Longitudinal monitoring of BKPyV miRNA levels in kidney transplant recipients with BKPyV-related pathology reflects viral DNA levels and remain high in viremia patients after clearance of viral DNA

Abstract

Introduction: It is unclear whether polyomavirus BK (BKPyV) microribonucleic acid (miRNA) measurement has additional diagnostic and predictive value in kidney transplant recipients (KTR) as compared to current methods of monitoring BKPyV DNA loads.

Patients and methods: A retrospective, longitudinal study was performed in 30 KTR with BKPyV viruria (n = 10), BKPyV viremia (n = 10), or BKPyV-associated neuropathy (BKPyVAN) (n = 10). Bkv-miR-B1-3p and 5p and BKPyV DNA load were measured in urine and plasma and compared using receiver operating characteristic (ROC) curves.

Results: Levels of Bkv-miR-B1-3p and 5p and BKPyV DNA correlated strongly. Overall, mostly analog courses of urinary and plasma miRNA and DNA loads were observed. Areas under the ROC curves were not significantly different between miRNAs and DNA. Only, in contrast to BKPyV DNA load, BKPyV miRNA levels increased from 6 to 12 months in the viremia group, while in the BKPyVAN group, a decline was seen in both DNA and miRNA.

Conclusions: In this study, we could not demonstrate an additional value of BKPyV miRNA detection compared to BKPyV DNA monitoring in the early phase after kidney transplantation. We did observe significant differences between the viremia and the BKPyVAN groups during follow-up. This study was performed with a small number of patients and therefore results should be verified in a larger patient cohort. Furthermore, future studies with larger patient groups are necessary to elucidate final clinical value of these data.

Keywords: BK virus nephropathy; BKPyV; kidney transplantation; longitudinal; marker; miRNA.

FIGURE 1

Correlation of polyomavirus BK (BKPyV) virus DNA with Bkv‐miR‐B1‐3p and 5p. Correlation between BKPyV miRNA and DNA load measured across the three research groups from 0 to 12 months after observed BKPyV replication. Correlation between Bkv‐miR‐B1‐3p and BKPyV (A). Correlation between Bkv‐miR‐B1‐5p and BKPyV (B). p‐Values were calculated using Pearson's correlation coefficient.

FIGURE 2

Longitudinal analysis of Bkv‐miR‐B1‐3p and 5p. Longitudinal course of polyomavirus BK (BKPyV) miRNA Ct‐values from t = 0 to 12 months after observed BKPyV replication by research groups, viruria (blue circles), viremia (red squares), and BKPyVAN (black crosses). Estimated marginal means (EMM) of Bkv‐miR‐B1‐3p in urine (A) and plasma (C). EMM of Bkv‐miR‐B1‐5p in urine (B) and plasma (D). p‐Values were calculated using generalized estimating equations (GEE) with an exchangeable correlation structure.

FIGURE 3

Longitudinal analysis of polyomavirus BK (BKPyV) viral load. Longitudinal course of BKPyV DNA load (cp/ml) from t = 0 to 12 months after observed BKPyV replication by research groups, viruria (blue circles), viremia (red squares), and BKPyVAN (black crosses). Estimated marginal means (EMM) of BKPyV DNA load in urine (A) and plasma (B). p‐Values were calculated using generalized estimating equations (GEE) with an exchangeable correlation structure.

FIGURE 4

Receiver operating characteristic (ROC) curves of Bkv‐miR‐B1‐3p and 5p and BKPyV genomic polymerase chain reaction (PCR). ROC curves for Bkv‐miR‐B1‐3p (blue line), Bkv‐miR‐B1‐5p (green line), and genomic viral DNA (red line). C‐statistics (area under the curve [AUC] of ROC curves) were calculated in SPSS using BKPyV virus nephropathy as state variable.