联合检测尿肾损伤标志物诊断早期糖尿病肾脏疾病的价值

Value of combined detection of urinary kidney injury markers in the diagnosis of earlystage diabetic kidney disease

目的探讨联合检测尿肾损伤标志物诊断早期糖尿病肾脏疾病(diabetic kidney disease,DKD)的价值,以期为临床开展早期DKD筛查提供依据。方法该研究为回顾性研究。收集2022年1月至2023年8月在海南医学院第二附属医院就诊的2型糖尿病(type 2 diabetes mellitus,T2DM)患者的临床资料。根据尿微量白蛋白/肌酐比值(UACR)将患者分为单纯糖尿病组(UACR<30 mg/g)、早期DKD组(30 mg/g≤UACR≤300 mg/g)和临床DKD组(UACR>300 mg/g),比较3组患者临床资料的差异。检测肾小球损伤标志物尿微量白蛋白、转铁蛋白、免疫球蛋白(Ig)、α2巨球蛋白,以及肾小管损伤标志物尿α1微球蛋白(α1-MG)、β2微球蛋白(β2-MG)、视黄醇结合蛋白(RBP)、N-乙酰-β-D-葡萄糖苷酶(NAG)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)水平。Spearman相关分析法分析尿肾损伤标志物与临床指标的相关性。采用多因素Logistic回归分析法分析T2DM患者发生DKD(UACR>300 mg/g)的危险因素。采用受试者工作特征曲线分析单独检测和联合检测尿肾损伤标志物诊断早期DKD(30 mg/g≤UACR≤300 mg/g)的价值。结果该研究纳入116例T2DM患者,年龄(61.99±12.56)岁(30~91岁),男性79例(68.1%)。单纯糖尿病组44例(37.9%),早期DKD组27例(23.3%),临床DKD组45例(38.8%)。临床DKD组患者血肌酐(H=34.183,P<0.001)和血尿素氮(H=34.082,P<0.001)均高于单纯糖尿病组和早期DKD组。Spearman相关分析结果显示,肾小球损伤标志物尿微量白蛋白、转铁蛋白、Ig、α2巨球蛋白与血肌酐、血尿素氮、UACR均呈正相关,与估算肾小球滤过率、血清白蛋白均呈负相关(均P<0.05);肾小管损伤标志物尿α1-MG、β2-MG、NAG、RBP、NGAL与血肌酐、血尿素氮、UACR均呈正相关,与估算肾小球滤过率、血清白蛋白均呈负相关(均P<0.05)。多因素Logistic回归分析结果显示,收缩压≥140 mmHg(OR=1.033,95%CI 1.008~1.060,P=0.010)、高尿微量白蛋白(OR=1.018,95%CI 1.007~1.030,P=0.001)、高尿RBP(OR=1.309,95%CI 1.086~1.577,P=0.005)、高尿NGAL(OR=1.004,95%CI 1.000~1.008,P=0.037)、低血清白蛋白(OR=0.833,95%CI 0.749~0.926,P=0.001)及低尿Ig(OR=0.994,95%CI 0.990~0.999,P=0.018)均为DKD发生的独立影响因素。受试者工作特征曲线分析结果显示,单独检测尿微量白蛋白诊断早期DKD的曲线下面积(AUC=0.976,95%CI 0.955~0.997,P<0.001)最大,敏感性及特异性分别为95.6%、90.1%。联合检测尿微量白蛋白+Ig+转铁蛋白+α2巨球蛋白+α1-MG+β2-MG+NAG+RBP+NGAL诊断早期DKD的AUC为0.986(95%CI 0.971~1.000,P<0.001),敏感性及特异性分别为93.3%、98.5%,优于各项单独检测指标。进一步优化检测组合后,以尿微量白蛋白+β2-MG+NGAL联合检测诊断效能最佳(AUC=0.978,95%CI 0.958~0.999,P<0.001),敏感性及特异性分别为95.6%、93.0%。结论相比各指标的单独检测,尿肾小球及肾小管损伤标志物联合检测有更高的早期DKD诊断价值。尿微量白蛋白+β2-MG+NGAL联合检测诊断早期DKD的价值最大。

Objective To explore the value of combined detection of urinary kidney injury markers in the diagnosis of early-stage diabetic kidney disease(DKD),and to provide evidence for early-stage DKD screening.Methods It was a retrospective study.The clinical data of patients with type 2 diabetes mellitus(T2DM)from the Second Affiliated Hospital of Hainan Medicine University from January 2022 to August 2023 were collected.According to urinary microalbumin/creatinine ratio(UACR),the patients were divided into three groups:isolated diabetes group(UACR<30 mg/g),early-stage DKD group(30 mg/g≤UACR<300 mg/g)and clinical DKD group(UACR≥300 mg/g),and the differences of clinical data among three groups were compared.Glomerular injury markers urinary microalbumin,transferrin,immunoglobulin(Ig)and α2 macroglobulin,and renal tubule injury markers α1 microglobulin(α1-MG),β2 microglobulin(β2-MG),retinol-binding protein(RBP),N-acetyl-β-D-glucosidase(NAG),neutrophil gelatinase-associated lipid carrier protein(NGAL)were measured.Spearman correlation method was used to analyze the correlation between urinary kidney injury markers and clinical indicators.Multivariate logistic regression analysis method was used to analyze the risk factors of DKD occurrence(UACR>300 mg/g).Receiver-operating characteristic curve was used to analyze the value of individual and combined detection of urinary renal injury markers in the diagnosis of early-stage DKD(30 mg/g≤UACR<300 mg/g).Results A total of 116 T2DM patients were enrolled in this study,aged(61.99±12.56)years old(30 to 91 years old),with 79 males(68.1%).There were 44(37.9%)isolated diabetes patients,27(23.3%)early-stage DKD patients,and 45(38.8%)clinical DKD patients.Serum creatinine(Scr,H=34.183,P<0.001)and blood urea nitrogen(BUN,H=34.082,P<0.001)in clinical DKD group were higher than those in isolated diabetes group and early-stage DKD group.Spearman correlation analysis showed that glomerular injury markers urinary microalbumin,transferrin,Ig and α2 macroglobulin were positively correlated with Scr,BUN and UACR,and negatively correlated with estimated glomerular filtration rate and serum albumin(all P<0.05).Renal tubule injury markers urinaryα1-MG,β2-MG,NAG,RBP,and NGAL were positively correlated with Scr,BUN and UACR,and negatively correlated with estimated glomerular filtration rate and serum albumin(all P<0.05).Multivariate logistic regression analysis indicated that systolic blood pressure≥140 mmHg(OR=1.033,95%CI 1.008-1.060,P=0.010),high urinary microalbumin(OR=1.018,95%CI 1.007-1.030,P=0.001),high urinary RBP(OR=1.309,95%CI 1.086-1.577,P=0.005),high urinary NGAL(OR=1.004,95%CI 1.000-1.008,P=0.037),low serum albumin(OR=0.833,95%CI 0.749-0.926,P=0.001)and low urinary Ig(OR=0.994,95%CI 0.990-0.999,P=0.018)were independent influencing factors of DKD occurrence.Receiver-operating characteristic curve revealed that the area under the curve(AUC)was the largest for diagnosing early-stage DKD when urinary microalbumin was detected alone(AUC=0.976,95%CI 0.955-0.997,P<0.001),with sensitivity and specificity of 95.6%and 90.1%,respectively.The combined detection of urinary microalbumin+Ig+transferrin+α2 macroglobulin+α1-MG+β2-MG+NAG+RBP+NGAL had an AUC of 0.986(95%CI 0.971-1.000,P<0.001),with sensitivity and specificity of 93.3% and 98.5%,respectively,which was better than each single index.Further optimized detection combination was urinary microalbumin combined with β2-MG and NGAL,which had the best diagnostic efficacy(AUC=0.978,95%CI 0.958-0.999,P<0.001),with sensitivity and specificity of 95.6%and 93.0%,respectively.Conclusions Compared with the single detection of each index,the combined detection of urinary glomerular injury and renal tubule injury markers has higher value in diagnosing early-stage DKD.The combined detection of urinary microalbumin combined with β2-MG and NGAL has the highest value in diagnosing early-stage DKD.