Effects of everolimus as an antiproliferative agent on regression of encapsulating peritoneal sclerosis in a rat model.
The most serious complication of peritoneal dialysis is encapsulating peritoneal sclerosis (EPS). The prolonged inflammatory stimuli, fibrogenic cytokine overexpression, and angiogenesis that underlie EPS ultimately result in increased production of fibrous tissue, encapsulating the bowel loops. In recent years, inhibitors of mammalian target of rapamycin (mTOR) as an alternative agent for calcineurin inhibitor toxicity have been widely used in organ transplantation. These agents have also been used since the 1990s in endovascular medicine for drug-eluting stents because of antiproliferative effects on vascular smooth muscle cells and potent anti-inflammatory properties by direct action on human immune cells. Because of the shared characteristics of EPS and other fibrotic processes, we hypothesized that everolimus, an mTOR inhibitor can reverse the process responsible for the eventual development of EPS. We allocated 32 non-uremic albino Wistar rats to 4 groups: control group, 2 mL isotonic saline injected intraperitoneally (IP) daily for 3 weeks; CG group, 2 mL/200 g (0.1%) chlorhexidine gluconate (CG) injected IP daily and ethanol (15%) dissolved in saline, for 3 weeks; resting group, CG (weeks 0 - 3), plus peritoneal rest (weeks 3 - 6); and Evo-R, CG (weeks 0 - 3), plus 0.3 mg/L everolimus in drinking water (weeks 3 - 6). At the end of the study, we performed a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution, and examined the dialysate-to-plasma ratio of urea (D/P urea), dialysate white blood cell count, ultrafiltration (UF) volume, and morphologic change in the parietal peritoneum. Exposure to CG for 3 weeks resulted in alterations in peritoneal transport (increased D/P urea, decreased UF volume, p < 0.05) and morphology (increased inflammation, neovascularization, fibrosis, and peritoneal thickness, p < 0.05). Peritoneal rest has some beneficial effect only on UF failure and dialysate cell count (p < 0.05). However; everolimus was more effective than peritoneal rest with regard to vascularity and peritoneal thickness (p < 0.05). Everolimus has beneficial effects on UF failure, inflammation, and fibrosis. Everolimus may have therapeutic value in the management of EPS.
Duman
Soner
S
Department of Nephrology, Ege University, Izmir, Turkey. soner.duman@ege.edu.tr
Bozkurt
Devrim
D
Sipahi
Savas
S
Sezak
Murat
M
Ozkan
Sultan
S
Ertilav
Muhittin
M
Sen
Sait
S
Ok
Ercan
E
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D000068338:Everolimus; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D010530:Peritoneal Dialysis / Q000009:adverse effects; D010532:Peritoneal Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012598:Sclerosis; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases
D007166:Immunosuppressive Agents; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus