Selection of Therapeutic Drugs for COVID-19 Infection in Adults with Chronic Kidney Disease Based on Medical Evidence

doi:10.12114/j.issn.1007-9572.2023.0156

Chinese General Practice ›› 2023, Vol. 26 ›› Issue (26): 3220-3229.DOI: 10.12114/j.issn.1007-9572.2023.0156

Special Issue: 新型冠状病毒肺炎最新文章合辑；泌尿系统疾病最新文章合辑； COVID-19疫情防控研究

• Evidence-based Medicine • Previous Articles Next Articles

Selection of Therapeutic Drugs for COVID-19 Infection in Adults with Chronic Kidney Disease Based on Medical Evidence

1. The Second Clinical Medical College of Guangzhou University of Chinese Medicine/Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine/National Clinical Research Base of Traditional Chinese Medicine for Chronic Kidney Disease, Guangzhou 510120, China
2. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm 11228, Sweden

Received:2023-03-13 Revised:2023-04-25 Published:2023-09-15 Online:2023-05-05
Contact: SU Guobin, LU Fuhua
About author:
SU Guobin, LING Xitao and DUAN Ruolan are the co-first authors

成年人慢性肾脏病患者感染新型冠状病毒治疗药物选择——基于循证医学证据

1．510120　广东省广州市，广州中医药大学第二临床医学院/广东省中医院肾内科/国家慢性肾脏病中医临床研究基地
2．11228 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

通讯作者: 苏国彬, 卢富华
作者简介:
作者贡献：苏国彬负责研究命题的提出、设计，文献质量筛选及评估，论文起草及最终版本修订；凌曦淘负责文献筛选、提取，协助论文撰写及修订，汇总数据并绘制表格；段若兰协助文献筛选、提取，协助论文撰写、核对参考文献，排版并绘制表格；张腊协助开展文献质量评估，协助论文修订及排版；许苑负责核对慢性肾脏病患者药物特殊用法及临床适应证；彭钰负责核对药物的相互作用、药物剂量及使用频次；侯海晶负责核对透析患者的药物特殊用法、适应证及注意事项；刘旭生负责论文起草及论文思路指导；卢富华负责最终版本的修订，对论文负责。所有作者均确认论文终稿。
注：苏国彬、凌曦淘、段若兰为共同第一作者
基金资助:
国家自然科学基金资助项目(82004205); 广东省中医院科学技术研究基金(YN2018QL08); 广东省中医院拔尖人才科研专项资助(BJ2022KY11); 广东省中医院中医药科学技术研究专项课题(YN2020QN18); 广东省中医院朝阳人才科研专项资助(ZY2022KY15); 国家中医药管理局中医药防治新型冠状病毒感染应急研究专项课题(2023ZYLCYJ02-18)

Abstract

Abstract:

Chronic kidney disease (CKD) is characterized by abnormal urine test or progressive kidney function decline. Patients with CKD are at a higher risk of COVID-19 infection with higher conversion and mortality rates after infection for their reduced kidney function, long-term use of immunosuppressive agents or combination of underlying diseases. Therefore, rational drug use is particularly important for CKD patients combined with COVID-19 infection. This article summarizes special considerations for the use of relevant medications in patients with CKD by integrating the current evidence of medications for the treatment of COVID-19 infection, including antiviral drugs, anti-inflammatory drugs, antithrombotic drugs, convalescent plasma and neutralizing monoclonal antibodies, as well as commonly used symptomatic drugs of respiratory system (such as antfebrile, antisputum and cough medicine and anti-allergic drugs), high lighting the modified medication regiments according to kidney function levels, in order to provide a reference for clinical professionals, assist in clinical decision-making and rational drug use, and ensure clinical efficacy and safety.

Key words: Kidney diseases, Chronic kidney disease, Corona Virus Disease 2019, Dialysis, Therapy, Medication, Guideline, Evidence-based medicine

摘要：

慢性肾脏病（CKD）以尿检异常或肾功能进行性下降为特征。CKD患者因肾功能受损、长期使用影响免疫系统的药物或合并基础疾病较多，较正常人群更容易感染新型冠状病毒（COVID-19），且感染后重症转化率及死亡率更高。对于CKD合并COVID-19感染的治疗，合理用药尤为重要。为此，本文通过整合目前治疗COVID-19相关药物的最新研究证据，包括抗病毒药物、抗炎药物、抗血栓药物、康复者恢复期血浆与中和单克隆抗体，以及呼吸系统疾病常用对症治疗药物（如解热、止咳化痰及抗过敏药物等），突出在不同肾功能水平的调整用药方案，总结在CKD患者中使用相关药物的特殊考虑要点，以期供临床专业人员参考，辅助临床决策和合理用药，保障临床疗效与安全性。

关键词: 肾疾病, 慢性肾脏病, 新型冠状病毒, 透析, 治疗, 药物, 指南, 循证医学

SU Guobin,LING Xitao,DUAN Ruolan, et al. Selection of Therapeutic Drugs for COVID-19 Infection in Adults with Chronic Kidney Disease Based on Medical Evidence[J]. Chinese General Practice, 2023, 26(26): 3220-3229. DOI: 10.12114/j.issn.1007-9572.2023.0156.
苏国彬,凌曦淘,段若兰等. 成年人慢性肾脏病患者感染新型冠状病毒治疗药物选择——基于循证医学证据[J]. 中国全科医学, 2023, 26(26): 3220-3229. DOI: 10.12114/j.issn.1007-9572.2023.0156.

Figures/Tables 5

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[75]	ARIKAWA S，FUKUOKA K，NAKAMOTO K，et al. Effectiveness of neutralizing antibody cocktail in hemodialysis patients：a case series of 20 patients treated with or without REGN-COV2[J]. Clin Exp Nephrol，2022，26（5）：476-485. DOI：10.1007/s10157-021-02151-3.
[76]	GUEGUEN J，COLOSIO C，DEL BELLO A，et al. Early administration of anti-SARS-CoV-2 monoclonal antibodies prevents severe COVID-19 in kidney transplant patients[J]. Kidney Int Rep，2022，7（6）：1241-1247. DOI：10.1016/j.ekir.2022.03.020.
[77]	US Food and Drug Administration. Fact sheet for health care providers emergency use authorization （EUA）of bamlanivimab and etesevimab[EB/OL]. （2022-01-24）[2023-01-10].
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药物	肌酐清除率（CrCl）>50 mL/min	CrCl 10~50 mL/min	CrCl<10 mL/min	透析
常用解热药
对乙酰氨基酚	每次给药间隔至少4 h以上	每次给药间隔6 h以上，定期监测肾功能	每次给药间隔8 h以上，定期监测肾功能	血液透析、腹膜透析（CAPD）模式和连续肾脏替代疗法（CRRT）均不主张透析后额外补充给药
布洛芬^a^[6]	一般情况下单次给药剂量无需调整，连续使用≤2 d
中成药	尚缺乏清肺排毒颗粒、藿香正气胶囊（软胶囊、丸、水、口服液）、疏风解毒胶囊（颗粒）、化湿败毒颗粒、宣肺败毒颗粒、散寒化湿颗粒、金花清感颗粒、连花清瘟胶囊（颗粒）等推荐中成药在CKD人群中的药物剂量调整数据。
止咳化痰药^[9]
溴己新	可选用，严重肝肾功能损伤时，溴己新代谢产物的清除率降低，说明书未提供具体调整方法
乙酰半胱氨酸	可选用，口服t_1/2 6.25 h，肾脏清除率占总清除率30%，说明书未提供具体调整方法
氨溴索	可选用，t_1/2约10 h，肾脏清除率占总清除率83%，肾功能不全者减量或延长两次给药间隔时间
愈创甘油醚	肾炎及肾功能受损者禁用
氯化铵	肾功能不全禁用铵盐，代谢性酸中毒禁用
右美沙芬	中枢性镇咳药，原型及代谢物主要经肾脏排泄，肾功能不全者慎用
福尔可定	仅供二线使用，严重肾功能受损时需调整剂量，说明书未提供具体调整方法
抗过敏药^[7，8]
苯海拉明	25~50 mg口服，给药间隔4~6 h；最大剂量≤300 mg/d	25~50 mg口服，给药间隔延长至6~12 h；最大剂量≤300 mg/d	25~50 mg口服，给药间隔延长至12~18 h；最大剂量≤300 mg/d	血液透析、CAPD模式和CRRT均不主张透析后额外补充给药
氯苯那敏	每次4 mg口服，给药间隔4~6 h			血液透析后无需额外补充，CAPD模式中疗效不明确，CRRT中无效
氯雷他定	10 mg/次，1次/d，使用过程注意监测不良反应和肾功能水平
西替利嗪	10 mg/次、1次/d；或5 mg/次、早晚各1次；或遵医嘱		5 mg/次、1次/d

药物	肌酐清除率（CrCl）>50 mL/min	CrCl 10~50 mL/min	CrCl<10 mL/min	透析
常用解热药
对乙酰氨基酚	每次给药间隔至少4 h以上	每次给药间隔6 h以上，定期监测肾功能	每次给药间隔8 h以上，定期监测肾功能	血液透析、腹膜透析（CAPD）模式和连续肾脏替代疗法（CRRT）均不主张透析后额外补充给药
布洛芬^a^[6]	一般情况下单次给药剂量无需调整，连续使用≤2 d
中成药	尚缺乏清肺排毒颗粒、藿香正气胶囊（软胶囊、丸、水、口服液）、疏风解毒胶囊（颗粒）、化湿败毒颗粒、宣肺败毒颗粒、散寒化湿颗粒、金花清感颗粒、连花清瘟胶囊（颗粒）等推荐中成药在CKD人群中的药物剂量调整数据。
止咳化痰药^[9]
溴己新	可选用，严重肝肾功能损伤时，溴己新代谢产物的清除率降低，说明书未提供具体调整方法
乙酰半胱氨酸	可选用，口服t_1/2 6.25 h，肾脏清除率占总清除率30%，说明书未提供具体调整方法
氨溴索	可选用，t_1/2约10 h，肾脏清除率占总清除率83%，肾功能不全者减量或延长两次给药间隔时间
愈创甘油醚	肾炎及肾功能受损者禁用
氯化铵	肾功能不全禁用铵盐，代谢性酸中毒禁用
右美沙芬	中枢性镇咳药，原型及代谢物主要经肾脏排泄，肾功能不全者慎用
福尔可定	仅供二线使用，严重肾功能受损时需调整剂量，说明书未提供具体调整方法
抗过敏药^[7，8]
苯海拉明	25~50 mg口服，给药间隔4~6 h；最大剂量≤300 mg/d	25~50 mg口服，给药间隔延长至6~12 h；最大剂量≤300 mg/d	25~50 mg口服，给药间隔延长至12~18 h；最大剂量≤300 mg/d	血液透析、CAPD模式和CRRT均不主张透析后额外补充给药
氯苯那敏	每次4 mg口服，给药间隔4~6 h			血液透析后无需额外补充，CAPD模式中疗效不明确，CRRT中无效
氯雷他定	10 mg/次，1次/d，使用过程注意监测不良反应和肾功能水平
西替利嗪	10 mg/次、1次/d；或5 mg/次、早晚各1次；或遵医嘱		5 mg/次、1次/d

药物	估算肾小球滤过率（eGFR）≥60 mL·min^-1·（1.73 m²）^-1	eGFR 30~59 mL·min^-1·（1.73 m²）^-1	eGFR 15~29 mL·min^-1·（1.73 m²）^-1
瑞德西韦^[10]	第1天：200 mg、1次/d，静脉滴注；第2~5天：100 mg、1次/d，静脉滴注（若临床表现未改善，或为维持机械通气或体外膜肺氧合治疗，疗程延长至10 d）		不建议使用
奈玛特韦/利托那韦^[8]	奈玛特韦300 mg+利托那韦100 mg、1次/12 h，口服；总疗程5 d	奈玛特韦150 mg+利托那韦100 mg、1次/12 h，口服^[8]；总疗程5 d	因缺乏数据，说明书中不推荐使用，确有需求者充分知情后建议采用减量方案：第1天：奈玛特韦300 mg+利托那韦100 mg、1次/24 h，口服；第2~5天：奈玛特韦150 mg+利托那韦100 mg、1次/24 h，口服^[11]；使用期间密切监测肾功能，透析日在血液透析后服用
莫诺拉韦^[8]	800 mg、1次/12 h，口服，连续使用5 d
阿兹夫定^[8]	5 mg、1次/d，口服，疗程≤14 d	中重度肾功能损伤慎用
氢溴酸氘瑞米德韦（VV116）^[12]	第1天：600 mg、1次/12 h，口服；第2~5天：300 mg、1次/12 h，口服	暂无研究数据

药物	估算肾小球滤过率（eGFR）≥60 mL·min^-1·（1.73 m²）^-1	eGFR 30~59 mL·min^-1·（1.73 m²）^-1	eGFR 15~29 mL·min^-1·（1.73 m²）^-1
瑞德西韦^[10]	第1天：200 mg、1次/d，静脉滴注；第2~5天：100 mg、1次/d，静脉滴注（若临床表现未改善，或为维持机械通气或体外膜肺氧合治疗，疗程延长至10 d）		不建议使用
奈玛特韦/利托那韦^[8]	奈玛特韦300 mg+利托那韦100 mg、1次/12 h，口服；总疗程5 d	奈玛特韦150 mg+利托那韦100 mg、1次/12 h，口服^[8]；总疗程5 d	因缺乏数据，说明书中不推荐使用，确有需求者充分知情后建议采用减量方案：第1天：奈玛特韦300 mg+利托那韦100 mg、1次/24 h，口服；第2~5天：奈玛特韦150 mg+利托那韦100 mg、1次/24 h，口服^[11]；使用期间密切监测肾功能，透析日在血液透析后服用
莫诺拉韦^[8]	800 mg、1次/12 h，口服，连续使用5 d
阿兹夫定^[8]	5 mg、1次/d，口服，疗程≤14 d	中重度肾功能损伤慎用
氢溴酸氘瑞米德韦（VV116）^[12]	第1天：600 mg、1次/12 h，口服；第2~5天：300 mg、1次/12 h，口服	暂无研究数据

药物	eGFR≥60 mL·min^-1·（1.73 m²）^-1	eGFR 30~59 mL·min^-1·（1.73 m²）^-1	eGFR 15~29 mL·min^-1·（1.73 m²）^-1	透析
地塞米松	5 mg^[8]或6 mg^[10，13]、1次/d，口服/静脉推注/静脉滴注，一般使用3~5 d，最长不超过10 d	5 mg或6 mg、1次/d，口服/静脉推注/静脉滴注，谨慎使用3~5 d，最长不超过10 d，期间监测肾功能，注意继发感染
巴瑞替尼	4 mg、1次/d，口服^[10]	2 mg、1次/d，口服^[10]	2 mg、1次/48 h，口服^[14]	不建议使用
托珠单抗	8 mg/kg、1次/d，静脉滴注（静脉滴注持续1 h以上）

Selection of Therapeutic Drugs for COVID-19 Infection in Adults with Chronic Kidney Disease Based on Medical Evidence

成年人慢性肾脏病患者感染新型冠状病毒治疗药物选择——基于循证医学证据

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分类	CrCl≥30 mL/min	CrCl<30 mL/min
COVID-19重症患者
肝素抗凝	建议使用预防剂量抗凝药物，如依诺肝素40 mg/d^[15，16]皮下注射或普通肝素5 000 U、2~3次/d^[15]	CrCl<30 mL/min时，预防剂量的依诺肝素应减量至30 mg/d；普通肝素无需调整^[17]
阿司匹林或P2Y12抑制剂^[18，19]	经验性予抗血小板药物无明确获益且出血风险增加，建议不新增使用
COVID-19住院患者（非重症）
肝素抗凝^a	建议使用治疗剂量的抗凝疗法。治疗剂量的抗凝治疗，如依诺肝素：1 mg/kg、2次/d^[20]皮下注射	CrCl<30 mL/min时，治疗剂量的依诺肝素需减量至1 mg/kg、1次/d^[17]皮下注射
直接口服抗凝剂（如利伐沙班）^[21]	在缺乏口服抗凝治疗指征的情况下，应避免使用治疗剂量的利伐沙班等直接口服抗凝药物
阿司匹林^[19]	经验性予抗血小板药物无明确获益且出血风险增加，建议不新增使用
COVID-19感染门诊患者^[22]	对于临床症状稳定的COVID-19感染门诊患者经验性使用阿哌沙班、阿司匹林没有明显获益，建议暂不新增使用
出院患者^[23]	存在高血栓风险但低出血风险者，口服利伐沙班10 mg/d预防血栓可能获益；暂无针对CKD的剂量调整数据

项目	eGFR≥60 mL·min^-1·（1.73 m²）^-1	eGFR 30~59 mL·min^-1·（1.73 m²）^-1
安巴韦单抗/罗米司韦单抗注射液	安巴韦单抗注射液1 000 mg、罗米司韦单抗注射液1 000 mg静脉滴注序贯给药，病程中仅给药1次^[8]	CKD患者中理论上无需调整剂量，有待研究数据验证
静注COVID-19人免疫球蛋白	轻型100 mg/kg、中型200 mg/kg、重型400 mg/kg，静脉滴注，根据患者病情改善情况，次日可再次静脉滴注，总次数≤5次^[8]	CKD患者中理论上无需调整剂量，有待研究数据验证
康复者恢复期血浆	200~500 mL（4~5 mL/kg），病程中一般给药1次，可根据患者个体情况及病毒载量等决定是否再次静脉滴注^[8]	CKD患者中理论上无需调整剂量，有待研究数据验证

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