MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF/TA

Mariano Scian, Daniel Maluf, Kenneth Brayman, Valeria Mas.

Department of Surgery, University of Virginia HS, Charlottesville, VA, USA.

Background: Despite the advances in immunosuppression and surgical innovations, long term kidney allograft outcomes over time remains poor due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA).

Patients and Methods: We evaluated microRNA (miRNA) signatures in primary cadaveric renal transplants (CAD) with IF/TA and appraised correlation with paired urine samples and potential utility in prospective evaluation of graft function. MicroRNA signatures were established between CAD with IF/TA vs. normal allografts by microarray. Allograft tissues (N=45) and urine samples (N=122) from 81 primary deceased donor kidney recipients were studied. Microarray result validation and prospective evaluation of urine samples was performed using RT-qPCR.

Results: Fifty-six miRNAs were identified in samples with CAD-IF/TA. Five miRNAs were selected for validation based on array fold change, p-value and in silico predicted mRNA targets. We confirmed the differential expression of these 5 miRNAs by RT-qPCR using an independent set of samples. Differential expression was detected for miR-142-3p, miR-204, miR-107, and miR-211 (P<0.001) and miR-32 (p<0.05). Furthermore, differential expression of miR-142-3p (p<0.01), miR-204 (p<0.01) and miR-211 (p<0.05) was also observed between patient groups in urine samples.

Conclusion: A characteristic CAD-IFTA miRNA signature that correlates with paired urine samples was identified. These results support the potential use of miRNAs as non-invasive markers of IF/TA and for monitoring graft function and furthermore, the development of graft dysfunction overtime.