HLA-Class I and II Antibodies, Proteinuria, and Transplant Glomerulopathy; a Retrospective Analysis of the Frankfurt Transplant Center

Abstract

A retrospective analysis investigating the significance of HLA specific- and/or cytotoxic antibodies (AB) for kidney graft survival was performed in the transplant center of the University Clinic Frankfurt/Main. Proteinuria was investigated in a cohort of transplant recipients without and with HLA specific- and/or cytotoxic AB. In 26 patients (pts) with HLA specific- and/or cytotoxic AB the kidney biopsies were performed for indication and were evaluated. Methods: AB were monitored by ELISA in combination with the lymphocyte cytotoxicity assay (LCT) and the Luminex assay in selected patients. To avoid hyperacute rejection of the transplanted kidney, no transplantation was performed against donor specific historic or acute HLA-class-I AB, detected by LCT or ELISA. Immunosuppression of HLA-class-I AB negative recipients was performed with cyclosporine A, mycophenolate mofetil, and steroids. Patients with HLA-class-I AB received intensified immunosuppression with tacrolimus, mycophenolate mofetil, antithymocyte globuline, and steroids. Proteinuria was determined by dipstick analysis. Biopsies were performed in case of impairment of renal function and /or proteinuria. Results: Kaplan Meier estimates revealed a significantly reduced long term kidney graft survival in pts immunized with both pre-transplant HLA-class-I AB and HLA-class-II AB detected by ELISA (91% vs. 65%; p = 0.008). A significantly reduced long term graft survival was found in pts with a positive LCT prior to transplantation (91% versus 67%, p= 0.004). Immunization with HLA class-I or HLA class-II AB was associated with a significantly increased proteinuria. Transplant glomerulitis or glomerulopathy was found in 43 % of pts positive in the LCT, 42 % and 50% pts positive for HLA class-I or -II AB in the ELISA, respectively, and in 62 % of pts positive for HLA class-I and II AB. Interstitial fibrosis was found in 25% of pts positive in the LCT, 37% and 42% of pts positive for HLA class-I or -II AB in the ELISA, respectively, and in 38% of pts positive for HLA class-I and -II AB. C4d was found in 25% of biopsies, and in 50% of pts positive for HLA class-I and -II AB. Almost all pts displayed tubular damage. 6/26 pts biopsied lost their transplants, at 21.5 ± 15.2 months after transplantation. In 4/6 graft losses transplant glomerulitis or glomerulopathy was diagnosed. The other 2 graft losses were due to combined vascular and interstitial rejection at an earlier time point. All 6 patients with graft losses and all 9 with the histological diagnosis of Glomerulitis/TP-glomerulopathy and 8/9 with C4d staining had DSA pretransplant, when we tested the blood retrospectively with the Luminex Assay. Conclusion: Our results confirm the significance of HLA-class-I and -II AB for graft loss both detected in the ELISA and LCT preoperatively even if they are not donor-specific. The increased proteinuria in immunized pts and the predominance of transplant glomerulopathy and glomerulitis as well as C4d staining in the biopsies support the immunological aetiology of chronic transplant failure in this cohort. In the future preoperative testing for DSA with the luminex-Assay might improve outcome due to the possibility of more tailored immunsosuppression.