The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy

Peritubular capillary C4d staining in allograft kidney is an important criterion for antibody-mediated rejection. Whether BK virus infection can result in complement activation is not known. We studied 113 renal allograft biopsies from 52 recipients with a history of BK virus activation. The samples were classified into four groups according to the concurrent detection of BK virus DNA in urine, plasma, and/or biopsy: BK-negative (n = 37), viruria (n = 53), viremia (n = 7), and nephropathy (n = 16) groups. The histological semiquantitative peritubular capillary C4d scores in the viremia (0.3 +/- 0.8) and BK nephropathy (0.6 +/- 0.9) groups were lower than those in the BK-negative group (1.2 +/- 1.1, P = 0.05 and P = 0.06, respectively) and the viruria group (1.2 +/- 1.1, P = 0.04 and P = 0.06, respectively). Diffuse or focal peritubular capillary C4d staining was present in 9/76 (12%) and 14/76 (19%) of all samples with concurrent BK virus reactivation (viruria, viremia, and nephropathy). The diagnosis of antibody-mediated rejection could be established in 7/9 (78%) and 5/14 (36%) of these samples, respectively. Diffuse tubular basement membrane C4d staining was restricted to BK nephropathy cases (4/16, 25%). Semiquantitative tubular basement membrane C4d scores were higher in BK nephropathy (1.2 +/- 1.3) compared with BK-negative (0.05 +/- 0.3, P = 0.017) and viruria (0.0 +/- 0.0, P = 0.008) groups. Bowman's capsule C4d staining was more frequent in BK nephropathy (5/16) compared with the aforementioned groups (2/36 (P = 0.023) and 4/51 (P = 0.03), respectively). Within the BK nephropathy group, samples with tubular basement membrane stain had more infected tubular epithelial cells (12.1 +/- 7.6% vs 4.4 +/- 5.0%, P = 0.03) and a trend toward higher interstitial inflammation scores. In conclusion, peritubular capillary C4d staining remains a valid marker for the diagnosis of antibody-mediated rejection in the presence of concurrent BK virus infection. A subset of biopsies with BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect. Modern Pathology (2009) 22, 1468-1476; doi: 10.1038/modpathol.2009.118; published online 4 September 2009