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尿α1-微球蛋白及N-乙酰-β-D-氨基葡萄糖苷酶/尿肌酐在慢性HBV感染相关肝病患者早期肾损伤中的检测价值
DOI: 10.3969/j.issn.1001-5256.2022.02.014
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：张静怡负责课题设计，数据收集，资料分析，拟定写作思路，撰写论文；杨娴、杨文霞参与收集数据及分析；唐映梅负责指导撰写文章并最后定稿。
Value of urinary α1-microglobulin and N-acetyl-β-D-glucosaminidase/urinary creatinine in monitoring early renal injury in patients with chronic hepatitis B virus-related liver diseases
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摘要:
目的 探究尿α1-微球蛋白(α1-MG)、N-乙酰-β-D-氨基葡萄糖苷酶/尿肌酐(NAG/UCr)在慢性HBV感染相关肝病患者肾损伤中的临床价值。 方法 纳入2019年8月—2020年8月就诊于昆明医科大学第二附属医院的慢性HBV感染相关肝病患者85例，根据患者核苷(酸)类似物(NUC)治疗史，将患者分为NUC治疗组(n=57)和未经NUC治疗组(n=28)，根据使用NUC种类，将患者分为ETV治疗组(n=32)和TDF治疗组(n=25)；根据HBV血清抗原、抗体标志物检测结果，将患者分为HBeAg阴性组(n=57)和HBeAg阳性组(n=28)；根据血清HBV DNA定量检测，将患者分为HBV DNA阴性组(n=47)和HBV DNA阳性组(n=38)；根据腹部影像学检查结果，将患者分为非肝硬化组(n=47)和肝硬化组(n=38)，收集纳入患者的病史资料及实验室指标，并进行组间比较。计量资料符合正态分布的两组间比较采用t检验；偏态分布两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ2检验。采用McNemar检验比较不同指标检测的优劣性。采用Spearman相关性分析探讨各因素与α1-MG、NAG/UCr之间的相关性。采用多元线性回归分析α1-MG、NAG/UCr的独立影响因素。 结果 未经NUC治疗组、HBeAg阳性组、HBV DNA阳性组的尿α1-MG水平分别较NUC治疗组(Z=-2.054, P=0.04)、HBeAg阴性组(Z=-2.293, P=0.022)、HBV DNA阴性组(Z=-2.229, P=0.026)明显升高。HBV DNA阳性组、肝硬化组的NAG、NAG/UCr水平分别较HBV DNA阴性组(Z值分别为-2.908、-2.824，P值均＜0.05)、非肝硬化组(Z值分别为-3.204、-3.412，P值均＜0.05)患者明显升高。α1-MG异常患者占比(31.8%)与eGFR异常占比(20.0%)相比较，二者差异有统计学意义(χ2=7.178，P=0.007)；α1-MG联合NAG/UCr检测异常占比(35.3%)较eGFR检测异常占比高，差异有统计学意义(χ2=8.049，P=0.005)。α1-MG联合NAG/UCr检测与eGFR检测优劣性比较，差异有统计学意义(P=0.015)。年龄(β=0.246)、HBeAg阳性(β=0.284)、合并肝癌(β=0.291)是α1-MG升高的独立危险因素(P值均＜0.05)；FIB-4值升高(β=0.352)、合并腹水(β=0.260)、食管胃底静脉曲张(β=-0.248)、HBV DNA阳性(β=0.197)、高水平TBil(β=0.257)均是NAG/UCr升高的独立危险因素(P值均＜0.05)。 结论 慢性HBV感染相关肝病患者的肾损伤可能发生在病毒复制活跃期、肝硬化以及肝脏功能恶化的整个病程进展中，使用NUC抗病毒治疗可以缓解HBV对肾功能的损伤，在一定治疗疗程内是安全可靠的；联合检测尿α1-MG、NAG/UCr诊断早期肾功能损伤较eGFR更具优势，是慢性HBV感染相关肝病患者更有效的肾功能监测方法。 Abstract:Objective To investigate the value of urinary α1-microglobulin (α1-MG) and N-acetyl-β-D-glucosaminidase/urinary creatinine (NAG/UCr) in monitoring renal injury in patients with chronic hepatitis B virus (HBV)-related liver diseases. Methods A total of 85 patients with HBV-related liver diseases who attended The Second Affiliated Hospital of Kunming Medical University from August 2019 to August 2020 were enrolled, and according to the history of treatment with nucleos(t)ide analogues (NUC), they were divided into NUC treatment group with 57 patients and non-NUC treatment group with 28 patients; according to the type of NUC used, the NUC treatment group was further divided into entecavir (ETV) treatment group with 32 patients and tenofovir disoproxil fumarate (TDF) treatment group with 25 patients; according to the results of HBV serum antigen and antibody markers, the patients were divided into HBeAg-negative group with 57 patients and HBeAg-positive group with 28 patients; according to the results of serum HBV DNA quantification, the patients were divided into HBV DNA-negative group with 47 patients and HBV DNA-positive group with 38 patients; according to abdominal imaging findings, the patients were divided into non-liver cirrhosis group with 47 patients and liver cirrhosis group with 38 patients. The data on medical history and laboratory markers were collected for comparison between two groups. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of data with skewed distribution between two groups; the chi-square test was used for comparison of categorical data between two groups. The McNemar test was used to compare the diagnostic merit of each index; a Spearman correlation analysis was used to investigate the correlation of each factor with α1-MG, and NAG/UCr; the multiple linear regression analysis was used to analyze the independent influencing factors for α1-MG and NAG/UCr. Results The non-NUC treatment group, the HBeAg-positive group, and the HBV DNA-positive group had significantly higher levels of urinary α1-MG than the NUC treatment group (Z=-2.054, P=0.04), the HBeAg-negative group (Z=-2.293, P=0.022), and the HBV DNA-negative group (Z=-2.229, P=0.026), respectively. The HBV DNA-positive group and the liver cirrhosis group had significantly higher levels of NAG and NAG/UCr than the HBV DNA-negative group (Z=-2.908 and -2.824, both P < 0.05) and the non-liver cirrhosis group (Z=-3.204 and -3.412, both P < 0.05), respectively. There was a significant difference in the proportion of patients with abnormal α1-MG and that of patients with abnormal estimated glomerular filtration rate (eGFR) (31.8% vs 20.0%, χ2=7.178, P=0.007), and the proportion of patients with abnormal α1-MG and NAG/UCr was significantly higher than that of patients with abnormal eGFR (35.3% vs 20.0%, χ2=8.049, P=0.005). There was a significant difference in diagnostic merit between α1-MG+NAG/UCr and eGFR (P=0.015). Age (β=0.246, P < 0.05), positive HBeAg (β=0.284, P < 0.01), and liver cancer (β=0.291, P < 0.01) were independent risk factors for the increase in α1-MG, while the increase in FIB-4 value (β=0.352, P < 0.05), ascites (β=0.260, P < 0.05), esophagogastric varices(β=-0.248, P < 0.05), positive HBV DNA (β=0.197, P < 0.05), and high total bilirubin (β=0.257, P < 0.05) were independent risk factors for the increase in NAG/UCr. Conclusion In patients with chronic HBV-related liver diseases, renal injury may occur during the whole course of active viral replication, liver cirrhosis, and deterioration of liver function. Antiviral therapy with NUC can alleviate renal impairment caused by HBV and is safe and reliable within a certain course of treatment. Combined measurement of urinary α1-MG and NAG/UCr has more advantages over eGFR in the diagnosis of early renal injury, and it is an effective method for renal function monitoring in patients with chronic HBV-related liver diseases. -
表 1 85例慢性HBV感染相关肝病患者基线资料
项目 结果 病史(年) 10.0(1.5~20.0) 用药疗程(月) 12.0(5.5~36.0) 肝硬化[例(%)] 38(44.7) 肝癌[例(%)] 6(7.1) 食管胃底静脉曲张[例(%)] 22(25.9) 脾大[例(%)] 33(38.8) 腹水[例(%)] 20(23.5) HBeAg阳性[例(%)] 28(32.9) HBV DNA阳性[例(%)] 38(44.7) 高血压[例(%)] 8(9.4) 糖尿病[例(%)] 14(16.5) 
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表 2 NUC治疗与未治疗的慢性HBV感染相关肝病患者肾功能指标比较
组别 例数 血磷(mmol/L) 血肌酐(μmol/L) eGFR(mL·min-1·1.73 m-2) α1-MG(mg/dL) NAG(U/L) NAG/UCr(U/g cr) 未经NUC治疗 28 1.06±0.21 69(57~78) 103(90~113) 1.11(0.76~2.37) 9.70(4.30~13.80) 7.80(3.65~16.33) NUC治疗 57 1.10±0.20 74(58~80) 101(91~110) 0.68(0.52~1.77) 6.40(4.30~11.70) 6.61(3.35~10.64) 统计值 t=-0.799 Z=-1.268 Z=-0.594 Z=-2.054 Z=-1.239 Z=-0.888 P值 0.427 0.205 0.552 0.040 0.215 0.374
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表 3 ETV与TDF治疗的慢性HBV感染相关肝病患者肾功能指标比较
组别 例数 血磷(mmol/L) 血肌酐(μmol/L) eGFR(mL·min-1·1.73 m-2) α1-MG(mg/dL) NAG(U/L) NAG/UCr(U/g cr) ETV 32 1.06±0.20 73.40±13.50 99.00(89.78~110.25) 0.67(0.52~1.20) 6.75(4.95~11.55) 6.44(3.40~10.05) TDF 25 1.15±0.19 68.50±13.20 102.50(94.00~109.25) 0.91(0.52~2.62) 5.40(3.58~13.30) 6.92(3.13~12.75) 统计值 t=-1.637 t=1.310 Z=-0.869 Z=-1.022 Z=-0.764 Z=-0.080 P值 0.107 0.195 0.385 0.307 0.445 0.936
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表 4 HBeAg阳性与HBeAg阴性慢性HBV感染相关肝病患者肾功能指标比较
组别 例数 血磷(mmol/L) 血肌酐(μmol/L) eGFR(mL·min-1·1.73 m-2) α1-MG(mg/dL) NAG(U/L) NAG/UCr(U/g cr) HBeAg阴性 57 1.12±0.19 70.94±14.29 100(90~108) 0.76(0.52~1.36) 6.5(4.5~11.0) 6.96(3.58~10.42) HBeAg阳性 28 1.02±0.21 70.04±15.51 105(95~116) 1.39(0.55~2.58) 10.2(4.2~19.6) 8.21(3.26~15.66) 统计值 t=1.949 t=0.300 Z=-1.198 Z=-2.293 Z=-1.230 Z=-1.103 P值 0.055 0.765 0.231 0.022 0.219 0.270
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表 5 HBV DNA阳性与HBV DNA阴性慢性HBV感染相关肝病患者肾功能指标比较
组别 例数 血磷(mmol/L) 血肌酐(μmol/L) eGFR(mL·min-1·1.73 m-2) α1-MG(mg/dL) NAG(U/L) NAG/UCr(U/g cr) HBV DNA阴性 47 1.10±0.19 71.45±14.68 100(89~111) 0.65(0.52~1.74) 5.25(3.33~10.45) 5.55(2.78~9.81) HBV DNA阳性 38 1.07±0.22 69.60±14.71 103(96~110) 1.11(0.76~2.37) 9.80(5.70~16.60) 8.40(5.53~17.69) 统计值 t=0.693 t=0.680 Z=-0.783 Z=-2.229 Z=-2.908 Z=-2.824 P值 0.491 0.498 0.434 0.026 0.004 0.005
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表 6 合并肝硬化与非肝硬化慢性HBV感染相关肝病患者肾功能相关指标比较
组别 例数 血磷(mmol/L) 血肌酐(μmol/L) eGFR(mL·min-1·1.73 m-2) α1-MG(mg/dL) NAG(U/L) NAG/UCr(U/g cr) 非肝硬化 47 1.08±0.19 73.5(57.8~79.3) 99.0(89.3~114.5) 0.93(0.60~1.97) 5.15(3.18~10.05) 4.36(2.67~10.58) 肝硬化 38 1.08±0.22 70.0(58.5~79.5) 103.0(97.5~109.0) 0.91(0.51~1.95) 9.80(6.10~18.70) 8.61(6.21~17.84) 统计值 t=-0.028 Z=-0.553 Z=-0.491 Z=-0.380 Z=-3.204 Z=-3.412 P值 0.978 0.580 0.624 0.704 0.001 0.001
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表 7 慢性HBV感染相关肝病患者α1-MG、NAG/UCr与eGFR异常情况比较
项目 eGFR α1-MG NAG/UCr α1-MG+NAG/UCr 异常[例(%)] 17(20.0) 27(31.8) 13(15.3) 30(35.3) 正常[例(%)] 68(80.0) 58(68.2) 72(84.7) 55(64.7)
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表 8 各影响因素与α1-MG、NAG/UCr的相关性分析
影响因素 α1-MG NAG/UCr r值 P值 r值 P值 年龄 0.261 0.016 0.498 ＜0.001 是否用药 -0.224 0.039 -0.097 0.387 肝癌 0.245 0.024 0.324 0.002 肝硬化 -0.042 0.706 0.372 ＜0.001 食管胃底静脉曲张 0.111 0.311 0.229 0.035 脾大 0.040 0.714 0.373 ＜0.001 腹水 0.221 0.042 0.390 ＜0.001 Child评分 0.106 0.336 0.550 ＜0.001 水肿 -0.123 0.261 0.231 0.033 FIB-4 0.142 0.205 0.545 ＜0.001 HBeAg 0.250 0.040 0.120 0.272 HBV DNA 0.243 0.025 0.308 0.004 ALT 0.121 0.269 0.345 0.001 AST 0.162 0.141 0.546 ＜0.001 ALP 0.104 0.351 0.493 ＜0.001 GGT 0.289 0.008 0.464 ＜0.001 Alb -0.147 0.182 -0.626 ＜0.001 TBil 0.098 0.376 0.373 ＜0.001
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表 9 各相关因素与α1-MG的多元线性回归分析
影响因素 Β值 标准误 β值 t值 P值 VIF 常数 -1.126 0.873 -1.289 0.201 年龄 0.036 0.015 0.246 2.422 0.018 1.166 是否用药 -0.104 0.425 -0.027 -0.245 0.807 1.345 HBeAg 1.114 0.377 0.284 2.952 0.004 1.041 HBV DNA 0.647 0.419 0.175 1.544 0.127 1.448 肝癌 2.067 0.699 0.291 2.958 0.004 1.091 腹水 0.454 0.438 0.106 1.037 0.303 1.170 GGT 0.001 0.003 0.024 0.240 0.811 1.109 注：VIF, 方差膨胀系数。
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表 10 各相关因素与NAG/UCr的多元线性回归分析
影响因素 Β值 标准误 β值 t值 P值 VIF 常数 1.242 2.271 0.547 0.586 食管胃底静脉曲张 -9.640 3.865 -0.248 -2.494 0.015 1.358 FIB-4 1.307 0.399 0.352 3.278 0.002 1.581 腹水 10.431 3.963 0.260 2.632 0.010 1.342 HBV DNA 6.870 3.061 0.197 2.245 0.028 1.056 TBil 0.081 0.030 0.257 2.690 0.009 1.250
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