MicroRNA Profiles in Allograft Tissues and Paired Urines Associate With Chronic Allograft Dysfunction With IF/TA

Abstract

Despite the advances in immunosuppression, renal allograft attrition over time remains unabated due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA). We aimed to evaluate microRNA (miRNA) signatures in CAD with IF/TA and appraise 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. Validation of the microarray results and prospective evaluation of urine samples was performed using RT-qPCR. Fifty-six miRNAs were identified in samples with CAD-IF/TA. Five miRNAs were selected for further 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. A characteristic miRNA signature for IF/TA 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.

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

“…Interestingly, others have shown identical miRs as in our study to be changed during ACR of transplanted organs 7, 9, 10, 11, 12, 13. We, therefore, hypothesize that a generic change in miR expression occurs during ACR, irrespective of the organ transplanted.…”

“…They are essential for cardiac development and homeostasis; miRs are also crucially involved in cardiac fibrosis, hypertrophy, and electrical remodeling 5. Several reports demonstrated altered serological and tissular miR expression following rejection of cardiac 6, 7, hepatic 8, renal 9, 10, 11, and intestinal 12, 13 allografts, yet these studied only one species, restricted the analysis to miR profiling without mRNA profiling and did not include a therapeutic intervention to demonstrate a causal role for specific miRs. One very recent report implicated miR‐155 in murine cardiac allograft rejection through its interaction with suppressor of cytokine signaling 1 (SOCS1) in dendritic cells.…”

Circulating and Urinary microRNAs in Kidney Disease

“…The work by Scian et al (34) investigated the miRNA expression profile in transplant patients with chronic allograft dysfunction characterized by interstitial fibrosis and tubular atrophy in kidney biopsies and paired urine samples. Differential expression was detected for miR-142-3p, miR-204, miR-107, miR-211, and miR-32 in kidney biopsies.…”

Urinary MicroRNA as Biomarker in Renal Transplantation

“…After identifying five microRNAs that were differentially expressed between normal allograft tissue and tissue with IF/TA, Scian et al measured the levels of these five microRNAs in the urinary cell pellets of seven kidney transplant patients with biopsy‐confirmed IF/TA and seven patients with normal allograft tissue 32. They observed a significant upregulation of miR‐142‐3p and downregulation of both miR‐211 and miR‐204 in the urine of patients with IF/TA (Table 1).…”

“…While in this phase complex patient populations are included with sometimes multiple conditions being present simultaneously, appropriate interpretation of the results requires detailed documentation of relevant donor and patient characteristics as outlined above. As demonstrated for mRNA as well as for microRNA, a panel of biomarkers forming a signature can be expected to be best suited for graft monitoring 9, 10, 32, 33, reflecting the fact that different molecular pathways are usually involved in the pathophysiology of any type of graft injury. Moreover, biomarkers should be measured at different time points during follow‐up, capturing the period preceding the presence of the pathological condition as well as the recovery phase, if applicable, to assess the prognostic potential of microRNAs and their value in monitoring response to therapy.…”