Three-Year Outcomes of a Randomized, 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

Background and objectivesDelayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial.Design, setting, participants, & measurementsThis is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model.ResultsThree deaths occurred among C1 esterase inhibitor–treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor–treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor–treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but was stable in C1 esterase inhibitor–treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2).ConclusionsTreatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation

“…Moreover, its deleterious effect on graft life further subjects ILDKTr to adverse long‐term outcomes 6 . However, as DGF and AR generally precede mortality and graft loss, anticipating these events may lead to more effective management and response to therapy 8,15,18,19 . Therefore, characterizing the risk of these outcomes in ILDKTr is important and would better inform patient counseling.…”

Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation

“…Although the primary end point of DGF incidence was not met, significant reductions in need for dialysis and improvements in long-term allograft function were seen with C1-INH treatment. Recently, the long-term outcome of the trial has been updated and the researchers found that berinert treatment is associated with a lower incidence of graft failure [ 32 ]. These encouraging data suggest that complement inhibition is potentially valuable to prevent IRI damage in the clinic.…”

Novel strategies to target the humoral alloimmune response

“…A phase 1/2 RCT (N = 70) reported a significant benefit of C1 esterase inhibitor (C1-INH) for 3.5-year allograft survival when given intraoperatively and 24 hours post-transplant. 130,131 In contrast, a large multi-centre registration RCT (PROTECT, N = 288) did not meet its primary endpoint to justify perioperative administration of eculizumab (a C5 inhibitor) to prevent delayed graft function, although long-term follow data were not collected (NCT02145182). In a cohort of pediatric kidney transplant recipients, a single pre-transplant dose of eculizumab led to significantly better graft function up to 3 years later, but was associated with an unacceptably high rate of early graft losses during a flu-like infection (all in non-vaccinated children).…”