A prospective randomized, controlled trial of eculizumab to prevent ischemia‐reperfusion injury in pediatric kidney transplantation

Abstract

Ischemia-reperfusion injury has multiple effects on a transplanted allograft, including delayed or impaired graft function, compromised long-term survival, and an association with an increased incidence of rejection. Eculizumab, a monoclonal antibody blocking terminal complement activation, has been postulated to be an effective agent in the prevention or amelioration of IRI. We performed a single-center prospective, randomized controlled trial involving 57 pediatric kidney transplant recipients between 2012 and 2016. The immunosuppressive protocol included two doses of alemtuzumab; half of the patients were randomized to receive a single dose of eculizumab prior to transplantation. Maintenance immunosuppression was based on a combination of low-dose tacrolimus and mycophenolate, without steroids. Eculizumab-treated patients had a significantly better early graft function, less arteriolar hyalinosis and chronic glomerulopathy on a protocol biopsies taken on day 30, 1 year, and 3 years after transplantation. In the eculizumab group, four non-vaccinated children lost their grafts during the course of a flu-like infection. Eculizumab is associated with better early graft function and improved graft morphology; however, there was an unacceptably high number of early graft losses among the eculizumab-treated children. While a promising strategy, the best approach to complement inhibition remains to be established.

Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials

“…The authors reported that a single pretransplant Ecu dose was associated with better early graft function and fewer chronic histological changes on long-term protocol biopsies. 16 The reason for the discrepancy between the convincing scientific evidence regarding the causal involvement of complement in the IR injury and lack of efficacy of Ecu in our current study and the PROTECT Study is unknown, but may relate to specificity of the Ecu's complement inhibitory function. 9,17,18 Ecu inhibits the C5 con- Alternatively, as complement activation initiates within the donor kidney coincident with donor death, 10,11 it is conceivable that initiating complement inhibition earlier than what was done in this study, eg, in the donor or during cold storage, could be efficacious.…”

“…16 Of note, in this latter study 68% were living donor kidney recipients. The inability of Ecu to improve early transplant outcome in our current study and the PROTECT study are in contrast to a single center, not-blinded, randomized, placebo controlled trial involving 57 pediatric kidney transplant recipients.…”

“…The inability of Ecu to improve early transplant outcome in our current study and the PROTECT study are in contrast to a single center, not-blinded, randomized, placebo controlled trial involving 57 pediatric kidney transplant recipients. 16 Of note, in this latter study 68% were living donor kidney recipients. The authors reported that a single pretransplant Ecu dose was associated with better early graft function and fewer chronic histological changes on long-term protocol biopsies.…”

Is there a case for eculizumab for pediatric renal transplantation?

“…Kabaak et al chose an immunosuppressive protocol with induction therapy with two doses of alemtuzumab at 1 mg/kg, a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, which is commonly used in the pediatric renal transplant program in Madison, WI . This was combined with tacrolimus (trough levels of tacrolimus were adjusted to 8‐12 ng/mL for the first 10 days and 2‐8 ng/mL thereafter) and MMF (fixed dose, no pharmacokinetic monitoring).…”

“…First of all, Michael Kaabak et al clearly chose an innovative approach. While underpowered to demonstrate a long‐term benefit, the significantly better early function resulted in a trend toward a better eGFR at 3 years and significantly better histopathology.…”