patient allowed us to summarize rates of administration of EPO and IV iron for each patient, and thereby assess the effects of these treatments on survival. Similarly, each hematological parameter for each patient was summarized by the mean value within that patient, thereby representing an average assessment over the duration of observation for that patient. The effects of various predictors on survival discussed herein should therefore be interpreted as "between-patient" rather than "within-patient" effects.

While EPO and IV iron dosages and hematological predictors are measured on interval scales, we examine these predictors both as continuous and as categorical variables for ease of interpretation. For Hb, serum iron, TSAT, serum ferritin, and other laboratory variables clinically relevant specific categorizations and cut-offs are used.

We employed standard regression techniques for survival data. Kaplan-Meier curves were obtained[18] for univariate analyses and, to ensure adequate consideration of confounding factors, Cox multivariate regression analysis.[19] The following co-variates were considered in the model building stage of analysis: age at treatment start, race, gender, primary renal disease leading to ESRD, presence or absence of one or more co-morbid conditions, EPO and IV iron dose administered, and hemoglobin, RBC, MCV, MCH, MCHC, serum iron, TSAT, TIBC, serum calcium, serum phosphorus, calcium × phosphorus product, iPTH, Kt/V, and serum albumin. We used a backward regression approach in multivariate set up to eliminate non-significant (p > 0.05) predictors from the model. We analyzed the EPO interaction effects on patient survival with IV iron, TSAT and serum ferritin in three models each of which contained EPO administered and one only of IV iron administered, TSAT, or serum ferritin along with all other significant predictors of survival. Thus, the above mentioned three interactions were assessed but only as two-factor interactions, and one interaction at a time with categorical characterization of the interacting variables. Only when the test for interactions was significant (P < 0.05), we looked at the pair-wise hazard ratios for assessing effects of interacting variables.

EPO was administered to 1731 patients (97.6%), TSAT values were available on 1690 patients (95.3%), and serum ferritin values on 1710 (96.4%). Certain variables which were skewed in nature were log transformed.

Study Approval

The study was approved by the Institutional Review Board of Weill Medical College of Cornell University.

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