Allogeneic Umbilical Cord Mesenchymal Stromal Cells for the Treatment of Chronic Antibody-Mediated Rejection in Kidney Transplantation

Kidney transplantation is the best treatment for end-stage chronic kidney disease (CKD), improving survival and quality of life, while reducing treatment costs. However, immunosuppressive therapies reduce acute rejection but have not significantly improved graft survival (60% at 10 years). Graft loss is largely due to chronic antibody-mediated rejection (cABMR), which remains a major challenge with no specific treatment. In our center, 20 cABMR cases confirmed by biopsy were identified in 2018-2019, with 40% of patients returning to dialysis. Cellular therapies aiming at graft tolerance induction are promising strategies. The European consortium The-One-Study conducts Phase II trials using non-mesenchymal immunoregulatory cells to reduce immunosuppressive treatment and/or prevent infections or tumors. Mesenchymal Stromal Cells (MSCs), not part of this consortium, modulate the function of cells involved in acute or chronic rejection. In kidney transplantation (living donor), MSCs reduce acute rejection by 64% at 6 months, infections by 36%, with lower doses of immunosuppressants. A recent randomized trial showed that injecting MSCs one and a half months after kidney transplantation allowed discontinuation of calcineurin inhibitors without increased rejection risk. At 6 months, there were no differences in renal function or tissue damage, indicating the potential to stop calcineurin inhibitors following MSC injection. Additionally, a significantly higher level of regulatory lymphocytes was observed. Previous attempts to discontinue calcineurin inhibitors early showed increased rejection risk. A recent study (Neptune Phase Ib) with allogeneic MSCs demonstrated that tacrolimus doses could be reduced without acute or chronic rejection. In the cABMR model, MSC injection reduced creatinine by 45%, proteinuria by 70%, and fibrotic lesions. A study by Wei et al. showed that allogeneic bone marrow MSCs improved renal function in chronic rejection. Given the easier availab