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

Abstract

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 ¼ 37), viruria (n ¼ 53), viremia (n ¼ 7), and nephropathy (n ¼ 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 ¼ 0.05 and P ¼ 0.06, respectively) and the viruria group (1.2±1.1, P ¼ 0.04 and P ¼ 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 ¼ 0.017) and viruria (0.0 ± 0.0, P ¼ 0.008) groups. Bowman's capsule C4d staining was more frequent in BK nephropathy (5/16) compared with the aforementioned groups (2/36 (P ¼ 0.023) and 4/51 (P ¼ 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 ¼ 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.

A Critical Appraisal of Methods to Grade Transplant Glomerulitis in Renal Allograft Biopsies

“…Panel reactive antibody (PRA) values <10% were regarded as 'unsensitized'. DSA detection was performed by ELISA (One Lambda, Canoga Park, CA, USA) or by single and multiplex bead arrays (Luminex, One Lambda, Inc., Canoga Park, CA, USA and Tepnel Life Codes Corporation, Stamford, CT, USA) usually when the PRA was ≥10% as previously described (15). Antibody testing was performed at different time points.…”

“…PTC-C4d was graded according to Banff 2007 recommendations (21). Since immunoperoxidase C4d was utilized on formalin-fixed paraffin-embedded tissue, both diffuse and focal PTC-C4d were regarded as a 'positive stain' as recently recommended (15,21,23).…”

Modifiers of complement activation for prevention of antibody-mediated injury to allografts

“…Notwithstanding that complement can be activated by other antibodies including anti-endothelial cell antibodies (AECAs) [47,48], C4d binding and immunostaining can also occur in the apparent absence of antibody, and in some cases, causes unrelated to AbMR may be responsible for initiating the complement cascade [49][50][51]. Interestingly, C4d staining has been reported following administration of lymphocyte depleting antibodies without AbMR [52,53].…”

BK Virus Infection in Renal Allograft Recipients

“…In patients with BKVN, renal tubules with intense cytopathic changes demonstrated positive C4d staining of the tubular basement membrane but not in peritubular capillaries. In a study of 113 biopsies of renal allograft from recipients with BKV replication, PTC (peritubular capillary) C4d staining was found to be a valid marker for antibody mediated rejection [50]. In patients with BKVN, renal tubules with intense cytopathic changes demonstrated positive C4d staining of the tubular basement membrane but not in peritubular capillaries.…”