研究背景：慢性腎病患者是心血管疾病的高危險群，而高血壓則是心血管疾病及腎功能惡化的重要危險因子，因此使用血管張力素轉化抑制劑與血管張力素受體阻斷劑（ACEI/ARB）作為控制高血壓並延緩腎功能惡化有其重要性。目前已有文獻與大型臨床研究證實使用ACEI/ARB在高血壓之糖尿病腎病患者有減低蛋白尿惡化與保護腎臟的效果，但在血壓原本正常或偏低的腎臟疾病患者，使用這類作用於RAAS (Renin-Angiotensin-Aldosterone System)的藥物在腎功能、蛋白尿(proteinuria)與心血管疾病的結果目前尚未有研究證實，其腎臟保護效果與理想的最低血壓值尚未得知。關於ACEI/ARB在血壓正常之慢性腎病患者在國外已有研究證實有降低蛋白尿的效果，而對於延緩腎功能惡化如血清肌酸酐（serum creatinine, Scr）上升或蛋白尿惡化，尚待研究進一步證實。
研究目的：評估ACEI/ARB在正常血壓與高血壓之慢性腎病患者之保護腎功能與心血管的效果。
研究流程：本研究共納入225位自民國90年至94年間於台南市成功大學醫學院附設醫院腎臟科門診接受長期治療之慢性腎病患者，這些患者在進入研究前後半年內其平均門診血壓值小於140/90 mmHg，分為正常血壓與高血壓控制良好兩組，並依有無使用ACEI/ARB再分為四組。每半年記錄病患相關資料，包括：病患基本資料、門診血壓值、腎功能指標（Scr與每日蛋白尿流失量, daily protein loss, DPL）、各項生化檢驗數值、追蹤時間用藥史與是否有發生心血管事件。期間不符合收納標準（包括罹患癌症或接受免疫抑制劑、資料不完整與追蹤時間不足）者共排除44位，最後納入研究分析者為181位。
研究方法：主要評估指標為Scr 或蛋白尿惡化程度達基礎值1.5倍以上為達到評估終點，次要評估指標為是否發生心血管事件。統計軟體採用SAS 9.1進行各項指標分析，統計方法主要以Kaplan-Meier存活分析主要與次要終點指標，並採用Log-Rank及Cox proportional hazard regression作為單變數與多變數的分析方法。
研究結果：181位慢性腎病患者中血壓正常且使用ACEI/ARB共53位，正常血壓未使用ACEI/ARB則有34位；高血壓控制良好且使用ACEI/ARB有57位，高血壓控制良好未使用ACEI/ARB則有37位。在正常血壓的兩組基本資料比較結果，以ACEI/ARB組平均年齡較輕、基礎腎功能較好、蛋白尿嚴重度較輕（48±16 vs. 65±13歲；119±5 vs. 124±11 mmHg；1.6±0.8 vs. 2.5±1.2 mg/dL, p<0.05)；在慢性腎病之病因比較，對照組中為慢性腎絲球腎炎比例較低(12% vs. 49%, p<0.001)；合併使用藥品方面，兩組在併用Non-dihydropyridine calcium channel blocker (NDHP CCB)有顯著差異（對照組：9% vs. ACEI/ARB組：0%, p<0.05）。存活率分析的結果在多變數分析下顯示：合併主要指標而言，ACEI/ARB組可降低71%危險性（95%CI 0.13-0.66, p=0.003）；單獨分析Scr的指標，ACEI/ARB組有降低腎功能惡化的趨勢（p=0.079）；而在蛋白尿的結果上，ACEI/ARB可顯著降低63%惡化之危險性。在高血壓控制良好之慢性腎病患者，兩組基本資料方面，ACEI/ARB組平均年齡、身體質量指數(BMI)、收縮壓與Scr均較對照組低（57±13 vs. 65±13歲, p=0.003；26±3.2 vs. 23±3.8 kg/m2, p=0.010；126±9 vs. 130±7 mmHg, p=0.021；1.9±1.0 vs. 2.6±1.0 mg/dL, p=0.003)、併用statin比率較高(54% vs. 30%, p=0.019），NDHP CCB的使用較低（5% vs 35%., p<0.001）。分析的結果，合併腎功能指標，在多變數分析下ACEI/ARB組未顯著減低惡化的危險性，若單獨分析Scr，ACEI/ARB可顯著減低危險性70% (95% CI 0.12-0.74, p=0.010)，但在蛋白尿的指標上，使用ACEI/ARB則無顯著效果。以整體使用ACEI/ARB之慢性腎病患者與對照組作分析， ACEI/ARB組平均年齡、BMI、收縮壓、基礎值Scr顯著低於對照組（53±15歲vs. 65±13 歲, p<0.001；25 ± 3.7 kg/m2 vs. 24 ± 3.7 kg/m2, p<0.001；123 ± 10.1 mmHg vs. 127 ± 9.5 mmHg, p=0.005；1.8 ± 0.9 mg/dL vs. 2.5 ± 1.1 mg/dL, p<0.001），併用statin比率較高、NDHP CCB合併使用較低（48% vs 32%, p=0.036；3% vs. 23%, p<0.001）與併有腦血管疾病較低（3% vs. 10%, p=0.040）。在多變數分析的結果方面，ACEI/ARB的使用在合併主要評估指標可降低危險性50% (95% CI 0.30-0.81, p=0.006)；單獨分析Scr及蛋白尿惡化，ACEI/ARB也顯著降低危險性各為49%與67% (95% CI 0.27-0.97, p=0.039；95% CI 0.18-0.62, p=0.010)。在次要評估指標心血管事件之分析上，ACEI/ARB在各組中均未有顯著影響，併有心血管疾病、腦血管疾病或基礎值蛋白尿，不論在單變數與多變數分析下會顯著增加心血管疾病的風險。
結論：本研究結果證實於慢性腎病患者使用ACEI/ARB可延緩Scr上升與蛋白尿惡化或合併兩者為評估指標時均有顯著的治療效果；其中在血壓正常之慢性腎病患者使用ACEI/ARB，有降低蛋白尿的顯著效果，對腎功能也具有保護的趨勢，合併兩項指標的分析也顯示具有降低腎功能惡化的顯著效果。在併有高血壓慢性腎病者，ACEI/ARB的使用及良好的血壓控制可達到保護腎功能的效果；在血壓正常的慢性腎病患者，使用ACEI/ARB治療，可延緩腎功能的下降(趨勢)與顯著減緩蛋白尿的惡化，不論是正常血壓或高血壓的慢性腎病患者，ACEI/ARB在腎臟保護有其重要的角色；但在心血管保護方面，因心血管事件的發生率不高，故其保護角色在統計學上不顯著。

Background：Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD), and hypertension is a risk factor for CKD and CVD. Clinically, ACE inhibitors or angiotensinⅡreceptor blockers (ACEI/ARB) is used for treatment of hypertension and CKD. Although most studies have proved the antihypertensive and antiproteinuric effects of ACEI/ARB, it is unclear of the reno-cardiac protection of ACEI/ARB and the ideal blood pressure (BP) in normotensive CKD patients. One study showed antiproteinuric effects of ACEI/ARB in normotensive CKD patients, but it has not been established the benefits of ACEI/ARB with regard to retarding the progression of renal function.
Objective：To evaluate the renal and cardiovascular protective effects of ACEI/ARB in normotensive and well-controlled hypertensive CKD patients.
Method：We enrolled 225 CKD patients of stage 1 to 4 with normal BP (<140/90 mmHg) at entry of the study in National Cheng Kung University Hospital from Jan, 2001 to Dec 2004. The patients were grouped into normotensive and well-controlled hypertensive groups according to the use of ACEI/ARB. We had followed these patients until Dec 2005 and recorded the clinical data every 6 month.There were 44 patients excluded because of receiving immunotherapy, incomplete clinical data or followed up less than 6 months. Finally, a total of 181 CKD patients were included for analysis.
Main Outcome Measures：The primary endpoint was defined as a 50% increase of Scr (including end-stage renal disease) or proteinuria from the baseline, and the secondary endpoints were the CV events and related mortality.
Statitistical Analysis：The event-free curves were based on Kaplan-Meier analysis and significances were assessed by the log-rank test. A Cox proportional hazard regression model was used to determine the independent variables. Results were reported as the relative risk and their 95% confidence intervals. P value less than 0.05 was considered significant. SAS 9.1 statistical software for windows was used for analyses.
Results：Among the 181 CKD patients with BP <140/90 mmHg, 53 were normotensive patients with the use of ACEI/ARB, 34 normotensive patients without use of ACEI/ARB (controlled group), 57 well-controlled hypertensive patients with the use of ACEI/ARB and 37 well-controlled hypertensive patients without the use of ACEI/ARB. In the normotensive study subjects, the ACEI/ARB group were younger, baseline renal function better and proteinuria milder than the controlled group. About the etiology of renal disease, there were significant differences between groups in chronic glomerular nephropathy (49% in ACEI/ARB and 12% in controlled groups) and with concomitant use of non-dihydropyridine calcium channel blocker (NDHP CCB)(none in ACEI/ARB and 9 % in controlled groups). The other baseline characteristics were not different between both groups. After adjustment of other baseline covariates, ACEI/ARB reduced the risk of composite renal endpoints by 71% (95% CI 0.13-0.66, p=0.003).There was a trend with regard to retarding the progression of renal function and a significant benefit on proteinuria, with risk reduction of 63% (95% CI 0.15-0.91, p=0.030) by using the ACEI/ARB. In well-controlled hypertensive subjects the baseline characteristics of ACEI/ARB group were younger, lower body mass index (BMI), lower systolic BP, better renal function, higher percentage of concomitant medication with statin and lower percentage with NDHP CCB than the controlled group. After adjustment of the other baseline covariates, ACEI/ARB demonstrated the benefit for preserving renal function, with a risk reduction of 70% (95% CI 0.12-0.74, p=0.010). Risk reduction of proteinuria and composite renal endpoints didn’t differ between ACEI/ARB and controlled groups. Furthermore, in the total study subjects, patients in ACEI/ARB group were younger, lower BMI and BP, better renal function and less cerebrovascular events history than controlled group. Besides, ACEI/ARB group had higher percentage of statin use and lower of NDHP CCB than controlled group. Similarly, after adjustment of other baseline covariates, ACEI/ARB significantly reduced the risks of renal function, proteinuria and composite renal endpoints as well by 49% (95% CI 0.27-0.97, p=0.039), 67% (95% CI 0.18-0.62, p=0.010) and 50% (95% CI 0.30-0.81, p=0.006), respectively. In the secondary outcome, the CV events didn’t differ between ACEI/ARB and controlled groups after univariate and multivariate analysis.
Conclusion：ACEI/ARB showed renoprotective effects in CKD patients with BP lower than 140/90 mmHg with regard to retarding the 50% increase of Scr level and proteinuria in our study. Among the normotensive subjects, ACEI/ARB had significant antiproteinuric effect and a trend for preserving renal function. Among the hypertensive CKD patients, renoprotection was achieved by means of using ACEI/ARB and good BP control. In conclusion, our study demonstrated renoprotective effects of ACEI/ARB. However, as for CV protection by ACEI/ARB, there was no significant beneficial effect between groups because of low incidence of CV events and small sample size.

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