Capillary Deposition of Complement Split Product C4d in Renal Allografts is Associated with Basement Membrane Injury in Peritubular and Glomerular Capillaries

TLDR

Endothelial C4d deposition is a recognized marker of antibody‑mediated acute rejection, but its role in chronic rejection remains debated. The study aimed to examine the relationship between immunohistochemically detected endothelial C4d in peritubular capillaries and histologic features of chronic allograft injury in a large cohort. Immunohistochemical staining of 213 late allograft biopsies performed more than 12 months post‑transplant was used to assess C4d deposition. C4d deposition in peritubular capillaries was found in 34 % of late biopsies and was strongly associated with chronic transplant glomerulopathy, basement membrane multilayering, and mononuclear inflammation, and its presence predicted subsequent glomerulopathy, indicating that complement activation in the renal microvasculature drives chronic rejection.

Abstract

Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. A contribution of alloantibody-dependent immune reactions to chronic rejection is under discussion. In this study, the association of immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTC) with morphologic features of chronic renal allograft injury was investigated in a large study cohort. C4d deposits in PTC were detected in 73 (34%) of 213 late allograft biopsies performed in 213 patients more than 12 mo after transplantation (median, 4.9 yr) because of chronic allograft dysfunction. Endothelial C4d deposition was found to be associated with chronic transplant glomerulopathy (CG) (P < 0.0001), with basement membrane multilayering in PTC (P = 0.01), and with an accumulation of mononuclear inflammatory cells in PTC (P < 0,001). Furthermore, C4d deposits in PTC (in biopsies with normal glomerular morphology) were associated with development of CG in follow-up biopsies. Other morphologic features of chronic allograft nephropathy (with exception of tubular atrophy) were not associated with C4d deposits in PTC. Analyses of previous and follow-up biopsies revealed that C4d deposits may occur de novo and may also disappear at any time after transplantation. In conclusion, the data suggest that complement activation in renal microvasculature, indicating humoral alloreactivity, contributes to chronic rejection characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTC.