免疫检查点抑制剂相关肾损伤发生情况及影响因素分析

Analysis of the occurrence and influencing factors of immune checkpoint inhibitor‑related kidney injury

目的探讨使用免疫检查点抑制剂(ICI)后出现肾功能生化指标异常患者肾损伤的发生特点及影响因素,为临床治疗方案的选择提供参考。方法通过中国医院药物警戒系统检索山东第一医科大学附属省立医院2021年3月1日至2022年2月28日收治的使用我国自主研发ICI(卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗)进行治疗并出现估算肾小球滤过率(eGFR)<90 ml/(min·1.73 m^(2))和/或血肌酐(Scr)>105μmol/L的肿瘤患者,收集患者基本信息、肿瘤治疗方案、实验室检查结果及合并用药等信息。根据是否发生肾损伤将患者分为肾损伤组和非肾损伤组,比较2组患者的临床特征,采用二元logistic回归模型分析患者发生肾损伤的影响因素,计算比值比(OR)及其95%置信区间(CI)。结果纳入分析的患者为222例,男性170例,女性52例;中位年龄67(36,85)岁;使用卡瑞利珠单抗者144例,信迪利单抗38例,替雷利珠单抗31例,特瑞普利单抗9例。222例患者中,有29例(13.1%)患者发生肾损伤,其中1级肾损伤26例,2级3例;肾损伤发生时间为首次应用ICI后19~355 d,中位发生时间为108 d。发现肾损伤后,29例患者中13例停用ICI,其中6例肾功能恢复正常,7例未改善;16例继续用药,其中10例肾功能恢复或好转,6例未好转。对2组患者的临床特征进行比较,筛选出患者年龄、性别、基线肾功能、既往使用卡铂、既往放疗、联合含顺铂化疗、联合紫杉醇化疗、联合酪氨酸激酶抑制剂(TKI)抗血管生成治疗、联用质子泵抑制剂以及联合放疗等10个变量纳入二元logistic回归分析,结果显示女性(OR=3.046,95%CI:1.149~8.077)、年龄≤65岁(OR=3.649,95%CI:1.435~9.274)、联合TKI抗血管生成治疗(OR=4.773,95%CI:1.496~15.227)和联合放疗(OR=8.655,95%CI:1.268~59.076)为发生肾损伤的独立危险因素。结论使用ICI后出现eGFR<90 ml/(min·1.73 m^(2))和/或Scr>105μmol/L的患者中,肾损伤发生率为13.1%,女性、年龄≤65岁、联合TKI抗血管生成治疗和联合放疗可能是此类患者发生肾损伤的危险因素。

Objective To explore the characteristics and factors affecting the occurrence of renal injury in patients with abnormal biochemical indexes of renal function after the use of immune checkpoint inhibitors(ICIs),and to provide reference for selection of clinical treatment regimen.Methods Patients who were treated with immune checkpoint inhibitors researched and developed independently in China including camrelizumab,sintilimab,tislelizumab,and toripalimab from March 1,2021 to February 28,2022 and showed estimated glomerular filtration rate(eGFR)<90 ml/(min·1.73 m^(2))and/or serum creatinine(Scr)>105μmol/L were retrieved from the China Hospital Pharmacovigilance System.The clinical data including general information,anti⁃tumor treatment regimen,laboratory test results,and concomitant medica⁃tions were collected.Patients were divided into kidney injury group and non⁃kidney injury group,and all the clinical characteristics were compared between the 2 groups,the influencing factors of kidney injury were analyzed using a binary logistic regression model,the odds ratio(OR)and its 95%confidence interval(CI)were calculated.Results A total of 222 patients were entered in the analysis,including 170 males and 52 females,with a median age of 67(36,85)years.Of them,144 patients were treated with carrilizumab,38 with sindilizumab,31 with tirelizumab,and 9 with treprolizumab;29 patients(13.1%)developed kidney injury,including 26 cases of grade 1 and 3 cases of grade 2 renal injuries;the time of renal injury occur⁃rence was 19⁃355 days after the first application of ICIs,and the median time was 108 days.After diag⁃nosed of kidney injury,13 out of 29 patients stopped ICIs,of which 6 had recovered kidney function and 7 had no improvement;16 patients continued the ICIs treatment,of which 10 patients had recovered or improved kidney function and 6 had no improvement.The clinical characteristics of patients in the 2 groups were compared,and 10 variables including age,gender,baseline renal function,previous use of carboplatin,previous radiotherapy,combined chemotherapy containing cisplatin,combined paclitaxel chemotherapy,combined tyrosine kinase inhibitor(TKI)anti⁃vascular therapy,combined proton pump inhibitors,and com⁃bined radiotherapy were screened for the binary logistic regression analysis.The results showed that female(OR=3.046,95%CI:1.149-8.077),≤65 years(OR=3.649,95%CI:1.435-9.274),combined TKI anti⁃vascular therapy(OR=4.773,95%CI:1.496-15.227),and combined radiotherapy(OR=8.655,95%CI:1.268-59.076)were independent risk factors for the development of kidney injury.Conclusions The incidence of kidney injury in patients with eGFR<90 ml/(min·1.73 m^(2))and/or Scr>105μmol/L after using ICIs is 13.1%.In these patients,female,≤65 years,combined TKI anti⁃vascular therapy,and combined radiotherapy may be risk factors for the development of ICI⁃associated kidney injury.