Early Ultrastructural Abnormalities of Transplant Glomerulopathy (TG): Correlation with C4d-Positive and C4d-Negative Antibody-Mediated Rejection (AMR) and Subsequent Development of Overt TG.
Mark Haas. Cedars-Sinai Medical Center, Los Angeles, CA
Background: TG is correlated with reduced renal allograft survival and with donor-specific antibodies (DSA). Overt TG, with double contours of the glomerular basement membrane (GBM) on PAS and silver stains, is typically seen >1 year post-transplantation (PT). However, electron microscopic (EM) changes correlated with development of overt TG may be seen much earlier; these include glomerular endothelial swelling, subendothelial electron-lucent widening, and early GBM duplication [Wavamunno et al, AJT 7: 1-12, 2007]. This study aims to examine the specificity of these early EM changes for AMR, both C4d-positive and C4d-negative, and determine if these are inevitably associated with later development of overt TG.
Design: From 1/07 – 12/09, 119 renal allograft biopsies were done within the first 3 months PT on patients followed at our center; of these 95 (from 91 patients) were examined by EM. The remaining 24 had inadequate tissue for EM or were repeat biopsies. The 95 biopsies form the study group; indirect immunofluorescence for C4d was done on all 95, and DSA data at the time of biopsy was available for 69.
Results: Of the 95 biopsies, 12 showed C4d+ AMR with glomerulitis and/or peritubular capillaritis (Banff g + ptc ≥2), peritubular capillary C4d (diffuse in 11), and DSA; 2 also had Banff type 1 cellular rejection (ACR). 7 biopsies showed histologic changes of AMR with DSA, but no C4d (C4d- AMR); 4 had type 1 ACR. 21 additional biopsies had type 1 (16) or type 2 (5) ACR; 55 had no diagnostic rejection. One or more early EM changes of TG were seen in 12/12 biopsies with C4d+ AMR, 6/7 with C4d- AMR, 8/21 with ACR (2 with histologic changes of AMR, but no DSA data), and 6/55 with no rejection. All 3 early EM changes of TG were seen in 7/12, 4/7, 3/21, and 0/55 biopsies, respectively. 14 patients (including 5 with C4d+ AMR and 4 with C4d- AMR) with ≥1 early EM changes had ≥1 follow-up biopsy 3.5 – 19 months PT. Of these 5/8 patients with persistent histologic changes of AMR and 0/6 without developed overt TG. All 5 patients with C4d+ AMR were treated for AMR and 1 developed overt TG; by contrast 0/4 patients with C4d- AMR were initially treated for AMR and 3/4 developed overt TG.
Conclusions: Early EM changes of TG are seen in most cases of C4d+ and C4d- AMR and are often associated with development of overt TG, especially if there are presistent histologic changes of AMR. However, this progression does not appear to be inevitable, at least during the first 2 years PT.
Category: Kidney (does not include tumors)
Monday, February 28, 2011 2:30 PM
Platform Session: Section H, Monday Afternoon