Pathology of Resolving Polyomavirus-Associated Nephropathy

Abstract

These authors contributed equally.Control of polyomavirus BK (BKV) is achieved by reducing immunosuppression allowing an effective BKV-specific T-cell response. The morphology of resolving BKV-associated nephropathy (PyVAN) has not been systematically investigated. Ninety-nine surveillance biopsies of 35 patients with BKV viremia treated exclusively by immunosuppression reduction were scored according to Banff criteria and grouped relative to BKV viremia as pre-, increasing, decreasing and post-BKV viremia. Thirty-four of 35 patients (97%) cleared BKV viremia after a median of 9 months posttransplantation. The tubulitis score, extent of tubules with intraepithelial lymphocytes, and interstitial inflammation significantly increased from the time of increasing to decreasing viremia. Tubulointerstitial inflammation, to a lower extent, persisted after clearance. The number of SV40þ tubules correlated with the BKV load in plasma, but SV40 immunohistochemistry was frequently negative (60%). During decreasing viremia, 31% of PyVAN cases were plasma cell-rich and 40% showed tubular HLA-DR expression. Compared to baseline 1 month posttransplantation, allograft function remained stable or improved in 29/35 patients (83%) after a median follow-up of 48 months. Within 1 year after clearance of BKV viremia, clinical rejection occurred in 2/35 patients (6%). Our data suggest that resolving PyVAN is typically characterized by a self-limiting acute interstitial nephritis, morphologically indistinguishable from interstitial rejection.

Intragraft Blood Dendritic Cell Antigen-1–Positive Myeloid Dendritic Cells Increase during BK Polyomavirus–Associated Nephropathy

“…9 However, recent studies showed that, in some of the patients with BKPyVAN, HLA-DR expression is also present. 5,10 Our study is in line with these recent publications. It is known that HLA-DR expression can stimulate an allogeneic lymphocytic reaction and enhance T cell-mediated lysis.…”

“…31 The biopsies of the BKPyVAN cohort were also scored according to the BKPyVAN grading system as proposed by Hirsch et al 18 HLA-DR expression on epithelial cells was not considered a sign of rejection, because it was also observed in patients with BKPyVAN. 10,11 The percentages of missing staining because of unavailability of material per diagnosis are shown in Supplemental Table 1.…”

“…The demonstration of lymphocytic infiltrates, marked tubulitis, and tubular HLA-DR expression in areas lacking polyomavirus replication may support the diagnosis of TCMR as proposed by Nickeleit et al 9 ; however, the former two criteria are often observed in BKPyVAN as well and therefore, cannot be considered pathognomic. 10,11 A newly appreciated feature of BKPyVAN is that it may cause immune complex deposition along the tubular basement membrane. Granular staining of IgG, C3, and C4d is focally present on immunofluorescence accompanied by amorphous electron-dense deposits on electron microscopy.…”

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

“…In kidney transplantation (KT), high‐level BKPyV viruria and viremia have been identified as markers of progression to PyVAN 25, thus current management strategies recommend screening KTRs for viremia followed by reducing immunosuppression 26, 27, 28. In prospective observational studies, this preemptive intervention has been successful, as shown by clearance of viremia and PyVAN in 80–100% of cases, with a low risk of subsequent acute rejection in 0–14% of patients 29, 30, 31, 32, 33. BKPyV viremia clearance has been paralleled by increasing BKPyV‐specific T cell responses in peripheral blood 30, 34, 35, 36.…”

Practical Applications in Immunohistochemistry: Evaluation of Rejection and Infection in Organ Transplantation

“…The concept of rebound inflammation after a successfully treated polyomavirus has recently been proposed, but additional data are needed (Table 4). 117,126,127 Sampling must also be factored in; tubular infection is patchy, and a core biopsy may miss diagnostic tubules, especially if the biopsy is solely from the renal cortex. 126 These observations emphasize the importance of correlating biopsy histology, IHC, trends in viral serology, and renal function in assessing patients with polyomavirus.…”