Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis

Nephrology Dialysis Transplantation, Aug 2015

Background A risk/benefit analysis of iron supplementation in pre-dialysis advanced chronic kidney disease (CKD) patients has not been conducted. We aim to assess the effectiveness and the safety of iron supplementation in patients with CKD Stage 5 who have not yet received dialysis (CKD 5 ND).

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Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis

Nephrol Dial Transplant Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis Ko-Lin Kuo 0 2 3 4 5 8 9 Szu-Chun Hung 0 2 3 4 5 8 9 Jia-Sin Liu 0 1 2 4 8 9 Yu-Kang Chang 0 1 2 4 8 9 Chih-Cheng Hsu 0 1 2 4 8 9 Der-Cherng Tarng 0 2 4 6 7 8 9 0 Veterans General Hospital , Taipei , Taiwan 1 Institute of Population Health Sciences, National Health Research Institutes , Miaoli , Taiwan 2 Health Services Administration, China Medical University , Taichung , Taiwan 3 School of Medicine , Tzu Chi 4 University , Hualien , Taiwan 5 Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation , New Taipei , Taiwan 6 Department and Institute of Physiology, National Yang-Ming University , Taipei , Taiwan 7 Division of Nephrology, Department of Medicine , Taipei 8 The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved 9 I r o n s u p p l e m e n t a t i o n i n a d v a n c e d C K D chronic kidney disease; dialysis; erythropoiesisstimulating agent; iron supplementation - A B S T R AC T Background. A risk/benefit analysis of iron supplementation in pre-dialysis advanced chronic kidney disease (CKD) patients has not been conducted. We aim to assess the effectiveness and the safety of iron supplementation in patients with CKD Stage 5 who have not yet received dialysis (CKD 5 ND). Methods. A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From 1 January 2000 to 30 June 2009, we enrolled 31 971 adult patients who had a serum creatinine >6 mg/dL and a haematocrit <28% and who were treated with erythropoiesis-stimulating agents (ESAs). All patients were further divided into two groups with or without iron supplementation within 90 days after starting ESA therapy. Patient follow-up took place until dialysis, death before initiation of dialysis or 31 December 2009. The primary outcomes were death before initiating dialysis, hospitalization before death or long-term dialysis. Results. After propensity score matching, the patients who received iron supplementation were associated with a lower risk of all-cause death [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.80–0.90] compared with non-users. The survival benefit of iron use was consistent across the majority of dosage groups, except for those who were treated with monthly IV iron >200 mg. Moreover, compared with the non-users, the iron users were associated with a lower risk of hospitalizations (HR, 0.97; 95% CI, 0.94–0.99) but with a higher risk of faster progression to end-stage renal disease (HR, 1.05; 95% CI, 1.01–1.08). Conclusions. Iron supplementation is associated with 15% risk reduction in death among CKD 5 ND patients who received ESA treatment. Randomized studies are needed to validate this association. I N T R O D U C T I O N Anaemia is frequently encountered in patients with chronic kidney disease (CKD). The correction of anaemia requires erythropoiesis-stimulating agents (ESAs) in most instances [1, 2]. Iron supplementation can reduce ESA requirements and increase haemoglobin levels in patients with CKD [3, 4]. Oral iron is easily offered in clinical practice, because it does not require intravenous (IV) access. However, in patients with CKD, oral iron is often poorly tolerated, and the efficacy of oral iron may not be fully effective by enteric absorption. Compared with oral iron, IV iron is effective in improving erythropoiesis with adherence to anaemia treatment. Nevertheless, excessive IV iron supplementation can exaggerate CKD-associated oxidative stress and inflammation [5–9], exacerbate endothelial dysfunction [10–12] and is associated with increased risks of cardiovascular (CV) disease and infection [12–14]. Therefore, for treating CKD patients with anaemia, the adverse effects of iron supplementation should be concerned and balanced with its therapeutic benefits. Few studies have investigated the long-term outcome of iron supplementation other than its direct effects in correcting renal anaemia. Moreover, some observational haemodialysis (HD) cohorts have reported controversial results concerning the adverse effects of iron therapy [15, 16]. Our recent study and a study by Kalantar-Zadeh et al. suggested that in HD patients, high-dose IV iron supplementation is associated with adverse CV outcome and mortality [10, 12]. To date, the survival benefit of iron supplementation remains largely undefined in advanced CKD patients not receiving dialysis. According to the National Health Insurance (NHI) reimbursement regulations, CKD patients in Taiwan who had a serum creatinine >6 mg/dL (approximately equivalent to an estimated GFR <15 mL/min/1.73 m2) and a haematocrit <28% could receive ESA treatment to maintain a haematocrit level not to exceed 36%. Administering ESA provides a unique opportunity to identify a study population with CKD Stage 5 who have not yet received dialysis (CKD 5 ND) and were anaemic. To bridge the evidence gap in the transition from HD to CKD 5 ND, we evaluated the association between iron supplementation and the risks of death and hospitalization in a nationwide population-based, propensity score-matched cohort of CKD 5 ND patients treated with ESAs. M AT E R I A L S A N D M E T H O D S Data source The present study was based on data obtained from the NHI Research Database, which contains healthcare data of >95% of the hospitals in Taiwan and 99% of the entire population of 23 million enrolled in the NHI programme [17]. The comprehensive healthcare information maintained in the NHI Research Database included date of birth, gender, residency area, diagnostic codes, medication prescriptions and medical procedures. International Classification of Diseases-9th revision (ICD-9) codes were used to define diseases. The study was approved by the Institutional Review Board at Taipei Tzu Chi Hospital, and the informed consent was waived due to personal information that had been de-identified in the NHI Research Database. Design and study participants The study was designed as a population-based, longitudinal, cohort study to investigate the association between iron supplementation and the occurrence of death before initiating dialysis, the first hospitalization before death or chronic dialysis in CKD 5 ND patients. The orders of the NHI-reimbursed ESA, usually prescribed by nephrologists, are generally accurate, because the Bureau of NHI regularly audited the claims. Individuals who had a primary diagnosis of CKD (ICD-9 codes: 016.0, 042, 095.4, 189, 223, 236.9, 250.4, 271.4, 274.1, 403–404, 440.1, 442.1, 446.21, 447.3, 572.4, 580–589, 590–591, 593, 642.1, 646.2, 753, 984) and received ESA treatments between 1 January 2000 and 31 December 2009 were selected. The cohort has been described in our previous study [18]. Based on an internal report of the Taiwan Department of Health, the ESA use rate was 85% in 2012 among Stage 5 CKD patients who had not yet commenced renal replacement therapy. The median haematocrit level of incident dialysis patients was 24.2% (interquartile range, 20.6–27.5%) in Taiwan. Therefore, the selected cohort in this study was the most representative of CKD 5 ND patients in Taiwan [19]. The first day of ESA prescription was defined as the index date. We excluded patients younger than 20 years or older than 100 years of age, patients who received dialysis or renal transplant before the index date and patients who died or had commenced renal replacement therapy within 90 days after the index date. Co-morbidities, including diabetes mellitus, coronary artery disease (CAD), stroke and cancer, were defined as the diseases diagnosed within 3 years before the index date. The Charlson comorbidity index (CCI) was used to quantify patient comorbidity profiles [20]. Exposure assessment The detailed iron supplementation classification is shown in Supplementary data, Table S1. Patients who had ever taken oral or IV iron within 90 days after the index date were defined as iron users; the remaining subjects were defined as iron non-users. We classified the oral iron users as those who used only oral iron dispensed within 90 days after the index date. The IV iron users were defined as patients who received IV iron with or without oral iron supplementation within 90 days after the index date. To clarify the effect of both the dosage and the therapy duration and to compare different types of oral iron, we propose the concept of cumulative defined daily doses (cDDDs) [21]. The cDDDs indicate that the sum of the dispensed DDD of any oral iron, which is an indicator of exposed duration, was used to associate their use with the risk of death or hospitalization. The oral iron groups were classified into cDDDs of <45 and ≥45 within 90 days after enrolment, and the IV iron groups were classified into IV iron users who received <100, 100–199 and ≥200 mg/month, respectively. Outcomes The observation period started 90 days after the index date until death or the commencement of chronic dialysis, whichever occurred first, or 31 December 2009. The primary outcomes were all-cause death before chronic dialysis and all-cause hospitalization before death or chronic dialysis. The onset of mortality was the date of death. The time for the first hospitalization was the date of hospitalization. Additionally, the onset of renal outcome was defined as the date of end-stage renal disease (ESRD) development and the commencement of chronic dialysis for at least 90 days. Statistical analysis The baseline characteristics were compared by the two-sided t-test and χ2 test. The differences of probability for mortality and hospitalization were compared using Kaplan–Meier methods and the log-rank test. In multivariable Cox’s proportional hazard models, the effects of iron supplementation were adjusted for age, gender, CCI score, presence of diabetes mellitus, CAD, stroke and cancer, the number of visits to nephrologists within 3 years before the index date (0, 1–6 or >6 visits), geographic location (northern, middle, southern or eastern/other islands, according to NHI registration locations) and antihypertensive medications. The study entry was defined as the 90th day after the index date. Patient follow-up visits took place up until the time of dialysis, pre-dialysis death or 31 December 2009. The primary outcomes were pre-dialysis death, hospitalization before death or chronic dialysis. The results were expressed as hazard ratio (HR) for iron users compared with non-users. The adjusted HRs for death and hospitalization associated with iron use were analysed among the subgroups based on the participants’ characteristics. Additionally, because iron users and non-users have different baseline characteristics, we performed a propensity score-matched analysis, in which we calculated a propensity score for the likelihood of using iron by multivariate logistic regression analysis, conditional on the baseline covariates listed in Table 1. All P-values were two-sided, and the significance level was set at 0.05. The statistical analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) and STATA SE version 11.0 (Stata Corp, College Station, TX, USA). Sensitivity analyses To assess the reliability of our findings, we conducted the following secondary analyses. First, the method of inverse probability weighting was performed to assure robustness of results found in our study [22]. Second, we conducted separate analyses for males, females, those with regular nephrologist visits and non-cancer subjects to look for any evidence of a cohort effect. Third, we conducted a series of analyses defining iron use at intervals of 60 and 120 days after the first ESA prescription to minimize misclassification bias. R E S U LT S Patient characteristics We enrolled 31 971 patients with CKD 5 ND in the present study (Figure 1). The baseline patient characteristics are summarized in Table 1. Among this population, 11 610 (36.3%) patients had at least one prescription for iron supplementation in the first 90 days after the index date. Among them, 82.8% were oral iron users and 17.2% were IV iron users. Compared with the iron non-users, the iron users were younger, predominantly female and more likely to visit nephrologists in the preceding 3 years; they had fewer co-morbidities and received higher doses of ESA. Additionally, for each iron user, we identified one nonuser from our selected cohort who was frequency matched with propensity scores that were calculated from all of the baseline covariates. The nearest-neighbour algorithm was applied to construct matched pairs, assuming that the proportion of 0.995–1.0 is perfect [23]. We finally matched 11 381 iron users with the same number of non-users (Table 1). Association between iron supplementation and risk of death in CKD 5 ND The Kaplan–Meier curve for the hazards of overalls mortality was statistically significantly different from the iron users and non-users (Figure 2A), indicating that the iron users had a lower risk of death. A total of 6556 (20.5%) patients died before they progressed to ESRD requiring dialysis during the mean follow-up period of 8 months (Table 2). The incidence of death was 16.0/100 person-years in the iron users and 22.3/100 person-years in the non-users. Compared with the non-users, the iron users were significantly associated with a lower risk of death [HR, 0.84; 95% confidence interval (CI), 0.80–0.89], and the results remained consistent in the propensity score-matching model (HR, 0.85; 95% CI, 0.80–0.90). Regarding the dose–response relationship, the respective HRs of mortality related to iron supplementation were 0.84 (95% CI, 0.77–0.92), 0.85 (95% CI, 0.79–0.92), 0.85 (95% CI, 0.73– 0.99) and 0.78 (95% CI, 0.64–0.96) for oral iron of cDDDs <45 and ≥45, and IV iron <100 and 100–199 mg/month within 90 days compared with the matched iron non-users in the multivariate Cox regression model (Table 2). However, the effect of IV iron ≥200 mg/month on survival advantage was modest without statistical significance (HR, 0.92; 95% CI, 0.71– 1.19). Association between iron supplementation and risk of hospitalization The Kaplan–Meier curve for the hazards of hospitalization from the data of the iron users and non-users was statistically significant (Figure 2B), indicating that the iron users also had a lower risk of hospitalization. The incidence of all-cause hospitalization was 101.2/100 person-years among the iron users and 120.3/100 person-years among the non-users. Compared with the non-users, the iron users were significantly associated with a lower risk of hospitalization (adjusted HR, 0.94; 95% CI, 0.93–0.98), and the association was consistent in the propensity score-matching model (HR, 0.96; 95% CI, 0.93–0.99). The respective HRs of hospitalization related to iron supplementation were 0.96 (95% CI, 0.93–0.99) and 0.88 (95% CI, 0.80–0.97) for oral iron of cDDDs ≥45 and IV iron 100–199 mg/month within 90 days compared with the matched iron non-users in the multivariate Cox regression model. Again, the relation of IV iron ≥200 mg/month to the risk of hospitalization was marginal (Table 2). Sensitivity analysis In sensitivity analyses, similar results were seen across various statistical models including inverse probability weighting (Supplementary data, Table S2). We also found that the risk pattern for mortality and the hospitalization of patients who received iron supplementation were consistent in the subgroups of male or female subjects, in those with regular nephrologist visits and in non-cancer patients (Supplementary data, Table S3). Again, similar results were found when we redefined the exposure time for iron (Supplementary data, Tables S4 and S5). Risk of chronic dialysis in CKD 5 ND patients receiving iron supplementation A total of 22 580 (70.6%) patients progressed to ESRD requiring maintenance dialysis during the median follow-up period of 8 months (Supplementary data, Table S6). Compared with the non-users, the iron users were associated with a higher risk of faster progression to ESRD necessitating maintenance Before matched Iron users (n = 11 610) Age, mean (SD), year 638 (13.3) Age, group, year 20–44 968 (8.3) 45–64 4641 (40.0) 65–74 3293 (28.4) 75–100 2708 (23.3) Gender Female 7019 (60.5) Co-morbid conditions within 3 years before the index date Diabetes 5126 (44.2) Coronary artery disease 2516 (21.7) Stroke 1632 (14.1) Cancer 1099 (9.5) CCI score 4.0 (2.3) Nephrologist visits within 3 years before the index date 0 2254 (19.4) 1–6 3224 (27.8) >6 6132 (52.8) Anti-hypertensive agents used ACEI/ARB 5073 (43.7) Beta-blockers 3989 (34.4) Calcium-channel blockers 7068 (60.9) Diuretics (any) 6421 (55.3) Statin 1665 (14.3) Aspirin 1844 (15.9) NSAID Non-COX-2 inhibitors 3790 (32.6) COX-2 inhibitors 459 (4.0) Acetaminophen 5186 (44.7) Iron used in 3 months <45 cDDDs 3384 (29.2) ≥45 cDDDs 6225 (53.6) IV <100 mg/month 1042 (9.0) IV 100–199 mg/month 655 (5.6) IV ≥200 mg/month 304 (2.6) ESA dose (1000 IU/month) 13 (11) RBC transfusion in 3 months (%) 3051 (26.3) Hospital location Northern 4665 (40.2) Middle 2508 (21.6) Southern 4239 (36.5) Eastern or other islands 198 (1.7) Propensity score 0.618 (0.359–0.970) Iron non-users (n = 20 361) 1283 (6.3) 7436 (36.5) 5890 (28.9) 5752 (28.3) 10 409 (51.1) 4370 (21.5) 5498 (27.0) 10 493 (51.5) 9044 (44.4) 8101 (39.8) 13 494 (66.3) 12 528 (61.5) 3390 (16.7) 4029 (19.8) 7143 (35.1) 970 (4.8) 9914 (48.7) Propensity score-matched Iron users (n = 11 381) 871 (7.7) 4530 (39.8) 3275 (28.8) 2705 (23.8) 5121 (45.0) 2503 (22.0) 1628 (14.3) 1092 (9.6) 4.1 (2.3) 2228 (19.6) 3139 (27.6) 6014 (52.8) 4941 (43.4) 3982 (35.0) 7015 (61.6) 6381 (56.1) 1658 (14.6) 1839 (16.2) 3730 (32.8) 459 (4.0) 5133 (45.1) Iron non-users (n = 11 381) 960 (8.4) 4496 (39.5) 3216 (28.3) 2709 (23.8) 5073 (44.6) 2446 (21.5) 1641 (14.4) 1101 (9.7) 4.1 (2.3) 2206 (19.4) 3144 (27.6) 6031 (53.0) 4967 (43.6) 3966 (34.9) 6964 (61.2) 6315 (55.5) 1637 (14.4) 1842 (16.2) 3693 (32.5) 472 (4.2) 5074 (44.6) dialysis (adjusted HR, 1.04; 95% CI, 1.01–1.07). Moreover, after adjusting for different covariates in the propensity scorematching model, the iron users still had a significantly higher risk for faster progression to ESRD necessitating maintenance dialysis (HR, 1.05; 95% CI, 1.02–1.08). D I S C U S S I O N The use of iron in CKD or dialysis patients has dramatically increased because of safety issues concerning ESA therapy following the publication of the TREAT study and reducing the cost by limiting ESA requirements following the bundled payment policy for dialysis treatment [24–26]. For patients with non-dialysis CKD, the administration route for iron therapy is controversial. Despite poor enteric absorption and uncertain efficacy for erythropoiesis by oral iron supplementation, our data revealed that only 17.2% of iron users were treated via IV route administration during ESA therapy. The majority of physicians preferred to prescribe oral iron to patients with non-dialysis CKD in Taiwan. Moreover, the doses of ESA and supplemental iron were lower than those in the HD cohorts of previous studies [10]. The reasons for this finding are due primarily to no consensus and definite recommendations in the current guidelines for optimal ESA and iron doses in patients with non-dialysis CKD, convenience of oral route to IV route for iron therapy in outpatient practice and physicians’ concerns regarding the adverse effect of arm veins damage of IV iron therapy. The FIND-CKD study was the first randomized trial to utilize a high or low serum ferritin target to adjust IV iron dosing in non-dialysis CKD [27]. The study demonstrated that compared with oral iron, IV ferric carboxymaltose targeting a ferritin of 400–600 μg/L quickly reached and maintained haemoglobin level, and reduced the need of ESA for anaemia management. However, evidence of iron supplementation on hard outcomes (i.e. overall mortality or long-term dialysis) in patients with non-dialysis CKD is lacking. To the best of our knowledge, our large-scale cohort study first demonstrated that oral iron as well as lower dose IV iron (<200 mg/month) supplementation were associated with a 15% reduced risk of death among CKD 5 ND under ESA therapy. Accordingly, we recommend F I G U R E 2 : Kaplan–Meier analysis of survival curves among predialysis Stage 5 CKD patients. Mortality-free (A) and hospitalization-free (B) survivals constitute the study end points. Difference between iron users and non-users was analysed by log-rank test. that oral route administration is an alternative option for iron supplementation in CKD 5 ND patients on account of the safety and convenience in outpatient practice. ESAs enhance erythropoietic activity and increase the iron demand for haemoglobin synthesis in CKD patients. However, thrombocytosis could develop as an adverse effect of high ESA dose in the presence of iron store depletion. Streja et al. [28] demonstrated that relative thrombocytosis was associated with iron depletion and might contribute to increased mortality when administering higher ESA doses to achieve haemoglobin levels of 13 g/dL or greater in HD patients. Therefore, timely supply of low-dose IV iron to combat iron depletion is a prerequisite to ESA response and reduction in the toxicity of higher ESA dose. As a result, in HD patients, Kalantar-Zadeh et al. and Pollak et al. reported that the supplemental IV iron dose <400 and <455 mg/month, respectively, could reduce the risk of mortality compared with those receiving ESA without iron supplementation [12, 29]. In our CKD 5 ND patients under ESA therapy, the supplemental IV iron not exceeding 200 mg/ month was also associated with lower risk for mortality and hospitalization compared with iron non-users. However, the survival benefits of low-dose IV iron might be overwhelmed by the pro-oxidant and pro-inflammatory effects of high-dose IV iron in HD [12, 29] or CKD 5 ND patients. The risk between iron supplementation and faster progression to starting dialysis in non-dialysis CKD remains a subject of debate, and the toxicity of IV iron may be different in patients who are either inflamed or not. Zager et al. [30, 31] demonstrated that parenteral iron not only induced intracellular iron accumulation, marked lipid peroxidation and cell injury in isolated mouse and human tubular epithelial cells but also showed nephrotoxicity after IV iron injection in vivo. Three small studies on patients with CKD demonstrated that short-term IV iron administration caused transient proteinuria and urinary excretion of tubular enzymes [32–34]. Because of the lack of data about baseline serum creatinine and proteinuria, our study results are not sufficient to demonstrate that the patients treated with iron really have a higher risk to reach dialysis. Moreover, patients receiving iron are more likely to have more severe anaemia because of more advanced CKD. However, a similar study on iron status by Kovesdy et al. [35] showed that higher transferrin saturation (TSAT) is associated with faster CKD progression in non-dialysis CKD. The result of Kovesdy et al. was in line with our data. Additionally, because iron supplementation decreased the competing risk of death, the survivors had more exposure time to pre-ESRD milieu and an increased risk for progression to ESRD and initiation of renal replacement therapy. Further long-term randomized studies are needed to validate this association. Our study was notable for its large sample size, its nationally representative nature and the fact that the selected cohort was validated by a strict NHI reimbursement regulation. However, several limitations and precautions are needed for interpreting the results. First, our study was observational in nature and cannot prove causality. To assure an adequate statistical power (α = 0.05; 1 − β = 0.8, no loss of follow-up), at least 9000 CKD 5 ND patients should be enrolled to examine a 15% relative risk reduction. Apart from the impracticability of conducting such a large-scale, randomized, controlled trial, emerging evidence suggests that well-designed observational studies can yield comparable outcomes [36, 37]. Second, the haematological data such as ferritin and TSAT are not available in the present study. Thus, it is not possible to evaluate whether iron was administered or not correctly. We also found that the iron users were younger and more likely to visit nephrologists in the preceding 3 years with a better general care. However, these confounding effects in our study could be minimized, because the model robustness has been tested in a propensity score-based matched design. In addition, we demonstrated that the consistency in the series of subgroup analyses assures robustness of results found in this study. Finally, in clinical practice of ESA prescription in CKD 5 ND, physicians in Taiwan should follow the NHI reimbursement criteria to keeping serum ferritin >100 ng/mL and/or TSAT > 20% during the ESA therapy. We believe that the baseline iron parameters in our study might be similar according to the NHI reimbursement criteria for all ESA users. Third, it can be argued that patients of acute renal failure with transient creatinine levels >6 mg/dL were likely included in our cohort. Therefore, we restricted our analysis to patients who persistently received ESA therapy at two or more consecutive ambulatory visits, and the result was not materially changed. In conclusion, our findings from this nationwide cohort can expand the existing knowledge of iron supplementation from dialysis to CKD 5 ND patients under ESA treatment. Our Before matching After matching Incidence rate (100 Crude HR (95% CI) Adjusted HR person-years) (95% CI) Incidence rate (100 Adjusted HR person-years) (95% CI) Hospitalization 1.0 (reference) 0.72 (0.68–0.75)* 0.76 (0.70–0.83)* 0.69 (0.65–0.74)* 0.69 (0.60–0.80)* 1.0 (reference) 0.84 (0.80–0.89)* 0.84 (0.77–0.91)* 0.84 (0.78–0.90)* 0.83 (0.72–0.96)* 0.60 (0.49–0.73)* 0.78 (0.64–0.95)* 1.05 (0.83–1.35) 1.07 (0.84–1.37) 1.0 (reference) 0.88 (0.86–0.90)* 0.91 (0.87–0.94)* 0.88 (0.85–0.91)* 0.86 (0.81–0.93)* 1.0 (reference) 0.96 (0.93–0.98)* 0.99 (0.95–1.03) 0.95 (0.92–0.99)* 0.92 (0.86–0.99)* 0.79 (0.72–0.86)* 0.89 (0.81–0.97)* 0.94 (0.82–1.07) 0.97 (0.84–1.11) 1.0 (reference) 0.85 (0.80–0.90)* 0.84 (0.77–0.92)* 0.85 (0.79–0.92)* 0.85 (0.73–0.99)* 0.78 (0.64–0.96)* 0.92 (0.71–1.19) 1.0 (reference) 0.96 (0.93–0.99)* 0.99 (0.97–1.04) 0.96 (0.92–0.99)* 0.93 (0.86–1.01) 0.88 (0.80–0.97)* 0.96 (0.84–1.10) A multivariate analysis was adjusted for all variables listed in Table 1. cDDD, cumulative defined daily dose; CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; IV, intravenous. *P < 0.05 compared with iron non-users. large-scale cohort study suggests that oral or lower dose IV iron supplementation was significantly associated with lower risks of death and hospitalization in CKD 5 ND patients. Further studies are needed to validate this association. Education’s Aim for the Top University Plan and Taipei Tzu Chi General Hospital (TCRD-TPE-100-C2-3, TCRD-TPENSC-102-05, TCRD-TPE-103-RT-4). S U P P L E M E N T A R Y D A T A C O N F L I C T O F I N T E R E S T S T A T E M E N T Supplementary data are available online at http://ndt.oxford journals.org. None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format. A U T H O R S ’ C O N T R I B U T I O N S Study concept and design: K.L.K., J.S.L., C.C.H., D.C.T.; acquisition of data: K.L.K., J.S.L., S.C.H., Y.K.C.; analysis and interpretation of data: K.L.K., J.S.L., S.C.H., Y.K.C., C.C.H., D.C.T.; manuscript draft: K.L.K., J.S.L.; critical revision of the manuscript for important intellectual content: C.C.H., D.C.T.; final approval of the article: C.C.H., D.C.T.; statistical analysis: J.S.L., Y.K.C.; obtaining of funding: K.L.K., C.C.H., D.C.T. All authors critically reviewed and approved the manuscript. A C K N O W L E D G E M E N T S This work was supported by grants from the Health Promotion Administration (03D9-PHBHP01), National Science Council (NSC 102-2314-B-010-004-MY3, NSC 99-2314-B-303-002MY3, NSC 102-2314-B-303-013-MY3), Taipei Veterans General Hospital (V102C-129, V103C-100) and the Ministry of LE tseug o n O c t o b e r 1 0 , 2 0 1 6 1. Parfrey PS , Foley RN , Wittreich BH et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease . J Am Soc Nephrol 2005 ; 16 : 2180 - 2189 2. Hörl WH . Clinical aspects of iron use in the anemia of kidney disease . J Am Soc Nephrol 2007 ; 18 : 382 - 393 3. Besarab A , Amin N , Ahsan M et al. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients . J Am Soc Nephrol 2000 ; 11 : 530 - 538 4. Sunder-Plassmann G , Hörl WH . 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Ko-Lin Kuo, Szu-Chun Hung, Jia-Sin Liu, Yu-Kang Chang, Chih-Cheng Hsu, Der-Cherng Tarng. Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis, Nephrology Dialysis Transplantation, 2015, 1518-1525, DOI: 10.1093/ndt/gfv085