- 學位論文
腎素-血管收縮素系統在缺血再灌流急性腎損傷後進展成慢性腎臟病所扮演的角色
The role of renin-angiotensin system in ischemia-reperfusion acute kidney injury–chronic kidney disease continuum
摘要
急性腎損傷近年在台灣及全球逐年增加，許多研究發現急性腎損傷會造成許多併發症與較高死亡率，急性腎損傷也會造成慢性腎臟病的產生，兩者互為因果關係，慢性腎臟病的產生與急性腎損傷的嚴重程度、持續時間長短與發生次數有正相關，過去認為急性腎損傷只要不要太嚴重都可恢復且不會有後遺症的想法是錯的，許多研究已發現即使急性腎損傷恢復後仍會增加後續慢性腎臟病的產生，但目前的研究多著重於如何避免與減少急性腎損傷的產生與傷害程度，對於急性腎損傷進展到慢性腎臟病的機轉尚未十分清楚且對於這些病人臨床的照顧指引仍無共識。 我們在CD-1和C57BL/6老鼠建立急性腎損傷轉變為慢性腎臟病的動物模式，CD-1老鼠有兩套renin基因分別是Ren1、Ren2，腎素-血管收縮素系統活性應比較高，而C57BL/6老鼠只有一套renin基因是Ren1與人類相同，我們先進行右側腎摘除2星期後，將左側腎進行缺血性再灌流傷害，儘管一個月後血中肌酸酐已恢復正常但組織切片仍看到腎小管、腎絲球萎縮、間質有發炎細胞浸潤及纖維母細胞增生合併纖維化的表現，追蹤5-8個月後出現肌酸酐再度逐漸上升、血壓增加、蛋白尿增加的情形，這些變化在CD-1老鼠較快發生，而C57BL/6較晚才會發生，分析腎素-血管收縮素系統相關基因表現都有增加，代表腎素-血管收縮素系統在急性腎損傷後一個月仍有活性增加的情形。 急性腎損傷後一個月我們將老鼠分為三群分別給予一般飲水、含losartan (anti-Type-1A angiotensin II receptor antagonist)的飲水、含hydralazine (vasodilator with anti-hypertensive effect)的飲水，加上一組控制組僅單側腎切除後給予一般飲水，共觀察5-8個月後分析結果，給予losartan那組的老鼠死亡率比較低且比較不會有血壓增加、腎功能變差、蛋白尿增加與纖維化的情形，給予hydralazine那組的老鼠雖然血壓沒有增加，但其他病理表現都比給予losartan那組的老鼠嚴重。 我們進一步想根據動物實驗的結果來看臨床病人急性腎損傷功能恢復後給予腎素-血管收縮素系統的抑制劑是否可減少後續慢性腎病變的產生，我們研究接受心臟手術術後發生急性腎損傷的病人，因為心臟手術造成急性腎損傷的機轉與我們的動物實驗較相似，病人的納入條件為1.術前無慢性腎臟病且未服用腎素-血管收縮素系統抑制劑；2.發生急性腎損傷且血中肌酸酐恢復正常後才開始使用腎素-血管收縮素系統抑制劑。 共有587人符合收案資格，病人平均追蹤2.99年，我們發現有使用腎素-血管收縮素系統抑制劑的病人較不會產生慢性腎臟病 (26.6% vs. 42.2%, p = 0.005)，且使用腎素-血管收縮素系統抑制劑的病人需較久的時間才會產生慢性腎臟病 (1079 days vs. 520 days, p = 0.01)，多項式迴歸分析指出使用腎素-血管收縮素系統抑制劑是降低急性腎損傷後產生慢性腎臟病的獨立相關因子 (風險比率 = 0.46, p < 0.001)，這些發現可作為之後大型臨床雙盲試驗的參考，並提供預防急性腎損傷轉變為慢性腎臟病治療的參考指引，我們也將進一步探究腎素-血管收縮素系統抑制劑在急性腎損傷的其他病生理的影響。
並列摘要
Acute kidney injury (AKI) is common and associated with higher morbidity and mortality globally. AKI has also been recognized as a major risk factor for the development of chronic kidney disease (CKD). Mounting evidence has shown that AKI and CKD appear to be an interconnected syndrome. The severity, duration and frequency of AKI has been linked to the development and progression of ensuing CKD. The previous conventional wisdom that AKI survivors with fully recovered renal function tend to do well appears to be flawed. Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI. Continuous monitoring of renal function should be emphasized, even if patients have shown functional recovery after AKI. Many studies have focused on the prevention and management of AKI to reduce the ensuing CKD development. Nevertheless, more efforts are needed to develop strategies for blocking AKI-CKD transition after functional recovery. We demonstrated AKI-CKD continuum in murine model of CD-1 and C57BL/6 mice. CD-1 mice have Ren1 and Ren2 gene which is supposed to have higher RAS activity. C57BL/6 mice have only Ren1 gene that is similar to humans. We performed left renal ischemia-reperfusion injury 2 weeks after right nephrectomy in both male murine model. Despite functional recovery, focal tubular atrophy, interstitial cell infiltration and fibrosis, upregulation of genes encoding angiotensinogen and AT1a receptor were shown in kidneys 4 weeks after AKI. Thereafter, mice manifested increase of blood pressure, albuminuria and azotemia progressively. C57BL/6 mice exhibited increase of blood pressure and azotemia progressively as well, but in a slower rate than CD-1 mice. Subsequently, drinking water with or without losartan or hydralazine was administered to mice from 4 weeks after AKI. Increase of mortality, blood pressure, albuminuria, azotemia and kidney fibrosis was noted in mice with vehicle administration during the 5 to 8 month experimental period. On the contrary, these parameters in mice with losartan administration were reduced to the levels shown in control group. Hydralazine did not provide similar beneficial effect though blood pressure was controlled. These findings demonstrated that losartan can reduce ensuing CKD and mortality after functional recovery from AKI. To get insight into the clinical application of RAS inhibitor and its impact on development of ensuing CKD in AKI survivors with complete renal recovery, we studied the outcomes and relevant risk factors of cardiac surgery–associated AKI (CSA-AKI) patients who did not have CKD history before surgery in our retrospective observational cohort. Patients with CKD, unrecovered AKI, and use of RAS inhibitor before surgery are excluded. Among 587 eligible patients, 94 patients are users of RAS inhibitor which is started and continued after complete renal recovery during median follow-up period of 2.99 years. The users of RAS inhibitor show significantly lower rate of ensuing CKD (users vs. non-users, 26.6% vs. 42.2%, p = 0.005) and longer median CKD-free survival time (users vs. non-users, 1079 days vs. 520 days, p = 0.01). Multivariate Cox regression analyses further demonstrate that use of RAS inhibitor is independently associated with lower risk of ensuing CKD (hazard ratio = 0.46, p < 0.001). We conclude that use of RAS inhibitor in CSA-AKI patients after renal functional recovery is associated with lower risk of ensuing CKD development. From bench to clinical study, RAS blockade seems to be a potential treatment to prevent AKI-CKD continuum. Further elucidation of RAS effect on renal recovery and randomized-controlled clinical study should be initiated in the future.
參考文獻
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