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.

Glomerular damage as a predictor of renal allograft loss

“…This finding agrees with recently published studies (25)(26)(27)(28)(29). Wavamunno et al (30) showed that endothelial and subendothelial ultrastructural abnormalities in glomerular and peritubular capillaries are sensitive early markers of CTG. They are associated with C4d deposition subsequently detected by light microscopy.…”

Markers of Endothelial-to-Mesenchymal Transition

“…Remarkably, in the cases previously diagnosed as TCMR or even in those without histologic lesions, the presence of EndMT marker expression was associated with progressive graft dysfunction and increased proteinuria during follow-up, which is compatible with indolent, subhistologic ABMR. 5,[21][22][23] Indeed, the diagnosis of ABMR was found in subsequent biopsies in a majority of those grafts with EndMT marker expression when a second biopsy was performed. In contrast, those with EndMT-negative grafts maintained very stable graft function for up to 4 years after the biopsy and none of those grafts had ABMR in subsequent biopsies.…”

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

“…8 Early, subdiagnostic findings include an "activated" aspect of glomerular endothelial cells (GECs), with accumulation of mitochondria, Golgi apparati, and ribosomes, and a transition from fenestrated to continuous endothelium. 9 Diagnostic findings are double contours of the glomerular basement membrane, visible by light microscopy, involving 10% or more of at least one glomerulus with mesangial proliferation. 2 Similar changes are frequently present in the peritubular capillaries.…”