臺灣博碩士論文加值系統

硫酸吲哚(IS)為一飲食中蛋白質來源的蛋白質結合性尿毒素，主要由腎臟排除。人醫研究指出，硫酸吲哚的濃度會隨著腎臟功能喪失而上升，且可能為慢性腎病病患出現骨質異常的原因之一。然而，在小動物醫學中，硫酸吲哚與慢性腎病的關係尚未被完全確立。因此本研究想評估血漿中硫酸吲哚與纖維母細胞生長因子-23(FGF-23)此一參與礦物質代謝的賀爾蒙之間的相關性，並進一步探討是否硫酸吲哚的累積會惡化纖維母細胞生長因子-23對於磷離子的正常調控。此外，也探討硫酸吲哚及纖維母細胞生長因子-23在貓是否可作為慢性腎病惡化的預測因子。本研究共納入20隻健康貓隻作為對照組及73隻臨床穩定的慢性腎病貓隻作為疾病組進行研究。所有納入的腎病貓隻均依照國際腎臟權益組織(IRIS)所制定之慢性腎病級別進行分組，並將血漿肌酸酐濃度在3個月的追蹤期間上升超過 0.5mg/dL 或進展到 IRIS 的下一個分期的病例定義為腎病惡化，依據惡化與否進行分組。結果顯示，血漿中硫酸吲哚與纖維母細胞生長因子-23的濃度均隨著腎病嚴重程度的增加而上升。纖維母細胞生長因子-23的濃度與尿素氮、肌酸酐、白蛋白、血容比、磷離子、鈉離子及硫酸吲哚均有顯著相關。而經逐步多項式線性回歸分析排除干擾因子後，僅硫酸吲哚與纖維母細胞生長因子-23存在統計學上的顯著關係。研究亦顯示相較於非惡化組別，第二期及第三期慢性腎病貓隻的硫酸吲哚與纖維母細胞生長因子-23濃度在腎病惡化組別均顯著上升。此外，以接收者操作特徵曲線(ROC)進行以硫酸吲哚及纖維母細胞生長因子-23的濃度預測腎病惡化能力之評估，結果可見不論是在第二期或第三期的慢性腎病貓隻，其曲線下面積均大於0.75 (P<0.05)，顯示此兩者均可作為一個有潛力的腎病惡化預測指標。總體而言，本研究顯示在慢性腎病貓隻中硫酸吲哚與纖維母細胞生長因子-23之間存在著顯著相關性。且硫酸吲哚與纖維母細胞生長因子-23均可作為貓隻早期偵測慢性腎病惡化之指標。

Indoxyl sulfate (IS), a protein-bound uremic toxin derived from dietary protein and mainly eliminated by renal excretion, was reported to not only increase with the severity of impaired renal function but also may be one of the factors involved in bone abnormalities in human CKD patients. It is not yet known whether or not the same correlation between IS and FGF-23 holds true in small animal. The purposes of this study are to measure the concentration of IS and fibroblast growth factor-23(FGF-23), a phosphaturic hormone involves in mineral metabolism, in various stages of CKD cats to elucidate whether the accumulation of IS making the level of phosphate higher by worsened FGF-23 secretion and to evaluate the possibility of using IS and FGF-23 as predictive markers of CKD progression in cats. Totally 93 feline cases, including 20 clinical healthy cats and 73 feline CKD case were collected from two veterinary teaching hospitals. All feline CKD cases were grouped by the standard of International Renal Interest Society (IRIS) staging system. Patient background, general biochemistry, plasma IS and FGF-23 levels were investigated at the same time. CKD progression was defined as increasing one IRIS stage and/or plasma creatinine level raises in 0.5 mg/dL in the same stage within 3 months. The results showed that plasma IS and FGF-23 concentrations elevated concurrently with impairing renal function. The FGF-23 levels were significantly associated with blood urea nitrogen, creatinine, albumin, hematocrit, phosphate, sodium and IS. After adjusting confounding factors by stepwise multiple linear regression analysis, only IS retained statistical significance in association with FGF-23. Comparing with non-progression group in cats, both IS and FGF-23 significantly increased in renal progression group (P<0.05). Area under curve (AUC) of IS, FGF-23 and the combination of both to predict renal progression were above 0.75 in receiver operator characteristic (ROC) curve analysis, which means both IS and FGF-23 could be valuable markers. In conclusion, this study indicated that IS retained independent correlation with FGF-23 in CKD, and both IS and FGF-23, as well as combination of both, could be indicators for early detection of CKD progression in cats.

中文摘要 .............................................i
Abstract……..........................................ii
Table of contents….................................iii
List of tables................ .................... viざ
List of figures.....................................viiし
List of abbreviation................................ixす
Chapter 1 Introduction...............................1
Chapter 2 Literature review…………………………………………3
2.1. Chronic kidney disease…………………………………3
2.1.1. Background of CKD………………………………3
2.1.2. IRIS Stages of feline CKD…………………………3
2.1.3. Chronic kidney disease- mineral and bone
disorder……5
2.1.4 Early indicators of CKD…………………………5
2.2. Uremic toxin………………………………………………5
2.2.1. Definition of Uremic toxin………………………6
2.2.2. Pathobiological origin and removal of uremic toxin…………………6
2.2.3. Classification of uremic toxins………………6
2.3. Indoxyl sulfate…………………………………………………10
2.3.1. Metabolism of indoxyl sulfate……………………10
2.3.2. Ways of Indoxyl sulfate accumulation………11
2.3.3. Toxic effect of indoxyl sulfate in CKD…13
2.4. Fibroblast growth factor-23 (FGF-23)……………………16
2.4.1. Physiological functions of FGF-23……………16
2.4.2. FGF-23-Kloth receptor complex…………………17
2.4.3. Target organ of FGF-23……………………18
2.4.4 Phosphate homeostasis in FGF-23-vitamin D-PTH axis…………………20
2.4.5. Actions of FGF-23 in CKD patients………22
2.5 The link between indoxyl sulfate and fibroblast growth factor-23………………23
Chapter 3 Materials and methods……………………………………………………25
3.1. Patient selection……………………………………………25
3.2. Sample collection………………………………………………25
3.3. Study design……………………………………………………26
3.4. Measurement of IS by high performance liquid chromatography………………28
3.4.1. Chemicals and reagents……………………………28
3.4.2. Supplies………………………………………………28
3.4.3. Apparatus………………………………………………28
3.4.4. HPLC conditions………………………………………29
3.4.5. Sample extraction..…………………………………30
3.4.6. Analytical standard…………………………………30
3.4.7 Calibration curve……………………………………31
3.4.8. Recovery……………………………………………31
3.4.9. Limit of detection and Limit of quantification……31
3.5. Measurement of FGF-23 by commercial feline FGF-23 ELISA kit…………31
3.6. Statistical analysis……………………………………………………………32
Chapter 4 Result…………………………………………………34
4.1. Validation of IS and FGF-23 measurement method………34
4.2 Characteristic of study population…………………………36
4.3 Plasma levels of indoxyl sulfate in cats with different CKD stages…………41
4.4 Plasma levels of FGF-23 in cats with different CKD stages………………41
4.5 Correlations between concentrations of indoxyl sulfate and clinical biochemical parameters in feline CKD …………42
4.6 Correlations between concentrations of FGF-23 and clinical biochemical parameters in feline CKD………………44
4.7 Correlations between concentrations of IS, FGF-23 and phosphate…………47
4.8 IS and FGF-23 as predictors for progression of CKD……48
4.9 The correlation between IS, FGF-23 and phosphate binder treatment…………59
Chapter 5 Discussion…………………………………………………61
5.1 The relationship between IS and FGF-23 in feline CK…61
5.2 The definition of CKD progression………………………62
5.3 IS and FGF-23 were both associated with CKD progression…63
5.4 The predictive ability of IS and FGF-23 in CKD progression…………63
5.5 Association of IS or FGF-23 to other parameters……65
5.6 The correlation between IS, FGF-23 and phosphate binder treatment…………66
5.7 Small scale study of SDMA in CKD…………………………67
5.8 Limitations in this study…………………………………67
5.9 Conclusion………………………………………………………67
Reference………………………………………………………………69

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