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研究生:吳寶婷
研究生(外文):WU, PAO-TING
論文名稱:探討補體抑制劑在腎臟移植抗體介導排斥反應的安全性及效應之系統性回顧及統合分析
論文名稱(外文):Safety and efficacy of complement inhibitors for antibody-mediated rejection in kidney transplantation:a systematic review and meta-analysis
指導教授:吳美儀吳美儀引用關係
指導教授(外文):WU, MEI-YI
口試委員:吳麥斯吳美儀譚家偉黃采薇羅偉成
口試委員(外文):WU, MAI-SZUWU, MEI-YITAM,KA-WAIHUANG, TSAI-WEILO, WEI-CHENG
口試日期:2022-07-13
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:臨床醫學研究所應用實證醫學碩士在職專班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:英文
論文頁數:64
中文關鍵詞:腎臟移植抗體介導排斥反應補體抑制劑效應及安全性
外文關鍵詞:kidney transplantationantibody-mediated rejectioncomplement inhibitorC1 esterase inhibitorEculizumabsafety and efficacy
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背景
Antibody-mediated rejection(AMR)抗體介導排斥反應之致病機轉為腎移植接受者體內的捐贈體特異性抗體donor specific antibody(DSA)與移植腎內皮上的人類白細胞抗原 human leukocyte antigen(HLA)或非 HLA 分子結合,進而活化補體途徑,導致移植腎之內皮損傷,造成移植腎損失。抗體排斥包含許多複雜的步驟,針對這些過程可使用不同的作用機轉方式來治療,包含抑制T 細胞和B 細胞、阻斷殘餘抗體、清除漿細胞及消除循環中的抗體、補體抑制劑…等。透過不同作用機轉以及藥品併用會有較佳的治療效果。若能妥善處理抗體介導排斥就可減少移植腎臟的損失。對於補體抑制劑是否能降低腎臟移植抗體排斥反應的發生率及改善移植腎存活率,目前臨床結果尚未有很明確的證據。因此我們進行了系統評價和統合分析,探討補體抑制劑對於腎臟移植中抗體性排斥反應的安全性和有效性。
方法
探討補體抑製劑在腎移植中 AMR 的安全性和有效性進行了系統性回顧及統合分析。經由電子資料庫(PubMed、Embase、Cochrane)搜尋關鍵詞包括: C1 esterase inhibitor、C1-INH、Eculizumab、C5 inhibitor、complement inhibitor、antibody mediated rejection和kidney transplantation。本研究搜尋至 2022 年 3 月 1 日之結果,並遵循 PRISMA 2020指導方針,納入條件為接受腎臟移植使用補體抑制劑預防或治療抗體排斥反應之隨機對照試驗或非隨機對照試驗及世代研究;排除條件為病例報告、案例系列、文獻回顧、會議摘要或非腎臟移植抗體介導排斥反應相關結果之文獻。 共有8項研究最終被納入此研究中,我們利用Risk ratio (RR)並選用random-effects model進行統合分析。統計軟體選用Review Manager Version 5.4。
結果
我們納入了 8 項研究,其中 4 項研究是隨機對照試驗,2 項研究是非隨機對照試驗,另外 2 項是世代研究,共納入 353 名受試者。補體抑製劑組與其他治療組相比,在9 週 AMR 發生率的風險比(RR 0.52, 95% CI: 0.15-1.84, P = 0.31)。 1 年移植物損失風險比(RR 0.56, 95% CI: 0.19-1.71, P = 0.31)。1 年腎臟切片證實移植腎小球病變風險比(RR 0.49, 95% CI: 0.03-7.09, P = 0.60)。藥物相關不良事件風險比( RR 7.46, 95% CI: 1.39-40.14, P = 0.02)。結果顯示補體抑製劑組與控制組相比於 9 週 AMR 發生率、1 年移植物損失功能、1年腎臟切片證實移植腎小球病變風險比均無顯著差異,藥物相關不良事件風險比治療組高於對照組。
結論
我們統合分析結果顯示,補體抑製劑與免疫球蛋白、血漿置換和皮質類固醇的標準治療在預防高度致敏腎移植中的急性 AMR 方面沒有顯示出更多的益處。 補體抑製劑與標準治療相比藥物相關不良反應的風險比更高。需要進一步的隨機對照試驗來評估補體抑製劑預防 AMR 的效應和安全性。

Background
Antibody-mediated rejection (AMR) is an important cause of graft loss after kidney transplantation. Several drugs have shown effectiveness in reducing the incidence of AMR after kidney transplant. As complement activation contributes to tissue damages in the setting of donor specific antibody (DSA), complement inhibitors may thus be effective at preventing AMR. Moreover, the combination of drugs targeting multiple mechanisms of action may provide better therapeutic effects. However, the safety and efficacy of complement inhibitors for reducing the incidence of AMR and raising the graft survival in patients with kidney transplantation is still unclear and should be verified.
Method
We conducted a systematic review and meta-analysis of complement inhibitors for AMR in kidney transplantation using PubMed, Embase, and Cochrane library from inception to March 1, 2022 for clinical trials and cohort studies. Keywords included C1 esterase inhibitor, C1-INH, Eculizumab, C5inhibitor, complement inhibitor, antibody mediated rejection, and kidney transplantation. Efficacy was evaluated by the 9-week incidence of AMR, one-year graft loss, and one-year biopsy-proved transplant glomerulopathy (TG). Safety was evaluated by drug related adverse events. We followed the PRISMA 2020 guidelines for data selection and extraction. We synthesize data using the random-effects model and expressed results as risk ratio (RR) with 95% confidence intervals (CIs). Statistical analysis was performed with Review Manager 5.4.
Result
We identified 8 studies, including four randomized controlled trials (RCTs), two non-randomized controlled trials, and two cohort studies, with 353 subjects. One study compared Eculizumab to plasma exchange, while another one compared Eculizumab to standard of care. Two studies compared C1-inhibitor to placebo, while one study compared the combination of C1 inhibitor and intravenous immunoglobulin (IVIG) to IVIG. One study compared Eculizumab to Eculizumab plus splenectomy, while another one was a single-arm study of Eculizumab.
The pooled RR of incidence of 9-week AMR for complement inhibitors in comparison with other treatments was 0.52 (95% CI: 0.15-1.84, P = 0.31). One-year graft loss RR was 0.56 (95% CI: 0.19-1.71, P = 0.31). One-year biopsy-proved transplant glomerulopathy (TG) RR was 0.49 (95% CI: 0.03-7.09, P = 0.60). Drug related adverse event (AE) RR was 7.46 (95% CI: 1.39-40.14, P = 0.02). No significant difference in 9-week incidence of AMR, one-year graft loss, one-year biopsy-proved TG was found between the complement inhibitor group and the control group. Drug related AE in the complement inhibitor group was higher than in the control group.
Conclusions
The results of our meta-analysis suggest that the combination of complement inhibitors with standard of care with IVIG, plasmapheresis and corticosteroids in preventing acute AMR in highly sensitized kidney transplants did not show more benefit comparing standard of care. The risk ratio of drug related adverse effects were higher combining complement inhibitors with standard of care. Further randomized control trials are needed to evaluate the efficacy and safety of combining complement inhibitors in preventing AMR.


目錄 v
中文摘要 1
英文摘要 4
1 Aim 7
2 Introduction 8
2.1 End-stage kidney disease incidence 8
2.2 ESKD renal replacement therapies overview 8
2.3 Kidney transplantation 9
2.4 Incidence of AMR and mechanism 9
2.5 AMR diagnosis and clinical features 10
2.6 AMR prevention and treatment 11
2.7 The role of complement system for AMR 12
2.8 C5 inhibitor-Eculizumab 12
2.9 C1 esterase inhibitor 13
3 Materials and Methods: 14
3.1 PICO 14
3.2 Search strategy 14
3.3 Inclusion and exclusion criteria 14
3.4 Data extraction 15
3.5 Quality assessment 15
3.6 Outcome measures 16
3.7 Data synthesis and analysis 17
4 Results: 18
4.1 Result of the search 18
4.2 Study characteristics 20
4.3 Risk of bias in the included studies 25
4.4 Primary outcome 28
4.5 Secondary outcome 29
4.5.1 1-year graft loss 29
4.5.2 1-year biopsy-proved TG 29
4.5.3 Graft function 30
4.5.4 Patient and graft survival 30
4.6 Safety outcome 32
4.6.1 Drug related AE 32
4.6.2 Peripheral edema 32
4.6.3 Anemia 33
4.6.4 Diarrhea 33
4.6.5 Hemorrhage 34
4.6.6 Deep vein thrombosis(DVT) 35
4.6.7 Urinary tract infection(UTI) 35
5 Discussion 37
5.1 Primary outcome: 9-week incidence of AMR 40
5.2 Secondary outcome: 1-year graft loss 42
5.3 Secondary outcome: 1-year biopsy-proved TG 43
5.4 Adverse event 43
5.5 Limitations 45
6 Conclusion 46
7 References 48
8 Tables and Figures 52
9 Appendix 63
圖目錄 viii
Figure 1. PRISMA flow diagram of the search process and search results.....19
Figure 2. Summary of risk of bias for RCTs. ..................................................26
Figure 3. Risk of bias in non- non-randomized studies - of interventions for
assessment of non-RCT studies summary .............................................27
Figure 4. Forest plot comparing incidence of 9-week AMR between the
complement inhibitor group and the control group ..............................28
Figure 5. Forest plot comparing 1-year graft loss between the complement
inhibitor group and the control group ....................................................29
Figure 6. Forest plot comparing 1-year biopsy-proved TG between the
complement inhibitor group and the control group ...............................30
Figure 7. Forest plot comparing drug related AE between the complement
inhibitor group and the control group ....................................................32
Figure 8. Forest plot comparing AE of peripheral edema between the
complement inhibitor group and the control group ...............................33
Figure 9. Forest plot comparing AE of anemia between the complement
inhibitor group and the control group ....................................................33
Figure 10. Forest plot comparing AE of diarrhea between the complement
inhibitor group and the control group ....................................................34
Figure 11. Forest plot comparing AE of hemorrhage between the complement
inhibitor group and the control group ....................................................34
Figure 12. Forest plot comparing AE of DVT between the complement
inhibitor group and the control group ..................................................35
Figure 13. Forest plot comparing AE of UTI between the complement
inhibitor group and the control group ..................................................36
表目錄 x
Table 1. Characteristics of included studies ....................................................22
Table 2. Risk of bias 2.0 assessment for the RCT studies...............................26
Table 3. Risk of bias in non-randomized studies of interventions for
assessment of non-RCT studies...........................................................27

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