BK Virus Nephropathy Revisited

This editorial comments on two studies that independently describe the complex interdependency between immunosuppression-induced BK polyomavirus nephropathy and rejection after reduction in immunosuppression, both equally leading to inflammation, progressive fibrosis and allograft failure. See the articles from Nankivell et al (page 2065) and Drachenberg et al (page 2078). This editorial comments on two studies that independently describe the complex interdependency between immunosuppression-induced BK polyomavirus nephropathy and rejection after reduction in immunosuppression, both equally leading to inflammation, progressive fibrosis and allograft failure. See the articles from Nankivell et al (page 2065) and Drachenberg et al (page 2078). More than 20 years after its first description and increased morbidity under powerful immunosuppression, the understanding of the pathogenesis of BK polyomavirus induced–allograft nephropathy (BKVN) has changed clinical practice in renal transplantation. Screening programs were introduced at most transplant centers, causing the prevalence of BKVN to decrease. However, BK viremia is still found in 10–30% of renal allograft recipients, with 1–10% developing BKVN. Once manifested, BKVN represents a serious disease of the renal transplant, causing allograft failure in 15–50% (1Hirsch HH Randhawa P AST infectious diseases community of practice. BK polyomavirus in solid organ transplantation.Am J Transplant. 2013; 13: 179-188Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar). In this issue of AJT, two transplant centers describe results from their comprehensively phenotyped cohorts of renal allograft recipients. The authors were well positioned to independently revisit the natural histologic and clinical evolution of BKVN under contemporary clinical screening protocols, maintenance immunosuppression, and immunosuppression reduction approaches in cases with viremia and BKVN (2Drachenberg CB Papadimitriou JC Chaudhry MR et al.Histological evolution of BK virus associated nephropathy: Importance of integrating clinical and pathological findings.Am J Transplant. 2017; (https://doi.org/10.1111/ajt.14314.)Abstract Full Text Full Text PDF Scopus (55) Google Scholar,3Nankivell BJ Renthawa J Sharma RN Kable K O’Connell PJ Chapman JR BK virus nephropathy: Histological evolution by sequential pathology.Am J Transplant. 2017; (https://doi.org/10.1111/ajt.14292.)Abstract Full Text Full Text PDF Scopus (63) Google Scholar). Both articles study kidney transplants with BKVN. Drachenberg et al (n = 71) and Nankivell et al (n = 63) discuss patients undergoing sequential biopsies (total number of BKVN biopsies analyzed from both studies, n = 660) and viral load measurements with available long-term follow-up. In the Nankivell study, the BKVN cohort was compared to an equally well-annotated and followed time-matched cohort of renal transplants (n = 490) without BKVN (975 protocol biopsies). Interesting and reassuring is the fact that both studies independently reveal almost identical major findings, discussed below. Early-stage disease (i.e. BKVN without inflammation) was very uncommon at initial clinical presentation, while early prodromal borderline-like interstitial inflammation in SV40-negative biopsies predated a later diagnosis of BKVN in up to 23% of cases with BK viremia. Also, resolving BKVN often featured SV40-negative interstitial inflammation. It is quite likely that in such scenarios the SV40 stain is false negative due to sampling error and/or limited staining sensitivity (4Adam B Randhawa P Chan S et al.Banff Initiative for Quality Assurance in Transplantation (BIFQUIT): Reproducibility of polyomavirus immunohistochemistry in kidney allografts.Am J Transplant. 2014; 14: 2137-2147Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Accordingly, an inadequate, SV40-negative biopsy in a patient with viremia should trigger early but modest reduction in immunosuppression and close follow-up, since presumptive (SV40-negative; 30% of cases) and definite (SV40-positive; 70% of cases) BKVN presented with an identical clinical course. However, these studies did not further clarify the complex relationship between various common features of BK infection including viral reactivation and viremia, interstitial inflammation, graft rejection, the progression of interstitial fibrosis and tubular atrophy (IFTA), and allograft failure. Viral infection induces tubular injury first manifested by acute tubular necrosis and cytopathic effects in the biopsy. In both studies, at clinical presentation viral injury was frequently (73–75% of cases) associated with inflammation, and in the Nankivell study with significantly more inflammation than in control cases with rejection. The extent of tubulointerstitial inflammation frequently remained stable over sequential biopsies, likely reflecting in part transition to increasing rejection after reducing immunosuppression. This was supported by the observation that a decrease in viremia correlated with increasing Banff t-scores (i.e. rejection in the Drachenberg study). As previously described by Menter et al (5Menter T Mayr M Schaub S Mihatsch MJ Hirsch HH Hopfer H Pathology of resolving polyomavirus-associated nephropathy.Am J Transplant. 2013; 13: 1474-1483Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar), inflammation was increased in patients who eventually cleared the virus with reduced tubular destruction, compared to patients who had persistent viremia. Failure of viral clearance, but also persisting inflammation (and increasing tubulitis) was associated with progressing of IFTA and allograft failure. Despite the richness of available data and comprehensive multivariate analysis, it was not possible to distinguish between inflammation due to viral infection or rejection; both eventually produced IFTA. Persisting and high-level viremia (i.e. failure of viral clearance) was the most significant risk factor for destructive chronic infection and eventual allograft loss, but no single clinical or pathological feature was identified that could predict the clinical course of BKVN in the individual patient. Over the course of sequential biopsies, the range of clinico-pathological phenotypes continuously diversified, likely reflecting the empirical attempts by physicians to manage the imbalance between immunosuppression and immune competence. Almost all (>85%) of BKVN kidneys evolved to IFTA, even in those that successfully cleared the virus. Again the degree of inflammation, peak viral load, and persistence of viremia were associated with more severe and progressive IFTA. While pulse steroid treatment of BKVN inflammation often stabilized creatinine, progression of IFTA was not prevented. Simultaneously, reduction of immunosuppression in BKVN patients was complicated by late rejection (and persisting inflammation) in 62% of cases, representing a significant and probably still underestimated issue. While approximately half of BKVN grafts that failed were the consequence of BK, the other 50% of failed grafts were due to rejection resulting from attempts to treat BKVN. Half of the cases of rejection presented with an antibody-mediated component. Both studies are limited by not having available standardized donor-specific antibody (DSA) screening data despite observing an association between BKVN and antibody-mediated rejection pathology. This further corroborates the previously described unfortunate relationship between BKVN, reduction in immunosuppression, and development of de novo DSA (6Dieplinger G Everly MJ Briley KP et al.Onset and progression of de novo donor-specific anti-human leukocyte antigen antibodies after BK polyomavirus and preemptive immunosuppression reduction.Transpl Infect Dis. 2015; 17: 848-858Crossref PubMed Scopus (23) Google Scholar). The studies also did not assess the impacts of cellular or humoral immunity to BK polyomavirus and clinical outcomes. No scoring of i-IFTA (inflammation in areas of IFTA) was done for the included biopsies, leaving unanswered the question of whether i-IFTA is a feature of ongoing disease, either chronic rejection or chronic BKVN. Despite state-of-the-art screening and clinical management efforts, these two scientifically robust studies confirm that effective antiviral treatment, like that now available for hepatitis C, remains the most pressing unmet clinical need for patients with BKVN. Until then, prevention of BKVN remains the priority for renal transplant recipients with the goal to avoid widespread BKVN manifestation in the allograft while facing the challenge of simultaneously avoiding allo-sensitization (1Hirsch HH Randhawa P AST infectious diseases community of practice. BK polyomavirus in solid organ transplantation.Am J Transplant. 2013; 13: 179-188Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar). The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.

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