臺灣博碩士論文加值系統

腎絲球腎炎 (Glomerulonephritis, GN) 是造成末期腎病 (end-stage renal disease，ESRD) 的主要原因之一；若早期給予藥物治療，能保留腎功能和減少腎衰竭的發生。目前治療腎絲球腎炎的藥物中，以類固醇 (steroids) 為第一線用藥物；若是治療失敗或容易復發時，可併用其他免疫抑制劑 (immunosuppressants) 作治療，因其具有細胞毒性和引發各種副作用，會造成治療之困難；Mycophenolate mofetil (MMF) 是一新的免疫抑制劑，先應用於腎移植，近年來陸續用來治療器官移植以外疾病，包括：腎絲球腎炎和自體免疫疾病。本研究的主要目的是經由回溯性觀察方式，從2002年10月至2003年4月，分析成大醫院十七位GN患者對MMF治療之反應。他們曾接受過三個月以上MMF之治療且對類固醇有依賴性 (十位) 或抗性 (兩位)，曾使用其他免疫抑制劑治療，但反應不佳或復發者有五位。腎臟切片的病理診斷，有七位為膜性腎病變 (membranous nephropathy, MN)，五位為微細病變 (minimal change disease, MCD)，以及五位其他組，包括：甲型免疫球蛋白腎病變 (IgA nephropathy) 一位，局部節段性腎絲球硬化 (focal segmental glomerulosclerosis, FSGS) 兩位和狼瘡性腎炎 (lupus nephritis) 兩位。男女的比例為9: 8，平均年齡為40.9 �b 14.3 歲。主要評估GN患者接受MMF治療前後的每日尿蛋白流失量 (daily protein loss, DPL) 和血清肌酸酐 (serum creatinine, SCr) 之變化，以中位數 (範圍) 來表示。另外，也評估患者在MMF治療前後的肌酸酐廓清率 (creatinine clearance, CrCl)、血清白蛋白和膽固醇濃度之變化，並觀察MMF治療期間的副作用以及類固醇、ACEI或AIIA和HMG CoA 還原酶抑制劑 (statins) 的併用情形。
MMF治療劑量與療程之中位數 (範圍) 分別為每天1 (0.5-1) 克的和治療14 (3-49) 個月，發現GN患者的DPL在MMF治療前為4.8 (1.7-15) 公克，治療後明顯降低為2.3 (0.3-14.1) 公克 (p = 0.009)；治療前後的SCr，則無顯著差異 (1.0 mg/dL vs. 1.0 mg/dL , p > 0.05)，而CrCl、血清白蛋白和膽固醇濃度在治療前後的變化，也沒有差異性。其中膜性腎病變的患者對MMF治療的反應最好，DPL由治療前的每天4.8 (1.8-8.6) 公克降低至治療後每天0.4 (0.3-2.3) 公克 (p = 0.018)，血清白蛋白由3.3 mg/dL 增加至3.8 mg/dL (p = 0.042)，膽固醇由290 mg/dL降低至213 mg/dL (p = 0.028)。MCD患者在MMF治療前後的DPL、SCr、CrCl、血清白蛋白和膽固醇濃度，都不具有顯著差異 (p > 0.05)；至於合併FSGS、IgAN和LN患者之「其他組」，接受MMF治療後，DPL由4.8公克下降至3.4公克(p = 0.043)。安全性方面，對MMF的耐受性良好，未出現嚴重的胃腸或白血球降低的副作用。由單變項分析發現，膜性腎病變患者接受MMF治療容易降低其DPL；多變項分析中，併用ACEI/AIIA、未使用過免疫抑制劑治療以及膜性腎病變患者，接受MMF治療容易降低其DPL。
因此，MMF治療對類固醇或其他免疫抑制劑反應不佳的GN患者，可有效地降低DPL，且穩定腎功能。而膜性腎病變患者，除降低DPL，也會改善血中白蛋白和膽固醇值。但微細病變患者接受MMF治療後未有明顯之反應，可考慮提高MMF的治療劑量或以其他免疫抑制劑（如：Cyclosporine）作治療。「其他組」的DPL，呈現有意義下降。未來可增加病人數或作前瞻性的GN研究，以評估MMF之確切療效。

Glomerulonephritis (GN) is a major cause of end-stage renal disease (ESRD). Glucocorsteroids alone or in combination with cytotoxic agents or cyclosporine have been used to treat GN patients with unsuccessful response or having potential toxicities. Mycophenolate mofetil (MMF) is an immunosuppressive agent widely used in transplant recipients. We retrospectively evaluated the effectiveness of MMF as the empirical treatment for refractory GN in Division of Nephrology, National Cheng Kung University Hospital, Tainan, Taiwan.
From October 2002 to April 2003, 17 GN patients with poor response or relapse after steroids or cytotoxic agents had received MMF therapy at least 3 months were enrolled into study. The pathologic findings were grouped into membranous nephropathy (MN, N = 7), minimal change disease (MCD, N = 5), and the other group including: focal segmental glomerulosclerosis (FSGS, N = 2), IgA nephropathy (IgAN, N = 1) and lupus nephritis (LN, N = 2). The median (range) of daily protein loss (DPL), serum creatinine, creatinine clearance, serum albumin and serum cholesterol at the start and the end of MMF therapy were compared using the Wilcoxon signed-ranks test. The use of steroid, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist (AIIA), and 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) was also analyzed.
The median (range) dose and duration of MMF therapy in these GN patients were 1 (0.5-1.0) g/day and 14 (3.0-14.0) months. The results showed that DPL decreased from 4.8 (1.7g - 15.0) g to 2.3 (0.3- 14.1; p < 0.05) g, but there was no significant change of serum creatinine (1.0 mg/dL vs. 1.0 mg/dL, p > 0.05), creatinine clearance (67.3 mg/dL vs. 78.0 mg/dL, p > 0.05), serum albumin (3.3 mg/dL vs. 3.8 mg/dL, p > 0.05), or serum cholesterol (290.0 mg/dL vs. 224.0 mg/dL, p > 0.05) in all GN patients at the end of MMF therapy. MN patients had better improvement of DPL (4.8 g decreased to 0.8 g, p = 0.018), serum albumin (3.3 g increased to 3.8 g, p = 0.042), and cholesterol (290.0 mg/dL decreased to 213.0 mg/dL, p = 0.028) than other patients at the end of MMF therapy. But MCD patients showed no significant difference of DPL, serum creatinine, creatinine clearance, serum albumin, or serum cholesterol at the end of therapy. The other group only had significant improvement of DPL at the end of therapy (4.8 g vs. 3.4 g, p = 0.043). Side effects of MMF were uncommon and generally mild. In multivavariate analysis,
decrease of DPL correlated with the concomitant use of ACEI/AIIA, no previous treatment of cytocoxic agents and MN patients.
In brief, MMF therapy for patients with refractory GN was well tolerated and can improve DPL and preserve the renal function.

中文摘要…………………………………………………………………...I
英文摘要…………………………………………………………………...IV
致謝………………………………………………………………………...VI
縮寫………………………………………………………………………...VII
目錄………………………………………………………………………...VIII
表目錄……………………………………………………………………...XIV
圖目錄……………………………………………………………………...XVI
第一篇 腎絲球腎炎的藥物治療………………………………………….1
第壹章 研究背景………………………………………………………….1
第貳章 文獻回顧………………………………………………………….2
第一節 腎絲球腎炎…………………………………………………….2
1.1 定義………………………………………………………………2
1.2 分類………………………………………………………………2
第二節 致病機轉……………………………………………………….4
第三節 臨床表徵……………………………………………………….6
第四節 評估與診斷…………………………………………………….7
第五節 藥物治療……………………………………………………….10
5.1 膜性腎病變(Membranous nephropathy, MN)的藥物治療……...13
5.1.1 類固醇單ㄧ療法…………………………………………….13
5.1.2.免疫抑制劑療法……..………………………………………16
5.1.2.1 Azathioprine (AZA)……………………………………...16
5.1.2.2 烷基化劑 (alkylating agents)…………………………...16
5.1.2.3 Cyclosporin (CsA)………………………………………..20
5.1.3 結論……………………………..……………………………20
5.2 微細腎病變 (Minimal change disease) MCD的藥物治療……...21
5.2.1 類固醇………………………………………………………...21
5.2.1.1 首次發作的治療…………………………………………21
5.2.1.2 復發性MCD的治療…………………………………….22
5.2.2 免疫調節劑 (Immunmodulator agents)……………………...23
5.2.2.1 Cyclophosphamide (CYC)………………………………..24
5.2.2.2 Chlorambucil……………………………………………...24
5.2.2.3 Cyclosporin A (CsA)……………………………………...24
5.2.2.4 Levamisole………………………………………………..24
5.2.3 結論…………………………………………………………...26
5.3 局部節段性腎絲球硬化 (Focal semential
glomerulosclerosis, FSGS) 的藥物治療………………………...28
5.3.1 類固醇………………………………………………………..28
5.3.2 烷基化劑……………………………………………………..31
5.3.3 Cyclosporin (CsA)…………………………………………….31
5.3.4 結論…………………………………………………………..33
5.4 狼瘡性腎炎 (Lupus nephritis, LN) 的藥物治療………………..34
5.4.1 類固醇………………………………………………………..34
5.4.2 Cyclophosphamide (CYC)……………………………..……..35
5.4.3 Azathiopurine (AZA)…………………………………………36
5.4.4 結論………………………………………………………….36
第六節 Mycophenolate Mofetil (MMF)…………………………………..39
6.1 藥理機轉……………………………………………………………40
6.2 藥動學特性…………………………………………………………43
6.2.1 吸收與分布…………………………………………………….43
6.2.2 代謝與排除…………………………………………………….46
6.3 藥物交互作用………………………………………………………47
6.4 副作用………………………………………………………………47
6.5 MMF用於GN的臨床治療………………………………………...48
6.5.1 背景…………………………………………………………….48
6.5.2 以MMF治療GN的可能機轉………………………………..49
6.5.3 MMF在原發性GN的臨床研究………………………………50
6.5.4 MMF在LN的臨床研究………………………………………54
第參章 研究目的…………………………………………………………….58
第肆章 研究方法…………………………………………………………….59
第一節 研究設計………………………………………………………….59
1.1研究類型……………………………………………...……………..59
1.2研究時間及對象…………………………………………………….59
1.3納入標準…………………………………………………………….59
第二節 研究流程………………………………………………………….60
第三節 評估指標與定義………………………………………………….61
3.1 主要評估指標 (primary endpoint)…………………………………61
3.2 次要評估指標 (secondary endpoint)………………………………61
3.3 評估指標之定義……………………………………………………61
3.4 紀錄方法……………………………………………………………63
第四節 統計方法…………………………………………………………64
4.1 統計模式設定……………………………………………………..64
4.2 資料分析方法……………………………………………………..64
4.3 統計軟體…………………………………………………………..64
第伍章 研究結果……………………………………………………………65
第一節 研究對象…………………………………………………………65
第二節 治療效果…………………………………………………………68
2.1 MN患者的MMF治療效果……………………………………….71
2.2 MCD患者的MMF之治療效果…………………………………..74
2.3 其他患者使用MMF之治療效果…………………………………77
第三節 單變項分析 ……………………………………………………..79
第四節 多變項分析………………………………………………………79
第六章 討論…………………………………………………………………82
第一節 研究對象…………………………………………………………82
第二節 MMF用於頑固性腎絲球腎炎的臨床療效……………………..83
2.1以MMF治療MN的效果…………………………………………84
2.2 以MMF治療MCD的效果………………………………………87
2.3 以MMF治療FSGS、IgAN和LN的效果………...……………89
第三節 以MMF治療GN的劑量與療程……………………………….91
第四節 併用藥品之使用…………………………………………………93
第五節 影響MMF治療後DPL降低的因子…………………………...94
第六節 MMF治療之副作用……………………………………………..96
第七節 研究限制…………………………………………………………97
第八節 未來研究方向……………………………………………………98
第柒章 結語…………………………………………………………………....99
參考文獻………………………………………………………………………100
附錄一 病患紀錄表格………………………………………………………..111
第二篇 臨床藥事服務 (Clinical Service)……………………………………113
一、目的………………………………………………………………………113
二、方法………………………………………………………………………113
三、紀錄方式…………………………………………………………………113
四、結果………………………………………………………………………114
第一節 腎衰竭患者的常見疾病與藥物治療…………………………….114
1.1急性腎衰竭 (Acute renal failure, ARF)…………………………….114
1.1.1 定義……………………………………………………………114
1.1.2 急性腎衰竭相關之危險因子…………………………………115
1.1.3 急性腎衰竭的分類和治療……………………………………116
1.1.4 急性腎衰竭相關檢驗數值的變化 (鑑別診斷)………………116
1.1.5 急性腎衰竭電解質異常的治療……………………………….117
1.1.6 急性腎衰竭的預防…………………………………………….118
1.2慢性腎衰竭 (chronic renal failure, CRF)……………………………119
1.2.1 慢性腎病 (chronic kidney disease, CKD) 之定義……………119
1.2.2 常見併發症與治療…………………………………………….120
1.2.3 慢性腎衰竭患者藥物治療注意事項………………………….124
1.3 血液透析 (Hemodialysis)…………………………………………..125
第二節 藥物諮詢…………………………………………………………..127
2.1 抗生素治療相關問題………………………………………………129
2.1.1腎衰竭患者預防術後感染抗生素之使用……………………..129
2.1.2 Teicoplanin用於CAPD患者腹膜炎的劑量…………………130
2.1.3血液透析患者抗結核藥物的使用……………………………131
2.1.4 Isepamicin 在透析患者的使用……………………………….133
2.2 腎病症候群患者的利尿劑治療…………………………………..135
2.3 腎功能不全患者的降血糖藥物…………………………………..138
第三節 藥物不良反應評估………………………………………………140
五 結語……………………………………………………………………….141
參考文獻……………………………………………………………………... 142
表目錄
第一部分 腎絲球腎炎之藥物治療
表一原發性腎絲球腎炎之組織學分類…………………………………3
表二次發性腎絲球腎炎之分類…………………………………………3
表三腎絲球腎炎以腎病症候群以及腎炎症候群表現的傾向…………8
表四腎絲球腎炎與診斷之特殊血清免疫學標記………………………9
表五腎絲球腎炎藥物治療的重大發展………………………………11
表六研究證據強度之分級 (Level of evidence for studies )…………12
表七建議等級 (Grades of recommendations)…………………………12
表八以類固醇 (pednisolone) 治療原發性MN的臨床研究…………15
表九免疫抑制劑治療MN的控制性試驗……………………………19
表十以類固醇治療局部節段性腎絲球硬化症（FSGS）患者
(療程大於六個月) 的研究報告…………………………………30
表十一狼瘡性腎炎 (LN) 的WHO病理分類 …………………………37
表十二以Cyclophophamide和azathiopurine治療狼瘡性腎炎 (LN)
之隨機控制研 (RCT)……………………………………………38
表十三一般健康者和器官移植患者的口服MMF藥動學參數 ………44
表十四口服一公克MMF在特殊族群的藥動學參數 …………………45
表十五MMF治療原發性GN的非控制性試驗…………………………53
表十六MMF治療LN的非控制性試驗…………………………………57
表十七17位接受MMF治療腎絲球腎炎病患之基本資料……………66
表十八17位病患之基本資料以及MMF使用之療程與劑量…………67
表十九全部病患以及各組中，接受MMF治療前後每日尿液
流失蛋白量 (DPL)、血清肌酐酸 (SCr)、肌酸酐廓清
率 (creatinine clearance, CrCl)、白蛋白 (albumin) 和
膽固醇 (choletserol) 的變化，以平均值 (b 標準差)
和中位數 (範圍) 表示。……………………………………………………70
表二十膜性腎病變 (MN) 患者接受MMF治療之過程…………………73
表二十一五位微細腎病變 (MCD) 患者接受MMF治療之過程…………76
表二十二FSGS、IgA和LN患者使用MMF治療之過程…………………78
表二十三17位GN患者接受MMF治療後，DPL降低與變異
因子之單變項分析…………………………………………………………80
表二十四17位GN患者接受MMF治療後，DPL降低與變異因子
之多變相分析…………………………………………………………………81
表二十五復發MN患者以MMF治療和追蹤…………………………………86
第二部分 臨床藥事服務
表一九十一年十月份至九十二年四月份藥物諮詢項目之統計………127
表二九十一年十月份至九十二年四月份藥物不良反應評估統計……140
附錄表格…………………………………………………………………………145

圖目錄
圖一腎絲球腎炎的調控機制…………………………………………………5
圖二MCD的藥物治療………………………………………………………27
圖三MMF與MPA的化學結構……………………………………………39
圖四MMF與其他免疫抑制劑藥理作用位置………………………………41
圖五MMF作用機轉與嘌呤生合成路徑……………………………………42
圖六MMF的體內代謝過程…………………………………………………46
圖七MMF治療GN的可能機轉……………………………………………49
圖八(A)每日尿液流失蛋白量 (DPL)、(B) 血清肌酐酸 (SCr)、
(B)肌酐酸廓清率 (CCr)、(D) 血清白蛋白 (serum albumin)、
(E) 膽固醇 (choletserol) 在MMF治療前後的變化……………69
圖九MN病患在MMF治療前後DPL的變化…………………………………72
圖十MCD病患在MMF治療前後DPL的變化………………………………75

第一篇　腎絲球腎炎的藥物治療
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第二篇　臨床藥事服務(Clinical Service)
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