Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant glomerulopathy: C4d beyond active antibody-mediated injury: a retrospective study

Abstract

Peritubular capillary C4d (ptc-C4d) usually marks active antibody mediated rejection, while pseudolinear glomerular capillary C4d (GBM-C4d) is of undetermined diagnostic significance, especially when seen in isolation without concurrent ptc-C4d. We correlated GBM-C4d with structural GBM abnormalities and active antibody mediated rejection in 319 renal transplant and 35 control native kidney biopsies. In kidney transplants ptc-C4d was associated with GBM-C4d in 97% by immunofluorescence microscopy (IF) and 61% by immunohistochemistry (IHC; p<0.001). Transplant glomerulopathy correlated with GBM-C4d (p<0.001) and presented with isolated GBM-C4d lacking ptc-C4d in 69% by IF and 40% by IHC. Strong isolated GBM-C4d was found post year-1 in repeat biopsies with transplant glomerulopathy. GBM-C4d staining intensity correlated with Banff cg scores (rs=0.45, p<0.001). Stepwise exclusion and multivariate logistic regression corrected for active antibody mediated rejection showed significant correlations between GBM duplication and GBM-C4d (p=0.001). Native control biopsies with thrombotic microangiopathies demonstrated GBM-C4d in 92% (IF, p<0.001), and 35% (IHC). In conclusion pseudolinear GBM-C4d staining can reflect two phenomena: 1) structural GBM changes with duplication in native and transplant kidneys, or 2) active antibody mediated rejection typically accompanied by ptc-C4d. While ptc-C4d is a dynamic ‘etiologic’ marker for active antibody-mediated rejection, isolated strong GBM-C4d can highlight architectural glomerular remodeling.