Immunologic risk factors and glomerular C4d deposits in chronic transplant glomerulopathy.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sijpkens
Yvo W
YW
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. y.w.j.sijpkens@lumc.nl
Joosten
Simone A
SA
Wong
Man-Chi
MC
Dekker
Friedo W
FW
Benediktsson
Hallgrimur
H
Bajema
Ingeborg M
IM
Bruijn
Jan A
JA
Paul
Leendert C
LC
D000328:Adult; D002908:Chronic Disease; D015331:Cohort Studies; D015935:Complement C4b / Q000378:metabolism*; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology* / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism*; D012307:Risk Factors
D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d