*Purpose: Spontaneous and rare cases of patients undergoing a functional renal transplant in the absence of immunosuppression represent a particular situation of immune tolerance. We previously established a blood score of operational tolerance (cSoT) that was reversed in patients developing anti-HLA and donor-specific antibodies (DSAs), suggesting an association with immune tolerance breakdown.

*Methods: We measured the cSoT using quantitative PCR and the NanoString enzyme-free method in blood from a multicenter cohort of 600 renal transplant patients with paired blood samples and biopsies at 1 year after transplantation.

*Results: We first confirmed the decrease in the cSoT in blood from patients displaying DSAs. We then tested the ability of this score to detect absence of subclinical rejection (SCR), a major threat associated with pejorative kidney allograft outcomes, that may not be diagnosed in the absence of allograft function decline. We showed a significant decrease of the score in patients with SCR and reported that a refinement of this score with only two genes, AKR1C3 and TCL1A, and 3 clinical parameters, was sufficient to allow the identification of patients unlikely to develop SCR at one year post-transplantation with an AUC of 0.84. The score was technically validated through two independent gene expression methods.

*Conclusions: In conclusion, we confirmed the association of our tolerance blood signature with low immunological risk in a large and independent cohort of patients and showed that the refinement of this score may enable its use in the exclusion of SCR as early as one year after transplantation. This noninvasive score could be instrumental to reduce unnecessary biopsies in patients with absence of allograft function decline unlikely to develop SCR.

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