臺灣博碩士論文加值系統

中文摘要

慢性腎臟疾病（chronic kidney disease, CKD）是指無論病因為何，當腎臟受到傷害或腎功能下降已持續數月或更久。一般多數患者會逐漸進展成末期腎病變（end stage renal disease, ESRD）。據統計指出，ESRD發生率及盛行率持續上揚，且相關醫療支出極為龐大。已知CKD進展的危險因子包括高血壓、蛋白尿、第二血管張力素過多、血糖控制不良和攝取過量蛋白質等。為預防或延緩腎臟疾病相關的不良反應，針對疾病惡化的機轉給予多重風險因子介入療法，可達到腎臟保護的作用。其中最主要的4種方法分別為控制血壓、給予血管張力素轉換酵素抑制劑或血管張力素接受器阻斷劑(ACEIs或ARBs)、控制血糖和飲食限制蛋白質。因為第二血管張力素在CKD進展的病態生理上佔相當重要角色，所以諸多研究探討ACEIs和ARBs的影響程度，已證實此兩類藥品可延遲腎臟疾病的進展。臨床比較ARBs和ACEIs的試驗多為短時間的小型研究，發現兩者降血壓效果和降蛋白尿效果相當。此外，因為ACEIs和ARBs的藥理機轉及其藥效學並不相同，所以合併治療或許具有加成效果。
由於大多數臨床證據來自國外非東方人的研究報告，是否台灣民眾使用此兩類藥品也有同樣效果仍未知，故我們評估國立成功大學醫學院附設醫院腎臟科門診之腎臟病患者，選擇血清肌酸酐濃度（serum creatinine, Scr）大於1.5 mg/dL或每天尿液中蛋白質流失量（daily protein loss, DPL）超過1 g的患者。以回溯性方式紀錄病患基本資料、疾病、所使用的降血壓藥品，以及血糖值、糖化血色素、膽固醇、血鉀、Scr、DPL的變化等生化檢查值。主要評估指標定義為Scr或DPL比基礎值增加50 %，次要評估指標為患者血壓控制情形及血鉀變化。利用Kaplan-Meier 存活分析與log-rank test檢定藥品使用及腎功能預後因子對存活率之影響，再以Cox proportional hazards model分析法校正基礎共變數。
本研究共納入132名患者，使用ACEIs或ARBs者歸為ACEIs/ARBs組，使用其他降血壓藥品視為對照組。兩組在疾病種類上均以高血壓佔多數，ACEIs/ARBs組的「慢性腎絲球腎炎」和「慢性腎絲球腎炎合併高血壓」高於對照組。降血壓用藥之處方型態分析中，兩組均主要使用單一藥品或併用兩種藥品，大致上可達良好的血壓控制（接近125/75 mmHg）。合併使用其他降血壓藥品以鈣離子阻斷劑最多，又以DCCBs (dihydropyridine calcium channel blockers)遠超過NDCCBs (non-dihydropyridine calcium channel blockers)。
兩組病患之基本性質大致無差異，只有對照組表現出年齡較大及Scr值較高的情形 (66.3±10.5 vs. 52.3±15.5 歲; 2.4±0.9 vs. 2.0±1.0 mg/dL; p均 < 0.05)。追蹤28.6-32.5個月後，結果發現ACEIs/ARBs組腎臟疾病表現較好（p < 0.05），患者Scr上升或DPL惡化較緩慢，此好處與血壓變化無關。藥品、性別、Scr和蛋白尿四者與腎臟病患的存活率表現在單變項分析中具相關性，但多變項分析只有藥品具顯著影響。
此外，我們也比較ACEIs與ARBs的使用效果。病患基本性質方面，以ACEIs組的男性顯著多於ARBs組，且血鉀值也以ACEIs組的濃度明顯較高，至於其他項目則無差異。平均追蹤24.6-31.1個月後，舒張壓和Scr均以ARBs組表現較好 (74.3±13 vs. 80.1±11.4 mmHg; 1.9±0.6 vs. 2.4±1.2 mg/dL, p 均< 0.05)。其他如血鉀和存活率，兩組則無顯著差異。
本研究證實ACEIs和ARBs的確具有腎臟保護效果，與文獻回顧所得一致，且本研究也發現ARBs比ACEIs在控制舒張壓及減緩Scr上升等方面更有效。由於只有3人併用此兩類藥品，故無法評估其合併使用後的影響。另外，在多變項分析中，Scr和蛋白尿兩者與存活率並無顯著相關，推測原因可能是樣本數太小所造成。

Abstract

Chronic kidney disease (CKD) is the presence of kidney damage or impaired kidney function for more than several months irrespective of the primary causes. Most of the patients with CKD progress to end-stage renal disease (ESRD) finally. The epidemiological data showed a rising incidence and prevalence of ESRD. ESRD patients consume a large and disproportionate share of national health care resources. Multiple risk factors contributing to progression of CKD include hypertension, proteinuria, excess angiotensin II, hyperglycemia, increased protein intake, etc. In order to slow progression of kidney disease and prevent ESRD, multiple risk factors intervention treatment (MRIFT) based on inhibiting the progression mechanism can provide effective renoprotection. Four major therapeutic strategies include strict control of blood pressure (BP), use of ACEIs (or ARBs), tight control of blood glucose in diabetes, and dietary protein restriction. Because angiotensin II plays a major role in the pathogenesis of CKD, both ACEIs and ARBs have demonstrated to retard renal progression. Comparing the two classes of drugs, although limited to short-term studies, it revealed that both have similar BP control and anti-proteinuric effect, and combination therapy may augment the individual benefit.
Because most clinical data came from non-oriental population, we have investigated the features and therapeutic responses of CKD patients in National Cheng Kung University Hospital, Tainan, Taiwan. From Oct. 2001 to Jan. 2002, renal patients with serum creatinine (Scr) > 1.5 mg/dL or daily urinary protein loss (DPL) > 1 g/day were enrolled into this study. Detailed medical records on the age, gender, smoking, underlying diseases, BP, anti-hypertensive medication, and biochemistry including fasting blood glucose, HbA1C, cholesterol, potassium, Scr and DPL were collected. The primary endpoint was defined as a 50 % increase of Scr or DPL from the baseline. The secondary endpoints included change in serum potassium and BP control. Kaplan-Meier survival analysis with log-rank test was performed to evaluate the impact of ACEIs and ARBs on renal progression, and Cox proportional-hazards model was introduced to adjust the confounding variables.
A total of 132 CKD patients were included in this study and were classified into the ACEIs/ARBs group, treating with ACEIs (n = 45), ARBs (n = 31) or ACEIs + ARBs (n = 3), and the control group, treating with other anti-hypertensive agents (n = 53). Hypertension is the most common underlying disease in both groups (35.4 % and 35.8 %). The incidences of chronic glomerulonephritis (GN) and chronic GN combined with hypertension were significantly higher in the ACEIs/ARBs group. Monotherapy and dual antihypertensive therapy were the main prescriptive types, and most patients could reach the therapeutic target of BP control (125/75 mmHg). Calcium channel blockers (CCBs) were the most commonly combined antihypertensive agents, and use of DCCBs was far more common than NDCCBs.
There were no significant differences in the baseline demographic, clinical and laboratory characteristics between the two groups, except an older age and a higher Scr (66.3±10.5 vs. 52.3±15.5 years; 2.4±0.9 vs. 2.0±1.0 mg/dL, p < 0.05) in the control group. After 28.6/32.5 months of follow-up, the ACEIs/ARBs group had better renal outcome (p < 0.05), and this benefit was not attributed to the BP change. By univariate analysis, medication, gender, Scr and proteinuria were found to have significant association with renal survival, but these effects were not significant in multivariate analysis except the medication.
Among the baseline and clinical characteristics, the ACEIs group was male predominant, and had a higher serum potassium level than that of the ARBs group. After a mean follow-up of 31.1/24.6 months, the diastolic BP and Scr in the ARBs group were significantly lower than the ACEIs group (74.3±13 vs. 80.1±11.4 mmHg; 1.9±0.6 vs. 2.4±1.2 mg/dL, p < 0.05). There were no differences in the renal survival and the change of serum potassium between the two groups.
In conclusion, consistent with the result from the literature review, our study demonstrated that ACEIs/ARBs did have renoprotective effect, and ARBs tended to be more renopratective than ACEIs. However, this study could not provide the evaluation on the effect of ACEIs/ARBs combination therapy, as limited by the small patient group. In addition, no correlations of renal survival with Scr and proteinuria were demonstrated by the multivariate analysis, probably due to our small sample size.

目錄
中文摘要 I
英文摘要 IV
誌謝 VII
目錄 VIII
表目錄 XII
圖目錄 XIV
第壹章 研究背景 1
第貳章 文獻回顧 3
第一節 慢性腎臟疾病 3
1.1 定義 3
1.2 疾病分期 3
1.3 危險因子 4
1.4 分類 5
第二節 流行病學 6
第三節 病態生理學 8
3.1 高血壓 10
3.2 高血糖 11
3.3 蛋白尿 14
3.4 過多的第二血管張力素(angiotensin II, AII) 14
3.5 其他 15
第四節 臨床表徵 18
第五節 評估和診斷 19
5.1 血清肌酸酐 19
5.2 腎絲球過濾速率 19
5.3 蛋白尿 20
5.4 其他指標 21
5.5 診斷 23
第六節 治療和適應症 25
6.1 多重風險因子介入療法 25
6.2 腎臟保護性療法之適應症 28
6.3 不適用腎臟保護性療法的患者 29
6.4 主要介入療法 30
6.4.1 控制血壓及給予ACEIs 31
6.4.2 控制血糖 35
6.4.3 限制攝取蛋白質 36
第七節 降血壓藥品之腎臟保護作用 37
7.1 背景 37
7.2 腎臟保護機轉 38
7.2.1 降血壓作用 38
7.2.2 腎臟內部作用 38
7.2.3 其他機轉 39
7.3 RAS和腎臟保護作用 41
7.4 臨床研究 47
7.4.1 ACEIs 47
7.4.2 ARBs 63
7.4.3 ACEIs與ARBs之合併治療 68
7.4.4 ACEIs與ARBs之比較 73
7.4.5 其他降壓藥品 74
7.4.6 使用ACEIs和ARBs的相關注意事項 76
7.4.7 總結 81
第參章 研究目的 82
第肆章 研究方法 83
第一節 研究設計 83
1.1 研究類型 83
1.2 研究時間和對象 83
1.3 納入標準 83
1.4 排除標準 83
第二節 研究流程 85
第三節 評估指標與定義 86
3.1 主要評估指標(primary endpoint) 86
3.2 次要評估指標(secondary endpoint) 86
3.3 紀錄方法 86
3.4 疾病及腎臟存活率之定義 86
第四節 統計方法 87
4.1 統計模式設定 87
4.2 資料分析方法 87
4.3 計軟體 88
第伍章 研究結果 89
第一節 ACEIS與ARBS的使用 89
1.1 患者腎臟疾病、降血壓藥品處方型態 89
1.2 使用ACEIs/ARBs與否對患者腎臟存活率表現之影響 91
1.3 腎臟存活率之預後因子 95
第二節 ACEIS與ARBS之比較 99
第陸章 討論 104
第一節 ACEIS與ARBS 104
1.1 ACEIs與ARBs之使用 104
1.2 ACEIs與ARBs之比較 105
第二節 腎臟疾病、降血壓藥品處方型態及血壓控制情形 107
2.1 腎臟疾病 107
2.2 處方型態 107
2.3 血壓控制 108
第三節 預後因子 109
3.1 性別 109
3.2 血清肌酸酐 111
3.3 蛋白尿 112
3.4 高血壓 112
第柒章 結語 113
參考文獻 115
附錄 129

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