慢性腎臟病患者常因為尿毒素的產生、抗氧化能力的降低或共病因子，造成患者體內的氧化壓力升高而加速病程進展。肝臟型脂肪酸結合蛋白雖然主要存在肝臟中但也存在於腎臟，通常由尿液排出體外，因具有高度結合脂肪酸過氧化產物的能力，被認為可以擔任人體內的內生性抗氧化物質，以及可做為腎臟疾病預測或預後的指標值。目前研究多著重在測量尿液肝臟型脂肪酸結合蛋白濃度以評估腎臟病患的病程及氧化壓力狀況，但血漿肝臟型脂肪酸結合蛋白濃度與患者的氧化壓力狀況及腎功能的相關性尚未被深入探討。因此，本研究目的是比較第一期至第四期慢性腎臟病患者血漿及尿液肝臟型脂肪酸結合蛋白濃度、氧化壓力指標以及抗氧化能力之差異；並探討血漿及尿液肝臟型脂肪酸結合蛋白與氧化壓力、抗氧化能力及腎功能指標之相關性。本研究是以醫院為基礎的橫斷面研究，於臺中榮民總醫院腎臟科門診進行，共招募185位慢性腎臟病第一期至第四期患者。結果顯示第一至四期的患者血漿氧化壓力指標（丙二醛、氧化型低密度脂蛋白）及血漿抗氧化能力指標（總抗氧化能力、肝臟型脂肪酸結合蛋白、穀胱甘肽過氧化酶）濃度皆無顯著差異。尿液肝臟型脂肪酸結合蛋白濃度在慢性腎臟病第二期顯著高於第一期及第三期患者。以 Partial Pearson correlation 調整年齡、性別、身體質量指數、收縮壓、有無糖尿病、抽菸及喝酒習慣，血漿及尿液肝臟型脂肪酸結合蛋白與氧化壓力、抗氧化能力及腎功能指標皆無顯著相關性。血漿及尿液肝臟型脂肪酸結合蛋白濃度可能皆無法反映第一至第四期慢性腎臟病患者的氧化壓力、抗氧化能力以及腎功能的狀況。

Uremic toxins, decreased antioxidant capacities or comorbidity may increase oxidative stress and further accelerate the disease progression in patients with chronic kidney disease (CKD). Liver type fatty acid binding protein (L-FABP) is expressed not only in the liver but also in the kidney, and is usually excreted in urine. Liver type fatty acid binding protein has a high affinity and capacity to bind the production of fatty acid peroxidation, it is thus considered to be an endogenous antioxidant and be a clinical biomarker for predicting the progression or prognosis of CKD. Recent studies were mainly focusing on the association of urinary L-FABP with the renal function and oxidative stress in patients with CKD. However, the associations of plasma L-FABP with renal function and oxidative stress have not been further examined yet. Therefore, the purpose of our study was to compare the differences among plasma and urinary L-FABP concentrations, oxidative stress and antioxidant capacities in patients with stage 1 - 4 CKD, and additionally evaluated the associations of plasma and urinary L-FABP with oxidative stress, antioxidant capacities and renal function. This research is a cross-sectional study and recruited 185 stage 1 - 4 CKD patients from the nephrology outpatient clinics of the Taichung Veterans General Hospital, Taichung. Results showed that there were no significantly differences in plasma oxidative stress markers (malondialdehyde and oxidized low-density lipoprotein), and antioxidant capacity markers (total equivalent antioxidant capacity, L-FABP and glutathione peroxidase) among different stage of CKD. However, urinary L-FABP levels in patients with stage 2 CKD were significantly higher than patients in stage 1 and stage 3 CKD. Partial Pearson correlation analysis indicated that plasma and urinary L-FABP were not associated with indicators of oxidative stress, antioxidant capacities and renal function after adjusting for age, sex, body mass index, systolic blood pressure, diabetes mellitus, smoking and drinking habits. In conclusion, plasma and urinary L-FABP may not reflect oxidative stress, antioxidant capacities and renal function in patients with stage 1 - 4 CKD.

目錄
壹、 摘要……………………………………………………………………1
中文摘要………………………………………………………………1
英文摘要………………………………………………………………2
貳、 縮寫名稱………………………………………………………………4
參、 文獻回顧………………………………………………………………5
一、 腎臟簡介………………………………………………………..5
二、 慢性腎臟病……………………………………………………..8
三、 慢性腎臟病與氧化壓力………………………………………10
四、 肝臟型脂肪酸結合蛋白………………………………………13
五、 肝臟型脂肪酸結合蛋白與腎功能……………………………15
肆、 研究動機……………………………………………………………..17
伍、 研究目的及假說……………………………………………………..18
陸、 材料方法……………………………………………………………..19
一、 研究設計………………………………………………………19
二、 研究對象………………………………………………………20
三、 研究方法………………………………………………………21
四、 實驗室生化分析………………………………………………24
五、 統計方法………………………………………………………29
柒、 結果………………………………………………………………….30
捌、 討論………………………………………………………………….36
玖、 研究限制…………………………………………………………….39
壹拾、 結論…………………………………………...…………..… ……..40
表1～表6…………………………………………………………41
壹拾壹、 參考文獻……………………………………………………...48
附錄一……………………………………………………………………...57

行政院衛生福利部，2016。民國105年死因結果摘要表。行政院衛生福利部統計處。台灣。
Abd El-Hamid AM, Noha NL. Comparative study on the protective role of vitamin C and L-arginine in experimental renal ischemia reperfusion in adult rats. Int J Phys Pathophysiol Pharmacol 2014;6:153-65.
Arnao MB, Cano A, Hernandez-Ruiz J, Garcia-Canovas F, &Acosta M. Inhibition by L-ascorbic acid and other antioxidants of the 2.2''-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) oxidation catalyzed by peroxidase: a new approach for determining total antioxidant status of foods. Anal Biochem 1996;236:255-61.
Atamer A, Kocyigit Y, Ecder SA, Selek S, Ilhan N, Ecder T, Atamer Y. Effect of oxidative stress on antioxidant enzyme activities, homocysteine and lipoproteins in chronic kidney disease. J Nephrol 2008;21:924-30.
Atshaves BP, Storey SM, Petrescu A, Greenberg CC, Lyuksyutova OI, Smith R, Schroeder F. Expression of fatty acid binding proteins inhibits lipid accumulation and alters toxicity in L cell fibroblasts. Am J Physiol Cell Physiol 2002;283:C688-C703.
Babbs CF. Oxygen radical in ulcerative colitis. Free Rad Biol Med 1992; 13:169-81.
Bakris GL. Protecting renal function in the hypertensive patient: clinical guidelines. Am J Hypertens 2005;18:112S-119S.
Basile DP, Leonard EC, Beal AG, Schleuter D, Friedrich J. Persistent oxidative stress following renal ischemia–reperfusion injury increases ANG II hemodynamic and fibrotic activity. Am J Physiol Renal Physiol 2012;302(11):1494-502.
Becker BN, Himmelfarb J, Henrich WL, Hakim RM. Reassessing the cardiac risk profile in chronic hemodialysis patients: a hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Nephrol 1997;8:475-86.
Capeillere-Blandin C, Gausson V, Descamps-Latscha B, Witko-Sarsat V. Biochemical and spectrophotometric significance of advanced oxidized protein products. Biochim Biophys Acta 2004;1689:91-102.
Chen LI, Kuo MC, Hwang SJ. The advantages and drawbacks of methods for assessing kidney function in clinical practice. J Intern Med Taiwan 2012;23:34-41.
Chmurzyńska A. The multigene family of fatty acid-binding proteins (FABPs)：function, structure and polymorphism. J Appl Genet 2006; 47:39-48.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 2003;329:23-38.
David A, Sweetser ROH, Jeffrey I. Gordon. The metabolic significance of mammalian fatty-acid binding proteins: abundant proteins in search of a function. Annu Rev Nutr 1987;7:337-59.
Descamps-Latscha B, Drueke T, Witko-Sarsat V. Dialysisinduced oxidative stress: biological aspects, clinical consequences, and therapy. Semin Dial 2001;14:193-9.
Diepeveen SH, Verhoeven GH, van der Palen J, Dikkeschei BL, van Tits LJ, Kolsters G, Offerman JJ, Bilo HJ, Stalenhoef AF. Oxidative stress in patients with end-stage renal disease prior to the start of renal replacement therapy. Nephron Clin Pract 2004;98:c3-7.
Dounousi E, Papavasiliou E, Makedou A, Ioannou K, Katopodis KP, Tselepis A, Siamopoulos KC, Tsakiris D.. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006;48: 752-60.
Douglas C. Eaton, John P. Pooler. Vander’s Renal Physiology 2013.
Durak I, Kaçmaz M, Elgün S, Oztürk HS. Oxidative stress in patients with chronic renal failure: effects of hemodialysis. Med Princ Pract 2004;13: 84-7.
Epperlein MM, Nourooz-Zadeh J, Jayasena SD, Hothersall JS, Noronha-Dutra A, Neild GH. Nature and biological significance of free radicals generated during bicarbonate hemodialysis. J Am Soc Nephrol 1998;9: 457–63.
Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277-85.
Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008 Jun;7:489-503.
Galle J. Oxidative stress in chronic renal failure. Nephrol Dial Transpl. 2001;16:2135-37.
Glatz JF, van der Vusse GJ. Cellular fatty acid-binding proteins: their function and physiological significance. Prog Lipid Res 1996;35:243-82.
Handelman GJ. Evaluation of oxidant stress in dialysis patients. Blood Purif 2000;18:343-9.
Huang H, Starodub O, McIntosh A, Atshaves BP, Woldegiorgis G, Kier AB, Schroeder F. Liver fatty acid-binding protein colocalizes with peroxisome proliferator activated receptor alpha and enhances ligand distribution to nuclei of living cells. Biochemistry 2004;43:2484-500.
Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA. Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol 2013;1:483-91.
Ichikawa I, Kiyama S, Yoshioka T. Renal antioxidant enzymes: their regulation and function. Kidney Int 1994;45:1-9
Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Feldman HI. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 2014;63:713-35.
Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW. Chronic kidney disease: global dimension and perspectives. Lancet 2013 20;382:260-72.
Kamijo A, Sugaya T, Hikawa A, Okada M, Okumura F, Yamanouchi M, Honda A, Okabe M, Fujino T, Hirata Y, Omata M, Kaneko R, Fujii H, Fukamizu A, Kimura K. Urinary excretion of fatty acid-binding protein reflects stress overload on the proximal tubules. Am J Pathol 2004;165:1243-55.
Kamijo A, Sugaya T, Hikawa A, Yamanouchi M, Hirata Y, Ishimitsu T, Numabe A, Takagi M, Hayakawa H, Tabei F, Sugimoto T, Mise N, Omata M, Kimura K. Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease. Mol Cell Biochem 2006;284:175-82.
Karamouzis I, Sarafidis PA, Karamouzis M, Iliadis S, Haidich AB, Sioulis A, Triantos A, Vavatsi-Christaki N, Grekas DM. Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease. Am J Nephrol 2008;28:397-404.
Kao MP, Ang DS, Pall A, Struthers AD. Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options. J Hum Hypertens 2010;24:1-8.
Kawai A, Kusaka M, Kitagawa F, Ishii J, Fukami N, Maruyama T, Sasaki H, Shiroki R, Kurahashi H, Hoshinaga K. Serum liver-type fatty acid-binding protein predicts recovery of graft function after kidney transplantation from donors after cardiac death. Clin Transplant 2014;28:749-54.
Kaya Y, Ari E, Demir H, Soylemez N, Cebi A, Alp H, Bakan E, Gecit I, Asicioglu E, Beytur A. Accelerated atherosclerosis in haemodialysis patients;correlation of endothelial function with oxidative DNA damage. Nephrol Dial Transplant 2012;27:1164-9.
Kuchta A, Pacanis A, Kortas-Stempak B, Cwiklińska A, Ziętkiewicz M, Renke M, Rutkowski B. Estimation of oxidative stress markers in chronic kidney disease. Kidney Blood Press Res 2011;34:12-19.
Kwiecien S, Jasnos K, Magierowski M, Sliwowski Z, Pajdo R, Brzozowski B, Mach T, Wojcik D, Brzozowski T. Lipid peroxidation, reactive oxygen species and antioxidatie factors in the pathogenesis of gastric mucosal lesions and mechanism of protection against oxidative stress induced gastric injury. J Physiol Pharmacol 2014;65:613-22.
Lamb EJ, Stevens PE, Deeks JJ. What is the best glomerular filtration marker to identify people with chronic kidney disease most likely to have poor outcomes? BMJ 2015;350:7667.
Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Cuccurullo F. Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxides in human plasma. Free Radic Biol Med 2001;31:331-35.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F. Using standardized serum creatinine values in the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-54.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.
Li HY, Hou FF, Zhang X, Chen PY, Liu SX, Feng JX, Liu ZQ, Shan YX, Wang GB, Zhou ZM, Tian JW, Xie D. Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model. J Am Soc Nephrol 2007;18:528-38.
Lim PS, Chang YM, Thien LM, Wang NP, Yang CC, Chen TT, Hsu WM. 8-iso-prostaglandin F2alpha as a useful clinical biomarker of oxidative stress in ESRD patients. Blood Purif 2002;20:537-42.
Maatman RG, van de Westerlo EM, van Kuppevelt TH, Veerkamp JH. Molecular identification of the liver- and the heart-type fatty acid-binding proteins in human and rat kidney. Use of the reverse transcriptase polymerase chain reaction. Biochem J 1992;288:285-90.
Martin-Mateo MC, Sanchez-Portugal M, Iglesias S, de Paula A, Bustamante J. Oxidative stress in chronic renal failure. Ren Fail 1999;21:155-67.
McMahon GM, Waikar SS. Biomarkers in nephrology: Core Curriculum 2013. Am J Kidney Dis 2013;62:165-78.
Meltzer J. Renal physiology. Pharmacology and Physiology for Anesthesia 2013;32:562-73
Mezzano D, Pais EO, Aranda E, Panes O, Downey P, Ortiz M, Tagle R, González F, Quiroga T, Caceres MS, Leighton F, Pereira J. Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia. Kidney Int 2001;60:1844-50.
Mimić-Oka J, Simić T, Djukanović L, Reljić Z, Davicević Z. Alteration in plasma antioxidant capacity in various degrees of chronic renal failure. Clin Nephrol 1999;51:233-41.
Michael F, Carroll and Jonathan L. Proteinuria in Adults: A Diagnostic Approach. Am Fam Physician 2000;62:1333-40.
Modaresi A, Nafar M, Sahraei Z. Oxidative stress in chronic kidney disease. Iran J Kidney Dis 2015;9:165-79.
Müller C, Eisenbrand G, Gradinger M, Rath T, Albert FW, Vienken J, Singh R, Farmer PB, Stockis JP, Janzowski C. Effects of hemodialysis, dialyser type and iron infusion on oxidative stress in uremic patients. Free Radic Res 2004;38:1093-100.
National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2012; 39(suppl 1):S1-S266.
Oberg BP, McMenamin E, Lucas FL, McMonagle E, Morrow J, Ikizler TA, Himmelfarb J. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int 2004;65:1009-16.
Palleschi S, De Angelis S, Diana L, Rossi B, Papa V, Severini G, Splendiani G. Reliability of oxidative stress biomarkers in hemodialysis patients: a comparative study. Clin Chem Lab Med 2007;45:1211-18.
Patrick ST, Aaron TS, Vincent JD. Chronic Kidney Disease Influences Multiple Systems: Describing the Relationship between Oxidative Stress, Inflammation, Kidney Damage, and Concomitant Disease. Oxid Med Cell Longev 2015;2015:1-8.
Pelsers MM, Morovat A, Alexander GJ, Hermens WT, Trull AK, Glatz JF. Liver fatty acid-binding protein as a sensitive serum marker of acute hepatocellular damage in liver transplant recipients. Clin Chem 2002;48:2055-7.
Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol 2007;18:3177-83.
Roselaar SE, Nazhat NB, Winyard PG, Jones P, Cunningham J, Blake DR. Detection of oxidants in uremic plasma by electron spin resonance spectroscopy. Kidney Int 1995;48:199-206.
Sasaki H, Kamijo-Ikemori A, Sugaya T, Yamashita K, Yokoyama T, Koike J, Sato T, Yasuda T, Kimura K. Urinary fatty acids and liver-type fatty acid binding protein in diabetic nephropathy. Nephron Clin Pract 2009;112:c148-56.
Sinha P, Hutter G, Kottgen E, Dietel M, Schadendorf D, Lage H. Increased expression of epidermal fatty acid binding protein, cofilin, and 14-3-3-sigma (stratifin) detected by two-dimensional gel electrophoresis, mass spectrometry and microsequencing of drug-resistant human adenocarcinoma of the pancreas. Electrophoresis 1999;20:2952-60.
Small DM, Coombes JS, Bennett N, Johnson DW, Gobe GC. Oxidative stress, anti-oxidant therapies and chronic kidney disease. Nephrology 2012;17:311-21.
Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function－measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473-83.
Stoyanova E, Sandoval SB, Zúñiga LA, El-Yamani N, Coll E, Pastor S, Reyes J, Andrés E, Ballarin J, Xamena N, Marcos R. Oxidative DNA damage in chronic renal failure patients. Nephrol Dial Transplant 2010;25:879-85.
Tepel M, Echelmeyer M, Orie NN, Zidek W. Increased intracellular reactive oxygen species in patients with end-stage renal failure: effect of hemodialysis. Kidney Int 2000;58:867-72.
Terawaki H, Yoshimura K, Hasegawa T, Matsuyama Y, Negawa T, Yamada K, Matsushima M, Nakayama M, Hosoya T, Era S. Oxidative stress is enhanced in correlation with renal dysfunction: examination with the redox state of albumin. Kidney Int 2004;66:1988-93.
Toborek M, Wasik T, Drózdz M, Klin M, Magner-Wróbel K, Kopieczna-Grzebieniak E. Effect of hemodialysis on lipid peroxidation and antioxidant system in patients with chronic renal failure. Metabolism 1992;41:1229-32.
Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol 2004;24:469-73.
Wang G, Gong Y, Anderson J, Sun D, Minuk G, Roberts MS, Burczynski FJ. Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells. Hepatol 2005;42:871-79.
Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 1996;49:1304-13.
Xu Y, Xie Y, Shao X, Ni Z, Mou S. L-FABP: A novel biomarker of kidney disease. Clin Chim Acta 2015;445:85-90.
Yamamoto T, Noiri E, Ono Y, Doi K, Negishi K, Kamijo A, Kimura K, Fujita T, Kinukawa T, Taniguchi H, Nakamura K, Goto M, Shinozaki N, Ohshima S, Sugaya T. Renal L-type fatty acid binding protein in acute ischemic injury. J Am Soc Nephrol 2007;18:2894-902.