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Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.

ABSTRACT: Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase?I-II of clinical trials. Thus the pipeline for the near future appears almost empty.

SUBMITTER: Salvadori M

PROVIDER: S-EPMC3964192 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.

Salvadori Maurizio M Bertoni Elisabetta E

World journal of transplantation 20140301 1

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies fro ...[more]

PMID: 24669363

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Project description:Rationale: There is significant variation in approach to pre-lung transplant donor-specific antibodies (DSA), with some centers declining to cross any DSA. We implemented a protocol for transplantation for candidates with pretransplant DSA so long as a prospective complement-dependent cytotoxicity crossmatch was negative, regardless of number, specificity, class, or mean fluorescence intensity.Objectives: To compare post-transplant outcomes including overall survival, chronic lung allograft dysfunction-free survival, antibody-mediated rejection, and acute cellular rejection in lung transplant recipients where pretransplant DSA was and was not present.Methods: This was a single-center retrospective cohort study. For recipients with pretransplant DSA, if the prospective complement-dependent cytotoxicity crossmatch was negative, the donor offer was accepted and plasmapheresis was performed within 24 hours of transplantation and continued until retrospective crossmatch results returned. Immunosuppression and post-transplant management were not otherwise modified.Results: Of the 203 included recipients, 18 (8.9%) had pretransplant DSA. The median DSA mean fluorescence intensity was 4,000 (interquartile range, 2,975-5,625; total range, 2,100-17,000). The median number of DSA present per patient was one (interquartile range, 1-2). The presence of pretransplant DSA was not associated with increased mortality (hazard ratio, 1.2; 95% confidence interval [CI], 0.4-3.4) or decreased chronic lung allograft dysfunction-free survival (hazard ratio, 1.1; 95% CI, 0.6-2.1). Recipients with pretransplant DSA were more likely to require prolonged mechanical ventilation (adjusted odds ratio, 7.0; 95% CI, 2.3-21.6) and to have antibody-mediated rejection requiring treatment (adjusted odds ratio, 7.5; 95% CI, 1.0-55.8).Conclusions: A protocol of accepting donor offers for lung transplant candidates with preformed, complement-dependent cytotoxicity crossmatch-negative DSA is associated with increased need for prolonged mechanical ventilation and antibody-mediated rejection without affecting short-term overall or chronic lung allograft dysfunction-free survival.

Project description:Due to the current organ shortage, living donor kidney transplantation is increasingly performed across HLA (human leukocyte antigen) or ABO antibody barriers. There is still uncertainty about the risk of antibody-mediated rejection (AMR) episodes, which may limit long-term graft survival. From March 2007 to December 2016, 58 sensitized living donor kidney transplant candidates were identified and 38 patients eventually included in the study: 36 patients (95%) had pre-transplant and pre-desensitization Luminex-detected donor-specific HLA antibodies (DSA), and 17/36 patients (47%) in addition had a positive crossmatch result. Two patients had no detectable DSA but a positive CDC B-cell crossmatch result. Patients were treated with pre- and post-transplant apheresis and powerful immunosuppression including the anti-CD20 antibody rituximab (N = 36) in combination with thymoglobulin (N = 20) or anti-IL2 receptor antibody (N = 18). The results of the 38 successfully desensitized and transplanted patients were retrospectively compared to the results of 76 matched standard-risk recipients. Desensitized patients showed patient and graft survival rates similar to that of standard-risk recipients (P = 0.55 and P = 0.16, respectively). There was a trend toward reduced death-censored graft survival in desensitized patients (P = 0.053) which, however, disappeared when the 34 patients who were transplanted after introduction of sensitive Luminex testing were analyzed (P = 0.43). The incidence of rejection episodes without borderline changes were in desensitized patients with 21% similar to the 18% in standard-risk patients (P = 0.74). Thirty-six patients had pre-transplant HLA class I and/or II DSA that were reduced by 85 and 81%, respectively, during pre-transplant desensitization (P < 0.001 for both). On day 360 after transplantation, 20 of 36 (56%) patients had lost their DSA. The overall AMR rate was 6% in these patients, but as high as 60% in 5 (14%) patients with persistent and de novo DSA during year 1; 2 (40%) of whom lost their graft due to AMR. Eleven (31%) patients with persistent DSA but without de novo DSA had an AMR rate of 18% without graft loss while one patient lost her graft without signs of AMR. Our desensitization protocol for pre-sensitized living donor kidney transplant recipients with DSA resulted in good graft outcomes with side effects and rejection rates similar to that of standard-risk recipients. Adequate patient selection prior to transplantation and frequent immunological monitoring thereafter is critical to minimize rejection episodes and subsequent graft loss.

Project description:Background and objectivesSmall donor and/or kidney sizes relative to recipient size are associated with a higher risk of kidney allograft failure. Donor and recipient ages are associated with graft survival and may modulate the relationship between size mismatch and the latter. The aim of this study was to determine whether the association between donor-recipient size mismatch and graft survival differs by donor and recipient age.Design, setting, participants, & measurementWe performed a retrospective cohort study of first adult deceased donor kidney transplantations performed between 2000 and 2018 recorded in the Scientific Registry of Transplant Recipients. We used multivariable Cox proportional hazards models to assess the association between donor-recipient body surface area ratio and death-censored graft survival, defined as return to dialysis or retransplantation. We considered interactions between donor-recipient body surface area ratio and each of recipient and donor age.ResultsAmong the 136,321 kidney transplant recipients included in this study, 23,614 (17%) experienced death-censored graft loss over a median follow-up of 4.3 years (interquartile range, 1.9-7.8 years). The three-way donor-recipient body surface area ratio by donor age by recipient age interaction was statistically significant (P=0.04). The magnitude of the association between severe size mismatch (donor-recipient body surface area ratio <0.80 versus ≥1.00) and death-censored graft survival was stronger with older donor age and recipient age. In all recipient age categories except the youngest (18-30 years), 5- and 10-year graft survival rates were similar or better with a size-mismatched donor aged <40 years than a nonsize-mismatched donor aged 40 years or older.ConclusionsThe association of donor-recipient size mismatch on long-term graft survival is modulated by recipient and donor age. Size-mismatched kidneys yield excellent graft survival when the donor is young. Donor age was more strongly associated with graft survival than size mismatch.

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Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.

Publications

Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.

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