Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.
We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death-censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor-specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T-cell-mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody-mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody-mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T-cell-mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.
Alberta Transplant Applied Genomics Centre, Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, AB, Canada.
G
G
Einecke
B
B
Sis
J
J
Reeve
M
M
Mengel
P M
PM
Campbell
L G
LG
Hidalgo
B
B
Kaplan
P F
PF
Halloran
D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001706:Biopsy; D015935:Complement C4b / Q000276:immunology; D051799:Delayed Graft Function / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology; D005260:Female; D005921:Glomerulonephritis / Q000453:epidemiology / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008833:Microcirculation / Q000276:immunology; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000276:immunology; D011237:Predictive Value of Tests; D012079:Renal Circulation / Q000276:immunology; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d