Effect of Optimized Immunosuppression (Including Rituximab) on Anti-Donor Alloresponses in Patients With Chronically Rejecting Renal Allografts

Kin Yee Shiu, Dominic Stringer, Laura McLaughlin, Olivia Shaw, Paul Brookes, Hannah Burton, Hannah Wilkinson, Harriet Douthwaite, Tjir-Li Tsui, Adam Mclean, Rachel Hilton, Sian Griffin, Colin Geddes, Simon Ball, Richard Baker, Candice Roufosse, Catherine Horsfield, Anthony Dorling

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Clinical Trial Registration: Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.