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  • 學位論文

長期腹膜透析併發症

Long-Term Complications in Peritoneal Dialysis

指導教授 : 蔡敦仁
共同指導教授 : 李心予
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摘要


研究背景 台灣末期腎臟病發生率及盛行率都高居全球第一名。透析人口至2007年已經約有52,537人。依盛行率在2007年約是每百萬人口2,288人。依發生率來算在2007年是每百萬人口415人。根據健保局統計,台灣目前一年有三三○多億元醫療費用是花在透析治療上,平均每位腎友一年花費約六十萬元,是一般人的卅倍。為了減少透析醫療的花費,目前健保局鼓勵使用腹膜透析來作為腎臟替代療法。 但是腹膜透析病患長期使用高葡萄糖腹膜透析液,來達到脫水的目標。此外腹膜透析液還有其他方面的生物不相容性,也可能會對腹膜本身造成不利變化,並且對於血脂肪及葡萄糖代謝方面有惡化的作用。針對這些可能的不利作用,對於長期腹膜透析的併發症,我們進行了一系列的研究。主要從兩方面:一是臨床上,高濃度葡萄糖對於腹膜透析患者存活及代謝的影響,另一方面是這些具有生物不相容性的透析液對局部腹膜的傷害及其治療方式。 針對病患的存活影響,我們進行了研究初始葡萄糖負荷對腹膜透析病患的長期的影響的回顧性分析,來觀察初始葡萄糖負荷對腹膜透析病患存活率及腹膜透析技術執行時間的影響。根據之前其他學者的研究發現,使用高濃度葡萄糖的腹膜透析液會造成不良的結果,但是,到底哪一些病患會使用較高濃度的葡萄糖透析液,也就是影響長期腹膜透析病患有較高葡萄糖濃度負荷的因素到底有哪些,也是需要進一步探討的。此外在代謝方面,脂肪組織會分泌adiponectin,這是一種細胞素,它的作用和胰島素抗性以及抗發炎有關。在一般健康族群與血液透析病患中,血清adiponectin是可以用來預測心血管疾病的。在腹膜透析病患中,因為長期暴露在高濃度葡萄糖透析液中,會吸收大量葡萄糖,對於脂肪組織分泌adiponectin的作用及角色所造成的影響仍然不清楚,而adiponectin在腹膜透析患者和哪些因素有關之前也是未有相關研究。 另一方面是在長期腹膜透析對於局部腹膜的影響,腹膜纖維化是一種長期腹膜透析病患會發生的併發症,包括了簡單的腹膜硬化和包覆性腹膜硬化症。其中包覆性腹膜硬化症是一種發生於腹膜透析患者非常嚴重的併發症。Tamoxifen和類固醇可以用於治療包覆性腹膜硬化症,但是相關治療的持續時間和治療結果經驗仍然有限。我們分析了使用Tamoxifen和類固醇合併治療包覆性腹膜硬化症系列的經驗。另外Tamoxifen雖然可以成功地治療包覆性腹膜硬化症,文獻上也指出可以治療其他的慢性纖維化病變,但是對於Tamoxifen治療包覆性腹膜硬化症的機制仍然不清楚。這些也是我們要進一步研究的方向。 研究方法 在對病患存活方面,我們一共分析了90名新開始接受腹膜透析作為末期腎衰竭的腎臟替代療法的病患。將所有病人,根據腹膜透析剛開始的前6個月內,病患所用的透析液,計算的平均透析液葡萄糖濃度,將其分為低、中、高三種葡萄糖濃度負荷。使用Cox回歸分析來統計葡萄糖濃度負荷對腹膜透析病患存活率及腹膜透析技術執行時間的影響。另外使用線性回歸來分析影響葡萄糖負荷因素。 另外在追蹤5年之中,針對這90位新開始的腹膜透析的病患,將每位病患每月的透析處方都調閱出來,計算每年暴露的葡萄糖重量和透析液體積,給予相除之後成為葡萄糖負荷。因為許多變項會隨時間改變,而且病患也會逐漸因死亡或轉出而退出這項觀察,所以我們利用多變數線性回歸分析來分析會隨時間變化的一些變項,再來確定影響每年的平均透析液葡萄糖濃度的因素。至於針對腹膜透析病患的adiponectin研究,我們納入血液透析病患、腹膜透析病患、以及相對應的腎功能正常健康人,每個組有 28名病患,使用酵素連結免疫法來測定他們的血清adiponectin濃度,用來分析adiponectin濃度與血脂肪包括三酸甘油脂及膽固醇,還有胰島素抗性的相關性。另外並總共檢測了104位長期腹膜透析病患血清adiponectin的濃度,來分析在腹膜透析病患中,adiponectin和殘餘腎功能、腹膜功能及 C-反應蛋白 (C-reactive protein, CRP)的相關性。並利用多變數線性回歸來找出決定血清adiponectin濃度的獨立因素。 對於腹膜局部的傷害,我們納入所以所有從2005年至2009年在臺大醫院及台北馬偕醫院兩個醫學中心發生包覆性腹膜硬化症病患。包覆性腹膜硬化症的診斷是由臨床上有腸阻塞的症狀和特定的電腦斷層影像來確定診斷。Tamoxifen與類固醇是在確定包覆性腹膜硬化症診斷以後開始給予。我們紀錄了所有的醫療紀錄和個別病患的實驗室資料進行分析。我們另外進行了一些細胞學及動物模式的 實驗來探討Tamoxifen的抗纖維化機制。我們使用了漂白水腹腔注射來誘發腹膜纖維化的大鼠模式,來試驗Tamoxifen的治療效果。在每日腹腔注入Tamoxifen來治療腹膜纖維化,以計算腹腔腹膜纖維化的嚴重分數和測量肝表面上的 submesothelial 區域的厚度來顯示治療效果。另外利用人類腹膜間皮細胞 (human peritoneal mesothelial cell, HPMC)培養作為體外模型,來研究tamoxifen的抗纖維化的分子作用機轉。我們使用定量聚合酶鏈反應quantitative polymerase chain reactions 來測定transforming growth factors beta (TGF-β) 、結締組織生長因數 connective tissue growth factor (CTGF)及膠原蛋白基因表現,來探討Tamoxifen對於這些纖維化相關基因的影響。 結果 在分析長期的高葡萄糖腹膜透析液對病患的影響研究中,所有腹膜透析病患的平均追蹤治療時間是 40.1 ± 11.8個月。在高葡萄糖濃度負荷那ㄧ組患者中,表現出比低葡萄糖濃度負荷那ㄧ組病患有較短的腹膜透析技術執行時間,這在統計上有顯著的差異 ( p < 0.002)。利用Cox回歸分析,可以發現較低葡萄糖負荷那ㄧ組的腹膜透析患者,有較佳的腹膜透析技術執行時間 (p < 0.05)。另外在利用回歸分析探討葡萄糖負荷的獨立決定因子中可以發現,糖尿病 (p<0.001),較低血清白蛋白 (p < 0.05),以及較低的每週殘餘腎功能(腎臟Kt/V,p < 0.05),是在統計上有意義的高葡萄糖濃度負荷的決定因子。另外將這些病患的葡萄糖透析液加以分年分析中,總共納入了47名男性及43名女性腹膜透析病患,平均年齡是 53.4 ± 13.9歲。他們的腹膜透析技術存活率分別是在第一年有91.0%、第二年有84%和第三年 有77%。糖尿病患者,較高的身體質量指數和較低殘餘腎功能,在統計上和透析液的平均葡萄糖糖濃度有相關。這些相關在第一年,第二年和第三年都有顯著意義。但是隨著,腹膜透析病患的殘餘腎功能經過三年的逐漸惡化,甚至已經到了無尿狀態,只剩下是否有糖尿病會顯著影響第四年的透析液的葡萄糖濃度。至於腹膜透析液對葡萄糖代謝的影響,以adiponectin為研究的指標方面,腹膜透析病患與血液透析病患的血清adiponectin濃度並無顯著差異,但是明顯高於對照的腎功能正常健康人(p<0.01)。在腹膜透析病患與血液透析病患這兩個組中,adiponectin與三酸甘油脂 (p < 0.01),胰島素濃度 (p<0.05) 以及胰島素抗性 (HOMAIR) (p < 0.01)呈負相關,但與高密度脂蛋白 (p <0.05) 則呈正相關。無論是血液透析或是腹膜透析,這兩種透析方式對於清除adiponectin的效果都不佳。所以病患仍有很高的adiponectin濃度。腹膜透析病患adiponectin濃度和殘餘腎功能 (p<0.01)以及C反應蛋白(p < 0.001)是呈負相關。有使用降血糖藥物的腹膜透析病患,他們的adiponectin濃度較低,但降血脂藥物或是腎素-血管張力素阻斷劑並不影響 adiponectin的濃度。腹膜透析病患的血清adiponectin濃度的獨立決定因素,在調整了年齡、性別、腹膜透析持續時間以及糖尿病之後分析,包括了:三酸甘油脂、高密度脂蛋白、C反應蛋白和身體質量指數。但是,adiponectin濃度並與左心室質量或是射出分率,在我們的研究中均無相關。 關於對腹膜局部的傷害研究中,共有十位包覆性腹膜硬化症病患接受治療納入這個分析中,男性3位,女性七位,平均年齡是 47.8 ± 9.6歲,平均腹膜透析持續時間是 8.7 ± 3.8年。有九名患者在發生包覆性腹膜硬化症之前有頑治性腹膜炎。在確立診斷後,通通投予病患tamoxifen 10 毫克,每日兩次和類固醇相當於每天每公斤體重 0.5-1.0 毫克的prednisolone。其中有八名患者有顯著改善腸道蠕動,並可以進行腸道營養,但其中兩人分別在治療後9 天因腸胃道出血和七個月因腸穿孔死亡。另1名病人,在兩個星期的治療後,臨床症狀有部分改善,但有另一名病人對於治療是完全無效的。這種治療方式的併發症如胃腸道出血、腸穿孔和心肌梗塞這些併發症主要都和類固醇治療有關。針對tamoxifen治療覆性腹膜硬化症病患的分子機制研究中,在漂白水誘發腹膜纖維化的模式中,tamoxifen可以減緩大鼠腹膜纖維化的程度,減少submesothelial 區域的厚度。在人類腹膜間皮細胞培養上,對於TGF-β和膠原蛋白,tamoxifen有相反的影響,也就是tamoxifen抑制膠原蛋白的表達卻也同時促進了TGF-β的表現。另一方面我們也發現,tamoxifen也抑制了由TGF-β誘導而產生的結締組織生長因數。 結論 腹膜透析病患在腹膜透析最初半年期間,高葡萄糖濃度負荷是和病患有糖尿病、較低的血清白蛋白以及較差的殘餘腎功能有關,而且這段時間的高葡萄糖濃度負荷是可以有效地預測腹膜透析病患接受腹膜透析治療技術執行時間。而當腹膜透析病患有糖尿病、較大的身體質量指數、較差的殘餘腎功能,都需要更高的葡萄糖負荷。這三個因素影響了平均透析液的葡萄糖濃度,而且在開始腹膜透析的前三年中特別明顯。但是在腹膜透析開始執行三年之後,因殘餘腎功能的喪失,糖尿病就變成了唯一一個需要高葡萄糖負荷的重要因素。為了減少慢性腹膜透析病患的葡萄糖負荷,應考慮在每日的腹膜透析治療時,使用其他可以達成脫水的分子,如 icodextrin增加oncotic pressure,或是使用氨基酸來增加滲透壓。至於和葡萄糖代謝有關的脂肪組織細胞素adiponectin研究,和血液透析病患一樣,腹膜透析病患也有較高的adiponectin濃度,而且adiponectin濃度與血脂肪和胰島素抗性是有相關的。此外,血清adiponectin濃度是與 C反應蛋白及殘餘腎功能的呈負相關的。在多變數線性回歸分析之後,C反應蛋白仍是血清adiponectin濃度的獨立決定因素。腹膜透析病患患者adiponectin與胰島素抗性和發炎有相關聯,但是adiponectin在腹膜透析病患心血管疾病中的角色,仍然需要進一步研究。 針對腹膜透析造成腹膜局部傷害的研究中,Tamoxifen與類固醇組合的治療是可以有效地改善包覆性腹膜硬化症中 80%的病人的症狀。太晚診斷出包覆性腹膜硬化症可能就會使治療失敗。對於治療的併發症通常是由類固醇所導致,所以當症狀改善之後,類固醇要儘快逐漸停止。至於Tamoxifen的治療機制,雖然Tamoxifen增強了TGF-β,這可能會增加了纖維化,但是我們的研究也指出Tamoxifen可能的抗纖維化作用是經由抑制結締組織生長因數進而抑制了膠原蛋白的製造。 這些結果可以提供Tamoxifen治療纖維化的分子機制。

關鍵字

腹膜透析 併發症

並列摘要


Background Both the prevalence and incidence of end-stage renal disease in Taiwan are the highest in the world. In 2007, the patients receiving dialysis were 52,537 persons in Taiwan. The prevalence was 2,288 per million population and the incidence was 415 patients per million population. According to the statistic data of Bureau of National Health Insurance (BNHI), dialysis therapy cost more than 330 billion NT dollars every year. In average, each dialyzed patient would spend 600 thousand NT dollars every year which is 30 times of the mean of general population. To reduce the medical cost on dialysis, BNHI promotes peritoneal dialysis as a long-term renal replacement modality. However, peritoneal dialysis patients will use high glucose content peritoneal dialysate to achieve ultrafiltration goal whenever they receive this renal replacement modality. Combine with other bio-incompatible factors in the peritoneal dilysate, peritoneum will be damaged by the dialysate and the metabolism of glucose and lipid will be affected by the dialysate in the long run. For these disadvantages of present dialysate, we conducted a serial of studies to investigate the long term complications of peritoneal dialysis. The effects of peritoneal dialysate was divided into two major portions: the first was the clinical effects of high glucose concentration in dialysate on patient survival, technique survival and metabolism in peritoneal dialysis patients. The second was local effects of bio-incompatible peritoneal dialysate on the peritoneum and their possible resolutions. For the long-term effects of peritoneal dialyate, we proposed that glucose content in peritoneal dialysate may result in unfavorable changes on peritoneal character and worsened metabolic profiles. We conducted a retrospective cohort analysis to investigate the impact of initial glucose load on long-term outcomes of peritoneal dialysis patients. In addition, since usage of high glucose concentrations in peritoneal dialyate may result in unfavorable results. We further conducted a study to analyze the factors associated with high glucose load in long-term peritoneal dialysis patients in each year. For the metabolism of glucose and lipid, adiponectin, a cytokine with anti-inflammatory properties that is secreted from adipose tissue, is associated with insulin resistance. It has been demonstrated that adiponectin is a predictor of cardiovascular events in both the general population and patients undergoing hemodialysis, however, its role in peritoneal dialysis patients remains unclear. For the local effect on peritoneum per se, peritoneal fibrosis is a common complication among long-term peritoneal dialysis patients including simple sclerosis and encapsulating peritoneal sclerosis. Encapsulating peritoneal sclerosis is a catastrophic complication of peritoneal dialysis patients. Tamoxifen and steroid are used to treat encapsulating peritoneal sclerosis but there is still limited experience about the therapeutic duration and outcome management. We provide a case series experience of treating encapsulating peritoneal sclerosis patients by using combination therapy of tamoxifen and steroid. Tamoxifen has successfully been used in treating encapsulating peritoneal sclerosis as well as other chronic fibrosis disorder, however, the mechanism of tamoxifen in treating encapsulating peritoneal sclerosis remains unclear. This issue deserve us to do further investigation. Methods In patient survival analysis, a total of 90 patients newly started on peritoneal dialysis were enrolled. All subjects were divided into low, medium, or high glucose load equally in patient number according to the average dialysate glucose concentration prescribed in the first 6 months from peritoneal dialysis initiation. Cox’s regression was used for survival analyses and linear regression was used for analyses of determinants for glucose load. In addition during the following up of these 90 newly-started peritoneal dialysis patients were surveyed for 5 years. We obtained glucose load by calculating annual glucose weight and dialysate volume that were administered. We conducted multiple linear regression analyses with time-dependent covariates to determine factors that influence the annual average dialysate glucose concentration. For analyzing the metabolic effects of adiponectin, serum adiponectin levels, measured using enzyme-linked immunosorbent assay in subjects with normal renal function and patients undergoing hemodialysis or peritoneal dialysis (28 subjects in each group), were analyzed to establish the relationship between adiponectin and lipid levels as well as insulin resistance. In the second study, 104 peritoneal dialysis patients were recruited to analyze the relationships between serum adiponectin level and residual renal and peritoneal function and C-reactive protein level. Independent factors for serum adiponectin level were determined from multiple linear regression. In treating the local effects on peritoneum of long term peritoneal dialysis, encapsulating peritoneal sclerosis patients were enrolled from two medical centers in northern Taiwan between 2005 and 2009. The diagnosis of encapsulating peritoneal sclerosis was made by clinical presentations of ileus and specific image findings. Tamoxifen and steroid were initiated after diagnosis. All medical records and individual laboratory data were reviewed. For investigating molecular mechanism of antifibrotic effects of tamoxifen, a bleach induced peritoneal fibrosis rat model was applied as the in vivo treatment target. Tamoxifen was intraperitoneally injected daily to treat peritoneal fibrosis. The peritoneal fibrosis scores and thickness of the submesothelial zone over the liver surface were measured as indicators for the severity of PF. Besides, human peritoneal mesothelial cells were used as an in vitro model to test the antifibrotic effect of tamoxifen. Gene expressions of transforming growth factors beta, connective tissue growth factor and collagen were investigated using quantitative polymerase chain reactions. Results In analysis of effects of glucose load, the mean follow-up period was 40.1 ± 11.8 months. Patients with higher glucose load showed a significantly worse cumulative technique survival (log rank p=0.002). In Cox’s regression analysis, patients with lower glucose load had significantly better technique survival (p=0.035). In linear regression analysis, preexisting diabetes mellitus (p<0.001), lower serum albumin (p=0.012), and lower weekly renal Kt/V (p=0.019) were significantly correlated with higher glucose load. In analyzing the dterminants of glucose load in each year, there were 47 men and 43 women and the mean age was 53.4 ± 13.9 years. The technique survival rates were 91.0%, 84.1%, and 77.6% for beginning of the second, third, and fourth year of peritoneal dialysis therapy, respectively. The presence of diabetes mellitus, high body mass index (BMI), and low weekly renal Kt/V were significantly correlated with high average glucose concentration of the dialysate during the first, second, and third years. For patients undergoing peritoneal dialysis for more than 3 years, residual renal function deteriorated, and only diabetes significantly affected higher glucose concentration of the dialysate in the fourth year. For analyzing the impacts of adiponecctin on peritoneal dialysis patients, No significant difference was demonstrated comparing the serum adiponectin levels of peritoneal dialysis and hemodialysis patients, however, both were significantly higher than that of the control subjects (p<0.01). Negative associations were demonstrated between adiponectin, and triglyceride (p<0.01) and insulin levels (p<0.05), and homeostatic model assessment of insulin resistance (HOMAIR) (p<0.01) for the former two groups, however, a positive association was demonstrated for high density lipoprotein (p<0.05). Neither hemodialysis nor peritoneal dialysis removed adiponectin significantly, with levels for the latter group negatively associated with residual renal function (p<0.01) and C-reactive protein (p < 0.001). Peritoneal dialysis patients using glucose-lowering agents had lower adiponectin levels, however, lipid-lowering agents and renin-angiotensin blockades did not appear to affect them. The independent determinants for serum adiponectin level in peritoneal dialysis patients were triglyceride, hemodialysis, CRP, and BMI, after adjustment for age, sex, peritoneal dialysis duration and diabetes. Adiponectin levels were not associated with left-ventricular mass or ejection fraction, however. In treating encapsulating peritoneal sclerosis, there was a total of 10 encapsulating peritoneal sclerosis patients (M/F: 3/7) with a mean age of 47.8 ± 9.6 years and a mean peritoneal dialysis duration of 8.7 ± 3.8 years. Refractory peritonitis was the preceding event in nine patients. Tamoxifen 10 mg twice daily and steroid equivalent to 0.5-1.0 mg/Kg/day were administered. Eight patients showed improvement of enteral feeding within 1 week of treatment but two of them died in the following period (nine days and seven months respectively). One patient achieved a partial improvement of clinical symptoms after two weeks of therapy and one patient was refractory to this regimen. Complications of this regimen such as gastrointestinal bleeding, perforation, and myocardial infarction mostly resulted from the steroid therapy. The study of molecular mechanism of antifibrotic effects of tamoxifen showed that tamoxifen could reduce the peritoneal fibrosis severity and submesothelial zone in bleach induced rat peritoneal fibrosis model. In HPMC, tamoxifen showed paradoxical effects between collagen I and TGF-β. Tamoxifen also inhibited TGF-β induced collagen and CTGF. Conclusion Form our serial studies, for the long term survival, higher glucose load during initial period of peritoneal dialysis was associated with higher prevalent diabetes, lower serum albumin, and lower residual renal function, and effectively predicted worse survival of peritoneal dialysis therapy. Patients with diabetes, high body mass index, and low residual renal function were more likely to require high glucose load for peritoneal dialysis therapy, especially during the first 3 years. After 3 years of peritoneal dialysis, diabetes was the only significant factor that determined a need for higher glucose load. In order to decrease the glucose load in chronic peritoneal dialysis patients, alternative osmotic agents such as icodextrin or amino acids should be considered in the daily peritoneal dialysis regimens. For the adiponectin, as for the hemodialysis patients, the peritoneal dialysis subjects had high adiponectin levels, not removed effectively using either of the studied dialysis modalities. In addition to a significant relationship with the components of insulin resistance, adiponectin was associated with CRP in these patients. These results indicate that adiponectin level in peritoneal dialysis patients may be a good indicator of cardiovascular disease risk. For treating encapsulating peritoneal sclerosis, the combination of tamoxifen and steroid is effective in ameliorating encapsulating peritoneal sclerosis symptoms in 80% of the patients. Chronicity of encapsulating peritoneal sclerosis might predict a treatment failure. Steroid could be tapered off if symptoms improve. And the possible antifibrotic effect of tamoxifen is through inhibiting CTGF to block collagen synthesis, although it enhances TGF-β which increases fibrosis. These results provide a possible molecular mechanism for tamoxifen.

並列關鍵字

Peritoneal dialysis Complication

參考文獻


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Rodriguez-Carmona, A., Perez Fontan, M., Garcia Lopez, E., Garcia Falcon, T., and Diaz Cambre, H. (2007). Use of icodextrin during nocturnal automated peritoneal dialysis allows sustained ultrafiltration while reducing the peritoneal glucose load: a randomized crossover study. Perit Dial Int 27, 260-266.
Williams, J.D., Craig, K.J., Topley, N., Von Ruhland, C., Fallon, M., Newman, G.R., Mackenzie, R.K., and Williams, G.T. (2002). Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 13, 470-479.
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