Pirfenidone Treatment During Peritoneal Dialysis Reduces Peritoneal Fibrosis in Rats

Lee, Chang Hwa; Kim, Eung Suk; Lee, Jeong Ho

Abstract

BACKGROUND
Peritoneal fibrosis is one of the most serious complications in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In order to determine the effects of pirfenidone treatment for reducing peritoneal fibrosis, we examined the changes of peritoneal permeability (for glucose and urea nitrogen) and peritoneal thickness in a rat model of chronic peritoneal dialysis. METHODS: Thirty male Sprague-Dawley rats were divided into the following three groups: group I (n= 6), control rats with normal chow; group II (n=10), rats dialyzed with standard 4.25% glucose solution maintained on normal chow; group III (n=8), rats dialyzed with standard 4.25% glucose solution and maintained on pirfenidone-mixed chow (pirfenidone 350 mg/kg/day). Dialysis exchanges were performed three times a day with an instillation volume of 25 mL for a period of 12 weeks. Morphometric analysis of the peritoneal membrane were carried out in tissue specimens obtained at the time of sacrifice. One- hour peritoneal equilibration test was done at the beginning and the end of the study to compare the transport characteristics in these groups. RESULTS: The peritoneal permeability of glucose and urea nitrogen was much higher in rats subjected to peritoneal dialysis (both in group II and group III), as compared with control rats (group I). In group II where rats received peritoneal dialysis without pirfenidone treatment, rats had the highest level of peritoneal permeability for glucose and urea nitrogen, suggesting the peritoneal hyperpermeability. In contrast, rats in group III dialyzed with pirfenidone treatment had an improved peritoneal hyperpermeability indicating that pirfenidone treatment may have a protective effect against peritoneal hyperpermeability. Consistent with this, rats subjected to peritoneal dialysis were associated with a marked thickening of peritoneal membrane in both parietal (group I: 13.7+/-3.3 micrometer, group II: 59.5+/-26.2 micrometer, group III: 36.5+/-11.2 micrometer) and visceral (group I: 3.1+/-0.9 micrometer, group II: 10.9+/-5.2 micrometer, group III: 6.1+/-1.7 micrometer) peritoneum. In particular, submesothelial region in peritoneum was significantly thickened by accumulation of collagen, demonstrated by Masson's trichrome staining. Pirfenidone treatment during peritoneal dialysis, however, significantly reduced the accumulation of collagen in mesothelial region of the parietal peritoneum. CONCLUSION: Peritoneal dialysis with high glucose containing dialysate is associated with significant peritoneal collagen accumulation in mesothelial region and an increased peritoneal permeability for glucose and urea nitrogen. In contrast, pirfenidone treatment during peritoneal dialysis significantly reduces peritoneal thickness as well as peritoneal hyperpermeability, suggesting a protective effect against peritoneal fibrosis induced by chronic peritoneal dialysis.