血管張力素抑制劑-氯沙坦鉀，能減少急性腎損傷後進展成慢性腎臟病甚至死亡的風險

許多臨床研究上的證據顯示，急性腎損傷是造成慢性腎臟病的發生，以及造成其惡化的重要風險因子。慢性腎臟病，除了會演變成末期腎臟病外，也會增加心血管疾病跟死亡的風險，從臨床研究上發現，不管急性腎損傷嚴重與否，都會提高未來發展成慢性腎臟病的機率。直到今日，關於急性腎損傷進展成慢性腎臟病的機制，仍然不清楚，也因此，在我們的研究中，我們建立了動物模型，用來研究在急性腎損傷發生，腎功能完全回復後，是透過什麼機制，進一步進展成慢性腎臟病並使其惡化。在我們的實驗中，首要目標，是建立能觀察到，因為急性腎損傷，而發展成慢性腎臟病的動物模型，我們採用CD-1八週大的公鼠，先將其右側的腎臟切除，在切除後兩週，於控制老鼠體溫於攝氏37度的環境下，利用微小的動脈夾，夾住左側腎臟血管28分鐘，使左側腎臟遭受缺血後再灌流的傷害，在傷害後兩天，小鼠血液中的尿素氮和肌酸酐的數值，都會顯著上升，在傷害後14天，約有20%的小鼠會死亡，活下來的小鼠，在傷害後一個月，其血液中尿素氮和肌酸酐濃度，都會回復到與只有單側腎切除以及假手術的組別無異的程度，但在這些受傷害小鼠，於傷害後一個月的腎臟組織切片中，發現到局部性的腎小管萎縮、腎間質有細胞浸潤，以及腎臟纖維化等異常的狀況，另外也觀察到腎臟內有些基因表現量發生改變，如第一、第三型膠原纖維、平滑肌動蛋白、腎損傷分子、嗜中性白血球明膠酶相關運載蛋白、第一型血管張力素受器、血管收縮素原等基因的表現量，都顯著上升，且在術後五個月的小鼠身上發現，其血壓會上升，尿液中微白蛋白/肌酸酐比值（蛋白尿）、血液中的尿素氮和肌酸酐都會惡化，腎臟纖維化的情形也會更嚴重。於是我們進一步研究在我們的動物模式中，高血壓跟腎臟內的腎素-血管張力素系統，是否在急性腎損傷復原後，到發生慢性腎臟病的過程，有其角色存在。我們在缺血後再灌流的術式之後一個月開始在老鼠的飲水中給予血管張力素受體阻斷劑，或者直接使血管舒張的單純降血壓藥物進行治療，以只有切除單側腎臟的老鼠作為控制組，觀察各組血壓、蛋白尿、以及血液中尿素氮和肌酸酐的數值，結果發現，在完全不治療的組別，其死亡率、蛋白尿、血壓、血液中的尿素氮和肌酸酐，以及腎臟纖維化的情況等指標，都較控制組要來得嚴重，但這些指標在給予血管張力素受體阻斷劑的組別，其血液中的尿素氮和肌酸酐都維持在與控制組相同的水準，但這樣的保護效果卻沒有出現在使用單純降血壓藥物將血壓控制良好的組別上。由我們動物實驗的結果，我們猜測在急性腎損傷發生後，儘管生化檢測的數值回復到正常，但腎臟病沒有完全修復，腎臟內的腎素血管收縮素系統會被活化，而這個系統的活化，是造成腎臟緊接著走向慢性腎臟病的一個可能機制。未來，我們希望能進一步在臨床的實驗上，證實給予曾經發生過急性腎損傷的病人血管張力素受體阻斷劑，能預防其進展為慢性腎臟病甚至死亡的風險。

關鍵字

急性腎損傷；慢性腎臟病；腎素血管收縮素系統

並列摘要

Evidence from many clinical studies supports that acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD) and disease progression. Not only does CKD lead to end-stage renal disease (ESRD), but it also increases the risk of cardiovascular disease or even death. Clinical studies often disclose that the higher the AKI severity of a patient is, the more likely her/his kidneys progress into CKD. To this day, the mechanism underlying the incident CKD and disease progression after AKI remains illusive. We therefore conducted this study to get insight into the mechanism underlying the development and progression of CKD after functional recovery from AKI in a murine model. In our pilot study to set up a murine model of AKI-CKD continuum, we performed right uni-nephrectomy (NX) first in a group of male adult CD-1 mice. We then induced ischemia-reperfusion injury (IRI) to left kidney using non-traumatic micro-aneurysm clip to clamp renal artery with core body temperature maintained at 370C under a homeothermic blanket system 2 weeks later. Severe AKI with significant elevation of plasma levels of blood urea nitrogen (BUN) and creatinine was demonstrated 2 days after 28-minute warm ischemia and then reperfusion. Although 20% of mice died within 2 weeks after NX+IRI, functional recovery shown by the decrease of plasma BUN and creatinine to the levels seen in sham and NX control mice was observed by 4 weeks after injury. However focal tubular atrophy, increased interstitial cell infiltration and fibrosis were seen in the kidneys of mice 4 weeks after NX+IRI. Gene expression, including Col1a1, Acta2, Lcn2, Havcr1, Agtr1a and Agt which encoded collagen I 1 chain, -smooth muscle actin, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, type 1a angiotensin II receptor and angiotensinogen respectively, was increased in the kidneys of mice 4 weeks after NX+IRI. Moreover, the systolic blood pressure (BP), urinary albumin-creatinine ratio (ACR), plasma levels of BUN and creatinine and kidney fibrosis increased in mice 5 months after NX+IRI. We then investigated the roles of hypertension and intrarenal RAS activation in the development and progression of CKD after functional recovery from AKI using the murine model of AKI-CKD continuum. Drinking water with or without type 1a angiotensin II receptor blocker losartan or direct vasodilator hydralazine was administered to NX+IRI mice from 4 weeks after injury. Mice with NX only were served as the control. Systolic BP, urinary ACR and plasma levels of BUN and creatinine were evaluated. Compared to NX group, NX+IRI mice showed acute rise of plasma BUN and creatinine on day 2 after IRI. Systolic BP, plasma levels of BUN and creatinine were not different between mice before starting different treatments at 4 weeks after IRI. During the 5-month experimental period, increase of mortality, systolic BP, urinary ACR, plasma levels of BUN and creatinine and kidney fibrosis was noted in NX+IRI group. On the contrary, these parameters in mice with losartan treatment were reduced to the levels observed in NX group. However hydralazine treatment did not provide similar protective effect even though systolic BP was controlled to the levels observed in NX group. These data suggest that kidneys do not repair completely and the CKD will progress even though the kidney function recovers initially in our murine AKI model. Intrarenal RAS activation may underlie one of the mechanisms for the subsequent CKD progression. Future studies are needed to explore the preventive effect of RAS blockade on incident CKD and disease progression in patients recovering from AKI.

並列關鍵字

Acute kidney injury ； Chronic kidney disease ； Renin-Angiotensin system

參考文獻

1. Himmelfarb, J., et al., Acute kidney injury: changing lexicography, definitions, and epidemiology. Kidney Int, 2007. 71(10): p. 971-6.

2. Devarajan, P., Biomarkers for the Early Detection of Acute Kidney Injury. Curr Opin Pediatr, 2011. 23(2): p. 194-200.

3. Xue, J.L., et al., Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol, 2006. 17(4): p. 1135-42.

4. Feest, T.G., et al., Incidence of severe acute renal failure in adults: results of a community based study. BMJ, 1993. 306(6876): p. 481-483.

5. Hoste, E.A., et al., RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care, 2006. 10(3): p. R73.

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血管張力素抑制劑-氯沙坦鉀，能減少急性腎損傷後進展成慢性腎臟病甚至死亡的風險

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