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. CONCLUSION: This study demonstrates potential mechanisms of mTOR inhibitor induced renal deterioration and proteinuria in the low nephron number remnant kidney model.
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. CONCLUSION: This study demonstrates potential mechanisms of mTOR inhibitor induced renal deterioration and proteinuria in the low nephron number remnant kidney model.
Authors: Heloisa Cristina Caldas; Thaís Amarante Peres de Paula Couto; Ida Maria Maximina Fernandes; Maria Alice Sperto Ferreira Baptista; Rosa Sayoko Kawasaki-Oyama; Eny Maria Goloni-Bertollo; Domingo Marcolino Braile; Mario Abbud-Filho Journal: Clin Exp Nephrol Date: 2015-01-29 Impact factor: 2.801
Authors: Eric S White; Rommel L Sagana; Adam J Booth; Mei Yan; Ashley M Cornett; Christopher A Bloomheart; Jessica L Tsui; Carol A Wilke; Bethany B Moore; Jeffrey D Ritzenthaler; Jesse Roman; Andrés F Muro Journal: Exp Cell Res Date: 2010-07-13 Impact factor: 3.905
Authors: Bairbre A McNicholas; Diana G Eng; Julia Lichtnekert; Peter S Rabinowitz; Jeffrey W Pippin; Stuart J Shankland Journal: Am J Physiol Renal Physiol Date: 2016-07-20