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成人实体器官移植后糖尿病管理专家共识

毕艳, 鹿斌, 中国康复医学会器官移植康复专业委员会. 成人实体器官移植后糖尿病管理专家共识[J]. 器官移植, 2023, 14(5): 623-642. doi: 10.3969/j.issn.1674-7445.2023110
引用本文: 毕艳, 鹿斌, 中国康复医学会器官移植康复专业委员会. 成人实体器官移植后糖尿病管理专家共识[J]. 器官移植, 2023, 14(5): 623-642. doi: 10.3969/j.issn.1674-7445.2023110
BI Yan, LU Bin, Organ Transplantation and Rehabilitation Committee of Chinese Medical Association of Rehabilitation. Expert consensus on diabetes mellitus after solid organ transplantation in adults[J]. ORGAN TRANSPLANTATION, 2023, 14(5): 623-642. doi: 10.3969/j.issn.1674-7445.2023110
Citation: BI Yan, LU Bin, Organ Transplantation and Rehabilitation Committee of Chinese Medical Association of Rehabilitation. Expert consensus on diabetes mellitus after solid organ transplantation in adults[J]. ORGAN TRANSPLANTATION, 2023, 14(5): 623-642. doi: 10.3969/j.issn.1674-7445.2023110

成人实体器官移植后糖尿病管理专家共识

doi: 10.3969/j.issn.1674-7445.2023110
详细信息
    通讯作者:

    毕艳, Email:biyan@nju.edu.cn

    鹿斌, Email:binlu@fudan.edu.cn

  • 中图分类号: R617, R587.1

Expert consensus on diabetes mellitus after solid organ transplantation in adults

More Information
    Corresponding author: Bi Yan, Department of Endocrinology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China, Email: biyan@nju.edu.cnLu Bin, Department of Endocrinology, Huashan Hospital, Affiliated to Fudan University, Shanghai 200040, China, Email: binlu@fudan.edu.cn
  • 摘要: 移植后糖尿病(PTDM)是成人实体器官移植(SOT)后常见的内分泌代谢紊乱疾病,累及10%~40%的受者,严重威胁受者生存质量与长期存活。为进一步规范PTDM的诊治,相关专家依据国内外成人PTDM的研究进展并结合我国实际情况,对PTDM的流行病学、危险因素与发病机制、筛查与诊断、治疗、预防、心血管危险因素管理以及微血管并发症筛查等方面达成一致意见,提出指导建议。旨在规范化综合管理PTDM,以提高SOT受者的生存质量与长期存活。

     

  • 表  1  不同免疫抑制剂的主要机制及与PTDM发生风险的关系

    Table  1.   The main mechanisms of different immunosuppressors and their relationship with the risk of PTDM

    免疫抑制剂主要机制与PTDM发生风险的关系
    糖皮质激素刺激胰高糖素分泌,增加肝糖输出,这一效应呈剂量相关性[39],增加胰岛素抵抗并抑制胰岛素分泌,诱导胰岛细胞凋亡[40]泼尼松龙逐渐减量至5 mg/d有助于改善肾移植后胰岛素敏感性[41],糖皮质激素减撤方案可以作为降低PTDM风险的一种优选方案[42]
    CNI(他克莫司、环孢素)抑制钙调神经磷酸酶活性,抑制细胞质钙调神经磷酸酶-活化T细胞的核因子亚单位的去磷酸化。CNI下调胰岛素受体底物2表达[43],影响胰岛β细胞中胰岛素和细胞增殖基因的转录,引起血糖升高。环孢素和他克莫司还可以通过增加脂肪细胞表面的葡萄糖转运蛋白4内吞速率,降低葡萄糖转运蛋白4表达来抑制葡萄糖摄取,而不依赖于胰岛素信号传导[44]。他克莫司减少胰岛素分泌效应更强,与环孢素相比更易导致PTDM。肾移植后使用他克莫司治疗1年的PTDM发病风险是环孢素的2.7倍[45-48]CNI减量可以作为降低PTDM风险的措施,肾移植后PTDM患者可将他克莫司调整为环孢素以减少PTDM发生[46]
    mTORi(西罗莫司、依维莫司和贝拉西普)mTORi干扰胰岛素信号传导,加重胰岛素抵抗;同时具有抗增殖作用,抑制胰岛β细胞增殖,促进β细胞凋亡。西罗莫司促进胰岛素受体底物2的磷酸化,抑制β细胞分泌胰岛素[47]mTORi会增加PTDM发生风险,但较CNI略低[48]
    ATG和阿仑单抗ATG诱导促进Treg细胞增多[49]。阿仑单抗是靶向CD52特异性单克隆抗体,CD52富集于B和T淋巴细胞表面,阿仑单抗可诱导T和B淋巴细胞凋亡[50],对糖代谢无直接影响阿仑单抗或ATG诱导不增加PTDM风险[51]
    巴利昔单抗IL-2受体的单抗(抗CD25),可显著抑制IL-2介导的T淋巴细胞增殖。动物实验中表明,巴利昔单抗使用后诱导Treg细胞减少,出现胰岛炎、胰岛β细胞破坏及糖尿病发生[52]巴利昔单抗诱导发生PTDM 的风险增加[53]
    其他免疫抑制剂(麦考酚酸、硫唑嘌呤和咪唑立宾)抑制嘌呤核苷酸的生物合成发挥抗增殖、抗代谢作用,对糖代谢无直接影响麦考酚酸或硫唑嘌呤单独应用对PTDM无影响,联合用药目前证据尚不足[54];吗替麦考酚酯是常用麦考酚酸类药物,与其他免疫抑制剂联用时,减少CNI、类固醇药物等药物的剂量,间接降低SOT受者PTDM的风险[55];咪唑立宾与PTDM的关系尚无研究报道
      注:mTORi为哺乳动物雷帕霉素靶蛋白抑制剂;ATG为抗人胸腺细胞免疫球蛋白;IL-2为白细胞介素-2。
    下载: 导出CSV

    表  2  PTDM的诊断标准

    Table  2.   Diagnostic criteria for PTDM

    诊断标准静脉血浆葡萄糖或HbA1c水平
    典型糖尿病症状
    加上空腹血糖≥7.0 mmol/L
    或加上随机血糖≥11.1 mmol/L
    或加上OGTT 2 h血糖≥11.1 mmol/L
    或加上HbA1c≥6.5%a
    无糖尿病典型症状者,需改日复查确认
      注:诊断时机为移植术后病情稳定且免疫抑制剂维持日常剂量时。典型糖尿病症状包括烦渴多饮、多尿、多食、不明原因体重下降;随机血糖指不考虑上次用餐时间,一天中任意时间的血糖,不能用来诊断空腹血糖受损或糖耐量减低;空腹状态指至少8 h没有进食热量。a移植术后1年内不建议单独使用HbA1c来诊断PTDM。
    下载: 导出CSV

    表  3  糖代谢状态分类

    Table  3.   Classification of glucose metabolism status

    糖代谢状态静脉血浆葡萄糖(mmol/L)
    FPG2 hPG
    正常血糖<6.1<7.8
    空腹血糖受损6.1≤FPG<7.0<7.8
    糖耐量减低<6.17.8≤2 hPG<11.1
    糖调节受损<7.07.8≤2 hPG<11.1
    糖尿病≥7.0≥11.1
      注:2 hPG为糖负荷后2 h血糖。FPG正常参考范围下限通常为3.9 mmol/L。
    下载: 导出CSV

    表  4  治疗PTDM非胰岛素类降糖药物的安全性、有效性、与免疫抑制剂的相互作用以及注意事项

    Table  4.   Safety, effectiveness, interaction with immunosuppressors and precautions of non-insulin hypoglycemic drugs for PTDM

    药物
    种类
    常用代表
    药物
    有效性a安全性药物相互
    作用
    心肾获益主要不良
    反应
    注意事项
    双胍类 二甲双胍 强效 循证证据较多,主要来源于肾移植受者,安全、优选用药。
    (1)肾移植:肾功能稳定情况下安全,降低全因死亡率、感染相关死亡率、恶性肿瘤相关死亡率[76-78];(2)肝、心、肺移植:证据缺乏
    降低超重T2DM患者心血管风险,SOT受者获益情况不明 胃肠道反应常见,乳酸酸中毒罕见 注意监测肾功能,禁用于eGFR<
    45 mL/ (min·1.73 m2 ) ;
    肝功能不全、严重感染、缺氧或接受大手术的患者禁用
    DPP-4i 西格列汀、沙格列汀、利格列汀、维格列汀、阿格列汀 中效 循证证据相对较少,安全。
    (1)肾移植:安全,耐受性良好[79-85];(2)心移植:安全,对体重无影响[86]; (3)肝、肺移植:证据缺乏
    西格列汀和CsA,维格列汀和TAC可能存在DDI T2DM人群中性,沙格列汀可能增加心力衰竭住院风险;SOT受者暂无依据 肾功能不全者需根据eGFR调整用量(利格列汀除外)
    α-糖苷酶抑制剂 阿卡波糖、伏格列波糖、米格列醇 中效 循证证据缺乏,但国内专家有限的使用经验提示安全有效 循证证据缺乏 T2DM人群中性,SOT受者暂无依据 胃肠道反应常见 严重肝功能或肾功能不全、肠粘连、肠梗阻病史患者禁用
    磺脲类 格列本脲、格列齐特、格列美脲、格列喹酮、格列吡嗪 强效 循证证据相对少,但临床使用经验较多。
    (1)肾移植:耐受性良好,存在一定程度低血糖风险[85, 87]
    (2)肝、心、肺移植:证据缺乏
    格列本脲、格列喹酮与CsA可能存在DDI T2DM人群中性,SOT受者暂无依据 低血糖、体重增加 eGFR下降者使用时低血糖风险增加;严重肝或肾功能不全、糖尿病急性并发症时禁用
    噻唑烷二酮类 吡格列酮、罗格列酮 中效 循证证据较少。
    (1)肾移植:安全,耐受性良好[88-89]
    (2)肝移植:样本量少,短期应用安全[89];(3)心、肺移植:证据缺乏
    吡格列酮与CNI无DDI T2DM人群心血管不良事件潜在获益(吡格列酮);心力衰竭风险增加;SOT受者暂无依据 体重增加、水肿、贫血、骨折等 心力衰竭、活动性肝病、严重骨质疏松和有病理性骨折病史的患者禁用
    格列奈类 瑞格列奈、那格列奈、米格列奈钙 强效 循证证据较少。(1)肾移植:安全,耐受性良好[85, 90-91];(2)肝、心、肺移植:证据缺乏 和CsA可能存在DDI T2DM人群中性;SOT受者暂无依据 低血糖、体重增加 可在肾功能不全患者中使用;与CsA联用时注意低血糖风险
    SGLT2i 达格列净、恩格列净、卡格列净、恒格列净、艾托格列净 中-强效 循证证据较少。
    (1)肾移植:安全,耐受性良好,减少胰岛素使用剂量,小样本研究中未发现泌尿系统感染风险
    增加[92-94];(2)心脏移植:小样本研究发现降低体重、血压,减少利尿剂剂量,耐受性良好,偶发尿路感染[95-96],部分RCT研究进行中[97];(3)肝、肺移植:证据缺乏
    与CNI、mTORi可能存在DDI T2DM人群获益,SOT受者使用大样本循证证据缺乏,小样本研究提示可能降低尿蛋白排泄;心脏移植PTDM者可能存在潜在获益 泌尿系统和生殖系统感染、血容量不足;糖尿病酮症酸中毒罕见 不建议用于eGFR<45 mL/(min·1.73 m2)患者
    GLP-1RA 日制剂:利拉鲁肽、艾塞那肽、贝那鲁肽、利司那肽;周制剂:度拉糖肽、洛塞那肽、艾塞那肽周制剂、司美格鲁肽 强效 循证证据较少。
    (1)肾、肝、心移植:降低体重、体重指数、胰岛素剂量,未增加心血管疾病、移植物失功或全因死亡等风险[98-99];(2)肺移植:证据缺乏
    T2DM人群获益,SOT受者大样本循证证据缺乏,获益情况不明 胃肠道反应 禁用于有甲状腺髓样癌病史或家族史的患者以及2型多发性内分泌肿瘤综合征患者;急性胰腺炎病史者慎用;严重高甘油三酯血症者建议降脂治疗后使用;使用司美格鲁肽时需注意监测糖尿病视网膜病变;需注意GLP-1RA致胃排空延迟可能影响免疫抑制剂的吸收
      注:CsA为环孢素;TAC为他克莫司;DDI为药物相互作用;mTORi为哺乳动物雷帕霉素靶蛋白抑制剂;eGFR为估算肾小球滤过率;RCT为随机对照试验。 a有效性依据T2DM患者使用的效果评价。
    下载: 导出CSV
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出版历程
  • 收稿日期:  2023-05-29
  • 录用日期:  2023-07-07
  • 网络出版日期:  2023-07-20
  • 刊出日期:  2023-09-15

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