A Novel Perspective on Tubular C4d Positivity in BK Polyomavirus Nephropathy

Tubular basement membrane (TBM) C4d staining has been frequently observed in BK polyomavirus nephropathy (BKPyVN); however, its specificity and clinical implications remain unclear.

Biopsy data from 272 patients with BK viruria, including 4 native BKPyVN, 150 allograft BKPyVN, and 118 non-BKPyVN were reviewed. C4d was assessed using immunohistochemistry (IHC) and compared with frozen tissue to evaluate its correlation with clinicopathological features. Immunofluorescence (IF) for Ig and complement components and electron microscopy were performed to assess complement activation.

TBM C4d staining was conducted in formalin-fixed paraffin-embedded (FFPE) slides for its superiority over frozen tissue and C4d positivity was detected in all 4 native and 121 kidney transplant recipients (KTRs) (81%) with BKPyVN, significantly higher than the 16 KTRs (14%) without BKPyVN (P < 0.001). Diffuse TBM and Bowman's capsule C4d staining were restricted to BKPyVN. C4d staining was grouped as no/minimal in 64 of 150 (43%), focal in 51/150 (34%), and diffuse in 35 of 150 (23%) of KTRs. Patients with diffuse TBM C4d staining exhibited higher tissue viral load, more severe chronic tubulointerstitial damage and lower graft survival (all P < 0.05). Multivariable Cox analysis verified that diffuse TBM C4d staining remained independently associated with poor graft prognosis after adjustment. IF confirmed TBM staining of IgG, IgA, C1q, C3c, and C5b-9 in BKPyVN, with colocalization most pronounced in cases with diffuse TBM C4d staining accompanied by electron-dense deposits on EM, whereas nonspecific C5b-9 and C4d staining tended to be entrapped in atrophic tubules.

TBM C4d positivity is a valuable marker of complement activation in BKPyVN, strongly correlating with the severity of kidney damage and serving as an independent risk factor for graft loss.