Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome
Authors: Zuber Julien , Frimat Marie , Caillard Sophie , Kamar Nassim , Gatault Philippe , Petitprez Florent , Couzi Lionel , Jourde-Chiche Noemie , Chatelet Valérie , Gaisne Raphael , Bertrand Dominique , Bamoulid Jamal , Louis Magali , Sberro Soussan Rebecca , Navarro David , Westeel Pierre-Francois , Frimat Luc , Colosio Charlotte , Thierry Antoine , Rivalan Joseph , Albano Laetitia , Arzouk Nadia , Cornec-Le Gall Emilie , Claisse Guillaume , Elias Michelle , El Karoui Khalil , Chauvet Sophie , Coindre Jean-Philippe , Rerolle Jean-Philippe , Tricot Leila , Sayegh Johnny , Garrouste Cyril , Charasse Christophe , Delmas Yahsou , Massy Ziad , Hourmant Maryvonne , Servais Aude , Loirat Chantal , Fakhouri Fadi , Pouteil-Noble Claire , Peraldi Marie-Noelle , Legendre Christophe , Rondeau Eric , Le Quintrec Moglie , Frémeaux-Bacchi Véronique 
Published: October 2019

Significance Statement
Although complement blockade is highly effective for preventing recurrence of atypical hemolytic uremic syndrome (HUS) after kidney transplant, debates regarding the use of eculizumab prophylaxis continue because of its very high cost. An individualized strategy—using eculizumab prophylaxis specifically in patients with moderate- to high-risk kidney transplants, determined by complement analysis and a medical history of a previous recurrence—was implemented in France in 2011 and subsequently adopted more widely. In the authors’ retrospective study of patients with atypical HUS in France, they found that prophylactic use of eculizumab almost abolished the risk of recurrence and significantly increased graft survival, especially in high-risk transplants. It also led to a substantial expansion after 2012 of the transplanted population among patients with atypical HUS and ESKD. These findings support use of eculizumab prophylaxis based on pretransplant risk stratification.

Background
Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade–based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.

Methods
To evaluate this strategy’s effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016.

Results
The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.

Conclusions
Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.