2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645188摘要：流行病學顯示過去二十多年來急性腎損傷的發生率在美國增加約三倍多，但處理伴隨急性腎損傷而來的合併症所付出之醫療成本仍相對龐大。尤其在術後危急患者合併急性腎衰竭之死亡率更高達百分之六、七十。外科重症加護病房裡病人缺血再灌流，和失調的發炎反應及接續產生氧化壓力被認為是急性腎衰竭的致病因。然而臨床醫療者對於併發急性腎衰竭病患的預後，大多是以醫師的臨床經驗，目前仍無適合敏感的生物指標，提供給醫療臨床做為預測病患腎衰竭之參考。我們延續以台大外科加護病房為主的多年性多中心前瞻性的急性腎衰竭(NSARF)研究，了解外科術後急性腎衰竭的特色多是因為體液灌流不足而引起，進一步想要了解如何早期診斷病人的腎衰竭，預測病人臨床的進程，併給予早期且正確的處置。本研究第一年目標：探討現今急性腎損傷之新式生物指標NGAL, L-FABP, KIM1, IL18和Hepcidin-25的角色，採用模組(AKI panel)的方式判讀心血管術後(缺血再灌注)病人在血液以及尿液成分中，利用NSARF 亞洲最大術後急性腎損傷檢體庫進行分析，以三維思考為主軸來發展新式生物指標(時序、腎損傷病因之診斷，及預後)。第二年目標：探討腎臟在發生缺血性腎損傷時，有無其他的生物指標可以早期預測急性腎損傷。我們利用蛋白質體學方法，分析術後符合RIFLE腎損傷定義的心血管術後(缺血再灌注)併發急性腎損傷病人的血、尿，利用質譜學技術找出術後病人表現出的特異性蛋白質(biomarkers)，尤其針對本團隊前驅研究發現的急性腎損傷生物指標(Hemojuvelin, HJV)進行臨床驗證(validation)。第三年目標：利用近端腎小管細胞株逕行缺氧模式、並利用缺血再灌注併發急性腎損傷之小鼠模式進行研究特異性生物指標表現方式；尤其探討前驅研究發現生物指標(HJV)在併發急性腎損傷過程在生物體內所扮演的角色，並且嘗試用此來減緩急性腎損傷的傷害。<br> Abstract: Postoperative acute renal failure is a serious complication resulting in a prolonged stay andhigh mortality. Acute renal failure (ARF) develops in 5 to 30% of patients who undergosurgery, and for all causes, it is associated with mortality rates of 60–70%. Despite significanttechnical advances in therapeutics, the mortality and morbidity rates associated with acutekidney injury remain dismally high and have not appreciably improved during the past fourdecades. Hypotension related ischemic reperfusion acute renal failure, and sepsis relatedoxidative stress and cytokines crisis could induced acute renal failure in postoperative patients.Although the serum creatinine concentration performs fairly well for estimating kidneyfunction in patients with stable chronic kidney disease, it performs poorly in the setting ofAKI. An ideal biomarker for acute kidney injury would help clinicians and scientists diagnosethe most common form of acute kidney injury in hospitalized patients, acute tubular necrosis,early and accurately and may aid to risk-stratify patients with acute kidney injury bypredicting the need for renal replacement therapy, the duration of acute kidney injury, thelength of stay, and mortality. In this pioneer study we will find types of biomarkers fall into (1)validation of the reported novel biomarkers in post-operative AKI, merged in the pattern ofpanel groups. (2) explore the novel biomarkers by proteomics using the urine before and postoperation. We also focus on validation the sensitivity and specificity of our newly discoveredprotein (Hemojuvelin, HJV),and (3) validate the above biomarkers in H2O2 injured humanproximal renal tubule cell line and ischemic reperfusion AKI mice. The effect of HJVinjection to rescue AKI mice will be evaluated. These markers might extend the therapeuticwindow during which timely and individualized patient management might be possible.流行病學顯示過去二十多年來急性腎損傷的發生率在美國增加約三倍多，但處理伴 隨急性腎損傷而來的合併症所付出之醫療成本仍相對龐大。尤其在術後危急患者合併急 性腎衰竭之死亡率更高達百分之六、七十。外科重症加護病房裡病人缺血再灌流，和失 調的發炎反應及接續產生氧化壓力被認為是急性腎衰竭的致病因。然而臨床醫療者對於 併發急性腎衰竭病患的預後，大多是以醫師的臨床經驗，目前仍無適合敏感的生物指 標，提供給醫療臨床做為預測病患腎衰竭之參考。我們延續以台大外科加護病房為主的 多年性多中心前瞻性的急性腎衰竭(NSARF)研究，了解外科術後急性腎衰竭的特色多是 因為體液灌流不足而引起，進一步想要了解如何早期診斷病人的腎衰竭，預測病人臨床 的進程，併給予早期且正確的處置。本研究第一年目標：探討現今急性腎損傷之新式生 物指標NGAL, L-FABP, KIM1, IL18和Hepcidin-25的角色，採用模組(AKI panel)的方式 判讀心血管術後(缺血再灌注)病人在血液以及尿液成分中，利用NSARF 亞洲最大術後 急性腎損傷檢體庫進行分析，以三維思考為主軸來發展新式生物指標(時序、腎損傷病 因之診斷，及預後)。第二年目標：探討腎臟在發生缺血性腎損傷時，有無其他的生物 指標可以早期預測急性腎損傷。我們利用蛋白質體學方法，分析術後符合RIFLE腎損傷 定義的心血管術後(缺血再灌注)併發急性腎損傷病人的血、尿，利用質譜學技術找出術 後病人表現出的特異性蛋白質(biomarkers)，尤其針對本團隊前驅研究發現的急性腎損傷 生物指標(Hemojuvelin, HJV)進行臨床驗證(validation)。第三年目標：利用近端腎小管細 胞株逕行缺氧模式、並利用缺血再灌注併發急性腎損傷之小鼠模式進行研究特異性生物 指標表現方式；尤其探討前驅研究發現生物指標(HJV)在併發急性腎損傷過程在生物體 內所扮演的角色，並且嘗試用此來減緩急性腎損傷的傷害。Postoperative acute renal failure is a serious complication resulting in a prolonged stay and high mortality. Acute renal failure (ARF) develops in 5 to 30% of patients who undergo surgery, and for all causes, it is associated with mortality rates of 60–70%. Despite significant technical advances in therapeutics, the mortality and morbidity rates associated with acute kidney injury remain dismally high and have not appreciably improved during the past four decades. Hypotension related ischemic reperfusion acute renal failure, and sepsis related oxidative stress and cytokines crisis could induced acute renal failure in postoperative patients. Although the serum creatinine concentration performs fairly well for estimating kidney function in patients with stable chronic kidney disease, it performs poorly in the setting of AKI. An ideal biomarker for acute kidney injury would help clinicians and scientists diagnose the most common form of acute kidney injury in hospitalized patients, acute tubular necrosis, early and accurately and may aid to risk-stratify patients with acute kidney injury by predicting the need for renal replacement therapy, the duration of acute kidney injury, the length of stay, and mortality. In this pioneer study we will find types of biomarkers fall into (1) validation of the reported novel biomarkers in post-operative AKI, merged in the pattern of panel groups. (2) explore the novel biomarkers by proteomics using the urine before and post operation. We also focus on validation the sensitivity and specificity of our newly discovered protein (Hemojuvelin, HJV),and (3) validate the above biomarkers in H2O2 injured human proximal renal tubule cell line and ischemic reperfusion AKI mice. The effect of HJV injection to rescue AKI mice will be evaluated. These markers might extend the therapeutic window during which timely and individualized patient management might be possible.Translational medicineAnimal models for human diseasesFunctional OMICs急性腎衰竭蛋白質基因體生物標記主要手術