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研究生:陳建男
研究生(外文):Chien-Nan Chen
論文名稱:評估犬貓慢性腎病口服活性碳降低硫酸吲哚濃度之效果及硫酸吲哚是否能作為慢性腎病之惡化因子
論文名稱(外文):Indoxyl Sulfate as a Progression Factor and the Effect of Oral Carbon Adsorbent for the Reduction of Indoxyl Sulfate Concentration in Dogs and Cats with Chronic Kidney Disease
指導教授:李雅珍李雅珍引用關係
口試委員:周濟眾蔡沛學賴俊夫
口試日期:2016-07-12
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床動物醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:108
中文關鍵詞:慢性腎病硫酸吲哚尿毒素活性碳高效液相層析法
外文關鍵詞:Chronic kidney diseaseIndoxyl sulfateUremic toxinAST-120HPLC
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硫酸吲哚是與蛋白質結合的一種尿毒素,飲食中的蛋白質為其主要的製造來源,且大部分經由腎臟排除。在人類醫學、實驗動物與犬貓的研究已證實硫酸吲哚的濃度會隨著腎功能的嚴重程度增加而升高。硫酸吲哚濃度的升高證實與慢性腎臟病病人的預後有關。然而,硫酸吲哚是否能夠預測犬貓腎臟病的惡化仍無相關研究。
本篇研究納入臨床穩定的36隻慢性腎病患犬與58隻患貓,研究中使用高效液相層析法測定血漿中硫酸吲哚濃度。所有病患依照慢性腎病級別進行分級。血漿肌酸酐濃度在3個月的追蹤期間上升超過0.5mg/dL或進展到IRIS的下個級別則定義為腎病惡化,依據惡化與否將病患分為腎病惡化組及非惡化組。研究目的為調查的硫酸吲哚血漿濃度是否可做為腎病惡化的指標。
數據顯示第二與第三期的慢性腎病犬貓中,惡化組別的硫酸吲哚血漿濃度皆顯著高於無惡化的組別(P<0.05)。以接收操作特殊曲線(ROC)作硫酸吲哚濃度預測腎病惡化的能力評估,不管是第二或三期的慢性腎病犬貓,曲線下面積均大於0.75 (P<0.05),表示硫酸吲哚是一個潛力的指標。在貓,硫酸吲哚也與血中尿素氮、肌酸酐、血容比與磷有關。然而,硫酸吲哚在狗僅與磷的濃度相關。
此外,本研究亦評估活性碳降低硫酸吲哚的效果。於三個月的追蹤期間中,每隻貓每天均餵食400毫克的活性碳。實驗結果顯示活性碳對於硫酸吲哚與血中生化數值無顯著影響。
總結來說,硫酸吲哚可作為預測慢性腎病犬貓的惡化因子,且可能與貧血及血磷濃度有關。活性碳應用於慢性腎病犬貓的臨床效果難以確定,仍需要更大型的研究來評估其臨床成效。


Indoxyl sulfate (IS) is a protein-bound uremic toxin derived from dietary protein and mainly eliminated by renal excretion. The concentration of IS were reported to increase with the severity of impaired renal function in human, laboratory animals, dogs and cats. Elevation of IS was ascertained to be related to the prognosis in people with chronic kidney disease (CKD). However, whether IS can predict the progression of CKD in dogs and cats was not studied yet.
In the present study, fifty-eight cats and thirty-six dogs with CKD were eligible and enrolled. Plasma IS for each patient was measured by high performance liquid chromatography. Renal progression was defined as increasing one International renal interest society (IRIS) stage and/or plasma creatinine level raises in 0.5mg/dL in the same stage within 3 months.
Comparing with non-progression group in both dogs and cats, baseline plasma IS concentration was significantly increased in renal progression group (P<0.05) especially at IRIS stage 2, stage 3. Area under receiver operator characteristic (AUROC) curves of IS to predict renal progression were above 0.75 in both dogs and cats, which means IS could be a valuable marker. IS levels were also significantly correlated with blood urea nitrogen (BUN), creatinine, hematocrit and phosphate in cats; whereas IS was only significantly correlated with phosphate levels in dogs.
Furthermore, the effects of kremezin to lower IS in cats with CKD were also studied. During the following 3 months, 400 mg of AST-120 was fed to 5 cats with CKD daily. The results revealed that kremezin doesn’t have significant impact on clinical parameters and IS levels beyond short-term follow up.
In conclusion, indoxyl sulfate can serve as a progression factor in dogs and cats with chronic kidney disease and is possibly associated with anemia and blood phosphate levels. Clinical usefulness of AST-120 cannot be determined in CKD cats and large studies are required to evaluate its benefits.


口試委員會審定書 #
誌謝 i
中文摘要 ii
ABSTRACT iii
CONTENTS iv
LIST OF FIGURES vii
LIST OF TABLES x
Chapter 1 Introduction 1
Chapter 2 Literature review---Uremic toxin 3
2.1 Definition of Uremic syndrome 3
2.2 Definition of Uremic toxin 3
2.3 Classification of Uremic toxins 4
2.4 Pathobiological Origin of Uremic toxins 6
2.5 Signs and Symptoms of Uremia 6
Chapter 3 Protein-bound uremic toxin 8
3.1 Metabolism of indoxyl sulfate (IS): Gut-kidney axis 8
3.2 Determinants of indoxyl sulfate accumulation 9
3.2.1 Protein intake on the generation of indoxyl sulfate 9
3.2.2 Renal clearance of indoxyl sulfate 10
3.2.3 Gut dysbiosis 12
3.3 Effects of indoxyl sulfate 13
3.3.1 Nephrotoxicity of indoxyl sulfate 13
3.3.2 Vascular toxicity of indoxyl sulfate 18
3.3.3 Neurotoxicity of indoxyl sulfate 20
3.3.4 Bone toxicity of indoxyl sulfate 20
3.3.5 Effect of indoxyl sulfate on EPO production 21
3.3.6 Role of predicting progression in CKD patients 22
3.4 Therapeutic methods to remove indoxyl sulfate 23
3.4.1 Oral Sorbent (AST-120) 23
3.4.2 Hemodialysis 26
3.4.3 Peritoneal dialysis (PD) 28
3.4.4 Probiotics and Prebiotics 28
3.4.5 Acarbose 30
3.4.6 Hepatic sulphation of indoxyl 31
3.4.7 Tubular filtration of indoxyl sulfate 32
Chapter 4 Material and method 33
4.1 Patient selection and sample collection 33
4.2 Study design 34
4.2.1 Experiment 1: Evaluation of predictive value of indoxyl sulfate on renal progression and relationship between indoxyl sulfate and clinicophathological results in dogs and cats with chronic kidney disease 34
4.2.2 Experiment 2: Effects of oral adsorbent AST-120 (Kremezin®) in cats with chronic kidney disease. 37
4.3 Quantitative analysis by high performance liquid chromatography 38
4.3.1 Materials and reagents 38
4.3.2 Preparation of IS standard and mobile phase for HPLC 40
4.4 Statistical analysis 42
Chapter 5 Results 44
5.1 Characteristics of study population 44
5.2 Plasma level of IS and IRIS CKD stage 48
5.3 IS and progression of CKD at different IRIS stages 49
5.4 Correlations between concentrations of IS and other clinicopathological parameters 73
5.5 Indoxyl sulfate and phosphate binder treatment 78
5.6 Effects of AST-120 (Kremezin®) on plasma level of indoxyl sulfate 83
Chapter 6 Discussion 91
Reference 99



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