Early fulminant BK polyomavirus-associated nephropathy in two kidney transplant patients with low neutralizing antibody titers receiving allografts from the same donor

Abstract

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 μmol/L in recipient #1 and recipient #2, respectively. Plasma BKPyV-DNAemia was first investigated at 5 and 8 weeks post-transplant being 8.58 × 10 4 and 1.12 × 10 6 copies/mL in recipient #1 and recipient #2, respectively. Renal function declined and biopsy-proven PyVAN was diagnosed in both recipients at 12 weeks posttransplant. 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 × 10 5 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 posttransplant, 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.

Variations in BK Polyomavirus Immunodominant Large Tumor Antigen-Specific 9mer CD8 T-Cell Epitopes Predict Altered HLA-Presentation and Immune Failure

“…Taken together, our results add another layer to interpreting the increased risk of BKPyV-DNAemia and nephropathy in KT patients in donor–recipient pairs having BKPyV-serotype mismatch [ 5 ], which has been solely attributed to lacking the corresponding genotype-specific NAbs [ 18 , 21 ]. Conversely, high NAbs in the recipient against the donor genotype may be a marker for matching genotype-specific T-cells [ 26 ], adding to the partial protection and earlier clearance of plasma BKPyV loads in many [ 22 , 49 , 50 ], but not all cases [ 28 ]. Other observational studies can also be discussed in the new light of our findings, which report significant correlations of decreasing BKPyV-specific T-cells from pre-transplant to post-transplant with increased risk [ 12 ].…”

“…Some variability in the viral DNA-genome may arise by deamination of the antisense strand by the apolipoprotein B editing complex (APOBEC) 3, thereby introducing point mutations in the VP1 -gene encoding the major viral capsid protein Vp1 [ 25 ]. Although antibody titers to BKPyV virus-like particles generally correlate with BKPyV-specific CD4 T-cells [ 26 ], some reports indicate lack of correlation of plasma BKPyV loads with the emergence of BC-loop mutations or with rising NAb titers [ 27 , 28 ]. Although immune control at the level of the viral capsid, and specifically by BKPyV-Nabs, is likely to be important in protecting from systemic spread of the virus, recent data have demonstrated that plasma BKPyV loads in KT patients do not result from BKPyV virions [ 29 ], but mostly represent DNAse-sensitive, unprotected genome fragments similar to what has been reported for cytomegalovirus (CMV) [ 30 , 31 ].…”

Risk factors for progression from low level BK dnaemia to unfavorable outcomes after BK management via immunosuppressive reduction

“…KTRs with low titers of genotype-specific neutralizing antibodies have also been identified as high risk for early fulminant donor-derived BKPyV-DNAemia and BKPyVAN. 35 In one study of 114 pediatric KTRs, BKPyV-specific CD4 T cells, ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0. This study has the expected limitations of a single-center observational study, reflecting our specific population and clinical approach to management.…”

Risk factors and outcomes of BK viremia among deceased donor kidney transplant recipients based on donor characteristics

“…However, this virus does not cause disease in immunocompetent individuals due to functional T-cell immunity. [1][2][3][4] In kidney transplant recipients (KTR), infection with BKV can be progressive, proceeding from viruria to viremia to nephropathy. 5,6 BK viremia is important, given the association with BK nephropathy (BKN), impaired graft function, and premature graft failure.…”

“…4,16,17 In one study, identical BK virus strains were detected in two KTRs who had each received a kidney from the same deceased donor. 3 To date, most literature describing BK viremia in KTRs has focused on recipient characteristics to assess risk.…”