2013-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645105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中心前瞻性的急性腎衰竭(NSARF)研究，藉由前一年國科會資助，發現尿液中的sHJV蛋白質在早期術後的人類或是動物的尿液檢體中顯著的增加。本計畫預計以三年期規畫進行更深入的研究；第一年以模擬腎小管細胞株的急性腎損傷模式，主要以本團隊前期國科會計畫發現的急性腎損傷生物標記調節鐵調素HJV進行細胞行為監控，以干擾核醣核酸(siRNA)技術分析HJV相關基因之影響，並以專一性蛋白脢抑制劑減緩HJV降解避免急性腎損傷。第二年以HJV 對於預測各種模式導致腎臟急性損傷的預測能力，藉以做病因的分層。第三年以HJV 搭配新式的生物標記驗證，利用我們NSARF 亞洲最大術後急性腎損傷檢體庫進行分析，判讀心血管術後(缺血再灌注)病人的血液以及尿液成分以做比較，作診斷和危險因子的分層(stratification)，以三維思考為主軸來驗證(時序、腎損傷病因之診斷，及病因分層)AKI，期待未來在重症腎臟醫學(critical nephrology)能有類似心肌酵素的急性生物標記(renal troponin)出現，帶給急性腎損傷在診斷上的突破。<br> Abstract: Postoperative acute renal failure is a serious complication resulting in a prolonged stay andhigh mortality. Acute kidney injury (AKI) 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. The serum creatinine concentration performs poorly in the setting of AKI. An idealbiomarker for acute kidney injury would help clinicians and scientists diagnose the mostcommon form of acute kidney injury in hospitalized patients, acute tubular necrosis, early andaccurately and may aid to risk-stratify patients with acute kidney injury by predicting the needfor renal replacement therapy, the duration of acute kidney injury, the length of stay, andmortality. In this pioneer study we find urine soluble hemojuvelin, (HJV) elevated duringAKI both in patients and mice model. Therefore, the program fall into (1) exam the signalpathway of mHJV, sHJV, SMAD/BMP pathway in human kidney tubule cell line (HK2) andrestored AKI by furin inhibitor, (2) stratification the disease severity and prognosis in kinds ofAKI rat models (3) validation of the HJV with reported novel biomarkers in post-operativeAKI to predict patients’ outcomes. We also focus on validation the sensitivity and specificityof our newly discovered protein HJV. Therefore, this study is novel with documentedpreliminary data. The markers might extend the therapeutic window during which timely andindividualized 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 為主的多中心前瞻性的急性腎衰竭(NSARF)研究，藉由前一年國科會資助，發現尿液 中的sHJV蛋白質在早期術後的人類或是動物的尿液檢體中顯著的增加。本計畫預計以 三年期規畫進行更深入的研究；第一年以模擬腎小管細胞株的急性腎損傷模式，主要 以本團隊前期國科會計畫發現的急性腎損傷生物標記調節鐵調素HJV進行細胞行為監 控，以干擾核醣核酸(siRNA)技術分析HJV相關基因之影響，並以專一性蛋白脢抑制劑 減緩HJV降解避免急性腎損傷。第二年以HJV 對於預測各種模式導致腎臟急性損傷的 預測能力，藉以做病因的分層。第三年以HJV 搭配新式的生物標記驗證，利用我們 NSARF 亞洲最大術後急性腎損傷檢體庫進行分析，判讀心血管術後(缺血再灌注)病人 的血液以及尿液成分以做比較，作診斷和危險因子的分層(stratification)，以三維思考為 主軸來驗證(時序、腎損傷病因之診斷，及病因分層)AKI，期待未來在重症腎臟醫學 (critical nephrology)能有類似心肌酵素的急性生物標記(renal troponin)出現，帶給急性腎 損傷在診斷上的突破。Postoperative acute renal failure is a serious complication resulting in a prolonged stay and high mortality. Acute kidney injury (AKI) 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. The serum creatinine concentration 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 find urine soluble hemojuvelin, (HJV) elevated during AKI both in patients and mice model. Therefore, the program fall into (1) exam the signal pathway of mHJV, sHJV, SMAD/BMP pathway in human kidney tubule cell line (HK2) and restored AKI by furin inhibitor, (2) stratification the disease severity and prognosis in kinds of AKI rat models (3) validation of the HJV with reported novel biomarkers in post-operative AKI to predict patients’ outcomes. We also focus on validation the sensitivity and specificity of our newly discovered protein HJV. Therefore, this study is novel with documented preliminary data. The markers might extend the therapeutic window during which timely and individualized patient management might be possible.HJV急性腎衰竭Furin生物標記主要手術HJVAcute kidney injuryFurinbiomarkermajor operation