In this study, use of high-dose IV iron was not associated with an increased risk of infection, cardiovascular events, hospitalizations, or mortality compared with low-dose IV iron in HD patients. After the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study was published, coadministration of iron and ESAs has led to increased interest in using low doses of ESAs (6). IV iron supplements administered are used widely to treat anemia in HD patients and have been shown to be effective in treating anemia (12–14). However, the safety of IV iron treatment of HD patients is less certain. In Korea, IV iron is used according to insurance standards, and oral iron is discontinued during the period of IV iron use. However, IV iron is being administered without clear guidelines for the treatment of anemia in HD patients, and the safe dosage has not been determined.
Iron supplementation may increase the risk of infection by impairing neutrophil and T-cell function and promoting microbial growth (15–17). This increased risk is particularly important because infections are a significant cause of mortality and morbidity in HD patients. A meta-analysis of 72 randomized controlled trials (RCTs) that included 10,605 people to evaluate the efficacy and safety of IV iron showed that this treatment was associated with an increase in hemoglobin concentration and a 26% reduced risk of needing red blood cell transfusion (18). However, IV iron was associated with a 33% higher risk of any infection compared with oral or no iron supplementation. The results of that meta-analysis remained similar when only high-quality trials were analyzed. A prospective study of 985 HD patients failed to find a significant association between IV iron administration and risk of bacteremia. However, there was a slightly increased risk of bacteremia in patients receiving high-frequency, high-dose IV iron (19). The DOPPS study results showed a trend toward increased infection-related mortality in patients receiving IV iron at doses > 300 mg/month, but this was not statistically significant (20). A systematic review and meta-analysis of seven RCTs and 15 observational studies of 140,000 participants undergoing HD found no evidence of increased risk of infection, cardiovascular events, hospitalizations, or mortality with the higher-dose compared with lower doses IV iron (21). Given the existing research, it is difficult to conclude that iron use in HD patients increases the risk of infection. The same conclusion was reached in this study: higher doses of IV iron, compared to the lowest dose of 1-100mg, did not contribute to increased infection rates or mortality.
The results to date have been inconsistent regarding the safety of IV iron in HD patients. Results from experimental studies of iron supplementation on infection risk do not always apply to clinical settings (16, 17), possibly because of the short-term use (1 to 6 months) of iron in previous studies (21). Our study also set the 6-month IV iron dose as the cutoff between the high- and low-dose groups. This time limit was chosen because of the high mortality and morbidity of HD patients; that is, a longer period of iron use may have captured the increasing incidence of adverse reactions to other causes, which would have made it difficult to determine the response to IV iron supplementation. These issues may also apply in studies with a long-term follow-up of the safety of IV iron. It is possible that the physical condition was more severe in patients receiving IV iron than in those receiving oral iron or no iron, which may have affected the interpretation of our results. In this study, the high-dose IV iron group was younger but included a higher percentage of patients with comorbid conditions compared with the low-dose group. However, the risk of outcome events did not differ after propensity score matching.
IV iron supplementation has beneficial effects in patients with heart failure, suggesting that iron acts directly on heart function (22). The possible mechanism may involve the important role of iron in cellular oxygen storage and cell metabolism in cardiomyocytes with a high energy demand (23). Iron replenishment may also benefit skeletal muscle function and contribute to the improvement in quality of life and general functional capacity after iron therapy in patients with chronic heart failure. RCTs have shown that IV iron improves exercise capacity and quality of life (24, 25). In a meta-analysis of 12 RCTs of patients with heart failure, IV iron administration reduced hospitalization rate for heart failure, but the association with cardiovascular death was not significant (22). The PIVOTAL trial showed that high-dose IV iron resulted in a significantly lower risk of major nonfatal cardiovascular events compared with a low-dose regimen among HD patients (13). In that study, high-dose IV iron administration had a positive effect on the cardiovascular system by reducing the use of ESAs and maintaining high blood hemoglobin concentration. The beneficial effects of iron on the cardiovascular system may have helped to counteract the risk of high-dose IV iron in our study.
This study has several limitations. First, this observational study cannot establish causality, and it remains susceptible to the possibility of residual confounding. Second, because this study included Korean HD patients, the ability to generalize the findings to other populations is limited. Third, we could not obtain data for the serum levels of ferritin and hemoglobin, and the doses of erythropoietin. However, it is known from previous research that IV iron administration increases hemoglobin concentration and reduces the dose of erythropoietin needed (4, 13). Fourth, the observation period was short, and larger and high-quality RCTs will be needed to confirm these findings.
This study found no evidence of excess infections, cardiovascular events, hospitalization, or death associated with high-dose IV iron supplementation. Given these results, the safety of IV iron administration cannot be assured in HD patients. However, 6 months of administration did not seem to increase mortality or morbidity in these HD patients. Considering that most patients do not receive IV iron therapy continuously but take a rest period while their ferritin level is monitored, the results of this study may help to alleviate nephrologists’ concerns about the potential side effects of IV iron therapy.