Polyomavirus Reactivation and Immune Responses to Kidney-Specific Self-Antigens in Transplantation

Abstract

Humoral immune responses against donor antigens are important determinants of long-term transplant outcomes. Reactivation of the polyomavirus BK has been associated with de novo antibodies against mismatched donor HLA antigens in kidney transplantation. The effect of polyomavirus reactivation (BK viremia or JC viruria) on antibodies to kidney-specific self-antigens is unknown. We previously reported excellent 5-year outcomes after minimization of immunosuppression for BK viremia and after no intervention for JC viruria. Here, we report the 10-year results of this trial (n=193) along with a nested case-control study (n=40) to explore associations between polyomavirus reactivation and immune responses to the self-antigens fibronectin (FN) and collagen type-IV (Col-IV). Consistent with 5-year findings, subjects taking tacrolimus, compared with those taking cyclosporin, had less acute rejection (11% versus 22%, P=0.05) and graft loss (9% versus 22%, P=0.01) along with better transplant function (eGFR 65±19 versus 50±24 ml/min per 1.73 m², P<0.001) at 10 years. Subjects undergoing immunosuppression reduction for BK viremia had 10-year outcomes similar to those without viremia. In the case-control study, antibodies to FN/Col-IV were more prevalent during year 1 in subjects with polyomavirus reactivation than in those without reactivation (48% versus 11%, P=0.04). Subjects with antibodies to FN/Col-IV had more acute rejection than did those without these antibodies (38% versus 8%, P=0.02). These data demonstrate the long-term safety and effectiveness of minimizing immunosuppression to treat BK viremia. Furthermore, these results indicate that polyomavirus reactivation associates with immune responses to kidney-specific self-antigens that may increase the risk for acute rejection through unclear mechanisms.

Keywords: immunosuppression; kidney transplantation; transplant outcomes; virology.

Figure 1.

Flow diagram showing the characteristics of the study cohort at 1, 5, and 10 years post-transplant. Subjects from the original randomized trial (n=200) had clinical data collected for up to 10 years post-transplant. Subjects who were alive with functioning grafts at the end of the original 1-year study (n=193) were included in this retrospective cohort analysis. Polyomavirus reactivation data on the left side of the figure reflects serial testing during year 1 post-transplant.

Figure 2.

Kaplan–Meier analysis of 10-year outcomes according to calcineurin inhibitor. (A) Ten-year incidence of the triple composite outcome, (B) 10-year incidence of acute rejection, and (C) 10-year incidence of death-censored allograft loss. Comparisons between survival curves were made using the log-rank test. CsA, cyclosporin; FK, tacrolimus.

Figure 3.

Kaplan–Meier analysis of the 10-year incidence of death with a functioning graft according to polyomavirus activation status. Comparisons between survival curves were made using the log-rank test.

Figure 4.

Histograms comparing time to initial polyomavirus reactivation (Polyoma+) and time to initial detection of antibodies to FN/Col-IV (FN/Col-IV Abs+) during year 1 post-transplant within each subject who experienced both end points (n=15). The median (minimum, maximum) time to polyomavirus reactivation (BK viremia or JC viruria) was significantly shorter (1.0 [0.2, 4.5] months) compared with the median time to detection of FN/Col-IV antibodies (4.0 [1.0, 9.0] months) (P<0.01, by Mann–Whitney U test).

Figure 5.

Kaplan–Meier analysis of (A) 10-year incidence of acute rejection and (B) 10-year incidence of death-censored allograft loss according to FN/Col-IV antibody status. Comparisons between survival curves were made using the log-rank test.