만성 복막투석 동물모델에서 복막 섬유화에 대한Pirfenidone의 억제 효과 = Pirfenidone Treatment During Peritoneal Dialysis Reduces PeritonealFibrosis in Rats

다국어 초록 (Multilingual 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 µm, group II:59.5±26.2 µm, group III:36.5±11.2 µm) and visceral (group I:3.1±0.9 µm, group II:10.9±5.2 µm, group III:6.1±1.7 µm) 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.

국문 초록 (Abstract)

배 경:복막 섬유화는 지속성 외래복막투석 환자에서 가장 중요한 합병증 중의 하나이며, 이와같은 형태학적 변화는 기능적으로도 복막투과도를 증가시켜 한외여과부전을 초래하는 것으로 알려져 있다. Pirfenidone (PFD)는 섬유화 억제제로 잘 알려져 있으며, 이에 대한 여러 선행연구가 보고되고 있으나 복막투석을 응용한 실험은 아직 보고되지 않은 실정이다. 이에 연구자는 만성 복막투석 동물모델을 이용하여 PFD의 복막 섬유화 억제정도 및 복막투과도에 미치는 영향을 알아보고자 하였다.
방 법:30마리의 흰쥐를 3군으로 나누어 I군 (n=6)은 복강 내 아무런 조작을 하지 않은 대조군, II군 (n=12)은 4.25% 포도당 투석액으로 투석한 군, III군 (n=12)은 4.25% 포도당 투석액으로 투석 및 PFD (350 mg/kg/day)을 투여한 군으로 하였다. 투석액 교환은 25 mL를 매일 3회 12주간 시행하였다. 복막투과도 비교를 위해 1시간 PET을 모든 군에서 시행하였고, 복막의 조직학적 분석을 위한 조직표본은 모든 군에서 채취하였다.
결 과:복막의 두께는 대조군에 비해 투석군에서 현저하게 증가하였으며 (p=0.03), PFD치료로 벽측복막 두께 (I군:13.7±3.3 µm, II군:59.5±26.2 µm, III군:36.5±11.2 µm)는 유의하게 감소하였으나 장측복막 (I군:3.1±0.9 µm, II군:10.9±5.2 µm, III군:6.1±1.7 µm)은 유의한 변화가 없었다. 복막투과도는 대조군에 비해 투석군에서 현저한 과투과도 현상을 보였으며, PFD치료는 과투과도를 유의하게 감소시켜 초여과도를 호전시켰다.
결 론:PFD이 복막 섬유화를 초래하는 복막 내 콜라겐의 축적을 효과적으로 억제시켜 복막 섬유화를 감소시켰으며 복막투과도를 향상시켰다.