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Background: The standard-of-care protocol, based on plasma exchanges, high-dose intravenous immunoglobulin and optimization of maintenance immunosuppression, can slow down the evolution of antibody-mediated rejection (AMR), but with high interindividual variability. Identification of a reliable predictive tool of the response to AMR treatment is a mandatory step for personalization of the follow-up strategy and to guide second-line therapies., Methods: Interrogation of the electronic databases of 2 French university hospitals (Lyon and Strasbourg) retrospectively identified 81 renal transplant recipients diagnosed with AMR without chronic lesions (cg score ≤1) at diagnosis and for whom a follow-up biopsy had been performed 3-6 months after initiation of therapy., Results: The evolution of humoral lesions on follow-up biopsy (disappearance versus persistence versus progression) correlated with the risk for allograft loss (logrank test, P = .001). Patients with disappearance of humoral lesions had ∼80% graft survival at 10 years. The hazard ratio for graft loss in multivariate analysis was 3.91 (P = .04) and 5.15 (P = .02) for patients with persistence and progression of lesions, respectively. The non-invasive parameters classically used to follow the intensity of humoral alloimmune response (evolution of immunodominant DSA mean fluorescence intensity) and the decline of renal graft function (estimated glomerular filtration rate decrease and persistent proteinuria) showed little clinical value to predict the histological response to AMR therapy., Conclusion: We conclude that invasive monitoring of the evolution of humoral lesions by the mean of follow-up biopsy performed 3-6 months after the initiation of therapy is an interesting tool to predict long-term outcome after AMR treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Donor-specific antibodies (DSA) play a major role in antibody-mediated rejection (AMR) and graft dysfunction. However, the clinical relevance of complement-binding anti-HLA antibodies remains unclear., Methods: Here, we analyzed DSA detected in the serum (sDSA) using single antigen bead, C1q, and C3d assays combined with the study of intragraft DSA (gDSA) in 86 patients who had DSA and underwent a kidney biopsy for cause (n = 58) or without evidence of kidney dysfunction (n = 28). DSA characteristics were collected and related to the presence of AMR, graft histological features, and allograft survival., Results: Forty-five patients (52%) had C1q DSA, and 42 (51%) had C3d DSA. Allograft biopsies revealed AMR in 63 cases (73%), regardless of kidney function. gDSA were identified in 74% of biopsies. We observed a strong correlation among single antigen bead mean fluorescence intensity and complement assays positivity, presence of gDSA, and AMR occurrence., Conclusions: Complement-binding DSA per se were not significantly associated with allograft survival in the entire study sample. Finally, gDSA predicted subsequent graft loss in patients who showed a stable renal function at the day of biopsy. Our data suggest that DSA mean fluorescence intensity and presence of gDSA might provide prognostic information during posttransplant monitoring.

Background: The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown., Methods: We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment., Results: Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect., Conclusion: The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.

Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We describe the decline in islet function, in relation to HLA sensitization, in an islet transplant recipient and the recovery of this function after treatment with anti-CD20 monoclonal antibody and IV immunoglobulins. A 51-year-old woman with type 1 diabetes received one intraportal islet infusion. Following this transplantation, she became insulin independent. A search for HLA antibodies by using an ELISA technique remained consistently negative for HLA class I and II. It was only 2 years after the islet transplantation that this search became positive against class II antigens, reaching a peak of reactivity concomitantly with the appearance of a deterioration of glucose control requiring low-dose insulin therapy. Luminex screening and single-antigen assays then revealed the presence of both nondonor-specific and donor-specific antibodies against HLA class II molecules. This immunization, already present in the pretransplant serum, had increased during the 6 months preceding the clinical deterioration. Since these data nevertheless pointed to antibody-mediated rejection of the islet allograft, treatment with anti-CD20 monoclonal antibody and IV immunoglobulins was initiated. One month later, the search by ELISA for antibodies against HLA class II antigens became negative, the Luminex tests normalizing more gradually. As the result of an improvement in glucose control, the patient was again insulin-free.

Background: Non-adherence with immunosuppressant medication (MNA) fosters development of de novo donor-specific antibodies (dnDSA), rejection, and graft failure (GF) in kidney transplant recipients (KTRs). However, there is no simple tool to assess MNA, prospectively. The goal was to monitor MNA and analyze its predictive value for dnDSA generation, acute rejection and GF. Methods: We enrolled 301 KTRs in a multicentric French study. MNA was assessed prospectively at 3, 6, 12, and 24 months (M) post-KT, using the Morisky scale. We investigated the association between MNA and occurrence of dnDSA at year 2 post transplantation, using logistic regression models and the association between MNA and rejection or graft failure, using Cox multivariable models. Results: The initial percentage of MNA patients was 17.7%, increasing to 34.6% at 24 months. Nineteen patients (8.4%) developed dnDSA 2 to 3 years after KT. After adjustment for recipient age, HLA sensitization, HLA mismatches, and maintenance treatment, MNA was associated neither with dnDSA occurrence, nor acute rejection. Only cyclosporine use and calcineurin inhibitor (CNI) withdrawal were strongly associated with dnDSA and rejection. With a median follow-up of 8.9 years, GF occurred in 87 patients (29.0%). After adjustment for recipient and donor age, CNI trough level, dnDSA, and rejection, MNA was not associated with GF. The only parameters associated with GF were dnDSA occurrence, and acute rejection. Conclusions: Prospective serial monitoring of MNA using the Morisky scale does not predict dnDSA occurrence, rejection or GF in KTRs. In contrast, cyclosporine and CNI withdrawal induce dnDSA and rejection, which lead to GF. [ABSTRACT FROM AUTHOR]