学龄后儿童肾移植后BK多瘤病毒感染的影响因素及其预测模型构建

Factors affecting BK polyomavirus infection after kidney transplantation in post-school children and a predictive infection model

目的分析影响儿童肾移植术后BK多瘤病毒(BKPyV)感染的相关因素,并构建儿童肾移植术后BKPyV感染的预测模型。方法回顾性收集2014年1月至2022年3月在郑州大学第一附属医院接受同种异体肾移植的332例儿童受者的临床资料。依据BKPyV载量水平,分析不同时间点淋巴细胞的动态变化过程。应用Cox回归模型分析筛查BKPyV感染的相关因素,采用受试者工作特征曲线(ROC)评估预测感染模型的灵敏度和特异度。结果332例患儿中,男215例,女117例;移植年龄(12.2±3.9)岁;学龄前(1~5岁)37例,学龄后(6~18岁)295例。对224例患儿尿液与30例患儿血液样本的BKPyV载量检测结果显示,学龄前BKPyV尿症9例,BKPyV血症3例;学龄后BKPyV尿症76例,BKPyV血症14例。多因素Cox回归模型分析显示,较高体质指数(HR=1.105,95%CI:1.020~1.197)、抗人胸腺细胞免疫球蛋白应用(HR=2.196,95%CI:1.335~3.613)、较高他克莫司浓度(HR=2.484,95%CI:1.298~4.753)、较高自然杀伤(NK)细胞计数(HR=1.193,95%CI:1.009~1.411)、较高CD14^(++)CD16^(-)细胞计数(HR=1.096,95%CI:1.024~1.173)是学龄后儿童BKPyV尿症发生的危险因素;移植肾功能延迟恢复(HR=4.993,95%CI:1.555~16.038)、急性排斥反应(HR=6.021,95%CI:1.930~18.787)、较高CD14^(++)CD16^(-)细胞计数(HR=1.227,95%CI:1.081~1.392)是学龄后儿童BKPyV血症发生的危险因素。ROC曲线分析结果显示,联合体质指数、免疫诱导用药、他克莫司浓度、NK细胞计数、CD14^(++)CD16^(-)细胞计数预测学龄后儿童肾移植术后0.5、1、2、5年BKPyV尿症发生的曲线下面积(AUC)分别为0.712(95%CI:0.626~0.798)、0.708(95%CI:0.612~0.804)、0.754(95%CI:0.668~0.840)和0.767(95%CI:0.685~0.849),预测模型的灵敏度和特异度分别为64.9%、61.4%、61.6%、55.8%和70.9%、72.4%、76.0%、84.0%。联合移植肾功能延迟恢复、急性排斥反应、CD14^(++)CD16^(-)细胞计数预测学龄后儿童肾移植术后0.5、1、2、5年BKPyV血症发生的AUC分别为0.791(95%CI:0.631~0.951)、0.744(95%CI:0.547~0.936)、0.786(95%CI:0.629~0.946)和0.812(95%CI:0.672~0.948),预测模型的灵敏度和特异度分别为76.1%、67.1%、75.0%、77.9%和88.9%、89.0%、89.9%、88.0%。结论术后CD14^(++)CD16^(-)细胞水平可作为学龄后儿童肾移植后BKPyV感染的预测因子。联合体质指数、免疫诱导用药、他克莫司浓度、NK细胞计数、CD14^(++)CD16^(-)细胞计数可预测学龄后儿童肾移植术后BKPyV尿症发生;联合移植肾功能延迟恢复、急性排斥反应、CD14^(++)CD16^(-)细胞计数可预测学龄后儿童肾移植术后BKPyV血症发生。

Objective To analyze high-risk factors affecting BK polyomavirus(BKPyV)infection and to construct a prediction model for BKPyV infection in children after renal transplantation.Methods The clinical data of 332 children who received allogeneic kidney transplantation in the First Affiliated Hospital of Zhengzhou University from January 2014 to March 2022 were retrospectively collected.According to the BKPyV load level,the dynamic change process of lymphocytes at different time points were analyzed.The factors that have potential influence on BKPyV infection were screened by Cox regression analysis,and the receiver operating characteristic curve(ROC)was used to evaluate the sensitivity and specificity of the predictive model of infection.Results Among the 332 children,there were 215 males and 117 females;the age of transplantation was(12.2±3.9)years old;37 cases were preschool(1-5 years old),and 295 cases were post-school age(6-18 years old).BKPyV load in 224 urine samples and 30 blood samples of children were detected.There were 9 cases of BKPyV-associated viruria and 3 cases of BKPyV associated viremia in pre-school children,76 cases BKPyV associated viruria and 14 cases of BKPyV associated viremia in post-school children.Multivariate Cox regression analysis showed that higher body mass index(BMI)(HR=1.105,95%CI:1.020-1.197),antithyroglobulin(ATG)application(HR=2.196,95%CI:1.335-3.613),and higher tacrolimus concentration(HR=2.484,95%CI:1.298-4.753),higher natural killer(NK)lymphocyte count(HR=1.193,95%CI:1.009-1.411),higher CD14^(++)CD16^(-)cell count(HR=1.096,95%CI:1.024-1.173)were independent risk factors for BKPyV associated viruria in post-school children.Delayed graft function(DGF)(HR=4.993,95%CI:1.555-16.038),Acute rejection(AR)(HR=6.021,95%CI:1.930-18.787),higher CD14^(++)CD16^(-)cell count(HR=1.227,95%CI:1.081-1.392)were independent risk factors for BKPyV associated viremia in post-school children.The results of ROC curve analysis showed that combined BMI,immune induction drugs,tacrolimus concentration,NK cell count,and CD14^(++)CD16^(-)cell count predicted the occurrence of BKPyV associated viruria in post-school children after kidney transplantation at 0.5,1,2,and 5 years with area under curve(AUC)of 0.712(95%CI:0.626-0.798),0.708(95%CI:0.612-0.804),0.754(95%CI:0.668-0.840)and 0.767(95%CI:0.685-0.849).The sensitivity and specificity of the model were 64.9%,61.4%,61.6%,55.8%and 70.9%,72.4%,76.0%,84.0%,respectively.Combined with DGF,AR,and CD14^(++)CD16^(-)cell counts predicted the occurrence of BKPyV-associated viremia at 0.5,1,2,and 5 years after renal transplantation in post-school children with AUC of 0.791(95%CI:0.631-0.951),0.744(95%CI:0.547-0.936),0.786(95%CI:0.629-0.946)and 0.812(95%CI:0.672-0.948).The sensitivity and specificity of the model were 76.1%,67.1%,75.0%,77.9%and 88.9%,89.0%,89.9%,88.0%,respectively.Conclusions The postoperative CD14^(++)CD16^(-)cell level can be used as an independent predictor of BKPyV infection in post-school children after renal transplantation.Combined BMI,immune induction drugs,tacrolimus concentration,NK cell count,CD14^(++)CD16^(-)cell count and combined DGF,AR,CD14^(++)CD16^(-)cell count show good fitting effect in predicting the occurrence of BKPyV-associated viruria and viremia after transplantation in post-school children respectively.