Beyond traditional roles: vitamin D and erythropoietin as immune modulators in kidney diseases

Vitamin D and erythropoietin (EPO) are kidney-derived hormones classically known for their roles in mineral metabolism and erythropoiesis, respectively. Beyond these functions, growing evidence indicates that both molecules exert broad immunomodulatory effects on innate and adaptive immunity. Vitamin D signalling through the vitamin D receptor shapes dendritic cell maturation, promotes regulatory T-cell induction, and suppresses pro-inflammatory T helper cell responses. Similarly, EPO acts as a pleiotropic cytokine capable of modulating macrophage activation, T-cell proliferation, and inflammatory signalling pathways through EPO receptor-dependent mechanisms. In chronic kidney disease (CKD), reduced renal synthesis of active vitamin D and impaired endogenous EPO production frequently coexist, contributing not only to disturbances in mineral metabolism and anaemia, but possibly also to immune dysregulation. Besides CKD, immune dysregulation is common across diverse nephrological conditions, including immune-mediated nephropathies and transplantation, where inflammatory and alloimmune responses critically influence disease progression and graft outcomes. Increasing experimental and clinical evidence suggests that vitamin D and EPO may modulate these processes and represent potential therapeutic targets. This narrative review summarizes current knowledge on the immunomodulatory properties of vitamin D and EPO, their mechanisms of action on immune cells, and their relevance in kidney disease and transplantation.