Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplant Recipients: A Pilot Randomized Controlled Trial

Am J Transplant. 2017 Mar;17(3):682-691 doi: 10.1111/ajt.14001.
Abstract

We hypothesized that de novo donor-specific antibody (DSA) causes complement-dependent endothelial cell injury in kidney transplants, as assessed by expression of endothelial cell-associated transcripts (ENDATs), that may be attenuated through complement inhibition. In total, 15 participants (five control, 10 treatment) with DSA and deteriorating renal function were enrolled. The treatment group received 6 mo of eculizumab followed by 6 mo of observation, whereas controls were observed. The primary end point was percentage change in estimated GFR (eGFR) trajectory over the treatment period. The treatment group had an improved eGFR trajectory versus control, based on our predetermined two-sided 0.10 significance level (p = 0.09). Within-subject analysis of treated participants at 6-mo intervals did not show significant change (p = 0.60). Modeling C1q status showed that C1q-positive patients had significantly higher mean eGFR than patients with negative C1q (p = 0.04). Biopsies revealed elevated renal ENDATs in most participants, but ENDATs were not reduced with complement inhibition. Our data suggest that eculizumab treatment may stabilize kidney function in patients with chronic persistent DSA based on our pilot a priori significance threshold. ENDAT expression predicative of acute humoral injury is not reduced with complement inhibition in this chronic setting. Further studies will be necessary to determine which patients may benefit from eculizumab.

CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This was a pilot study of some interest. It was powered for a significance level of 0.10, with 2:1 randomisation given the cost of the study drug (eculizumab). Only 16 patients were included in the study, over an enrollment period of 3 and a half years. Treatment with eculizumab was associated with stabilization of renal function compared to no treatment in patients with de novo DSA. The study is limited by its size and the variability in the trajectory of renal function of the included patients. It is too small to really comment on the impact of the study drug on safety outcomes, such as infection rates.
Expert Review
Reviewer: Associate Professor John Kanellis, Department of Nephrology, Monash Health and Centre for Inflammatory Diseases, Department of Medicine, Monash University. Clayton, Melbourne, Australia
Conflicts of Interest: Our centre has participated in trials using eculizumab sponsored by Alexion Pharmaceuticals
Clinical Impact Rating 1
Review: This study examined the use of eculizumab to treat chronic antibody-mediated rejection in renal transplant recipients in the presence of de-novo DSA. The findings suggest a possible role for eculizumab in stabilizing allograft function. The study was small and the benefit was evident in the last two months of treatment (months 5-6). Prior to that, no difference could be discerned. A longer treatment duration may have revealed greater separation of the groups and may have demonstrated greater clinical significance. Given the slow rate of deterioration in this condition (eGFR loss of 3.63ml/min/year) the control group showed little change in eGFR over 6 months. The treatment group were slightly more stable however the clinical difference between groups is minor and it is hard to draw conclusions from this short duration of treatment. Additionally, the study was unable to demonstrate a difference in endothelial cell associated transcript (ENDAT) expression between the groups. Again, a longer duration of treatment may have been necessary to show a difference in this chronic disease process. Further studies with a longer treatment period and with greater subject numbers would need to be performed in order to further determine the benefit of this treatment approach.
Methodological quality
Jadad score 2
Allocation concealment NO
Data analysis MODIFIED INTENTION TO TREAT
Study Details
Aims: To determine whether prolonged treatment with eculizumab would stabilize graft function in kidney transplant recipients that had developed de novo donor specific antibody (DSA).
Interventions: Participants were randomized to receive either eculizumab for 6-months followed by observation for 6-months (treatment group), versus observations over a 12-month period (control group).
Participants: 16 patients aged 18-65 years, > 6-months from their first kidney transplant with a measured de novo DSA of greater than Mean Fluorescence Intensity (MFI)>1100.
Outcomes: The primary outcome measured was the difference in percent change of estimated glomerular filtration rate trajectory over time. Secondary outcomes included 1-year graft survival, incidence of biopsy-proven acute rejection, incidence of treatment failure and expression of endothelial cell associated transcripts (ENDATs).
Follow Up: 12 months
Metadata
Funding: Funding not described
Publication type: Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: Clinicaltrials.gov - NCT01327573
Organ: Kidney
Language: English
Author email: Sanjay.Kulkarni@Yale.Edu
MeSH terms: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Chronic Disease; Complement C5; Complement Inactivating Agents; Early Intervention, Educational; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Isoantibodies; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Pilot Projects; Prognosis; Risk Factors; Tissue Donors; Transplant Recipients; Young Adult; 0 (Antibodies, Monoclonal, Humanized); 0 (Complement C5); 0 (Complement Inactivating Agents); 0 (Isoantibodies); A3ULP0F556 (Eculizumab)