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Background: Antibody-mediated rejection (AMR) can cause graft loss and reduces long-term graft survival after kidney transplantation. Human leukocyte antigen (HLA) and/or non-HLA antibodies play a key role in the pathogenesis of AMR by targeting the allograft epithelium via complement activation and complement-independent mechanisms. However, the precise mechanisms of AMR remain unclear and treatment is still limited., Methods: In this study, we investigated the role of the endothelial-associated transcription factor Sox7 in AMR, using the anti-HLA antibody W6/32, shRNA-mediated Sox7 knockdown, and by manipulating the Notch pathway. We used an in vitro human kidney glomerular endothelial cells (HKGECs) model and an in vivo MHC-mismatched kidney transplantation model., Results: Sox7 expression was upregulated and the Jagged1-Notch1 pathway was activated in HKGECs after W6/32 activation. W6/32 antibodies increased the expression of adhesion molecules (VCAM-1, ICAM-1), inflammatory cytokines (IL-6, TNF-α), and chemokines (CXCL8, CXCL10), and Sox7 knockdown and inhibition of the Notch pathway by DAPT significantly reduced these effects. Jagged1 overexpression rescued the inhibitory effects of Sox7 knockdown. In addition, Sox7 knockdown attenuated acute allograft kidney injury in mice and reduced the expression of adhesion molecules and Jagged1-Notch1 signaling after transplantation., Conclusions: Our findings suggest that Sox7 plays an important role in mediating HLA I antibody-dependent endothelial cell activation and acute kidney allograft rejection via the Jagged1-Notch1 pathway. Manipulating Sox7 in donor organs may represent a useful treatment for AMR in solid organ transplantation., (Copyright © 2019. Published by Elsevier Inc.)

Single nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte associated antigen-4 gene (CTLA-4) have been associated with graft rejection and long-term clinical outcome after organ transplantation. Our aim was to examine the association between CTLA-4 SNPs (rs733618, rs4553808, rs5742909, rs231775, rs3087243) and long-term allograft function in Chinese renal transplant recipients. Genotyping of CTLA-4 SNPs was performed in 292 renal transplantation recipients. To assess long-term allograft function, the estimated glomerular filtration rate (eGFR) was determined 1, 3, 6, 12, 24, 36, 48 and 60 months after renal transplantation. CTLA-4 rs733618 and rs3087243 alleles and genotypes as well as the rs5742909 and rs231775 genotypes were significantly associated with long-term allograft function after transplantation (P<0.05). Patients with favorable genotypes had higher allograft function during the 60 months after transplantation. The TACGG, CACAG and CGTAA haplotypes were also associated with long-term kidney function after renal transplantation (P<0.05 or P<0.01). In sum, the favorable CTLA-4 rs5742909TT genotype, CTLA-4 rs733618C and rs3087243A alleles, and CACAG and CGTAA haplotypes, as well as the unfavorable rs733618TT, rs3087243GG and rs231775GG genotypes and TACGG haplotype could potentially serve as effective indicators of long-term allograft function in Chinese renal transplantation recipients., Competing Interests: The authors disclosed no potential conflicts of interest.

Objective: To evaluate the long-term use of ciclosporin on kidney transplant recipients who survived more than 10 years., Methods: We reviewed cadaveric kidney transplant patients who had survived 10 years or longer in this study. Patients were divided into five groups based on their ciclosporin concentration at one year: group 1 (> 250 ng/ml), group 2 (200-250 ng/ml), group 3 (150-200 ng/ml), group 4 100-150 ng/ml) and group 5 (< 100 ng/ml). Lab parameters were compared among these groups over time., Results: There were no differences in lab parameters among the five groups. At five years, systolic blood pressures (SBP), TG, CH, DB, TB were significantly higher in groups 3, 4, and 5. Uric acid was also higher but albumin was lower in group 5 compared to those in all other groups. Prevalence of proteinuria in both groups 4 and 5 were lower. At 10 years, SBP in group 3 was lower while both uric acid and ALT in all groups were decreased., Conclusion: In patients who survived for more than 10 years after kidney transplantation, serum lipid levels were markedly elevated, indicating the increase of cardiovascular risk factors for patients, which might impact long-term survival benefit.

Objectives: Accumulating evidence supports the hypothesis that HLA antibodies play an important role in early renal allograft injury. However, the effects of HLA antibodies on long-term graft survival are still poorly understood. In this study, we examined the impact of HLA antibodies on graft survival in long-term renal recipients with functional grafts for 10 years., Material and Methods: In this retrospective study, long-term renal recipients were defined as kidney transplant recipients who had normally functioning renal grafts (serum creatinine level <2.0 mg/dl) for 10 years. Posttransplant serum samples from a total of 92 long-term renal allograft recipients on cyclosporine-based triple maintenance drug therapy (121.6 ± 0.886 months) were screened for the specificities of anti-HLA antibodies. The results of HLA antibodies before the transplantation, assessed using the same test method, were compared with those after their transplantations. Moreover, these 92 patients who received cadaveric renal transplant between January 2000 and December 2002 were followed up for about 10 years (range 107-135 months)., Results: 27 patients had HLA-I antibodies and 16 patients had HLA-II antibodies before the transplantation, whereas 12 patients had HLA-I antibodies and 18 patients had HLA-II antibodies after the transplantation. Moreover, the types of HLA antibodies were different from those found before the transplantation. In these renal recipients with functioning renal grafts, the estimated glomerular filtration rate was 66.52 ± 14.52 ml/min/1.73 m(2) in the HLA antibody-positive group (n = 23) and 69.09 ± 25.54 ml/min/1.73 m(2) negative in the HLA antibody-negative group (n = 69, p > 0.05). Three patients (3.26%) (3 out of 92) had donor-specific anti-HLA antibodies (DSA). The frequency of DSA in this study was lower than that in the general Chinese Han renal recipient population., Conclusions: We find that all HLA antibodies in the long-term renal grafts are newly formed after the transplantation. The HLA antibody status has little impact on the renal graft function in the long-term renal recipients., (2014 S. Karger AG, Basel.)

Background: Immunosuppressive therapy is usually administered following renal transplantation to protect the graft from rejection. However, this often causes complications such as infections to occur. Single nucleotide polymorphisms (SNPs) within the CTLA4 gene, such as -1772T/C (rs733618), +49A/G (rs231775) and +6230 G/A (rs3087243), can affect graft rejection and the long-term clinical outcome of organ transplantation. The role of CTLA4 SNPs in T cell-mediated immunity in renal transplantation and association with infection after transplantation is unknown., Methods: In this study, the risk of infection according to CTLA4 SNPs was investigated in 304 patients who received kidney graft transplants between 2008 and 2012., Results: The frequency of the rs4553808 GG genotype was significantly higher in recipients with viral infection (14.89%) than in those without infections (3.50%) (Bonferroni-adjusted p = 0.005). A significant difference (p = 0.001) in patients with the rs4553808 GG genotype from those with the AA+AG genotypes was found in the viral cohort using the log-rank test. A significant association was found between the rs4553808 genotype and onset of viral infection in transplant recipients (p = 0.001). The frequencies of the CGTAG and CGCAG haplotypes were significantly higher in the viral infection group (9.6% and 5.3%) than in the non-viral infection group (3.8% and 1.4%) (p = 0.0149 and p = 0.0111). No association between any CTLA4 SNP and bacterial infection was found. Multivariate analyses revealed that one risk factor, the use of antibody induction therapy (p = 0.007), was associated with bacterial infection, and two risk factors, antibody use (p = 0.015) and recipient rs4553808 genotype (p = 0.001), were associated with viral infection., Conclusions: The rs4553808 GG genotype may be a risk factor for viral infection in kidney transplantation. The CTLA4 haplotypes CGTAG and CGCAG were partially associated with the development of viral infection in Chinese kidney transplant recipients.

Genetic polymorphisms in cytotoxic T lymphocyte-associated antigen 4 (CTLA4) play an influential role in graft rejection and the long-term clinical outcome of organ transplantation. We investigated the association of 5 CTLA4 single-nucleotide polymorphisms (SNPs) (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A) with drug-induced liver injury (DILI) in Chinese renal transplantation (RT) recipients. Each recipient underwent a 24-month follow-up observation for drug-induced liver damage. The CTLA4 SNPs were genotyped in 864 renal transplantation recipients. A significant association was found between the rs231775 genotype and an early onset of DILI in the recipients. Multivariate analyses revealed that a risk factor, recipient rs231775 genotype (p = 0.040), was associated with DILI. Five haplotypes were estimated for 4 SNPs (excluding rs733618); the frequency of haplotype ACGG was significantly higher in the DILI group (68.9%) than in the non-DILI group (61.1%) (p = 0.041). In conclusion, CTLA4 haplotype ACGG was partially associated with the development of DILI in Chinese kidney transplant recipients. The rs231775 GG genotype may be a risk factor for immunosuppressive drug-induced liver damage.

Since the first kidney transplantation was performed in 1976, 4,306 renal transplantations have been performed at Shanghai No. 1 People's Hospital and Fujian Oriental Hospital. Nearly all (99%) of the grafts were from deceased donors. Graft survival rates in the era of modern immunosuppression and HLA-based organ allocation have improved substantially. The one-, 5- and 10-year graft survival rates for 2,575 transplants performed during 1995-2004 were 93.9%, 71.8% and 53.9%, respectively. Chronic rejection accounted for 54.3% of graft failures and 54.2% of patient deaths resulted from graft failure. We performed 48 combined liver-kidney transplants since 2001 and the first simultaneous human islet-kidney transplantation last year.