Urinary exosomal viral microRNA as a marker of BK virus nephropathy in kidney transplant recipients

Abstract

ObjectiveBkv-miR-B1-5p, one of the microRNAs encoded by BK virus, was recently reported to be elevated in the blood among the patients with BK virus nephropathy (BKVN). Urinary exosome was suggested to be a possible source of biomarker for kidney diseases, but it was unknown whether it could contain viral microRNA as well as human microRNAs. The aim of this study was to evaluate whether urinary exosomal BK viral microRNA were expressed during replication and could be used to diagnose BKVN in kidney transplant recipients.Materials and methodsIn a cross-sectional multicenter study, we collected and analyzed 458 graft biopsies from 385 kidney transplant recipients. Urine samples were collected at the time of graft biopsy, and microRNAs in urinary exosome were measured once. For 13 patients with BKVN and 67 age, sex-matched kidney transplant recipients, we measured BK viral microRNA B1-5p, 3p and human microRNA-16 in urinary exosomal fraction and compared the diagnostic value with BK viral load in plasma and urine.ResultsPathology proven BKVN was diagnosed in 13 patients (2.8%). High levels of bkv-miR-B1-5p and bkv-miR-B1-3p were shown in all patients with BKVN. Meanwhile, plasma BK viral load assay (cut-off value of ≥ 4.0 log10 copies/mL) showed false negative in 3 cases and urinary BK viral load assay (cut-off value of ≥ 7.0 log10 copies/mL) showed false negative in 1 case among these 13 patients. The receiver operator characteristics curve analysis for bkv-miR-B1-5p and bkv-miR-B1-5p/miR-16 showed excellent discriminative power for the diagnosis of BKVN, with area under the curve values of 0.989 and 0.985, respectively.ConclusionsThis study suggests that urinary exosomal bkv-miR-B1-5p and bkv-miR-B1-5p/miR-16 could be surrogate markers for the diagnosis of BKVN.

BK Polyomavirus MicroRNA Levels in Exosomes Are Modulated by Non-Coding Control Region Activity and Down-Regulate Viral Replication When Delivered to Non-Infected Cells Prior to Infection

“…Moreover, miRNAs of BKPyV and the closely related JCPyV miRNAs have been detected in blood, urine and cerebrospinal fluid samples, often together with the corresponding viral loads with few cases reporting the nature of the NCCR structures [ 42 , 43 ]. It has been suggested that urinary exosomes associated BKPyV -miRNA may be a surrogate marker for BKPyV pathology [ 44 ]. Thus, the association between miRNAs and exosomes has also raised questions about their regulatory potential in non-infected neighbouring cells [ 43 , 45 , 46 ].…”

BK virus: Current understanding of pathogenicity and clinical disease in transplantation

“…Studies of urinary chemokines, including CXCL9 and CXCL10, have shown potential benefit and correlate with our own centre experience. Similarly, urine exosomal microRNA signatures, urine proteinase inhibitor 9 (PI 9) mRNA, cellular assays for IFN‐gamma, and plasma donor‐derived cell‐free DNA have all demonstrated the ability to differentiate between various immune‐mediated causes of transplant dysfunction. Furthermore, developments in urine proteomic profiling from Pittsburgh show promise in differentiating BKVN from acute rejection .…”

Viral Infections after Kidney Transplantation: CMV and BK

“…Several biomarkers had been proposed in order to enable noninvasive diagnosis of definitive BKN without the risk of renal biopsy; these include heat shock protein 90alfa, CXCL9, neutrophil gelatinase-associated lipocalin, urinary exosomal biomarkers, urinary VP1, and urinary Haufen [65][66][67].…”

“…BK virus VP1 mRNA and urinary exosomal miRNA biomarkers have been described as potential surrogate markers for the diagnosis of PVN, with high sensitivity and specificity for BKN [66,67]. Detection of additional urine biomarkers not only offers additional strategies for noninvasive PVN diagnosis but might also predict graft outcome.…”