Donor-specific tolerance induction by combined kidney and hematopoietic stem cell transplantation

ABSTRACT

Background: Long-term survival of kidney allografts is limited by either inadequately controlled rejection and/or by side effects of long-term immunosuppression (drug toxicity, infections and neoplasia). Induction of donor-specific tolerance would resolve most, if not all of these limitations. Here, we report on 6 patients included in the first European trial of combined kidney and hematopoietic stem cell transplantation (HSCT;swisstolerance. CH). Methods or Case description Six patients (3 female / 3 male) underwent combined kidney and hematopoietic stem cell transplantation from their HLA-identical living siblings between 2016 and 2022. Conditioning therapy for HSCT and immunosuppression was performed according to the Stanford protocol including total lymphoid irradiation, anti-thymocyte globulin followed by corticosteroids (3 days), mycophenolate (1 months) and cyclosporine for 6-15 months. After 9-15 months all immunosuppression was withdrawn. Results or Learning points Five out of six patients were completely withdrawn from all immunosuppression (follow-up between 6 years and 4 months). No rejection or graft-versus-host disease episodes and no relevant infections occurred. Initial donor chimerism was seen in all patients. However, in 5/6 patients the chimerism level was declining, whereas one patient remained a stable mixed chimera. Specificity of tolerance was tested by molecular microscope analysis (absence of rejection signature) and by successful SARS CoV2 vaccination in some of the patients. One patient experienced a relapse of her primary glomerulonephritis in the allograft. She developed proteinuria, but renal function remained normal so far. Conclusion(s) Combined HSCT and kidney transplantation from the same living donor provides tolerance to a kidney allograft. This tolerance is donor-specific, as shown by protective immune responses against a SARS-CoV2-specific vaccine and absence of "molecular rejection".