Thursday, November 21, 2024
11/21/2024
Kidney transplantation is the optimal therapy for end stage kidney disease (ESKD) but current transplant outcomes are suboptimal, particularly for recipients of organs obtained from deceased donors (DD). Ischemia Reperfusion Injury (IRI), which occurs in essentially all recipients following DD kidney transplantation, contributes to poorer outcomes in DD transplant recipients. Preclinical studies implicate activation of the complement system through the mannan binding lectin (MBL) pathway as one crucial driver of post-transplant IRI and its downstream effects on allograft function. Additional preclinical work showed that blockade of MBL complement activation using peri-transplant administration of C1 esterase inhibitor (C1INH) can promote recovery of allograft function following ischemia-reperfusion-(IR)-induced acute kidney injury. Our research group performed two single center randomized controlled pilot trials of C1INH therapy to limit the downstream consequences of IRI in human kidney transplant recipients. The results of these pilot trials support the novel hypothesis that complement system inhibition with pre-implantation injection of C1 esterase inhibitor (C1INH) into the donor organ renal artery alters the reparative process induced by IR following DD kidney transplantation and improves allograft function at 1 year. We propose to determine the effects of pre- implantation, intrarenal artery injection of C1INH on kidney transplant outcomes through a randomized controlled, double blind, multicenter trial (aim 1). We will follow subjects for 12-months post-transplant to assess the primary endpoint of eGFR. Secondary endpoints will be biopsy proven acute rejection (BPAR) efficacy failure (composite of BPAR, graft loss, death, and loss to follow up), and the 12-month abbreviated iBOX score. Multiple exploratory endpoints include DGF incidence/severity. All subjects will be followed for 3 years to assess the impact of the intervention on long term outcomes. Associated mechanistic studies (aim 2) using biopsy tissue and peripheral blood samples will provide insight into detected endpoint differences between study arms, if observed, and if no differences are detected, will determine why the intervention was ineffective. Approaches will include spatial transcriptomics, functional immune assays, and studies of graft- derived exosomes, all performed using state-of-the-art techniques. The work will be completed over 7 years, with the ability to deliver the primary endpoint clinical results within 4-5 years. The additional time permits extended follow-up and mechanistic analyses. This proposed work addresses a key unmet need in kidney transplantation, employs a unique therapeutic strategy, and will be performed by an experienced team. We contend that if the study is successful in improving posttransplant outcomes, it could transform the field.
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