BACKGROUND

Sub-clinical acute rejection (subAR) in kidney transplant recipients (KTR), defined as histological rejection on surveillance biopsy (Bx) in a patient with stable renal function, signals under-immunosuppression (IS) and can lead to chronic rejection and graft loss. Surveillance Bx are invasive and are not performed routinely in all centers. Non-invasive biomarkers are needed to detect rejection in KTR with stable renal function.

METHODS

KTR were enrolled into a multi-center 24-month observational study at 5 US transplant centers that used routine surveillance Bx as standard of care at 2-6, 12 and 24 months. Precise clinical phenotypes (PCP) were used to define subAR. Differential gene expression (DGE) from peripheral blood samples, all paired with surveillance biopsies, were used to train a Random Forests (RF) model to develop a gene expression profile (GEP) for subAR. A separate cohort of paired samples with prevalent incidence of subAR was used to validate the GEP. A clinical 24-month composite endpoint (CCE: Grade 2+ IFTA, BPAR, [Delta]eGFR >10cc/min) was used to assess clinical validity for both the PCP and the GEP.

RESULTS

DGE from 530 paired samples (130 subAR; 80% borderline) collected from 250 KTR with a prevalent incidence of subAR yielded a RF model: AUC 0.85; 0.84 after internal validation with bootstrap resampling. We selected a predicted probability threshold favoring specificity and NPV (87% and 88%) over sensitivity and PPV (64% and 61%), respectively. We tested the locked model/threshold on a separate cohort of 138 KTR undergoing surveillance Bx at our institution (NPV 78%; PPV 51%). Based on the CCE, both the PCP (p<0.001) and GEP (p=0.009) of subAR within the first 12 months following transplant were independently associated with worse graft outcomes, compared to non-rejection controls.

CONCLUSIONS

A novel, validated peripheral blood molecular biomarker for the detection of subAR demonstrates clinical validity, setting the stage for biomarker-informed IS management that can complement current practice, potentially leading to improved outcomes following kidney transplantation.

CITATION INFORMATION: Friedewald J., Kurian S., Whisenant T., Heilman R., Poggio E., Marsh C., Baliga P., Bridges N., Odim J., Brown M., Ikle D., Armstrong B., Charette J., Brietigam S., Sustento-Reodica N., Zhao L., Kandpal M., Salomon D., Abecassis M. A Novel Peripheral Blood mRNA Biomarker Predicts Subclinical Rejection and Kidney Transplant Outcomes Am J Transplant. 2017;17 (suppl 3).

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