**1. Introduction**

Renal transplant recipients (RTRs) have a high residual risk of all-cause and cardiovascular death, compared to the general population [1]. Previous studies demonstrated an independent association between higher circulating endogenous erythropoietin (EPO) levels and risk of all-cause and cardiovascular death among RTRs, similar to other patient populations such as chronic heart failure patients and the elderly [2–4]. In addition, administration of exogenous EPO may increase the risk of cardiovascular events in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD) [5,6]. However, the underlying mechanisms responsible for the link between endogenous and exogenous EPO and adverse outcomes are unknown.

Studies from our group and others sugges<sup>t</sup> that EPO is prominently involved in fibroblast growth factor-23 (FGF23) physiology [7–10]. FGF23 is an osteocyte-derived hormone that plays an essential role

in regulating phosphate and vitamin D metabolism. In RTRs, increased FGF23 levels post-transplant are independently associated with an increased risk of graft failure and death [11,12]. Hypoxia, the main stimulus for EPO synthesis, stabilizes hypoxia-inducible factor (HIF)-1<sup>α</sup>, which is a heterodimeric transcription factor that regulates oxygen homeostasis [13,14]. Subsequently, stabilized HIF1-α upregulates FGF23 production while concomitantly increasing FGF23 cleavage into inactive fragments, resulting in elevated total FGF23 levels but normal levels of intact, bioactive FGF23 [15–18].

In the current study, we hypothesized that the previously established, but hitherto unexplained association between EPO levels and adverse outcomes may be attributable to increased levels of total FGF23. Therefore, we investigated the associations between EPO and total FGF23 levels and prospective outcomes in our RTRs cohort.
