乙型肝炎肝硬化患者发生慢性肾病的影响因素分析

杨莉; 时克; 高方媛; 冉崇平; 侯杰; 王宪波

doi:10.3969/j.issn.1001-5256.2021.08.015

乙型肝炎肝硬化患者发生慢性肾病的影响因素分析

DOI: 10.3969/j.issn.1001-5256.2021.08.015

杨莉¹,
时克^{1, 2},
高方媛¹,
冉崇平¹,
侯杰^{1, 2},
王宪波^1, ,

1.
首都医科大学附属北京地坛医院中西医结合中心，北京 100015
2.
北京中医药大学第一临床医学院，北京 100700

基金项目:

首都卫生发展科研专项 (2018-1-2172);

北京市科学技术委员会资助 (Z191100006619033);

国家中医药管理局重大疑难疾病中西医临床协作试点项目 (2018-6-4);

国家中医药管理局区域中医诊疗中心建设项目 (2019-3-18)

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：杨莉、时克负责资料分析，撰写论文；高方媛、侯杰、冉崇平参与收集数据，图表制作，修改论文；王宪波指导修改文章并最终定稿。

详细信息

通信作者:
王宪波，wangxianbo638@163.com

杨莉、时克对本文的贡献相同，同为第一作者

中图分类号: R512.62;R575.2
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- 被引次数: 0
出版历程
- 收稿日期: 2021-01-03
- 录用日期: 2021-01-26
- 出版日期: 2021-08-20

Influencing factors for chronic kidney disease in patients with hepatitis B cirrhosis

Li YANG¹,
Ke SHI^{1, 2},
Fangyuan GAO¹,
Chongping RAN¹,
Jie HOU^{1, 2},
Xianbo WANG^{1
, ,}

1.
Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
2.
The First Clinical Medical College of Beijing University of Chinese Medicine, Beijing 100700, China

Research funding:

Capital Health Development Research Project (2018-1-2172);

Beijing Municipal Commission of Science and Technology (Z191100006619033);

National Administration of Traditional Chinese Medicine Clinical Cooperation Pilot Project of Traditional Chinese and Western Medicine for Major and Difficult Diseases (2018-6-4);

Regional TCM Diagnosis and Treatment Center Construction Project of State Administration of Traditional Chinese Medicine (2019-3-18)

摘要

摘要: 目的探讨乙型肝炎肝硬化患者3年内发生慢性肾病(CKD)的影响因素。方法纳入2014年1月—2017年7月就诊于首都医科大学附属北京地坛医院的乙型肝炎肝硬化患者376例，随访3年，根据是否发生CKD分为CKD组(n=23)和非CKD组(n=353)。收集患者一般情况和实验室指标。计量资料两组间比较采用t检验或Mann-Whitney U检验。计数资料两组间比较采用χ²检验或Fisher精确概率法。采用多因素Cox逐步向前回归方法，分析乙型肝炎肝硬化患者3年内发生CKD的独立影响因素。采用受试者工作特征曲线下面积(AUC)评估影响因素对乙型肝炎肝硬化患者发生CKD的预测价值，Kalplan-Merier法进行生存分析，log-rank检验比较不同风险患者CKD累积发生率。结果 Cox多因素分析显示，年龄(HR=1.078，95%CI：1.007~1.114，P=0.026)、Alb(HR=0.923，95%CI：0.860~0.989，P=0.024)、肾小球滤过率(eGFR)(HR=0.977，95%CI：0.955~0.999，P=0.037)是乙型肝炎肝硬化患者3年内发生CKD的独立影响因素。年龄、Alb、eGFR对CKD发生的预测价值较好(受试者工作特征曲线下面积分别为0.701、0.710、0.706)。Kalplan-Merier生存曲线显示，基线年龄≥55岁、Alb＜32 g/L、60 ml·min^-1·1.73m^-2≤eGFR＜76 ml·min^-1·1.73m^-2的患者发生CKD的风险高(χ²值分别为9.647、13.621、30.940，P值均＜0.05)。结论高龄、低Alb水平及eGFR较低的患者建议密切监测肾功能。
- 肝硬化 /
- 肾疾病 /
- 影响因素分析
Abstract: Objective To investigate the influencing factors for chronic kidney disease (CKD) in patients with hepatitis B cirrhosis within 3 years. Methods A total of 376 patients with hepatitis B cirrhosis who attended Beijing Ditan Hospital, Capital Medical University, from January 2014 to July 2017 were enrolled and followed up for 3 years, and according to the presence or absence of CKD, they were divided into CKD group with 23 patients and non-CKD group with 353 patients. Related general information and laboratory markers were collected. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups; a stepwise forward Cox regression analysis was used to screen out the independent influencing factors for CKD within 3 years in patients with hepatitis B cirrhosis. The area under the receiver operating characteristic curve (AUC) was used to investigate the value of the influencing factors in predicting CKD in patients with hepatitis B cirrhosis; the Kaplan-Meier method was used for survival analysis, and the log-rank test was used for comparison of the cumulative incidence rate of CKD between the patients with different risks. Results The multivariate Cox regression analysis showed that age (hazard ratio [HR]=1.078, 95% confidence interval [CI]: 1.007-1.114, P=0.026), albumin (Alb) (HR=0.923, 95% CI: 0.860-0.989, P=0.024), and estimated glomerular filtration rate (eGFR) (HR=0.977, 95% CI: 0.955-0.999, P=0.037) were independent influencing factors for CKD within 3 years in patients with hepatitis B cirrhosis. Age, Alb, and eGFR had a relatively good value in predicting CKD, with AUCs of 0.701, 0.710, and 0.706, respectively. The Kaplan-Meier survival curve showed that the patients with baseline age ≥55 years, Alb < 32 g/L, and eGFR ≥60 ml·min^-1·1.73 m^-2 and < 76 ml·min^-1·1.73 m^-2 had a higher risk of CKD (χ²=9.647, 13.621, and 30.940, all P < 0.05). Conclusion Renal function should be closely monitored for patients with old age and low Alb and eGFR levels.
- Liver Cirrhosis /
- Kidney Diseases /
- Root Cause Analysis

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图 1 年龄、Alb、eGFR的ROC曲线

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图 2 不同年龄、Alb和eGFR患者CKD发生率

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表 1 CKD组和非CKD组患者基线特征比较

指标	CKD组(n=23)	非CKD组(n=353)	统计值	P值
年龄(岁)	56.1±10.2	48.7±9.9	t=1.516	＜0.001
男/女(例)	18/5	259/94	χ²=0.011	0.978
失代偿期肝硬化[例(%)]	19(82.6)	216(61.2)	χ²=1.300	0.039
饮酒史[例(%)]	2(8.7)	54(15.3)	χ²=0.647	0.389
吸烟史[例(%)]	4(17.4)	88(24.9)	χ²=1.220	0.415
腹水[例(%)]	11(47.8)	108(30.6)	χ²=3.522	0.152
上消化道出血[例(%)]	7(30.4)	63(17.8)	χ²=0.066	0.181
肝性脑病[例(%)]	1(4.3)	11(3.1)	χ²=0.175	0.077
ALT(U/L)	36.9(17.9~53.4)	37.0(22.8~75.5)	Z=-0.752	0.209
AST(U/L)	43.8(31.9~71.7)	39.6(26.5~81.3)	Z=-0.560	0.053
TBil(μmol/L)	22.2(15.3~30.5)	22.7(13.8~35.7)	Z=5.136	0.521
Alb(g/L)	27.8(26.0~31.0)	33.2(28.3~38.3)	Z=-0.794	0.004
ALP(U/L)	93.9(68.8~130.1)	79.3(59.7~106.4)	Z=-0.199	0.088
GGT(U/L)	38.2(16.5~76.0)	37.4(19.4~84.5)	Z=-0.564	0.336
TC(mmol/L)	2.7(2.4~3.6)	3.2(2.6~3.9)	Z=-1.675	0.230
TG(mmol/L)	0.6(0.5~1.0)	0.7(0.5~1.0)	Z=-0.681	0.104
HDL(mmol/L)	0.9(0.5~1.2)	0.8(0.5~1.1)	Z=-0.802	0.986
LDL(mmol/L)	1.4(1.1~1.5)	1.6(1.3~2.1)	Z=-2.310	0.114
WBC(×10⁹/L)	4.2(2.8~5.4)	3.6(2.7~5.1)	Z=1.180	0.521
PLT(×10⁹/L)	79.5(44.0~98.4)	72.0(49.0~108.0)	Z=0.127	0.583
BUN(mmol/L)	5.1(4.0~6.5)	5.4(4.2~6.5)	Z=0.527	0.217
Cr(μmoI/L)	71.0(62.0~85.0)	66.0(56.0~75.0)	Z=0.302	0.116
PT(s)	14.9(13.6~16.3)	14.3(12.9~16.0)	Z=1.410	0.211
INR	1.3(1.2~1.4)	1.2(1.1~1.4)	Z=0.923	0.523
HBeAg阳性[例(%)]	10(43.5)	175(49.6)	χ²=0.065	0.799
HBV DNA(log₁₀拷贝/ml)	4.3(2.7~5.7)	3.5(2.7~5.5)	Z=-0.105	0.731
eGFR(ml·min^-1·1.73 m^-2)	75.9(67.7~106.5)	102.7(87.1~119.5)	Z=-0.774	0.016

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表 2 乙型肝炎肝硬化患者发生CKD的单因素分析

因素	HR(95%CI)	P值
年龄(岁)	1.090(1.040~1.141)	＜0.001
男性	1.009(0.398~2.258)	0.986
失代偿期肝硬化	2.892(1.048~8.500)	0.045
吸烟史	0.650(0.221~1.909)	0.433
饮酒史	0.541(0.127~2.305)	0.406
腹水	1.421(0.096~1.969)	0.053
上消化道出血	1.852(0.762~4.502)	0.863
肝性脑病	0.852(0.215~3.377)	0.819
ALT(U/L)	0.996(0.991~1.003)	0.215
AST(U/L)	0.998(0.992~1.002)	0.412
TBil(μmol/L)	1.002(0.996~1.009)	0.499
Alb(g/L)	0.904(0.884~0.970)	0.005
ALP(U/L)	1.008(0.999~1.116)	0.076
GGT(U/L)	0.996(0.989~1.004)	0.331
WBC(×10⁹/L)	1.071(0.868~1.321)	0.523
PLT(×10⁹/L)	0.997(0.988~1.007)	0.583
BUN(mmol/L)	1.119(0.077~1.328)	0.126
Cr(μmoI/L)	1.033(0.997~1.062)	0.118
PT(s)	1.079(0.964~1.208)	0.186
INR	1.620(0.401~6.565)	0.498
TC(mmol/L)	0.759(0.482~1.194)	0.223
TG(mmol/L)	0.387(0.124~1.203)	0.101
HDL(mmol/L)	0.984(0.337~2.875)	0.997
LDL(mmol/L)	0.588(0.305~1.135)	0.113
HBeAg阳性	0.901(0.398~2.043)	0.809
HBV DNA(log₁₀拷贝/ml)	1.043(0.838~1.299)	0.704
eGFR(ml·min^-1·1.73 m^-2)	0.968(0.950~0.984)	0.005

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表 3 不同抗病毒药物对CKD发生影响

抗病毒药物	CKD组 (n=23)	非CKD组 (n=353)	P值
恩替卡韦(例)	14	194	0.221
替诺福韦(例)	5	42	0.449
拉米夫定(例)	0	8
替比夫定(例)	1	5
阿德福韦酯(例)	0	13	0.449
阿德福韦酯+拉米夫定(例)	1	11	0.942
阿德福韦酯+恩替卡韦(例)	1	19	0.667
阿德福韦酯→恩替卡韦(例)	0	10
阿德福韦酯→阿德福韦酯+恩替卡韦(例)	0	13
拉米夫定→恩替卡韦(例)	1	26	0.406
其他(例)	0	12

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参考文献(20)

[1]	FABRIZI F, CERUTTI R, RIDRUEJO E. Hepatitis B virus infection as a risk factor for chronic kidney disease[J]. Expert Rev Clin Pharmacol, 2019, 12(9): 867-874. DOI: 10.1080/17512433.2019.1657828.
[2]	HONG YS, RYU S, CHANG Y, et al. Hepatitis B virus infection and development of chronic kidney disease: A cohort study[J]. BMC Nephrol, 2018, 19(1): 353. DOI: 10.1186/s12882-018-1154-4.
[3]	CHACKO EC, SURRUN SK, MUBARACK SANI TP, et al. Chronic viral hepatitis and chronic kidney disease[J]. Postgrad Med J, 2010, 86(1018): 486-492. DOI: 10.1136/pgmj.2009.092775.
[4]	GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet, 2020, 395(10225): 709-733. DOI: 10.1016/S0140-6736(20)30045-3.
[5]	Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[6]	Chinese Society of Hepatology, Chinese Medical Association. Chinese guidelines on the management of liver cirrhosis[J]. J Clin Hepatol, 2019, 35(11): 2408-2425. DOI: 10.3969/j.issn.1001-5256.2019.11.006. 中华医学会肝病学分会. 肝硬化诊治指南[J]. 临床肝胆病杂志, 2019, 35(11): 2408-2425. DOI: 10.3969/j.issn.1001-5256.2019.11.006.
[7]	STEVENS PE, LEVIN A, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: Synopsis of the kidney disease: Improving global outcomes 2012 clinical practice guideline[J]. Ann Intern Med, 2013, 158(11): 825-830. DOI: 10.7326/0003-4819-158-11-201306040-00007.
[8]	LEVEY AS, BOSCH JP, LEWIS JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group[J]. Ann Intern Med, 1999, 130(6): 461-470. DOI: 10.7326/0003-4819-130-6-199903160-00002.
[9]	CARNEY EF. Glomerular filtration rate: CKD risk factors are associated with increased single-nephron GFR[J]. Nat Rev Nephrol, 2017, 13(8): 443. DOI: 10.1038/nrneph.2017.95.
[10]	ISHANI A, XUE JL, HIMMELFARB J, et al. Acute kidney injury increases risk of ESRD among elderly[J]. J Am Soc Nephrol, 2009, 20(1): 223-228. DOI: 10.1681/ASN.2007080837.
[11]	LOW S, LIM SC, ZHANG X, et al. Development and validation of a predictive model for chronic kidney disease progression in type 2 diabetes mellitus based on a 13-year study in Singapore[J]. Diabetes Res Clin Pract, 2017, 123: 49-54. DOI: 10.1016/j.diabres.2016.11.008.
[12]	CHEN PM, WADA T, CHIANG CK. Prognostic value of proteinuria and glomerular filtration rate on Taiwanese patients with diabetes mellitus and advanced chronic kidney disease: A single center experience[J]. Clin Exp Nephrol, 2017, 21(2): 307-315. DOI: 10.1007/s10157-016-1290-8.
[13]	KEANE WF, ZHANG Z, LYLE PA, et al. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: The RENAAL study[J]. Clin J Am Soc Nephrol, 2006, 1(4): 761-767. DOI: 10.2215/CJN.01381005.
[14]	KIKUCHI H, KANDA E, MANDAI S, et al. Combination of low body mass index and serum albumin level is associated with chronic kidney disease progression: The chronic kidney disease-research of outcomes in treatment and epidemiology (CKD-ROUTE) study[J]. Clin Exp Nephrol, 2017, 21(1): 55-62. DOI: 10.1007/s10157-016-1251-2.
[15]	TRAWALÉ JM, PARADIS V, RAUTOU PE, et al. The spectrum of renal lesions in patients with cirrhosis: A clinicopathological study[J]. Liver Int, 2010, 30(5): 725-732. DOI: 10.1111/j.1478-3231.2009.02182.x.
[16]	MORINAGA J, KADOMATSU T, MIYATA K, et al. Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease[J]. Kidney Int, 2016, 89(2): 327-341. DOI: 10.1016/j.kint.2015.12.021.
[17]	SI J, YU C, GUO Y, et al. Chronic hepatitis B virus infection and total and cause-specific mortality: A prospective cohort study of 0.5 million people[J]. BMJ Open, 2019, 9(4): e027696. DOI: 10.1136/bmjopen-2018-027696.
[18]	SARAFIDIS PA, RUILOPE LM. Insulin resistance, hyperinsulinemia, and renal injury: Mechanisms and implications[J]. Am J Nephrol, 2006, 26(3): 232-244. DOI: 10.1159/000093632.
[19]	LAMPERTICO P, CHAN HL, JANSSEN HL, et al. Review article: Long-term safety of nucleoside and nucleotide analogues in HBV-monoinfected patients[J]. Aliment Pharmacol Ther, 2016, 44(1): 16-34. DOI: 10.1111/apt.13659.
[20]	HAGER MR, NARLA AD, TANNOCK LR. Dyslipidemia in patients with chronic kidney disease[J]. Rev Endocr Metab Disord, 2017, 18(1): 29-40. DOI: 10.1007/s11154-016-9402-z.