First Successful Tolerance Induction in a Haploidentical Sibling Simultaneous Kidney and Hematopoietic Stem Cell Transplant without Multiagent Chemotherapy or Total Body Irradiation

Body: Recipients of kidney transplants require lifelong immunosuppressive treatment, which is toxic and leads to many
comorbidities. Combining kidney and hematopoietic stem cells (HSCs) from the same HLA-matched living donor has
shown prolonged graft survival after immunosuppression withdrawal. However, most candidates lack a matched living
donor, and this strategy has not mitigated graft-versus-host (GVHD) toxicity in HLA-mismatched recipients. Tregs
improve allograft tolerance but are difficult to obtain. Here we employ a novel use of the FDA-approved Rock-2 inhibitor
belumosudil (KD025) to increase Treg number and function, enhancing immune tolerance without toxic
immunosuppression. A 40-year-old man with end-stage renal disease secondary to chronic glomerulonephritis received
an HLA-mismatched renal transplant and an infusion of HSCs from his haploidentical brother using a novel protocol
without chemotherapy or total body irradiation. The recipient received anti-thymocyte globulin induction and
conditioning with total lymphoid irradiation prior to donor stem cell infusion. He received tapered corticosteroids for the
first four months and mycophenolate for the first year and a tapering dose of tacrolimus over the first 18 months posttransplant. Belumosudil was initiated at one-month post-transplant. The patient achieved allograft tolerance without
evidence of biopsy-proven acute rejection, donor HLA-specific antibodies, GVHD, or transplant loss. Post-transplant
creatinine levels improved with tacrolimus withdrawal from 1.8-2 while on tacrolimus to 1.5-1.6 mg/dL off. Mixed
chimerism was established at 30 days post-infusion at 70% PB and 3% CD3+ T cells and maintained at 2% PB and in all
subsets tested through M18 post-transplant (Fig 1A). Tregs (CD4+Foxp3+) were 3.9% pre-transplant, increased to 15.1%
at month 2, and stabilized around 6-8% through M18. (Fig 1B). IL-10 levels followed a similar pattern (Fig 1C)
indicating both Treg numbers and function were increased.

Conclusion: HSCT and belumosudil can be considered as a strategy to decrease dependence on post-kidney transplant
immunosuppression in HLA haploidentical siblings without multiagent chemotherapy or total body irradiation