ABSTRACT

Non-invasive approaches to detect kidney graft injury and distinguish donor-specific immune-mediated injury from other causes of inflammation are needed to guide recipient therapy while avoiding the morbidities of transplant biopsies. We used a multi-plex platform to interrogate RNA isolated from kidney transplant recipient urine to investigate gene expression patterns distinguishing grafts with no injury vs. ongoing injury and further differentiate acute T cell-mediated rejection (TCMR) from BK virus nephropathy (BKVN). As a training set we quantified expression of 796 immune function genes from 25 control recipients with stable graft function, 17 with biopsy-proven acute TCMR, and 13 with biopsy-proven BKVN. We identified a 20-gene signature that differentiated intragraft injury from grafts with stable function (area under the curve (AUC), 0.991) and a distinct 40-gene signature distinguishing acute TCMR from BKVN (AUC = 1.00). Validation in separate 118 urine RNA samples obtained at time of surveillance or for-cause biopsies from Clinical Trials in Organ Transplantation (CTOT)-08 and CTOT-19 studies showed AUC of 0.77 for the 20-gene injury signature and AUC of 0.79 for the 40-gene signature. Our results highlight the utility of this flexible, non-invasive biomarker platform for rapid detection and differentiation of immune processes causing ongoing kidney graft injury.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by the National Institutes of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers UO1 AI84150, UO1 AI84146, and U01 AI063594 and by the Clinical Trials in Organ Transplantation Consortium NanoString Core (U01 AI063594).

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IRBs of Cleveland Clinic, University of Alabama Birmingham, University of Maryland School of Medicine, Northwestern University, Emory University, Icahn School of Medicine at Mt. Sinai gave ethical approval for this work.

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DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

AbbreviationsABMRantibody-mediated rejectionAUCarea under the curveBKVNBK virus nephropathyCTOTClinical Trials in Organ TransplantationDEGdifferentially expressed genesFSGSfocal segmented glomerular sclerosisGEPgene expression profilesKTRkidney transplant recipientsTCMRT cell mediated rejection