Immunologic risk factors and glomerular C4d deposits in chronic transplant glomerulopathy

Abstract

Chronic transplant glomerulopathy is an uncommon cause of chronic transplant dysfunction of unknown pathogenesis. We evaluated the epidemiologic, clinical, and histologic features of chronic transplant glomerulopathy. To determine the possible contribution of humoral immune responses, we assessed glomerular deposition of C4d. From a cohort of 1111 kidney transplants (1983 to 2001) with at least 6 months of graft function, we identified 18 cases with chronic transplant glomerulopathy (1.6%) showing double contours of the glomerular basement membrane (GBM) on light microscopy. To assess the risk factors, this group was compared with 739 patients with stable function using multivariate Cox regression analysis. Paraffin sections of 11/18 biopsies were stained with polyclonal C4d antibodies. Sera of 13/18 patients could be tested for antidonor human leukocyte antigen (HLA) antibodies by enzyme-linked immunosorbent assay (ELISA). Patients with chronic allograft nephropathy without chronic transplant glomerulopathy or predominant cyclosporine nephrotoxicity were used as controls. Chronic transplant glomerulopathy was diagnosed at a median of 8.3 (range 2.6-12.5) years posttransplantation. Panel reactive antibodies at time of transplantation, RR 1.23 (1.05-1.45) per 10% increase, and late acute rejection episodes, RR 7.6 (1.8-31.7), were independently associated with chronic transplant glomerulopathy. We found glomerular C4d deposits in 10/11 biopsies showing chronic transplant glomerulopathy and in only 2/13 controls. Peritubular capillary C4d deposits and donor-specific anti-HLA antibodies were demonstrated in 4 and 3 of the 10 patients with glomerular C4d deposits, respectively. Presensitization and late acute rejection episodes were the risk factors identified. Glomerular C4d deposits suggest that chronic transplant glomerulopathy emerges from in situ humoral rejection. Chronic transplant glomerulopathy should be considered as a manifestation of immune-mediated injury.