Biomarkers of tolerance in kidney transplantation – are we predicting tolerance or response to immunosuppressive treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing differential-expression of B-cell related genes and relative expansions of B-cell subsets. However, in all of these studies, the index group, namely the tolerant recipients, were not receiving immunosuppressive (IS) treatment unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene-expression in three independent kidney transplant patient cohorts (232-recipients +14-tolerants), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B-cells. We have defined and validated a new gene-expression signature that was independent of drug effects and also differentiated tolerant patients from healthy controls (Cross-validated-AUC=0.81). In a prospective cohort we have demonstrated that the new signature remained stable before and after steroid withdrawal. Concisely, we report on a validated and highly accurate gene-expression signature that could be used reliably to identify patients suitable for IS reduction (~12% stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS-minimization safe, and hence allow critical improvements in kidney post-transplant management.