Veronika Grau1, Philip Zeuschner, Stephan Immenschuh, Clemens Luitpold Bockmeyer, Stefanie Zell, Juliane Wittig, Karen Säuberlich, Mahmoud Abbas, Winfried Padberg, Catherine Meyer-Schwesinger, Melanie von Brandenstein, Monika Schlosser, Georg Dieplinger, Jack Galliford, Candice Clarke, Candice Roufosse, Jan Ulrich Becker. 1. 1 Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Germany. 2 Institute of Pathology, University Hospital of Cologne, Cologne, Germany. 3 Institute of Transfusion Medicine, Hannover Medical School, Hannover, Germany. 4 Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. 5 Institute of Pathology, Hannover Medical School, Hannover, Germany. 6 PATHOCOM, Rheine, Germany. 7 Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Germany. 8 Medical Clinic III, University Hospital Hamburg-Eppendorf, Hamburg, Germany. 9 Department of General, Visceral and Cancer Surgery, Transplant Center Cologne, University of Cologne, Cologne, Germany. 10 Imperial College Kidney and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom. 11 Department of Cellular Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.
Abstract
BACKGROUND: Antibody-mediated rejection is a leading cause for renal transplant loss. Rodent models are useful to dissect pathomechanisms and to develop treatment strategies. Although used for decades as a model, glomerular histopathological findings of Fischer-344 kidneys transplanted into Lewis rats have never been comprehensively described. METHODS: Kidneys from Fischer-344 rats were transplanted into Lewis rats as life-sustaining allografts without immunosuppression. Lewis isografts and normal Fischer-344 kidneys served as controls. Grafts were harvested at 9 days, 6 and 26 weeks. Histopathological examination included light microscopy, immunohistochemistry, and morphometry. Findings were compared with 51 human biopsies with transplant glomerulopathy. RESULTS: Most glomerular findings in rat allografts resembled human acute and chronic antibody-mediated rejection with glomerulitis, microthrombosis, microaneurysms, glomerular hypertrophy, podocyte loss, glomerular basement membrane splitting, and secondary focal and segmental glomerulosclerosis. In line with previous reports on nonendothelial antigens, glomerular immunoglobulin and C4d deposition was mostly nonendothelial. Only in 26-week allografts, we found mesangial and subendothelial immune complex-type electron-dense deposits. Similar deposits were found in 8 of 51 human biopsies with transplant glomerulopathy after rigorous exclusion of immune complexes of other cause, particularly recurrent glomerulonephritis and hepatitis C. CONCLUSIONS: Thus, our model closely reflects the glomerular changes of acute antibody-mediated rejection in humans and of a special subset of human transplant glomerulopathy. The significance of alloimmune immune complex-type deposits in human transplants deserves further investigation.
BACKGROUND: Antibody-mediated rejection is a leading cause for renal transplant loss. Rodent models are useful to dissect pathomechanisms and to develop treatment strategies. Although used for decades as a model, glomerular histopathological findings of Fischer-344 kidneys transplanted into Lewis rats have never been comprehensively described. METHODS: Kidneys from Fischer-344 rats were transplanted into Lewis rats as life-sustaining allografts without immunosuppression. Lewis isografts and normal Fischer-344 kidneys served as controls. Grafts were harvested at 9 days, 6 and 26 weeks. Histopathological examination included light microscopy, immunohistochemistry, and morphometry. Findings were compared with 51 human biopsies with transplant glomerulopathy. RESULTS: Most glomerular findings in rat allografts resembled human acute and chronic antibody-mediated rejection with glomerulitis, microthrombosis, microaneurysms, glomerular hypertrophy, podocyte loss, glomerular basement membrane splitting, and secondary focal and segmental glomerulosclerosis. In line with previous reports on nonendothelial antigens, glomerular immunoglobulin and C4d deposition was mostly nonendothelial. Only in 26-week allografts, we found mesangial and subendothelial immune complex-type electron-dense deposits. Similar deposits were found in 8 of 51 human biopsies with transplant glomerulopathy after rigorous exclusion of immune complexes of other cause, particularly recurrent glomerulonephritis and hepatitis C. CONCLUSIONS: Thus, our model closely reflects the glomerular changes of acute antibody-mediated rejection in humans and of a special subset of humantransplant glomerulopathy. The significance of alloimmune immune complex-type deposits in human transplants deserves further investigation.
Authors: Shannon R Reese; Nancy A Wilson; Yabing Huang; Lucille Ptak; Kenna R Degner; Ding Xiang; Robert R Redfield; Weixiong Zhong; Sarah E Panzer Journal: Transplantation Date: 2021-07-01 Impact factor: 5.385