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Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.

Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4+T cells lacking costimulatory CD28 (CD4+CD28nullcells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4+CD28nullcells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation period. These cells were predominantly effector-memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4+CD27−CD28nullcells proliferated in response to peripheral blood mononuclear cells previously exposed to CMV-derived (but not HLA-derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4+CD28nullcell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow-up. This study suggests an important role for this atypical cytotoxic CD4+CD28nullcell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes.

Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4+T cells lacking costimulatory CD28 (CD4+CD28nullcells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4+CD28nullcells were found predominantly in CMV‐seropositive patients and expanded in the posttransplantation period. These cells were predominantly effector‐memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4+CD27−CD28nullcells proliferated in response to peripheral blood mononuclear cells previously exposed to CMV‐derived (but not HLA‐derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D‐blocking antibody. Increased CD4+CD28nullcell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow‐up. This study suggests an important role for this atypical cytotoxic CD4+CD28nullcell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes. This prospective study shows the importance of cytomegalovirus in the genesis of atypical cytotoxic CD4 cells, highlighting the in vitroendothelial toxicity and in vivorelationships with inferior early‐ and medium‐term kidney allograft function. See the companion article from Espinosa et al on page 1102, and the editorial from Murakami and Riella (page 1045).

Recent cross-sectional studies suggest an important role for transitional B lymphocytes (CD19 + CD24hiCD38hi) in promoting transplant tolerance, and protecting from late antibody-mediated rejection (ABMR). However, prospective studies are lacking. This study enrolled 73 de novotransplant recipients, and collected serial clinical, immunological and biochemical information over 48 ± 6 months. Cell phenotyping was conducted immediately prior to transplantation, and then on five occasions during the first year posttransplantation. When modeled as a time-dependent covariate, transitional B cell frequencies (but not total B cells or “regulatory” T cells) were associated with protection from acute rejection (any Banff grade; HR: 0.60; 95% CI: 0.37–0.95; p = 0.03). No association between transitional B cell proportions and either de novodonor-specific or nondonor-specific antibody (dnDSA; dnNDSA) formation was evident, although preserved transitional B cell proportions were associated with reduced rejection rates in those patients developing dnDSA. Three episodes of ABMR occurred, all in the context of nonadherence, and all associated with in vitroanti-HLA T cell responses in an ELISPOT assay (p = 0.008 versus antibody-positive patients not experiencing ABMR). This prospective study supports the potential relevance of transitional (“regulatory”) B cells as a biomarker and therapeutic intervention in transplantation, and highlights relationships between humoral immunity, cellular immunity and nonadherence.

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n 25) or azathioprine (AZA, n 25). Biopsies (n 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p?< 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p?< 0.05-0.001), mesangial matrix accumulation (p?< 0.01), chronic glomerulopathy scores (p?< 0.05) and glomerulosclerosis (p?< 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p?< 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection.

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection.