HBV相关肾小球肾炎的研究进展

李朝霞; 李楠; 辛桂杰

doi:10.3969/j.issn.1001-5256.2023.03.027

HBV相关肾小球肾炎的研究进展

DOI: 10.3969/j.issn.1001-5256.2023.03.027

吉林大学第一医院肝胆胰内科，长春 130021

基金项目:

吉林省卫生厅重点实验室项目 (2018J043)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李朝霞负责文献检索和撰写；李楠负责文献审核，修改文章；辛桂杰负责拟定写作思路，终审定稿。

详细信息

通信作者:
辛桂杰，xingj@jlu.edu.cn (ORCID：0000-0002-0868-0317)

计量
- 文章访问数: 700
- HTML全文浏览量: 187
- PDF下载量: 177
- 被引次数: 0
出版历程
- 收稿日期: 2022-06-23
- 录用日期: 2022-08-08
- 出版日期: 2023-03-20

Research advances in hepatitis B virus-associated glomerulonephritis

Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, China

Research funding:

Jilin Province Health Department Key Laboratory Program (2018J043)

More Information

Corresponding author: XIN Guijie, xingj@jlu.edu.cn (ORCID: 0000-0002-0868-0317)

摘要

摘要: 慢性HBV感染人群数量庞大，HBV不仅损害肝脏，肾脏也是主要受累器官之一，HBV相关肾小球肾炎(HBV-GN)是由HBV感染引起的继发性肾小球肾炎，是HBV感染最常见的肝外并发症之一。HBV-GN多见于儿童及中青年人，男性多见，临床上以不同程度蛋白尿为主要表现，可伴有血尿和高血压，最常见病理类型为膜性肾病，其次为系膜增生性肾小球肾炎和IgA肾病。HBV-GN起病隐匿，缺乏特征性的症状及病理学表现，易与各种肾小球肾炎混淆，导致漏诊误诊。HBV-GN发病机制复杂，涉及免疫紊乱、病毒直接损伤、遗传等诸多环节，其中免疫复合物沉积学说已得到广泛认可。近年来关于HBV-GN发病机制、诊断及治疗方面的研究取得了一些重要进展。本文将对此进行综述，希望为临床诊治提供参考。
- 肾小球肾炎 /
- 肝炎病毒, 乙型 /
- 诊断 /
- 治疗学
Abstract: There is are large number of patients with chronic hepatitis B virus (HBV) infection. HBV not only damages the liver, but also involves the kidney. Hepatitis B virus-associated glomerulonephritis (HBV-GN) is secondary glomerulonephritis caused by HBV infection, and it is one of the most common extrahepatic complications of HBV infection. HBV-GN is mainly observed in children and young and middle-aged adults, with varying degrees of proteinuria as the main clinical manifestation, and it may be accompanied by hematuria and hypertension. Membranous nephropathy is the most common pathological type, followed by membrano-proliferative glomerulonephritis and IgA nephropathy. HBV-GN has an insidious onset and lacks characteristic symptoms and pathological manifestations, and thus it may be easily confused with various types of glomerulonephritis, which may lead to missed diagnosis and misdiagnosis. HBV-GN has a complex pathogenesis involving various links such as immune disorders, direct viral damage, and genetics, among which the theory of immune complex deposition has been widely recognized. In recent years, some important advances have been made in the research on the pathogenesis, diagnosis, and treatment of HBV-GN. This article summarizes the above issues, so as to provide a reference for clinical diagnosis and treatment.
- Glomerulonephritis /
- Hepatitis B Virus /
- Diagnosis /
- Therapeutics

HTML全文

图 1 HBV-GN发病机制图

注：NTCP，钠离子-牛磺胆酸共转运蛋白；JNK，c-Jun氨基末端蛋白激酶。

Figure 1. Pathogenesis of HBV-GN

下载: 全尺寸图片幻灯片

参考文献(41)

[1]	SCHWEITZER A, HORN J, MIKOLAJCZYK RT, et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013[J]. Lancet, 2015, 386(10003): 1546-1555. DOI: 10.1016/S0140-6736(15)61412-X.
[2]	Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study[J]. Lancet Gastroenterol Hepatol, 2018, 3(6): 383-403. DOI: 10.1016/S2468-1253(18)30056-6.
[3]	HUANG Y, SHI KW, ZHU XJ, et al. Disease spectrum of 9310 cases of renal biopsy pathological diagnosis from a single center in China[J]. J Cent South Univ(Med Sci), 2022, 47(5): 546-554. DOI: 10.11817/j.issn.1672-7347.2022.210487. 黄瑶, 施克雯, 朱雪婧, 等. 中国单中心9310例肾活检病理诊断疾病谱[J]. 中南大学学报(医学版), 2022, 47(5): 546-554. DOI: 10.11817/j.issn.1672-7347.2022.210487.
[4]	COMBES B, SHOREY J, BARRERA A, et al. Glomerulonephritis with deposition of Australia antigen-antibody complexes in glomerular basement membrane[J]. Lancet, 1971, 2(7718): 234-237. DOI: 10.1016/s0140-6736(71)92572-4.
[5]	FERDEK PE, JAKUBOWSKA MA, GERASIMENKO JV, et al. Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake[J]. J Physiol, 2016, 594(21): 6147-6164. DOI: 10.1113/JP272774.
[6]	DÖRING B, LVTTEKE T, GEYER J, et al. The SLC10 carrier family: transport functions and molecular structure[J]. Curr Top Membr, 2012, 70: 105-168. DOI: 10.1016/B978-0-12-394316-3.00004-1.
[7]	YAN H, ZHONG G, XU G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife, 2012, 1: e00049. DOI: 10.7554/eLife.00049.
[8]	WANG R, WU Y, ZHENG B, et al. Clinicopathological characteristics and prognosis of hepatitis B associated membranous nephropathy and idiopathic membranous nephropathy complicated with hepatitis B virus infection[J]. Sci Rep, 2021, 11(1): 18407. DOI: 10.1038/s41598-021-98010-y.
[9]	LI D, GAO G, JIANG H, et al. Hepatitis B virus-associated glomerulonephritis in HBsAg serological-negative patients[J]. Eur J Gastroenterol Hepatol, 2015, 27(1): 65-69. DOI: 10.1097/MEG.0000000000000236.
[10]	PRESCOTT NA, BRAM Y, SCHWARTZ RE, et al. Targeting hepatitis B virus covalently closed circular DNA and hepatitis B virus X protein: recent advances and new approaches[J]. ACS Infect Dis, 2019, 5(10): 1657-1667. DOI: 10.1021/acsinfecdis.9b00249.
[11]	LIANG DY, SHA S, YI Q, et al. Hepatitis B X protein upregulates decoy receptor 3 expression via the PI3K/NF-κB pathway[J]. Cell Signal, 2019, 62: 109346. DOI: 10.1016/j.cellsig.2019.109346.
[12]	HAN W, LUO M, HE M, et al. HBx gene transfection affects the cycle of primary renal tubular epithelial cells through regulating cyclin expression[J]. Mol Med Rep, 2018, 18(2): 1947-1954. DOI: 10.3892/mmr.2018.9197.
[13]	LI M, HU L, ZHU F, et al. Hepatitis B virus X protein promotes renal epithelial-mesenchymal transition in human renal proximal tubule epithelial cells through the activation of NF-κB[J]. Int J Mol Med, 2016, 38(2): 513-520. DOI: 10.3892/ijmm.2016.2637.
[14]	FENG Y, CUI Y, GAO JL, et al. Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-κB signaling pathway in experimental traumatic brain injury[J]. Int J Mol Med, 2016, 37(4): 921-930. DOI: 10.3892/ijmm.2016.2495.
[15]	YANG YT, WANG X, ZHANG YY, et al. The histone demethylase LSD1 promotes renal inflammation by mediating TLR4 signaling in hepatitis B virus-associated glomerulonephritis[J]. Cell Death Dis, 2019, 10(4): 278. DOI: 10.1038/s41419-019-1514-4.
[16]	ZHOU Y, ZHU N, WANG X, et al. The role of the toll-like receptor TLR4 in hepatitis B virus-associated glomerulonephritis[J]. Arch Virol, 2013, 158(2): 425-433. DOI: 10.1007/s00705-012-1508-3.
[17]	LEE WM. Hepatitis B virus infection[J]. N Engl J Med, 1997, 337(24): 1733-1745. DOI: 10.1056/NEJM199712113372406.
[18]	STARKE A, LINDENMEYER MT, SEGERER S, et al. Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses[J]. Kidney Int, 2010, 78(1): 38-47. DOI: 10.1038/ki.2010.97.
[19]	LEE VW, QIN X, WANG Y, et al. The CD40-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis[J]. Nephrol Dial Transplant, 2010, 25(3): 717-730. DOI: 10.1093/ndt/gfp569.
[20]	WANG X, WANG L, ZHU N, et al. Hepatitis B virus X protein modulates renal tubular epithelial cell-induced T-cell and macrophage responses[J]. Immunol Cell Biol, 2016, 94(3): 266-273. DOI: 10.1038/icb.2015.85.
[21]	WANG X, ZHOU Y, ZHU N, et al. The deposition of Notch1 in hepatitis B virus-associated nephropathy and its role in hepatitis B virus X protein-induced epithelial-mesenchymal transdifferentiation and immunity disorder in renal tubular epithelial cells[J]. J Viral Hepat, 2014, 21(10): 734-743. DOI: 10.1111/jvh.12244.
[22]	ZHEN J, ZHANG L, PAN J, et al. AIM2 mediates inflammation-associated renal damage in hepatitis B virus-associated glomerulonephritis by regulating caspase-1, IL-1β, and IL-18[J]. Mediators Inflamm, 2014, 2014: 190860. DOI: 10.1155/2014/190860.
[23]	BHIMMA R, HAMMOND MG, COOVADIA HM, et al. HLA class Ⅰ and Ⅱ in black children with hepatitis B virus-associated membranous nephropathy[J]. Kidney Int, 2002, 61(4): 1510-1515. DOI: 10.1046/j.1523-1755.2002.00287.x.
[24]	PARK MH, SONG EY, AHN C, et al. Two subtypes of hepatitis B virus-associated glomerulonephritis are associated with different HLA-DR2 alleles in Koreans[J]. Tissue Antigens, 2003, 62(6): 505-511. DOI: 10.1046/j.1399-0039.2003.00141.x.
[25]	HUI D, YAN X, WEI J, et al. Significance of mutations in hepatitis B virus X gene for the pathogenesis of HB-associated glomerulonephritis[J]. Acta Virol, 2014, 58(3): 278-281. DOI: 10.4149/av_2014_03_278.
[26]	CHENG WR, SUN LJ, DONG HR, et al. Clinical and pathological characteristics of hepatitis B virus -associated glomerulonephritis in adults[J]. Int J Virol, 2021, 28(3): 231-235. DOl: 1073760/maj. sis 1673-4092.2021.03.013. 程文荣, 孙丽君, 董鸿瑞, 等. 成人乙型肝炎病毒相关性肾小球肾炎的临床及病理特点分析[J]. 国际病毒学杂志, 2021, 28(3): 231-235. DOl: 1073760/maj. sis 1673-4092.2021.03.013.
[27]	FRESQUET M, JOWITT TA, GUMMADOVA J, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy[J]. J Am Soc Nephrol, 2015, 26(2): 302-313. DOI: 10.1681/ASN.2014050502.
[28]	XIE Q, LI Y, XUE J, et al. Renal phospholipase A2 receptor in hepatitis B virus-associated membranous nephropathy[J]. Am J Nephrol, 2015, 41(4-5): 345-353. DOI: 10.1159/000431331.
[29]	DONG H, XU Y, XU T, et al. The role of HBx gene mutations in PLA 2R positive hepatitis-B-associated membranous nephropathy[J]. Biomed Environ Sci, 2020, 33(4): 269-272. DOI: 10.3967/bes2020.036.
[30]	TU TQ, ZHENG XM, YANG Y, et al. Role of serum anti-phospholipase A2 receptor antibody level in diagnosis and prognosis assessment of hepatitis B virus-related membranous nephropathy[J]. J Chin Pract Diagn Ther, 2021, 35(1): 7-10. DOI: 10.13507/j.issn.1674-3474.2021.01.002. 涂天琪, 郑旭敏, 杨悦, 等. 血清抗磷脂酶A2受体抗体水平在乙型肝炎病毒相关膜性肾病诊断及预后评估中的价值[J]. 中华实用诊断与治疗杂志, 2021, 35(1): 7-10. DOI: 10.13507/j.issn.1674-3474.2021.01.002.
[31]	RADHAKRISHNAN J, CATTRAN DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines-application to the individual patient[J]. Kidney Int, 2012, 82(8): 840-856. DOI: 10.1038/ki.2012.280.
[32]	SHAH HH, PATEL C, JHAVERI KD. Complete remission of hepatitis B virus-associated nephrotic syndrome from IgA nephropathy following peginterferon therapy[J]. Ren Fail, 2013, 35(2): 295-298. DOI: 10.3109/0886022X.2012.745785.
[33]	LAI MW, CHANG MH. Updates in the management of hepatitis B in children[J]. Expert Rev Gastroenterol Hepatol, 2019, 13(11): 1065-1076. DOI: 10.1080/17474124.2019.1686975.
[34]	FU B, JI Y, HU S, et al. Efficacy and safety of anti-viral therapy for Hepatitis B virus-associated glomerulonephritis: A meta-analysis[J]. PLoS One, 2020, 15(1): e0227532. DOI: 10.1371/journal.pone.0227532.
[35]	UDOMPAP P, KIM D, AHMED A, et al. Longitudinal trends in renal function in chronic hepatitis B patients receiving oral antiviral treatment[J]. Aliment Pharmacol Ther, 2018, 48(11-12): 1282-1289. DOI: 10.1111/apt.15020.
[36]	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.
[37]	NOTSUMATA K, NOMURA Y, TANAKA A, et al. Early changes in tubular dysfunction markers and phosphorus metabolism regulators as a result of switching from entecavir to tenofovir alafenamide fumarate nucleoside analog therapy for chronic hepatitis B patients[J]. Hepatol Res, 2020, 50(3): 402-404. DOI: 10.1111/hepr.13451.
[38]	OGAWA E, NOMURA H, NAKAMUTA M, et al. Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B[J]. Liver Int, 2020, 40(7): 1578-1589. DOI: 10.1111/liv.14482.
[39]	ZHENG XY, WEI RB, TANG L, et al. Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis[J]. World J Gastroenterol, 2012, 18(8): 821-832. DOI: 10.3748/wjg.v18.i8.821.
[40]	WANG L, YE Z, LIANG H, et al. The combination of tacrolimus and entecavir improves the remission of HBV-associated glomerulonephritis without enhancing viral replication[J]. Am J Transl Res, 2016, 8(3): 1593-1600.
[41]	XIE XF, XIE BY, ZHANG WH, et al. The efficacy and safety of tacrolimus and entecavir combination therapy in the treatment of hepatitis B virus-associated glomerulonephritis: a multi-center, placebo controlled, and single-blind randomized trial[J]. Ann Palliat Med, 2022, 11(5): 1762-1773. DOI: 10.21037/apm-22-328.