Pretransplant natural antibody levels identify a subset of deceased donor kidney transplant recipients that benefit from infliximab induction

Abstract

Targeting peritransplant inflammation via tumor necrosis factor alpha blockade failed to improve kidney transplantation outcomes in the CTOT-19 trial that tested infliximab (IFX) induction. As natural antibodies (nAbs) to cardiolipin and phosphatidylethanolamine promote graft injury, we hypothesized that CTOT-19 outcomes were confounded by nAb levels. Pretransplant plasma anticardiolipin (aCL) and antiphosphatidylethanolamine (aPE) immunoglobulin M/immunoglobulin G (IgM/IgG) were measured in 177 CTOT-19 subjects and analyzed in relation to delayed graft function (DGF), 2-year estimated glomerular filtration rate, and infection. Bayesian modeling with a nonlinear treatment–antibody interaction estimated that the IFX effects depend on aCL IgG/IgM and aPE IgG. In patients with low aCL IgG, IFX reduces DGF risk (odds ration [OR] at the fifth percentile, 0.13; 95% credible interval (95% CrI), 0.03-0.49) but increases risk at the 95th percentile of aCL IgG levels (OR, 6.24; 95% CrI, 1.38-30.32). In patients with aCL IgG below the median, IFX has a positive indirect effect on the estimated glomerular filtration rate via reducing DGF rates. Finally, IFX increases infection risk in patients with low aPE IgG (OR at the fifth percentile, 3.12; 95% CrI, 1.11-9.08). This analysis identifies a subset of CTOT-19 subjects who likely benefit from IFX and suggests pretransplant nAb levels may serve as biomarkers for response to early posttransplant anti-inflammatory therapies.