Mechanisms of everolimus-induced glomerulosclerosis after glomerular injury in the rat.
Despite the lack of nephrotoxicity, adverse effects of the new antiproliferative immunosuppressant everolimus have been reported. By varying time point and dose of everolimus treatment as well as the degree of glomerular injury, the specific conditions and potential mechanisms leading to adverse actions in the anti-Thy1 model have been determined. Only the combination of early and high-dose everolimus treatment (1-3 mg/kg bw) with a severe glomerular lesion ('full-dose' anti-Thy1 model) caused adverse effects with a high mortality rate, progressive apoptosis, crescent formation and glomerulosclerosis. In contrast, either later start or low-dose (0.3 mg/kg bw) therapy or treatment of a less severe lesion ('reduced dose' anti-Thy1 model) appeared to be relatively safe for the glomerular architecture. The adverse effects of everolimus were linked to its marked inhibition of endothelial cell, but not necessarily mesangial cell proliferation. In addition, everolimus markedly inhibited the angiogenic cytokine vascular endothelial growth factor in nephritic glomeruli in vivo. These experimental results suggest special caution regarding the use of everolimus in all situations of severe glomerular cell injury requiring extensive capillary repair, where at least adaption to a low dose needs to be considered.
Daniel
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Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Germany.
Renders
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L
Amann
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Schulze-Lohoff
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E
Hauser
I A
IA
Hugo
C
C
D000783:Aneurysm / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D000068338:Everolimus; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000633:toxicity*; D007518:Isoantibodies; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007166:Immunosuppressive Agents; D007518:Isoantibodies; D042461:Vascular Endothelial Growth Factor A; C035678:anti-Thy antibody; D000068338:Everolimus; D020123:Sirolimus