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Background: ABO-incompatible kidney transplantation (ABOi-KTx) represents a possible solution to address the shortage of kidney donors. However, these transplants present immunological challenges, particularly when isoagglutinin titers are elevated pretransplant., Methods: Single-center retrospective study describing clinical and biological outcomes of 8 patients who underwent ABOi-KTx with initial isoagglutinin titers ≥ 1/512. All patients followed a desensitization protocol combining immunosuppression (rituximab, tacrolimus, mycophenolate mofetil, steroids), and specific or semi-specific apheresis sessions. Clinical and biological data were extracted from electronic medical records., Results: There were 5 males; median age of 62 years [34-82 years]; all achieved an isoagglutinin titer of ≤1/8 before transplantation after a median of 13 (range: 9-15) apheresis sessions. Three patients (37%) experienced acute humoral rejection, which required additional plasmapheresis sessions. Two patients developed chronic active rejection, successfully treated. On the infectious side, three patients developed BK-virus reactivation. Two patients developed cytomegalovirus viremia, and two others presented with bacterial infections. Surgically, two patients developed a lymphocele, and one had a perirenal hematoma. All patients survived the transplant with stable renal function: mean serum creatinine was 138 ± 15 µmol/L after four years of follow-up., Conclusion: ABO-incompatible kidney transplantation, even in patients with high isoagglutinin titers, is feasible and can achieve favorable long-term graft and patient survival outcomes. However, these procedures require substantial clinical expertise and close follow-up to monitor and manage the elevated risks of infection and rejection in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Naciri Bennani, Bobo Barry, Noble, Malvezzi, Jouve and Rostaing.)

Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants ( CYP3A4*22 / CYP3A5*3 ) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99-79.36, p = 0.007, and HR 4.532, 95% CI 1.10-18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99-6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63-11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22-3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08-0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer L.R has declared a shared affiliation with the author T.J to the handling editor at the time of review., (Copyright © 2022 Crespo, Vidal-Alabró, Jouve, Fontova, Stein, Mocka, Meneghini, Sefrin, Hruba, Gomà, Torija, Donadeu, Favà, Cruzado, Melilli, Moreso, Viklicky, Bemelman, Reinke, Grinyó, Lloberas and Bestard.)

Introduction: Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols., Materials and Methods: We systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR., Results: Most studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy., Conclusion: TCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cabezas, Jouve, Malvezzi, Janbon, Giovannini, Rostaing and Noble.)

Outcomes after kidney transplantation are largely driven by the development of de novo donor-specific antibodies (dnDSA), which may be triggered by blood transfusion. In this single-center study, we investigated the link between early blood transfusion and dnDSA development in a mainly anti-thymocyte globulin (ATG)-induced kidney-transplant cohort. We retrospectively included all recipients of a kidney transplant performed between 2004 and 2015, provided they had >3 months graft survival. DSA screening was evaluated with a Luminex assay (Immucor). Early blood transfusion (EBT) was defined as the transfusion of at least one red blood-cell unit over the first 3 months post-transplantation, with an exhaustive report of transfusion. Patients received either anti-thymocyte globulins (ATG) or basiliximab induction, plus tacrolimus and mycophenolic acid maintenance immunosuppression. A total of 1088 patients received a transplant between 2004 and 2015 in our center, of which 981 satisfied our inclusion criteria. EBT was required for 292 patients (29.7%). Most patients received ATG induction (86.1%); the others received basiliximab induction (13.4%). dnDSA-free graft survival (dnDSA-GS) at 1-year post-transplantation was similar between EBT+ (2.4%) and EBT- (3.0%) patients (chi-squared p=0.73). There was no significant association between EBT and dnDSA-GS (univariate Cox's regression, HR=0.88, p=0.556). In multivariate Cox's regression, adjusting for potential confounders (showing a univariate association with dnDSA development), early transfusion remained not associated with dnDSA-GS (HR 0.76, p=0.449). However, dnDSA-GS was associated with pretransplantation HLA sensitization (HR=2.25, p=0.004), hemoglobin >10 g/dL (HR=0.39, p=0.029) and the number of HLA mismatches (HR=1.26, p=0.05). Recipient's age, tacrolimus and mycophenolic-acid exposures, and graft rank were not associated with dnDSA-GS. Early blood transfusion did not induce dnDSAs in our cohort of ATG-induced patients, but low hemoglobin level was associated with dnDSAs-GS. This suggests a protective effect of ATG induction therapy on preventing dnDSA development at an initial stage post-transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jouve, Noble, Naciri-Bennani, Dard, Masson, Fiard, Malvezzi and Rostaing.)

Recent data from the World Population Prospects projects that, by 2050, nearly all regions in the world will have a quarter or more of the population aged 60 and above. Chronic kidney disease (CKD) has a high global prevalence (~13%) worldwide, and the prevalence of chronic kidney disease and end-stage kidney disease increase with age. Kidney transplantation remains the best therapeutic option for end-stage kidney disease, offering a survival benefit in comparison with dialysis maintenance for most patients. This review focuses on immunological aspects of kidney transplantation in older patients and marginal donors, i.e., 60 years or older deceased kidney donors or 50-59 years old deceased kidney donors with comorbidities. Clinical outcomes of kidney recipients in terms of renal and patient survival are more than acceptable even for patients over 70. In this population, the first cause of graft loss is death with a functional graft. However, the inherent issues of these transplantations are the acceptance or refusal of frail kidney from an old donor and the increased immunogenicity of these organs in balance with potential frail and immunosenescent recipients. Finally, the immunosuppressive regimen itself is a challenge for the future of the transplant, to prevent adverse effects such as nephrotoxicity and higher risk of infections or cancer in a population already at risk. Belatacept may have a good place in the immunosuppressive strategy to improve efficacy and the safety posttransplantation., (Copyright © 2020 Noble, Jouve, Malvezzi, Süsal and Rostaing.)