Pre-transplant HLA antibodies and delayed graft function in the current era of kidney transplantation
Christian Morath1, Bernd Döhler2, Florian Kälble1, Luiza Pego da Silva1, Fabian Echterdiek3, Vedat Schwenger3, Stela Živčić-Ćosić4, Nataša Katalinić5, Dirk Kuypers6, Peter Benöhr7, Marion Haubitz7, Malte Ziemann8, Martin Nitschke9, Florian Emmerich10, Przemyslaw Pisarski11, Hristos Karakizlis12, Rolf Weimer12, Martin Zeier1, Caner Suesal2.
1Division of Nephrology, University Hospital Heidelberg, Heidelberg, Germany; 2Transplantation Immunology, University Hospital Heidelberg, Heidelberg, Germany; 3Department of Nephrology and Autoimmune Diseases, Transplantation Center, Klinikum Stuttgart, Stuttgart, Germany; 4Department of Nephrology, Dialysis and Kidney Transplantation, Clinical Hospital Center Rijeka, Rijeka, Croatia; 5Clinical Institute of Transfusion Medicine, Clinical Hospital Center Rijeka, Rijeka, Croatia; 6Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; 7Department of Nephrology and Hypertension, Klinikum Fulda, Fulda, Germany; 8Institute of Transfusion Medicine, University Hospital of Schleswig-Holstein, Lübeck, Germany; 9Medical Clinic 1, University of Lübeck, Lübeck, Germany; 10Institute for Cell and Gene Therapy, University Medical Centre Freiburg, Freiburg, Germany; 11Department of General and Digestive Surgery, University Medical Centre Freiburg, Freiburg, Germany; 12Department of Internal Medicine, University of Giessen, Giessen, Germany
Collaborative Transplant Study.
Introduction: We reported previously that early adverse events in deceased donor kidney transplantation, such as delayed graft function (DGF) and rejection episodes, are associated with pre-transplant presence of HLA antibodies and that patients with adverse events show significantly impaired graft survival rates. In the meantime, the introduction of sensitive antibody detection techniques is expected to have diminished the involvement of overlooked HLA antibodies in DGF. On the other hand, DGF risk might have increased due to growing use of kidneys from elderly donors. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of HLA antibodies in the new era of transplantation.
Methods: 1,724 patients who received a deceased donor kidney transplant during 2008–2017 and on whom a pre-transplant serum sample and the information on immediate function within the first 24 hours after transplantation, dialysis during the first week, and biopsy-proven rejection during the first 3 months were available. Graft survival after day 7 during the first 3 years post-transplant was analyzed by multivariable Cox regression. Predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections during days 8–90 were determined by multivariable logistic regression. DGF was defined as either no graft function during the first 24 hours and/or dialysis during the first week. In 44% of cases, we were informed by the centers on the presence or absence of pre-transplant donor-specific antibodies (DSA) as determined by single antigen technique.
Results and Discussion: Donor age ≥50 years, simultaneous presence of HLA class I and II antibodies pre-transplant, diabetes mellitus as original disease, cold ischemia time ≥18 hours, and time on dialysis >5 years were associated with an increased risk of DGF. DGF alone doubled the risk for all cause graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (HR=4.75, P<0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P<0.001) were present prior to transplantation. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1 post-transplant, whereas patients with both DGF and rejection showed the lowest rate of good kidney function. Our data indicate that, in the current era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF.
Conclusion: Patients with DGF require special attention, especially in the presence of HLA antibodies.
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