Introduction:The significance of aggressive intravenous iron supplementation for preventing major adverse cardiovascular events (MACE) in patients undergoing hemodialysis (HD) has been increasingly emphasized.However, how serum ferritin and transferrin saturation (TSAT), two fundamental iron status indicators, should be interpreted in terms of cardiovascular risk prediction remains unclear.The objective of this analysis was to investigate the association between these two markers and MACE including hospitalization due to heart failure.Methods: Among HD patients enrolled in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 2-7 (2002-2023), an international prospective cohort study, we included patients with at least one serum ferritin and TSAT measurement during follow-up, dialyzing in a facility where cause-specific hospitalizations were well captured, and completed a baseline questionnaire.We defined the event of interest, 3-P MACE+, as the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization due to heart failure.To estimate the associations between serum ferritin and TSAT and 3-P MACE+, we used Cox proportional hazards regression with time-varying covariates where available.We included both serum ferritin and TSAT in all statistical models.To adjust for potential confounding, we fit models adjusted for sex, age, presence of 15 comorbidities, hemoglobin, albumin, intradialytic weight loss, primary cause of end stage kidney disease, and country.To investigate potential effect modification by country and history of congestive heart failure, we fit our primary adjusted regression models stratified by country (Japan vs. all other countries) and history of congestive heart failure.Results: Our analysis included 43,920 patients.When modelled as linear continuous variables, we found one IQR higher serum ferritin was associated with 14% higher hazards of 3-P MACE+ (adjusted hazard ratio: 1.14, 95% CI: 1.11, 1.17) while one IQR higher TSAT was associated with 16% lower hazards of 3-P MACE+ (adjusted hazard ratio: 0.84, 95% CI: 0.81, 0.87).When modelling serum ferritin as continuous using natural splines (5 knots) and TSAT as categorical, the hazards of 3-P MACE+ increased with increasing serum ferritin particularly at lower ranges of serum ferritin for patients with TSAT 500 ng/mL to 200-500 ng/mL (adjusted hazard ratio: 1.20, 95% CI: 1.13, 1.28).Those results were similar across stratifications of countries, despite substantial variation in iron storage markers between countries, and history of congestive heart failure.Conclusion: Patients undergoing HD with high serum ferritin or low TSAT are at higher risk of MACE regardless of the history of heart failure.Upon closer analysis, increased risk with lower TSAT was constant regardless of the level, whereas the increased risk associated with higher serum ferritin was only found at >500 ng/mL.Among patients with TSAT levels <20%, the association between serum ferritin and MACE was especially strong.When iron is supplemented in the hope of reducing MACE risk, this slightly different predictability of two markers should be considered.I have potential conflict of interest to disclose.HN and MN have consultancy agreements with Kyowa Kirin Co., Ltd.
Oya et al. (Wed,) studied this question.