- Open Access
Association between serum ferritin levels and clinical outcomes in maintenance hemodialysis patients: a retrospective single-center cohort study
© The Author(s) 2019
- Received: 20 September 2018
- Accepted: 8 April 2019
- Published: 8 May 2019
Ferritin is a well-known marker of iron deficiency anemia, but the target in maintenance hemodialysis (MHD) patients remains controversial. This study examined the association between baseline ferritin levels and clinical outcomes.
We retrospectively collected the data of outpatients on MHD for 5 years at St. Luke’s International Hospital from July 2009. Patients with baseline ferritin levels of > 100 ng/mL in June 2009 were defined as the high-ferritin (HF) group and the remaining patients as the low-ferritin (LF) group. The primary endpoint was all-cause mortality. The secondary endpoints included cardiovascular events and infection-related hospitalizations. Log-rank test and Cox proportional hazard analysis were performed.
Of 116 patients (age, 65.4 ± 13.4 years, 70% males), 29 (25%) and 87 (75%) belonged to the HF and LF groups, respectively. During the follow-up period of 1825 (interquartile range 819–1825) days, 38 patients (23 in the HF and 15 in the LF groups) died. According to the Kaplan–Meier survival curves, the HF group had significantly poor survival compared with the LF group (p = 0.0089). After adjusting for age, sex, vintage of hemodialysis, C-reactive protein levels, and history of cardiovascular events, the hazard ratio (HR) for the HF group was 2.49 (95% confidence interval (CI), 1.21–5.12). The multivariate analysis of cardiovascular events revealed a similar result with statistical significance (HR 2.69; 95% CI 1.12–6.46). Infection-related hospitalizations did not exhibit any statistically significant difference.
In MHD patients, ferritin levels > 100 ng/mL is associated with increased rates of all-cause mortality and cardiovascular events.
- Cardiovascular events
The management of anemia is important in maintenance hemodialysis (MHD) patients and is mainly achieved by the administration of iron and erythropoietin-stimulating agents (ESAs) . MHD patients are predisposed to iron deficiency due to residual blood loss during hemodialysis treatment and frequent blood sampling . Serum ferritin is an established marker for detecting absolute iron deficiency. However, the optimal target ferritin level in MHD patients remains controversial. Recommendations for iron supplementation with ESA treatment differ among guidelines: according to the Kidney Disease: Improving Global Outcomes guideline , iron supplementation should be considered when transferrin saturation (T-SAT) is ≤ 30% and ferritin is ≤ 500 ng/mL, whereas the Kidney Disease Outcomes Quality Initiative recommends maintaining T-SAT at > 20% and ferritin at > 200 ng/mL . The Japanese Society for Dialysis Therapy sets the target ferritin level at 100 ng/mL, which is much lower than that described in other recommendations. Iron is given when T-SAT is ≤ 20% and ferritin is ≤ 100 ng/mL . This practice was recently revised, and iron supplementation is currently considered when T-SAT is ≤ 20% or ferritin is ≤ 100 ng/mL .
Some observational studies have demonstrated a correlation between high ferritin levels and poor clinical outcomes in MHD patients, using a cut-off ferritin level of 600–1200 ng/mL [6–8]. However, two observational studies from Japan have provided evidence for a cut-off ferritin level of 100 ng/mL [9, 10]. Of the two, the Nishinomiya study reported increased mortality and a combined hazard ratio (HR) of mortality and cardiovascular events during an 8-year follow-up period , and the other study assessed the fluctuation of ferritin levels to demonstrate increased adverse events during a 2-year follow-up period . Another study pointed out possible U-shape relation of ferritin levels and prognosis in MHD patients when stratified by inflammation . In Japanese MHD patients, the most important causes of death are cardiovascular events and infections . However, no study has directly specified the relationship between absolute ferritin levels and detailed causes of death, which may explain the increased mortality in hyperferritinemia.
This study was conducted to provide a better understanding of the relationship between high ferritin levels and detailed complications, including the top two causes of death (cardiovascular events and infection), using a cut-off ferritin level of 100 ng/mL over a long follow-up period in MHD patients.
All outpatients aged > 18 years who were receiving MHD at St. Luke’s International Hospital on July 1, 2009 were included in this study. Patients treated less frequently than three times per week or with a hemodialysis vintage of < 3 months were excluded. Laboratory tests, including hemoglobin levels, iron concentration, total iron binding capacity (TIBC), and ferritin levels, were performed in June 2009 for all patients. Anemia was treated with weekly darbepoetin and/or ten consecutive doses of weekly intravenous saccharated ferric oxide (40 mg). Treatment was adjusted based on the laboratory results of hemoglobin levels every other week and iron status every 3 months, which were determined by the physicians according to 2008 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease . In the guideline, the target hemoglobin level was 10–12 g/dL, and saccharated ferric oxide was recommended only when T-SAT was ≤ 20% and the serum ferritin level was ≤ 100 ng/mL. No oral iron supplements were used.
This was a single-center retrospective cohort study. Patients with baseline ferritin levels > 100 ng/mL in June 2009 were defined as the high-ferritin (HF) group, and the rest were defined as the low-ferritin (LF) group. Patients were followed for 60 months from July 1, 2009 to June 30, 2014, unless they received a kidney transplant or were lost to follow-up. Baseline characteristics that could influence the iron status or long-term prognosis in MHD patients were reviewed. Baseline clinical data, including age, gender, cause of end-stage renal disease (ESRD), hemodialysis vintage, body mass index (BMI), and histories of coronary artery diseases (CAD), arterial fibrillation, diabetes mellitus, hypertension, dyslipidemia, cardiovascular events [defined as acute cardiac infarction (AMI), cerebral infarction, or cerebral hemorrhage], gastrectomy, malignancy, positive fecal occult blood, liver disorders, and recent hospitalization within 3 months, were collected by reviewing medical records. Laboratory data that were measured in June 2009 included hemoglobin levels, iron concentration, TIBC, creatinine levels, BUN, calcium levels, phosphate levels, LDL-cholesterol levels, albumin levels, and C-reactive protein (CRP) levels. T-SAT was calculated as iron concentration divided by TIBC and calcium values were corrected based on serum albumin levels. The total ESA dose (darbepoetin) in the first month (July 2009), total intravenous iron dose per month in the first month (July 2009), and the Kt/V were also calculated.
Endpoints and statistics
The primary endpoint was all-cause mortality. The secondary endpoints were cardiovascular events (AMI confirmed by coronary angiography and cerebral infarction or cerebral hemorrhage confirmed by computed tomography or magnetic imaging) and infection-related hospitalizations. Secondary endpoints were assessed based on the frequency with which they caused death in hemodialysis patients . Data of patients who were transferred to another hospital were collected from the medical records.
Patient characteristics were analyzed using the t test, chi-square test, and Fisher’s exact test, as appropriate. We performed receiver operating characteristic (ROC) analysis to examine the validity of using cut-off level of serum ferritin 100 ng/mL based on the highest Youden index (sensitivity + specificity − 1) . We used the Kaplan–Meier method to draw time-to-event curves and the log-rank test to compare the HF and LF groups. Cox proportional hazard analysis was performed for univariate and multivariate analysis. We chose age, gender, vintage of hemodialysis, CRP levels, and history of cardiovascular events as confounding factors based on previous studies  and the results of Cox proportional hazard analysis. Alpha level of 0.05 was used in all analyses. All statistical analyses were performed using JMP version 9.0 (SAS Institute, Cary, NC).
Demographic, laboratory, and clinical characteristics
Total (n = 116)
LF (n = 87)
HF (n = 29)
Serum ferritin, ng/mL
Cohort time, day
65.4 ± 13.4
64.8 ± 13.5
66.9 ± 13.3
Cause of ESRD
IgA nephropathy or chronic glomerulonephritis
Rapid progressive glomerulonephritis
Polycystic kidney disease
10.8 ± 1.15
10.9 ± 1.08
10.7 ± 1.34
Serum iron, μg/dL
Iron dose, mg/month
42.1 ± 85.8
45.5 ± 92.1
31.7 ± 63.6
ESA dose, μg/week
29.9 ± 25.1
30.2 ± 24.7
29.3 ± 26.7
HD vintage, month
Kt/V (single pool)
Serum creatinine, mg/dL
11.9 ± 3.04
12.0 ± 3.16
11.5 ± 2.66
64.9 ± 16.0
64.7 ± 15.6
65.5 ± 17.3
Serum calciumb, mg/dL
9.33 ± 0.67
9.33 ± 0.67
9.35 ± 0.70
Serum phosphate, mg/dL
21.6 ± 3.50
21.8 ± 3.28
21.4 ± 4.07
Serum albumin, g/dL
History of CADa
History of atrial fibrillationa
History of diabetes mellitus
History of hypertensiona
History of dyslipidemiaa
History of CV events
History of gastrectomya
History of malignancya
Positive fecal occult blooda
History of liver disordersa
Detailed causes of death (n%)
Cause of death
Total (n = 116)
LF (n = 87)
HF (n = 29)
Multivariate analysis of all-cause mortality and cardiovascular events
HR (95% CI)
HD vintage, month
Ferritin > 100 ng/mL
History of CV events
Secondary endpoints (cardiovascular events and infection-related hospitalizations) in low- and high-ferritin patients
Total (n = 116)
LF (n = 87)
HF (n = 29)
Bacteremia and sepsis
Gastrointestinal and hepatobiliary
Skin and soft tissue
Bone and joint
In this single-center retrospective cohort study, ferritin levels > 100 ng/mL were related with poor long-term survival in MHD patients, even after adjusting for age, gender, hemodialysis vintage, CRP levels, and history of cardiovascular events. Elevated ferritin levels were also associated with increased cardiovascular events.
Ferritin and all-cause mortality in MHD patients
Cut-off of ferritin (ng/mL)
Kletzmayr (2002) 
Austria n = 100
HR of all-cause mortality increased in ferritin > 600 ng/mL
Kalantar-Zadeh (2005) 
the USA n = 58,058
N/A (12 groups)
HR of all-cause mortality increased in ferritin > 1200 ng/mL
Jenq (2009) 
3 centers in Taiwan n = 187
More all-cause mortality in ferritin > 700 ng/mL than in two other groups
Hasuike (2010) 
7 centers in Japan n = 94
HR of all-cause mortality was 4.18 in ferritin > 100 ng/mL
A single center in Japan n = 116
HR of all-cause mortality was 2.49 in ferritin > 100 ng/mL
To determine the frequency of the various causes of death in MHD patients with high ferritin levels, we reviewed the details of all deaths, which revealed that cardiovascular events and infections were the two leading causes. Several reports have demonstrated the association of cardiovascular events and infections with hyperferritinemia. Analysis of a nationwide database based on an increased trend of ferritin levels identified increased cardiovascular events in patients on MHD (n = 1086) . Another clinical study suggested that the ferritin level in ESRD patients was correlated with the carotid intima-media thickness, which reflects the extent of atherosclerosis . Our study demonstrated that cardiovascular events, either fatal or non-fatal, increased (HR, 2.69) with ferritin levels, even after adjusting age, sex, vintage of hemodialysis, CRP levels, and history of cardiovascular events. Regarding infections, a previous study described three times higher risk of bacterial infections in hemodialysis patients with higher ferritin levels . Our study did not find such a correlation between hyperferritinemia and infection-related hospitalization.
The causality for elevated ferritin and increased all-cause mortality remains to be explored. One explanation is that the underlying cause of elevated ferritin levels is associated with poor survival (i.e., ferritin is a surrogate marker of prognosis in MHD patients). Ferritin is elevated not only by stored iron but also by inflammation, infection, malignancy, and liver diseases . In our study, all the factors that may alter ferritin levels, including CRP levels, presence of malignancy, and liver diseases, did not differ between the LF and HF groups. CRP was also not independently correlated with prognosis in multivariate analysis. The results did not change even if we excluded patients with history of malignancy and liver disorders, and recent hospitalization, which was compatible with previous reports . Ferritin may be a surrogate marker of prognosis in MHD patients that cannot be detected by evaluating past medical histories listed above or CRP levels. Whether ferritin itself or the comorbidities underlying elevated ferritin levels are the cause of a poor prognosis in MHD patients remains to be studied.
Our study had several limitations. First, the number of samples was small. We observed 38 primary endpoint events, which allowed six factors as a reasonable maximum number to perform the multivariate analysis. There might be a possibility that this adjusting of confounding factors was not sufficient to evaluate the association between ferritin levels and outcomes because of our study sample size. However, we have carefully examined the selection of variables that should be adjusted based on previous studies [7, 9] as well as backgrounds of the cohort. We assume that this study has substantially adjusted confounding factors. Second, this was a single-center study. The population may be biased by the baseline characteristics of the patients in our hospital. However, as shown in Table 1, in terms of major demographic baseline characteristics of the patients, for example, age, sex, and vintage of hemodialysis, our cohort showed similar characteristics with data reported in Japanese MHD national survey . Although prospective larger studies assessing ferritin levels and prognosis or causes of death are warranted, our study clarified the association between high ferritin levels > 100 ng/mL and mortality and cardiovascular events in MHD patients. This result will potentially help to assess both mortality and cardiovascular risks and to improve prognosis in MHD patients.
In conclusion, in patients receiving MHD, ferritin levels > 100 ng/mL were associated with increased rates of all-cause mortality and cardiovascular events.
Availability of data and materials
The data will not be shared because the informed consent from the subjects regarding the public availability for their personal data was not obtained.
Research idea and study design: RS, TF, TK; data acquisition: RS, TF, FT, MF, MN (Masahiko Nagahama), YK; data analysis/interpretation: RS, TF, TK; supervision or mentorship: TF, TK, MN (Masaaki Nakayama), YK. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee at which the studies were conducted (IRB approval number 14-J010) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. We provided all individual patients with the option to opt out of participation.
Consent for publication
Honoraria: YK received lecture fees from Chugai Pharmaceutical Co., Ltd. Other authors have declared that no competing interest exists.
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