The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat.
BACKGROUND
Under certain circumstances the nonnephrotoxic, antiproliferative, immunosuppressive mammalian target of rapamycin (mTOR) inhibitors can cause renal deterioration and proteinuria after conversion from calcineurin inhibitors, especially in long-term renal transplant patients with low glomerular filtration rates. The mTOR inhibitors also show an impaired glomerular healing reaction during acute renal injury in experimental mesangial proliferative glomerulonephritis. In this study, everolimus treatment was investigated in a low nephron number model, the remnant kidney model in rats.


METHODS
The remnant kidney model was induced by uninephrectomy and infarction of 2/3 of the remaining kidney in 31 male Sprague-Dawley rats. Three days after disease induction, rats were randomly treated either with everolimus or vehicle. Changes in progression of renal disease were investigated by immunohistochemistry on days 22 and 38 after disease induction.


RESULTS
In the remnant kidney model, everolimus treatment worsened chronic disease progression as assessed by increased proteinuria, glomerulosclerosis, interstitial fibrosis, glomerular inflammation as well as decreased creatinine-clearance. This result was due to a markedly increased fraction of glomeruli with a defective glomerular architecture in the everolimus group. Everolimus apparently inhibited the chronic glomerular repair reaction via inhibition of the proliferative but not apoptotic activity of the glomerular endothelial and mesangial cells, which was associated with reduced glomerular vascular endothelial growth factor mRNA and protein. In contrast, the fraction of glomeruli with an intact glomerular architecture within the everolimus group showed clearly less glomerular enlargement compared to vehicle-treated nephrectomy rats.


CONCLUSIONS
This study demonstrates potential mechanisms of mTOR inhibitor induced renal deterioration and proteinuria in the low nephron number remnant kidney model.
Vogelbacher
Regina
R
Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Germany.
Wittmann
Sandra
S
Braun
Andrea
A
Daniel
Christoph
C
Hugo
Christian
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects; D000068338:Everolimus; D005920:Glomerular Mesangium / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D011494:Protein Kinases / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013927:Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000068338:Everolimus; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus