Levels of donor‐derived cell‐free DNA and chemokines in BK polyomavirus‐associated nephropathy

Abstract

Background: BK polyomavirus-associated nephropathy (BKPyVAN) carries a risk of irreversible allograft injury. While detection of BK viremia and biopsy assessment are the current diagnostic gold standard, the diagnostic value of biomarkers reflecting tissue injury (donor-derived cell-free DNA [dd-cfDNA]) or immune activation (C-X-C motif chemokine ligand [CXCL]9 and CXCL10) remains poorly defined. Methods: For this retrospective study, 19 cases of BKPyVAN were selected from the Vienna transplant cohort (biopsies performed between 2012 and 2019). Eight patients with T cell-mediated rejection (TCMR), 17 with antibody-mediated rejection (ABMR) and 10 patients without polyomavirus nephropathy or rejection served as controls.Fractions of dd-cfDNA were quantified using next-generation sequencing and CXCL9 and CXCL10 were detected using multiplex immunoassays.Results: BKPyVAN was associated with a slight increase in dd-cfDNA (median; interquartile range: .38% [.27%-1.2%] vs. .21% [.12%-.34%] in non-rejecting control patients; p = .005). Levels were far lower than in ABMR (1.2% [.82%-2.5%]; p = .004]), but not different from TCMR (.54% [.26%-3.56%]; p = .52). Within the BKPy-VAN cohort, we found no relationship between dd-cfDNA levels and the extent of tubulo-interstitial infiltrates, BKPyVAN class and BK viremia/viruria, respectively. In some contrast to dd-cfDNA, concentrations of urinary CXCL9 and CXCL10 exceeded those detected in ABMR, but similar increases were also found in TCMR. Conclusion:BKPyVAN can induce moderate increases in dd-cfDNA and concomitant high urinary excretion of chemokines, but this pattern may be indistinguishable from that of TCMR. Our results argue against a significant value of these biomarkers to reliably distinguish BKPyVAN from rejection.

Anti-interleukin-6 Antibody Clazakizumab in Antibody-mediated Kidney Transplant Rejection: Effect on Donor-derived Cell-free DNA and C-X-C Motif Chemokine Ligand 10

“…Aside from immunologic rejection, there can be various triggers for the release of dd-cfDNA and chemokines, such as polyomavirus nephropathy, urinary tract infection, and acute renal failure. 20,35,42 None of the study participants had BK or JC viremia, and only 1 developed moderate acute renal failure due to diarrhea, but this event was not associated with any of the time points, wherein biomarker testing was performed. During the trial, 10 episodes of lower urinary tract infection were recorded, and, in addition, 1 had pyelonephritis.…”

Progress in kidney transplantation: The role for systems immunology

“…While studies have generalized that patients with higher dd-cfDNA experience higher rates of rejection, the ability to accurately predict adverse events among these patients is still lacking (97). This is because dd-cfDNA is elevated in a multitude of pathologies and lacks the ability to distinguish among infectious or immunologic etiologies of graft injury (98). In fact, some studies suggest that among low-risk kidney transplant recipients, the benefit provided from early dd-cfDNA monitoring may only be marginally better than current clinical management (99).…”

Detection of BK polyomavirus-associated nephropathy using plasma graft-derived cell-free DNA: Development of a novel algorithm from programmed monitoring

“…Kant et al suggested that GcfDNA may be a useful noninvasive test to assess progression of BKPyV to BKPyVAN (14). BKPyVAN can induce moderate increases in GcfDNA (15). Goussous et al suggested that elevations in GcfDNA are not specific to kidney allograft rejection and can be associated with BK viremia affecting the transplanted kidney (16).…”

“…suggested that GcfDNA may be a useful noninvasive test to assess progression of BKPyV to BKPyVAN ( 14 ). BKPyVAN can induce moderate increases in GcfDNA ( 15 ). Goussous et al.…”