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Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy.

ABSTRACT: BK polyomavirus-associated nephropathy (BKPyVAN) is a common cause of allograft failure. However, differentiation between BKPyVAN and type I T cell-mediated rejection (TCMR) is challenging when simian virus 40 (SV40) staining is negative, because of the similarities in histopathology. This study investigated whether donor-derived cell-free DNA (ddcfDNA) can be used to differentiate BKPyVAN. Target region capture sequencing was applied to detect the ddcfDNAs of 12 recipients with stable graft function, 22 with type I TCMR, 21 with proven BKPyVAN, and 5 with possible PyVAN. We found that urinary ddcfDNA levels were upregulated in recipients with graft injury, whereas plasma ddcfDNA levels were comparable for all groups. The median urinary concentrations and fractions of ddcfDNA in proven BKPyVAN recipients were significantly higher than those in type I TCMR recipients (10.4 vs. 6.1 ng/mL, P<0.001 and 68.4% vs. 55.3%, P=0.013, respectively). Urinary ddcfDNA fractions (not concentrations) were higher in the BKPyVAN-pure subgroup than in the BKPyVAN-rejection-like subgroup (81.30% vs. 56.64%, P=0.025). With a cut-off value of 7.81 ng/mL, urinary ddcfDNA concentrations distinguished proven BKPyVAN from type I TCMR (area under the curve (AUC)=0.848, 95% confidence interval (95% CI): 0.734 to 0.963). These findings suggest that urinary ddcfDNA is a non-invasive biomarker which can reliably differentiate BKPyVAN from type I TCMR.

SUBMITTER: Shen J

PROVIDER: S-EPMC8593525 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:BK Polyomavirus (BKPyV) causes premature graft failure in 1 to 15% of kidney transplant (KT) recipients. High-level BKPyV-viruria and BKPyV-DNAemia precede polyomavirus-associated nephropathy (PyVAN), and guide clinical management decisions. In most cases, BKPyV appears to come from the donor kidney, but data from biopsy-proven PyVAN cases are lacking. Here, we report the early fulminant course of biopsy-proven PyVAN in two male KT recipients in their sixties, receiving kidneys from the same deceased male donor. CASE PRESENTATIONS:Both recipients received intravenous basiliximab induction, and maintenance therapy consisting of tacrolimus (trough levels 3-7?ng/mL from time of engraftment), mycophenolate mofetil 750?mg bid, and prednisolone. At 4?weeks post-transplant, renal function was satisfactory with serum creatinine concentrations of 106 and 72??mol/L in recipient #1 and recipient #2, respectively. Plasma BKPyV-DNAemia was first investigated at 5 and 8?weeks post-transplant being 8.58?×?104 and 1.12?×?106 copies/mL in recipient #1 and recipient #2, respectively. Renal function declined and biopsy-proven PyVAN was diagnosed in both recipients at 12?weeks post-transplant. Mycophenolate mofetil levels were reduced from 750?mg to 250?mg bid while tacrolimus levels were kept below 5?ng/mL. Recipient #2 cleared BKPyV-DNAemia at 5.5?months post-transplant, while recipient #1 had persistent BKPyV-DNAemia of 1.07?×?105 copies/mL at the last follow-up 52?weeks post-transplant. DNA sequencing of viral DNA from early plasma samples revealed apparently identical viruses in both recipients, belonging to genotype Ib-2 with archetype non-coding control region. Retrospective serological work-up, demonstrated that the donor had high BKPyV-IgG-virus-like particle ELISA activity and a high BKPyV-genotype I neutralizing antibody titer, whereas both KT recipients only had low neutralizing antibody titers pre-transplantation. By 20?weeks post-transplant, the neutralizing antibody titer had increased by >?1000-fold in both recipients, but only recipient #2 cleared BKPyV-DNAemia. CONCLUSIONS:Low titers of genotype-specific neutralizing antibodies in recipients pre-transplant, may identify patients at high risk for early fulminant donor-derived BKPyV-DNAemia and PyVAN, but development of high neutralizing antibody titers may not be sufficient for clearance.

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Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy.

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