Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling

Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

A randomized controlled trial to evaluate efficacy and safety of early conversion to a low-dose calcineurin inhibitor combined with sirolimus in renal transplant patients

Background:The calcineurin inhibitor(CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation;however,the long-term prognosis of grafts has not been significantly improved.The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts.Sirolimus(SRL)has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts.Presently,the regimen and timing of SRL application after renal transplantation vary,and clinical data are scarce.Multicenter prospective randomized controlled studies are particularly rare.This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation.Methods:Patients who receive four weeks of a standard regimen with CNI+mycophenolic acid(MPA)+glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study.At week 5,after the operation,patients in the experimental group will receive an additional administration of SRL,a reduction in the CNI drug doses,withdrawal of MPA medication,and maintenance of glucocorticoids.In addition,patients in the control group will receive the maintained standard of care.The patients’vital signs,routine blood tests,routine urine tests,blood biochemistry,serum creatinine,BK virus(BKV)/cytomegalovirus(CMV),and trough concentrations of CNI drugs and SRL at the baseline and weeks 12,24,36,48,72,and 104 after conversion will be recorded.Patient survival,graft survival,and estimated glomerular filtration rate will be calculated,and concomitant medications and adverse events will also be recorded.Conclusion:The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients.