Reltecimod

治疗急性肾损伤的新药 New drugs for acute kidney injury Citation: Hariri G, Legrand M. New drugs for acute kidney injury. J Intensive Med. 2024;5(1):3–11. doi: 10.1016/j.jointm.2024.08.001. 核心结论 急性肾损伤（AKI）在重症及围术期患者中发病率高达30%-60%，目前仍无高级别证据支持的预防或治疗药物。本文系统综述了基于最新病理生理机制（炎症应答、代谢重编程、血流动力学调节、补体活化及细胞凋亡/修复）的在研新药，涵盖碱性磷酸酶、Reltecimod、血管紧张素II、维生素B3类、CD39重组蛋白、Ravulizumab、siRNA QPI-1002及间充质干细胞等。多项II/III期临床试验正在评估其疗效，为降低AKI发生率及严重程度带来新希望。 正文 急性肾损伤（AKI）是全球性健康问题，每年影响超过1300万人，并导致约170万例死亡[1]。从病理生理角度看，AKI以肾小球滤过率（GFR）快速下降为特征，数小时或数日内表现为血清肌酐急剧升高。2004年之前由于缺乏统一定义，AKI的诊断标准从轻度肌酐升高至需要肾脏替代治疗（RRT）范围广泛[2]。RIFLE、AKIN及KDIGO分级系统的建立，依据血清肌酐和尿量变化提供了结构化诊疗路径，实现了早期识别与干预[3-5]。在重症监护环境中，AKI发病率异质性较大（15%-60%），且与死亡率升高、住院时间延长及慢性肾脏病（CKD）风险增加密切相关[6-8]。尽管过去二十年危重症患者管理取得显著进步，但预防或治疗AKI的有效药物干预仍十分缺乏。近期对AKI病理生理机制的深入理解揭示了炎症、代谢紊乱及细胞修复障碍等共同通路，为新型药物研发提供了方向（图1，表1）。 图1：重症及围术期急性肾损伤预防或治疗新药的作用机制概览。HGF: 肝细胞生长因子；MSC: 间充质干细胞。 基于上述机制，目前处于研发阶段的药物涵盖了免疫调节、血流动力学优化、细胞能量代谢支持、补体抑制及抗凋亡/促修复等多个维度。下文按照靶点分类逐一阐述代表性药物的临床证据。1. 炎症调控 碱性磷酸酶（ALP）可通过去磷酸化脂多糖（LPS）及胞外ATP/ADP，减轻Toll样受体介导的先天免疫反应。STOP-AKI试验（n=301）中，重组ALP（ilofotase alfa）虽未改善7天肾功能，但28天肌酐清除率提升18.5 mL/min（95%CI: 5.3-31.7），死亡率降低（14.4% vs 26.7%）[18]。然而后续III期REVIVAL试验（n=655）未显示28天全因死亡率获益，但MAKE90复合终点（56.7% vs 64.6%, P=0.02）提示可能降低RRT需求[19]。针对CSA-AKI的II期预防试验（NCT06168799）正在进行。 Reltecimod是一种靶向T细胞表面CD28的肽类，可调节脓毒症免疫应答。在坏死性软组织感染III期试验中虽未达到主要复合终点，但第14天SOFA评分改善（65.1% vs 52.6%, P=0.04）[24]。目前针对KDIGO 2-3期AKI合并腹腔脓毒症的III期试验（NCT03403751）正在评估28天AKI恢复率。 活性维生素D（骨化三醇）可通过下调核因子κB减轻炎症。但ACTIVATE-AKI试验（NCT02962102）未显示7天内死亡或RRT需求的显著差异。RBT-1（锡原卟啉+蔗糖铁）通过上调HO-1、铁蛋白发挥预适应保护，PROTECT III期研究（n=400）正在进行，主要终点为死亡、透析需求、ICU住院日及30天再入院复合指标。 TIN816（重组CD39）可水解胞外ATP/ADP，抑制炎症及血小板聚集。针对SA-AKI的II期试验（NCT05996835）以第1-8天时间校正肌酐清除率曲线下面积为主要终点；CSA-AKI预防试验（NCT05524051）计划纳入120例患者。2. 血流动力学调节 血管紧张素II选择性收缩肾出球小动脉，提升GFR。ATHOS-3试验显示，血管紧张素II显著提高顽固性血管扩张性休克患者3小时平均动脉压（69.9% vs 23.4%, OR=7.95）[46]，且在需RRT的亚组中28天生存率更高（53% vs 30%）[47]。预防CSA-AKI的可行性研究提示AKI发生率降低（25% vs 38%, P=0.31），III期试验（NCT05199493）正在开展。 血管加压素：心脏术后血管麻痹性休克患者中，血管加压素较去甲肾上腺素显著降低CSA-AKI（10.3% vs 35.8%, P<0.0001）[52]；但在脓毒性休克中未显示AKI预防获益。个体患者数据Meta分析提示可能降低RRT需求（RR=0.86）。两项RCT（NCT04602767, NCT06125184）将进一步明确。 左西孟旦：钙增敏剂兼有入球小动脉扩张作用。心脏手术Meta分析显示可减少CSA-AKI（OR=0.51）及RRT（OR=0.43），但大型RCT未证实获益[57]。LEVO-AKI试验（NCT02531724）正在评估已发生CSA-AKI的治疗效果。3. 细胞代谢与线粒体功能 维生素B3类（烟酰胺、烟酰胺核糖）通过补充NAD+保护肾小管。心脏手术II期试验显示烟酰胺使AKI发生率降低35%[59]。多项RCT正在验证其预防CSA-AKI（NCT04750616）、肾移植后移植物功能（NCT05513807）及脓毒性休克相关AKI（NCT04589546）的疗效。ASP1128（PPARδ调节剂）在心脏手术高危患者中未减少AKI发生率（24.6% vs 21%, P=0.595）[62]。SIRT1激活剂NRPT（烟酰胺核糖+紫檀芪）II期试验（NCT04342975）正在主动脉弓置换患者中评估预防效果。 表1：重症及围术期急性肾损伤预防/治疗新药汇总 药物 机制 靶点 相关临床试验 研究人群 Angiotensin II 血流动力学 肾出球小动脉 NCT05199493 预防CSA-AKI Angiotensin II 血流动力学 肾出球小动脉 NCT04592744 肝移植后AKI预防 Angiotensin II 血流动力学 肾出球小动脉 NCT04901169 肝移植后AKI预防 Vasopressin 血流动力学 V1a受体 NCT04602767 预防CSA-AKI Vasopressin 血流动力学 V1a受体 NCT06125184 预防SA-AKI(脓毒性休克) Levosimendan 血流动力学/正性肌力 肾入球小动脉 NCT02531724 CSA-AKI治疗 Reltecimod 免疫调节 CD28 NCT03403751 SA-AKI(腹腔脓毒症) Activated vitamin D 免疫调节 NF-κB NCT02962102 高危患者AKI预防 ALP (Ilofotase alfa) 免疫调节 TLR-4/LPS NCT06168799 预防CSA-AKI RBT-1 缺血预适应 HO-1/铁蛋白 PROTECT study 预防CSA-AKI TIN816 ATP/ADP水解 CD39 NCT05996835 SA-AKI TIN816 ATP/ADP水解 CD39 NCT05524051 预防CSA-AKI Vitamin B3 (Nicotinamide) 细胞代谢 NAD+合成 NCT04750616 预防CSA-AKI Nicotinamide 细胞代谢 NAD+ NCT05513807 肾移植后移植物功能延迟 NR (Nicotinamide riboside) NAD+前体 SIRT1 NCT04818216 COVID-19相关AKI ASP1128 PPARδ激动剂 脂肪酸氧化 II期(已停止) CSA-AKI高危 NRPT (NR+Pterostilbene) SIRT1激活 NAD+/SIRT1 NCT04342975 主动脉弓置换后AKI预防 Ravulizumab 补体C5抑制剂 C5 NCT05746559 预防CSA-AKI siRNA QPI-1002 抗凋亡 p53 NCT02610296 肾移植后移植物功能延迟 HGF-mimetic (BB3) 细胞修复/抗凋亡 cMet/Bcl-2 NCT02771509 预防CSA-AKI Mesenchymal Stem Cells 免疫调节/修复 多靶点 NCT04445220 COVID-19合并RRT Umbilical cord MSC 组织修复 多靶点 NCT04194671 AKI治疗 补体抑制剂Ravulizumab（长效C5单抗）在COVID-19相关AKI的小样本试验中显示透析需求降低（P=0.03），III期ARTEMIS试验（NCT05746559）正在心脏手术CKD患者中验证其预防CSA-AKI的效果。4. 凋亡抑制与细胞修复 siRNA药物QPI-1002（靶向p53）在心脏手术高危患者中使AKI发生率降低13%（37% vs 50%, P=0.02）[75]，但MAKE90无差异；III期预防试验因无效而终止。HGF模拟物BB3在肾移植后未改善360天eGFR（P=0.32）[80]，GUARD试验（NCT02771509）正在评估其对CSA-AKI的预防效果。间充质干细胞（MSC）在CSA-AKI的II期试验中未显示获益，但体外扩增MSC可能具有免疫修复潜力，相关试验仍在进行（NCT04445220, NCT04194671）。 综上所述，目前尚无获批的AKI特效药，但基于精准病理生理靶点的多种药物已进入后期临床试验阶段，为改善重症及手术患者AKI结局带来了切实希望。 参考文献 Mehta R.L., Cerdá J., Burdmann E.A., Tonelli M., García-García G., Jha V., et al. 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