High tacrolimus intra-patient variability is associated with graft rejection,and de novo donor-specific antibodies occurrence after liver transplantation

AIM To investigate the role of tacrolimus intra-patient variability(IPV) in adult liver-transplant recipients.METHODS We retrospectively assessed tacrolimus variability in a cohort of liver-transplant recipients and analyzed its effect on the occurrence of graft rejection and de novo donor-specific antibodies(dn DSAs), as well as graft survival during the first 2 years posttransplantation. Between 02/08 and 06/2015, 116 patients that received tacrolimus plus mycophenolate mofetil(with or without steroids) were included. RESULTS Twenty-two patients(18.5%) experienced at least one acute-rejection episode(BPAR). Predictive factors for a BPAR were a tacrolimus IPV of > 35% [OR = 3.07 95%CI(1.14-8.24), P = 0.03] or > 40% [OR = 4.16(1.38-12.50), P = 0.01), and a tacrolimus trough level of < 5 ng/mL [OR=3.68(1.3-10.4), P =0.014]. Thirteen patients(11.2%) developed at least one dn DSA during the follow-up. Tacrolimus IPV [coded as a continuous variable: OR = 1.1, 95%CI(1.0-1.12), P = 0.006] of > 35% [OR = 4.83, 95%CI(1.39-16.72), P = 0.01] and > 40% [OR = 9.73, 95%CI(2.65-35.76), P = 0.001] were identified as predictors to detect dn DSAs. IPV did not impact on patient-or graft-survival rates during the follow-up. CONCLUSION Tacrolimus-IPV could be a useful tool to identify patients with a greater risk of graft rejection and of developing a de novo DSA after liver

Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity

After the first observation of the immunosuppressive effects of ultraviolet(UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells(Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40th anniversary of its discovery.

Combined liver-kidney transplantation for rare diseases

Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT.They are major indications for CLKT in children.However,in some of them(e.g.,atypical hemolytic uremic syndrome or primary hyperoxaluria),CLKT may be required in adults as well.Primary hyperoxaluria is divided into three types,of which type 1 and 2 lead to ESKD.CLKT has been proven effective in renal function replacement,at the same time preventing recurrence of the disease.Nephronophthisis is associated with liver fibrosis in 5%of cases and these patients are candidates for CLKT.In alpha 1-antitrypsin deficiency,hereditary C3 deficiency,lecithin cholesterol acyltransferase deficiency and glycogen storage diseases,glomerular or tubulointerstitial disease can lead to chronic kidney disease.Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality.In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H,successful CLKT has been reported in a small number of patients.However,for this indication,CLKT has been largely replaced by eculizumab,an anti-C5 antibody.CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA,facilitating transplantation in a highly sensitized recipient.