Pretransplant erythroferrone levels are predictive of 1-year all-cause mortality or acute rejection after heart transplantation

Abstract Background/Introduction Heart transplantation (HTx) remains the treatment of choice for selected advanced heart failure (HF) patients. Iron deficiency is a significant factor in the prognosis of HF, and iron metabolism may play a role after HTx since pretransplant hemoglobin levels predict posttransplant 1-year all-cause mortality. In addition, iron deficiency (ID) is known to impact antigen-specific immune response. Purpose The aim of this study was to quantify the impact of pretransplant iron metabolism components on the primary composite outcome 1-year all-cause mortality (ACM) or 1-year acute cellular rejection. Methods This prospective Swiss national cohort study included consecutive patients with HTx between 2008 to 2017. Iron metabolism was assessed measuring plasma iron, ferritin, erythroferrone (ERFE), hepcidin and interleukin-6 immediately before transplant surgery. Endomyocardial biopsies were procured in accordance with the common national posttransplant surveillance protocol. Acute cellular rejection was defined as histological 2R or 3R rejection according to the ISHLT nomenclature 2004 in the diagnosis of heart rejection. Results A total of 276 HTx recipients were included, median age was 52 [IQR 41;59] years, 24.6% (n=68) were females. HTx recipients with incident combined endpoint (n=118, 42.8%) were not significantly different from controls for demographic or transplant operation parameters, donor/recipient gender or HLA mismatch, ferritin, hepcidin (0.5 [IQR 0.5-1.5] vs. 0.5 [IQR 0.5-1.2]; p=0.382) µg/L), interleukin-6, and most biological parameters associated with posttransplant risk. However, participants with incident combined endpoint had lower haemoglobin levels (125 [IQR 102-134] vs. 128 [IQR 114-141 ] g/L; p=0.004), lower Na+ levels (137.5 [IQR 135-139 ] vs. 138 [IQR 136-140] mmol/L; p=0.017), and higher ERFE levels (1.40 [IQR 0.84-1.84 ] vs. 1.19 ng/mL [IQR 0.91-2.92]; p=0.013) compared to those without the endpoint (n=158, 57.2%). The incidence of the combined endpoint was higher in patients presenting with ERFE levels above the third quartile (>2.25 ng/mL; p=0.003). Multivariable analysis using stepwise backward elimination (table) showed that ERFE levels >2.25 ng/mL predicted the incidence of the combined endpoint with an OR of 2.17 (95% CI: 1.19-3.94) (p=0.011). Conclusion The study demonstrates that increased pretransplant ERFE levels are independently associated with 1-year posttransplant all-cause mortality and 1-year acute cellular rejection. This association is in line with results from chronic kidney disease indicating association of ERFE levels with cardiovascular outcome and studies showing iron-induced immune cell activation. In fact, ERFE reduces hepcidin expression as shown in the present and other studies. Thereby, intestinal iron uptake increases resulting in immune cell activation which may explain the higher incidence of heart rejection observed in the present study.FigureTable