Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

 

Abstract

Background

Target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus) are immunosuppressive agents with a novel mode of action but an uncertain clinical role.

Objectives

To investigate the benefits and harms of immunosuppressive regimens containing TOR-I when compared to other regimens as initial therapy for kidney transplant recipients.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), the specialised register of the Cochrane Renal Group (June 2005)., and contacted authors and pharmaceutical companies to identify relevant studies.

Selection criteria

All randomised controlled trials (RCTs) and quasi-RCTs where drug regimens containing TOR-I were compared to alternative drug regimens in the immediate post-transplant period were included, without age restriction, dosage or language of report.

Data collection and analysis

Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Main results

Thirty three trials (142 reports) were included (sirolimus (27), everolimus (5), head-to-head (1)). When TOR-I replaced CNI there was no difference in acute rejection, but serum creatinine was lower (MD -18.31 μmol/L, -30.96 to -5.67), and bone marrow more suppressed (leucopenia: RR 2.02 1.12 to 3.66; thrombocytopenia: RR 6.97 2.97 to 16.36; anaemia: RR 1.67, 1.27 to 2.20). When TOR-I replaced antimetabolites, acute rejection (RR 0.84, 0.71 to 0.99) and cytomegalovirus infection (CMV) (RR 0.49; 0.37 to 0.65) were reduced, but hypercholesterolaemia was increased (RR 1.65, 1.32 to 2.06). For low versus high-dose TOR-I, with equal CNI dose, rejection was increased (RR 1.23, 1.06 to 1.43) but calculated GFR higher (MD 4.27 mL/min, 1.12 to 7.41), and for low-dose TOR-I/standard-dose CNI versus higher-dose TOR-I/reduced CNI, acute rejection (RR 0.67, 0.52 to 0.88) and calculated GFR (MD -9.46 mL/min, -12.16 to -6.76) were reduced. There was no significant difference in mortality, graft loss or malignancy risk for TOR-I in any comparison.

Authors' conclusions

TOR-I have been evaluated in four different primary immunosuppressive algorithms; as replacement for CNI and for antimetabolites, in combination with CNI at low and high dose and with variable dose of CNI. Generally, surrogate endpoints for graft survival favour TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust RCTs are still needed.

 

Plain language summary

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD). Strategies to increase donor organ availability and to prolong the transplanted kidney's survival have become priorities in kidney transplantation. This review aimed to evaluate the short and long-term benefits and harms of sirolimus and everolimus (TOR-I) when used in primary immunosuppressive regimens for kidney transplant recipients. Thirty three trials investigating the use of TOR-I in four different settings were evaluated in this review. No differences in the hard-end points of patient and graft survival were demonstrated for or against TOR-I in any comparison. Generally surrogate endpoints for graft survival favour TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed.

 

摘要

背景

以雷帕脢素靶點抑制劑 (TORI; sirolimus與everolimus) 作為腎臟移植接受者主要免疫系統抑制劑的效用

雷帕脢素靶點抑制劑 (TORI) (sirolimus, everolimus) 是具有新的作用模式的免疫抑制劑，但在臨床上的角色目前並不確定。

目標

評估以其他處方作為腎臟移植接受者的第一線治療方式，與以含TORI之免疫系統抑制療法作為第一線治療方式的優劣。

搜尋策略

我們搜尋Cochrane對照試驗登錄資料庫 (CENTRAL) (Cochrane資料庫中2005年第2刊) 、MEDLINE (1966年2005年六月) 、EMBASE (1980年2005年六月) 、Cochrane腎臟組的專業登錄、與聯繫作者及製藥公司以確認相關的研究。

選擇標準

移植後立即接受其他替代藥物療法與移植後立即使用內含TORI之藥物療法的所有隨機對照臨床試驗 (RCTs) 與半隨機對照臨床試驗 (quasiRCTs) 皆納入分析範圍，研究年齡層、藥物劑量及語言都不在選取的限制範圍。

資料收集與分析

由2位審查者個別針對試驗的合格性、品質、與取得資料進行評估，而結果則以擁有95% 信賴區間 (CI) 的相對風險 (RR) 或加權平均差異 (MD) 表示。

主要結論

共33項臨床試驗 (142份報告) [其中sirolimus (27) 項、everolimus (5) 項、直接比較 (1)]被納入分析。當以TORI取代鈣調磷酸脢抑制劑 (CNI) 時，在急性排斥反應方面並無差異，但血清肌酸酐較低 (平均差異 −18.31μmol/L ， −30.96 – 5.67) 骨髓受到較多抑制 (白血球減少: 相對風險2.02 1.12 – 3.66; 血小板減少: 相對風險 6.97 2.97 – 16.36; 貧血: 相對風險1.67 1.27 – 2.20) 。以TORI取代抗代謝藥物時，可降低急性排斥反應 (相對風險 0.84 0.71 – 0.99) 與巨大細胞病毒感染 (CMV) (相對風險 0.49 0.37 – 0.65) 的發生率，但卻會增加高膽固醇血症的發生率 (相對風險 1.65 1.32 – 2.06) 。以相同劑量的CNI藥比較，則低劑量TORI會增加排斥反應的發生率 (相對風險 1.23 1.06 – 1.43) ， 但計算所得的腎小球濾過率 (GFR) 較高 (平均差異4.27 mL/min，1.12 – 7.41) 而針對以低劑量TORI/標準劑量CNI對較高劑量TORI/劑量減少之CNI而言，可降低急性排斥反應的發生率 (相對風險0.67 0.52 – 0.88) 與計算所得之腎小球濾過率的濃度 (平均差異 −9.46 mL/min， −12.16 – −6.76) 。針對TORI的所有比較結果而言，在死亡率、移植失敗、或惡性腫瘤的風險方面並無明顯差異。

作者結論

利用4種不同的主要免疫抑制使用規則，進行TORI評估；一是作為CNI與抗代謝藥物的替代物、一是以低或高劑量結合使用CNI、及結合使用不同劑量的CNI。大體而言，以移植腎存活率為研究終點則偏向使用TORI (因為較少發生急性排斥及有較高的腎小球過濾率) ，若以病人的最終結果比較，則使用TORI較不好 (因為較易有骨髓抑制及血中脂質混亂) 。但仍需要研究方法健全之隨機對照臨床試驗 (RCTs) 的長期觀察資料。

翻譯人

本摘要由馬偕醫院郭馨仁翻譯。

此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。

總結

腎臟移植是很多末期腎病變患者治療的選擇。如何增加捐贈腎臟的可利用率，和延長移植腎的存活是很重要的課題。這篇文章主要是在評估，以sirolimus 和 everolimus (TORI) 當作腎臟移植接受者之主要免疫抑制治療方式，其短期與長期使用的利與弊。共有33項臨床試驗評估了在4種不同的免疫抑制使用規則下，使用TORI的情況。在任何情況下比較，不論贊成或反對TORI的使用，最終關於病人和移植腎的存活率上都沒有任何差異。一般而言，以移植腎存活率為研究終點，會傾向於使用 TORI (因為有較低的急性排斥率，較高的腎絲球過濾率) 。若以病人的最終結果為研究終點，則使用TORI較不好 (因為較易有骨髓抑制及脂肪代謝異常) 。但這樣的結論仍有賴研究方法健全之隨機對照臨床試驗 (RCTs) 的長期觀察資料佐證。