title: Transplant glomerulopathy: ultrastructural abnormalities occur early in longitudinal analysis of protocol biopsies.
abstract: Transplant glomerulopathy (TXG) presents a distinctive pattern of glomerular abnormalities. The aim of this study was to describe its sequential ultrastructural pathology. A paired cohort study of 228 protocol biopsies, from our longitudinal database (n = 1345), compared TXG (7 patients, 95 biopsies) and controls (8 patients, 133 biopsies). Ultrastructural morphometry and C4d immunoperoxidase were evaluated from implantation to 5 years after transplantation against sequential histology and functional changes. TXG was predated by early glomerular endothelial cell activation; typified by vacuolation, hypertrophy, serration and expansion of lamina rara interna from 39 +/- 23 days after transplantation. Endothelial cells were transformed into an activated phenotype, containing numerous mitochondria, Golgi and ribosomes. Transition from fenestrated to continuous endothelium, mesangial matrix expansion and podocyte fusion occurred late. Endothelial cell activation also occurred in peritubular capillaries (PTC) followed by basement membrane multi-lamination (p < 0.05-0.001). Light microscopy changes of TXG occurred at 2.3 years. PTC C4d deposition was intermittently expressed over time, correlating with endothelial abnormalities, glomerular C4d and donor-specific antibodies (DSA) (p < 0.05-0.001). In summary, endothelial and subendothelial ultrastructural abnormalities in glomerular and peritubular capillaries are sensitive, early markers of TXG, likely due to stimulation of endothelial cells into an activated phenotype by antibody-mediated sub-lytic complement deposition.
authors.affiliation: Department of Renal Medicine, University of Sydney, Westmead Hospital, Sydney, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Wavamunno
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: M
authors.initials: M
authors.lastname: Vitalone
authors.forename: C L-S
authors.initials: CL
authors.lastname: Fung
authors.forename: R D M
authors.initials: RD
authors.lastname: Allen
authors.forename: J R
authors.initials: JR
authors.lastname: Chapman
authors.forename: B J
authors.initials: BJ
authors.lastname: Nankivell
mesh_terms: D000328:Adult; D001706:Biopsy; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015935:Complement C4b / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology* / Q000648:ultrastructure*; D016030:Kidney Transplantation / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D050527:Mesangial Cells / Q000473:pathology; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D050199:Podocytes / Q000473:pathology; D013997:Time Factors
chemical_list: D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d