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Background: Renal resistive index (RI) predicts mortality in renal transplant recipients, but we do not know whether this is true in diabetic patients. The objective of this study was to analyse the long-term predictive value of RI for death with a functioning graft (DWFG) in renal transplant recipients with or without pre-transplant diabetes., Methods: We conducted a retrospective study in 1800 renal transplant recipients between 1985 and 2017 who were followed for up to 30 years (total observation period: 14 202 patient years). Donor and recipient characteristics at time of transplantation and at 3 months were reviewed. The long-term predictive value of RI for DWFG and the age-RI and arterial pressure-RI relationships were assessed., Results: A total of 284/1800 (15.7%) patients had diabetes mellitus before transplantation. RI was <0.75 in 1327/1800 patients (73.7%). High RI was associated with a higher risk of DWFG in non-diabetic patients [hazard ratio (HR) = 3.39, 95% confidence interval 2.50-4.61; P < 0.001], but not in patients with pre-transplant diabetes (HR = 1.25, 0.70-2.19; P = 0.39), even after multiple adjustments. There was no interaction between diabetes and age. In contrast, there was an interaction between RI and pulse pressure., Conclusion: Our study indicates that RI is not a predictor of DWFG in diabetic renal transplant recipients, in contrast to non-diabetic recipients. These findings could be due to a different age-RI or pulse pressure-RI relationship., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Depleting induction therapy is recommended in sensitized kidney transplant recipients (KTRs), though the detrimental effect of nondonor-specific anti-HLA antibodies is not undeniable. We compared the efficacy and safety of basiliximab and rabbit anti-thymocyte globulin (rATG) in sensitized KTRs without pre-existing donor-specific antibodies (DSAs). This monocentric retrospective study involved all sensitized KTR adults without pre-existing DSAs (n = 218) who underwent transplantation after June 2007. Patients with basiliximab and rATG therapy were compared for risk of biopsy-proven acute rejection (BPAR) and a composite endpoint (BPAR, graft loss and death) by univariate and multivariate analysis. Patients with basiliximab (n = 60) had lower mean calculated panel reactive antibody than those with rATG (n = 158; 23.7 ± 24.2 vs. 63.8 ± 32.3, P < 0.0001) and more often received a first graft (88% vs. 54%, P < 0.0001) and a transplant from a living donor (13% vs. 2%, P = 0.002). Risks of BPAR and of reaching the composite endpoint were greater with basiliximab than rATG [HR = 3.63 (1.70-7.77), P = 0.0009 and HR = 1.60 (0.99-2.59), P = 0.050, respectively]. Several adjustments did not change those risks [BPAR: 3.36 (1.23-9.16), P = 0.018; composite endpoint: 1.83 (0.99-3.39), P = 0.053]. Infections and malignancies were similar in both groups. rATG remains the first-line treatment in sensitized KTR, even in the absence of pre-existing DSAs., (© 2019 Steunstichting ESOT.)

We aimed to determine the role of cytomegalovirus (CMV)-infected donor cells in the development of a CMV-specific immune response in kidney transplant recipients. We assessed the CMV pp65-specific immune response by using interferon-ɣ ELISPOT and dextramers in peripheral blood mononuclear cells from 115 recipients (D+R- 31, D+R + 44, D-R + 40) late after transplantation (mean 59 ± 42 months). Receiving a kidney from a D+ donor resulted in a higher number of IFN-ɣ-producing anti-CMV T cells (P = .004). This effect disappeared with the absence of shared HLA class I specificities between donors and recipients (P = .430). To confirm the role of donor cells in stimulating the expansion of newly developed CMV-specific CD8 + T cells after transplantation, we compared the number of HLA-A2-restricted CMV-specific CD8 + T cells in primo-infected recipients who received an HLA-A2 or non-HLA-A2 graft. The median of anti-CMV pp65 T cells restricted by HLA-A2 was very low for patients who received a non-HLA-A2 graft vs an HLA-A2 graft (300 [0-14638] vs. 17972 [222-85594] anti-CMV pp65 CD8 + T cells/million CD8 + T cells, P = .001). This adds new evidence that CMV-infected kidney donor cells present CMV peptides and drive an inflation of memory CMV-specific CD8 + T cells, likely because of frequent CMV replications within the graft., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A)., Methods: We performed a retrospective study to assess the impact of PD-1.3 on graft outcome in donor CMV seropositive (D+) and donor CMV seronegative (D-) KTx and LTx. We also performed a case-control study to evaluate the anti-CMVpp65 response according to genotype., Results: PD-1.3 was determined in 1,119 KTx and 181 LTx. In 481 D+ KTx, A allele carriers (24%) experienced significantly less graft failure compared with GG carriers (p = 0.001). Multivariate analysis showed that this association was independent of donor and recipient age, acute rejection episodes, and number of human leukocyte antigen mismatches (hazard ratio, 0.381; 95% confidence interval, 0.209-0.696; p = 0.002). Analysis in 85 D+ LTx showed similar results: A allele carriers had better survival (hazard ratio, 0.302; 95% confidence interval, 0.128-0.716; p = 0.006) and greater 6-month forced expiratory volume (71% ± 17% vs 54% ± 16%, p = 0.001). In D- recipients, PD-1.3 did not affect KTx or LTx outcome. Finally, AA recipients had a stronger anti-CMVpp65 T-cell response than matched GG recipients (p = 0.003)., Conclusions: The A variant allele in PD-1.3 single nucleotide polymorphism improved graft survival in kidney and lung transplant recipients receiving grafts from CMV-positive donors., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

A large body of evidence has been accumulated from experimental models in the past decade to support the critical role of Foxp3-expressing regulatory T cells (Tregs) in the suppression of alloimmune responses. This has prompted transplant clinicians to investigate whether Foxp3 analysis might be used as an immunodiagnostic tool for better assessment of the significance of graft infiltrate and to predict its impact on graft outcome. However, conflicting results have emerged from these studies and may have generated more confusion than clarification. Foxp3 expression has been antagonistically correlated with either good or poor prognosis. We discuss here how methodological issues and specific clinical settings may have accounted for the discrepancies between the results of these studies. Depending on many factors, including the techniques used, the method of sampling normalization, the extent of intra-graft inflammation, the immunosuppressive regimen and the depletion or repletion of T lymphocyte compartment, the significance of Foxp3 expression may vary. We propose here the conditions to be fulfilled in order to use Foxp3 analysis as a relevant biomarker for graft outcome assessment. Far from challenging the key role of Tregs in dampening alloimmune responses, this review highlights the need for technical harmonization and standards.

Purpose of the Review: Indirect effects of cytomegalovirus (CMV) in transplantation are of three types: increase in systemic immunosuppression, increased risk of malignancy (especially Epstein-Barr virus-related B-cell lymphoproliferative disease), and the possible contribution to allograft injury. Despite modern and potent antiviral drugs, the real impact of CMV in transplantation, especially kidney transplantation, remains a challenge because many confounding factors arise when analyzing this question.This review will fuel the discussion and review some of the recent data., Recent Findings: A recent study on cardiac allograft in mice has shown that CMV in latently infected recipients could break graft acceptance. Although the exact nature of response was not addressed, this study suggested that CMV reactivation inside the graft played an important part in graft losses. Other recent results suggest that the quality of immune response against CMV influences graft outcome in both cardiac and kidney transplant patients. Other evidence suggests the link between CMV infection, immune senescence and vascular disease in the whole population. Studies have opened the perspective for new strategies to prevent indirect effects of CMV., Summary: Although a causal relationship between CMV reactivation and graft injury is supported by a large body of experimental and clinical data, definitive proof in clinical transplantation is still lacking to exclude an associative relationship. Large randomized clinical trials analyzing long-term graft survival and comparing prophylaxis with preemptive, especially D/R, is probably an efficient way to establish a causal relationship. Research on new antiviral strategies applicable over the long term is important.

Acute graft pyelonephritis is a common complication in renal transplant recipients. The consequences of this complication on kidney allograft survival remain controversial. Bacterial infection is likely to activate the immune system, potentially leading to acute or chronic rejection. Here, we report for the first time two documented cases of acute rejection occurring shortly after acute graft pyelonephritis, suggesting that pyelonephritis can initiate acute rejection. The immunologic process leading to the alloimmune response is discussed. These reports suggest that acute rejection should be questioned in case of atypical graft outcome in the context of acute graft pyelonephritis.

Background: Because histopathologic criteria cannot always predict the pathogenesis and response to curative antirejection therapy, new hope derives from the molecular analysis of intragraft immunologic markers. We studied whether the cutoff of intragraft expression level of T-cell activation markers may define subgroups of acute rejection differing either in type of rejection or clinical outcome., Methods: Forty-three human renal-allograft biopsies were quantified for mRNA expression of granzyme B, Fas ligand, interferon (IFN)gamma, interleukin (IL)-4, and IL-6 with a reverse-transcriptase real-time quantitative polymerase chain reaction (RT-PCR) method. Expression levels were correlated with the histopathologic rejection type according to the Banff 1997 classification criteria, and with the sensitivity to the antirejection immunosuppressive therapy, by means of receiver operating-characteristic (ROC) curves., Results: Granzyme B and Fas ligand mRNA expression up-regulation correlated with all allograft rejection types (P<0.01 for all). Moreover, granzyme B showed the highest sensitivity (90%) and specificity (78%) for the potential detection of histologic borderline changes that will require immunosuppressive therapy (area under the curve [AUC]=0.856, P<0.01). Curative antirejection-therapy resistance of overt, acute-rejection episode was significantly associated with higher Fas ligand gene expression (AUC=0.764, P<0.01, sensitivity [71%], specificity [99.5%])., Conclusions: Real-time RT-PCR quantification of the over-expression of the granzyme B gene in kidney-graft biopsies has proved to be as reliable in detecting acute rejection as histologic assessment. Furthermore, we demonstrate that the simultaneous measurement of the mRNA up-regulation of Fas ligand might represent an efficient new tool for the prediction of pejorative outcome of acute rejection.

Background: Pilot clinical studies have shown that the rat anti-human-CD2 monoclonal antibody, LoCD2a/BTI-322, can efficiently prevent and treat acute kidney rejection. However, the in vivo mechanism by which it prevents allograft rejection has not been studied. BTI-322 and its humanized form have been shown to mediate in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) against CD2 cells through the activation of monocytes or natural killer (NK) cells., Methods: Human fetal skin samples were grafted into severe combined immunodeficient/nonobese diabetic mice. Five weeks later (day 0), the mice were injected with human allogeneic peripheral blood lymphocytes (PBL). Either on day 0 or on day 14, mice were treated with BTI-322, hu-BTI-322, or their F(ab')2 fragments. Peripheral blood mononuclear cells (PBMC) thoroughly devoid of NK cells were also assayed., Results: After injection of PBL, the human skins became heavily infiltrated with activated human T lymphocytes, resulting in dermal microvascular injuries indicative of graft rejection. Early treatment with BTI-322 and hu-BTI-322 prevented all these events. These CD2 antibodies rapidly eliminated human T lymphocytes that had already infiltrated the grafts, with no evidence of recirculation toward the spleen. Their F(ab')2 fragments were, in contrast, ineffective. Elimination of NK cells from injected PBMC prevented the curative effect exerted by whole CD2 antibodies. It also abrogated their cytotoxicity potential against CD2 cells in ADCC assays., Conclusion: F(ab')2 fragments of the CD2 antibodies could not prevent allograft rejection, whereas whole immunoglobulin G could, and human NK cells were required for the curative effect exerted by these antibodies. The results are consistent with an FcgammaR-dependent ADCC mechanism mediated in vivo by human NK cells.

Background: Acute rejections are scored according to three main criteria: vasculitis, tubulitis and interstitial infiltration as defined in the Banff classification. Typically, B cells account for <8% of the infiltrates and oedema is limited. The clinical significance of severe interstitial oedema and plasma cell-rich infiltrates (OPcR) are still a matter of debate., Methods: Kidney graft biopsies performed between 1991 and 1998 were retrospectively evaluated for these two criteria., Results: Among the 826 biopsies performed during the study period, 14 samples in 12 patients met these criteria; 11 were of Banff type I acute rejection and three were borderline. Based on clinical data, all were treated as acute rejections. OPcR occurred at a median of 187 days post-transplantation. All episodes were steroid resistant. Graft survival was 40% at 1 year following the rejection. Circulating antibodies reactive either to donor HLA or to endothelial cells were present in eight of 12 patients and widespread C4d deposit in peritubular capillary were present in three out of five patients studied. Level of gamma-interferon mRNA within the graft was significantly higher than in standard acute cellular rejection (ACR)., Conclusion: This study showed that OPcR rejections portend a poor outcome irrespective of the Banff score. Our data strongly support the hypothesis that a humoral component participated in the graft injuries. Altogether, the data suggest that OPcR rejection might represent a late and attenuated variant of acute humoral rejection that should be classified separately from ACR.

Aims: Basiliximab, an anti‐CD25 chimeric monoclonal antibody, is approved in prevention of acute kidney transplant rejection. This study aims at investigating target‐mediated pharmacokinetics of basiliximab. Methods: Data from the IDEALE study, where 16 kidney transplant patients were treated with 2 40‐ or 80‐mg basiliximab injections, were reanalysed. Basiliximab pharmacokinetics was described using a population 2‐compartment target‐mediated drug disposition model with the quasi‐steady‐state approximation. Results: Volume of distribution was significantly higher in males (P =.029). Estimated baseline target antigen (CD25) level was lower is patients cotreated with cyclosporine (P =.026). Conclusion: This analysis allows the first description of the target‐mediated nonlinear elimination of basiliximab. Our results suggest that cyclosporine cotreatment is associated with decreased target level and that an optimized dosing regimen may improve basiliximab effects. [ABSTRACT FROM AUTHOR]

Human iTreg cells regulate CD8+ T cell cytotoxicityRegulatory T cells (Treg) play a crucial role in controlling immunity and transplant rejection. Two main groups of Treg have been described: antigen-induced Treg (iTreg) and natural Treg (nTreg). The ways to induce and the mechanisms of action of Treg subsets remained ill defined, particularly for their effects on CD8+ T cells. CD8+ T cells are major agents in the rejection of allografts; the aim of this study is to investigate the effects exerted on CD8+ T cells by human CD4+ iTreg induced by mycophenolic acid-treated dendritic cells. iTreg suppress the proliferation of CD8+ T cells by allogeneic cell–cell interaction with mature dendritic cells and irrespectively of the TCR specificity of the CD8+ T cells and cell–cell contact of iTreg with CD8+ T cells. In our model, this suppression is independent of the action of IL-10 and TGF-β1. iTreg were able to modify phenotype and inhibited IFN-γ and TNF-α secretion by CD8+ T cells. Most interestingly, iTreg inhibit the synthesis of perforin and of granzymes A and B by CD8+ T cells and impaired their cytotoxicity against allogeneic targets. In summary, our study showed the involvement of iTreg in the down-regulation of cytotoxic responses mediated by CD8+ T cells in an allospecific context. Following studies that have shown the existence of a regulation control exerted by iTreg on CD4+ T cells and dendritic cells, this work ultimately shows that this regulation can reach CD8+ T-cell functions. [ABSTRACT FROM PUBLISHER]