A phase I/II, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients

Abstract

Delayed graft function (DGF) is defined as need for dialysis early posttransplant. DGF is related to ischemia-reperfusion injury (IRI) that diminishes allograft function and may be complement dependent. Here, we investigate the ability of C1 esterase inhibitor (C1INH) to prevent IRI/DGF in kidney transplant recipients. Seventy patients receiving deceased donor kidney transplants at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours. The primary end point was need for hemodialysis during the first week posttransplant. Assessments of glomerular filtration rate and dialysis dependence were accomplished. Complications and safety of therapy were recorded. Similar characteristics with no significant differences in cold-ischemia time or risk factors for DGF were seen. C1INH did not result in reduction of dialysis sessions at 1 week posttransplant, but significantly fewer dialysis sessions (P = .0232) were required 2 to 4 weeks posttransplant. Patients at highest risk for DGF (Kidney Donor Profile Index ≥85) benefited most from C1INH therapy. Significantly better renal function was seen at 1 year in C1INH patients (P = .006). No significant adverse events were noted with C1INH. Although the primary end point was not met, significant reductions in need for dialysis and improvements in long-term allograft function were seen with C1INH treatment.

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

“…However, clinical data on the protective effect of C1 inhibition in the context of IRI and DGF are limited. Jordan et al recently published the results of a phase I/II trial showing that patients receiving C1INH required fewer dialysis sessions in weeks 2‐4 posttransplant and had superior renal function 12 months after surgery; this effect was most significant in those receiving low‐quality grafts. These encouraging results support complement blockade in the peritransplant period as a valid and attractive approach to protect kidneys from IRI, prevent dysfunction, and improve long‐term renal function after transplant.…”

The Impact of Therapeutic Hypothermia Used to Treat Anoxic Brain Injury After Cardiopulmonary Resuscitation on Organ Donation Outcomes

“…Clinically, DGF is relevant as it has been associated with negative recipient outcomes (Butala et al, 2013;Fonseca et al, 2015;McLaren et al, 1999;Tapiawala et al, 2010;Yarlagadda et al, 2009). First and foremost, DGF increases resource consumption, total cost of care, and emotional distress (Buchanan et al, 2008;Jordan et al, 2018;Mannon, 2018;Serrano et al, 2018;Zens et al, 2018). In addition, results of a large systematic review and metaanalysis of 33 studies have suggested that DGF is associated with a 38% higher risk of acute rejection and 41% increased risk of graft loss compared to recipients without DGF at 3.2 years of follow-up (Yarlagadda et al, 2009).…”

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

“…C1‐INH regulates several pathways which contribute to both acute and chronic graft injuries. Extensive data from animal models, and a recent human trial by Jordan et al suggest that C1‐INH ameliorates IRI 49 . Subsequently, the authors assessed the long‐term, 3.5 years outcomes of patients treated with C1INH vs placebo and demonstrated a sustained improvement in eGFR for C1INH‐treated patients.…”