【作者】 刘群；

【导师】 许钟镐；

【作者基本信息】 吉林大学 ， 临床医学硕士（内科学）（专业学位）， 2020， 硕士

【摘要】 目的:分析乙型肝炎病毒相关性肾炎(Hepatitis B virus-associated glomerulonephritis,HBV-GN)患者的临床特点、病理类型及实验室指标,分别比较不同临床表现、不同血清学乙型肝炎病毒表面抗原(Hepatitis B virus surface antigen,HBsAg)状态的HBV-GN的特点,提高对HBV-GN的认识,为临床诊治提供新的观察指标。方法:回顾性分析2010年10月-2019年12月于吉林大学第一医院肾病内科行肾穿刺活检且符合1989年在我国召开的“乙型肝炎病毒相关性肾炎”座谈会制定的诊断标准的HBV-GN患者96例。根据不同临床表现、不同血清学HBsAg状态分组,采用SPSS19.0软件建立数据库并进行统计学分析,比较不同组间的一般情况、病理类型、血清学乙型肝炎病毒(Hepatitis B virus,HBV)标志物和实验室资料。结果:1、2010年10月-2019年12月于吉林大学第一医院肾病内科行肾穿刺活检者共3598例,其中96例明确诊断为HBV-GN,占同期肾活检的2.7%。96例包括男性68例,女性28例,男:女=2.43:1,平均年龄43.86±15.07岁。37.5%的患者既往有乙肝病史,其余62.5%的患者以肾脏疾病表现为首发症状。2、96例HBV-GN患者中,HBsAg阳性者49例,HBsAg阴性者47例,其中血清学全阴性者9例。高病毒载量者共36例,占37.5%。所有患者均有蛋白尿,4.2%患者可见肉眼血尿,89.6%患者伴有显性水肿,79.2%患者表现为肾病综合征(Nephrotic syndrome,NS),20.8%患者表现为肾炎综合征。转氨酶升高者24例,占25.0%。肾小球滤过率下降者14例,占14.6%。3、96例HBV-GN患者共有3种病理类型,包括膜性肾病(Membranous nephropathy,MN)87例(占90.6%)、膜增生性肾小球肾炎(Membranoproliferative glomerulonephritis,MPGN)6例(占6.3%)以及继发性IgA肾病3例(占3.1%)。病理免疫荧光见多种免疫球蛋白及补体沉积,其中“满堂亮”现象23例,占24.0%。4、96例患者根据临床表现分为NS组76例和肾炎综合征组20例。两组均以HBV-MN为主要病理类型,肾炎综合征组继发性IgA肾病发生率高于NS组(P<0.05)。与肾炎综合征组相比,NS组血清IgG水平低(P<0.01),血清学HBsAg和乙型肝炎病毒e抗原(Hepatitis B virus e antigen,HBeAg)阳性率低(P<0.05),肾脏组织IgG沉积阳性率高(P<0.05),两组肾脏组织“满堂亮”患者比例差异无统计学意义(P>0.05)。与肾炎综合征组相比,NS组丙氨酸氨基转移酶(Alanine aminotransferase,ALT)、总蛋白、白蛋白、球蛋白、总胆红素、直接胆红素、间接胆红素、总胆汁酸水平低(P<0.01),门冬氨酸氨基转移酶(Aspartate aminotransferase,AST)水平低(P<0.05),总胆固醇、甘油三酯、24小时尿蛋白定量、24小时尿微量白蛋白定量高(P<0.01),胆碱酯酶、低密度脂蛋白(Low density lipoprotein,LDL)水平高(P<0.05)。两组间血肌酐、血尿酸、高密度脂蛋白(High density lipoprotein,HDL)水平、高病毒载量患者比例、估算肾小球滤过率(Estimated glomerular filtration rate,eGFR)差异无统计学意义(P>0.05)。5、96例患者根据血清学HBsAg状态分为HBsAg阴性组49例和HBsAg阳性组47例。两组均以HBV-MN为主要病理类型。HBV-MPGN在HBsAg阳性组的分布高于HBsAg阴性组(P<0.05),且6例HBV-MPGN患者均为血清学HBsAg、HBeAg和抗-HBc阳性并具有高病毒载量。与HBsAg阳性组相比,HBsAg阴性组血清IgG水平低(P<0.01),补体C4水平高(P<0.01),补体C3水平高(P<0.05),肾脏IgM、C1q沉积率、“满堂亮”患者比例低(P<0.01),肾脏IgA、C4沉积率低(P<0.05)。与HBsAg阳性组相比,HBsAg阴性组间接胆红素水平低(P<0.05),高病毒载量患者比例、AST、ALT、总蛋白、球蛋白、总胆红素、直接胆红素、总胆汁酸水平低(P<0.01),24小时尿蛋白定量、24小时尿微量白蛋白定量、胆碱酯酶、甘油三酯水平高(P<0.05)。两组间血肌酐、血尿酸、eGFR、白蛋白、胆固醇、LDL、HDL差异无统计学意义(P>0.05)。结论:1、本研究中,HBV-GN患者以男性多见,膜性肾病为主要病理类型,免疫荧光可见多种免疫球蛋白及补体沉积,IgG沉积率最高,部分患者可见“满堂亮”现象。部分患者血清学HBV标志物全阴性,但肾组织可检测到HBV标志物,推荐对肾活检进行HBV标志物常规染色。2、本研究中,HBV-GN的病理类型与临床表现、血清学HBsAg状态间存在一定关联。病理类型为继发性IgA肾病的HBV-GN患者以肾炎综合征为主要临床表现。血清学HBsAg阳性的HBV-GN患者,尤其是“大三阳”患者更易发生HBV-MPGN。3、表现为NS的HBV-GN患者血清学HBsAg、HBeAg阳性率、肝组织炎症活动度低于表现为肾炎综合征的患者,考虑表现为NS的HBV-GN患者HBV感染的实际病程长,对于HBV-GN患者出现蛋白尿、低蛋白血症,即使未达到NS水平也应给予重视。4、与血清学HBsAg阴性HBV-GN患者相比,血清学HBsAg阳性者血清补体水平及尿蛋白定量低,肝组织炎症活动度及肾组织“满堂亮”患者比例高。更多还原

【Abstract】 Objectives:To analyze the clinical,pathological and laboratory characteristics of patients with hepatitis B virus-associated glomerulonephritis(HBV-GN),compare the characteristics of HBV-GN with different clinical manifestations and different serological HBsAg status,so as to improve the understanding of HBV-GN and find new observation indicators for diagnosis and treatment.Methods:The retrospective analysis was performed on 96 patients with HBV-GN who underwent renal biopsy in the First Hospital of Jilin University from October 2010 to December 2019 and met the diagnostic criteria formulated in the symposium on " hepatitis B virus-associated glomerulonephritis" held in China in 1989.SPSS19.0 software was used to establish the database and conduct statistical analysis to compare the general situation,pathological types,serological Hepatitis B virus(HBV)markers and laboratory data according to different clinical manifestations and different serological HBsAg status.Results:1.From October 2010 to December 2019,a total of 3598 patients underwent renal biopsy in the First Hospital of Jilin University,among which 96 were diagnosed as HBV-GN,accounting for 2.7% of the renal biopsy in the same period.Among them,there were 68 males and 28 females,male: female =2.43:1,the mean age was 43.86±15.07 years old.37.5% of the patients had a history of hepatitis B,and 62.5% of the patients had renal disease as the first symptom.2.Among the 96 patients,49 were HBsAg positive and 47 were HBsAg negative,among which 9 were serologically negative.There were 36 cases with high viral load,accounting for 37.5%.All patients had proteinuria,4.2% had macroscopic hematuria,89.6% had dominant edema.Nephrotic syndrome(NS)was observed in 79.2% and nephritis syndrome in 20.8% of the patients.Transaminase increased in 24 cases,accounting for 25.0%.The glomerular filtration rate decreased in 14 cases,accounting for 14.6%.3.There were 3 pathological types of the 96 patients with HBV-GN,followed by membranous nephropathy(MN)in 87 cases(90.6%),membranoproliferative glomerulonephritis(MPGN)in 6 cases(6.3%)and IgA nephropathy in 3 cases(3.1%).Pathological immunofluorescence revealed multiple immunoglobulins and complements deposition,among which 23 cases(24.0%)showed “full-house” immunofluorescent staining.4.The 96 patients were divided into NS group(76 cases)and nephritis syndrome group(20 cases)according to clinical manifestations.HBV-MN was the main pathological type in both groups,and the distribution of IgA nephropathy in nephritis syndrome group was higher than that in NS group(P<0.05).Compared with nephritis syndrome group,patients in NS group had lower level of serum IgG(P<0.01),lower positive rate of serological HBsAg and Hepatitis B virus e antigen(HBeAg)(P<0.05),higher deposition rate of IgG in kidney tissue(P<0.05),the proportion of patients with “full-house” immunofluorescent staining in renal tissue of two groups had no statistically significant difference(P>0.05).Compared with nephritis syndrome group,NS group had lower level of serum Alanine aminotransferase(ALT),total protein,albumin,globulin,total bilirubin,direct bilirubin,indirect bilirubin and total bile acid(P<0.01),lower level of serum Aspartate aminotransferase(AST)(P<0.05),higher level of serum total cholesterol,triglyceride,24-hour urine protein quantification and 24-hour urine microalbumin quantification(P<0.01)and higher level of serum cholinesterase and Low density lipoprotein(LDL)(P<0.05).There was no statistically significant difference in the level of serum creatinine,serum uric acid,high density lipoprotein(HDL),the proportion of patients with High viral load and estimated glomerular filtration rate(eGFR)of two groups(P>0.05).5.The 96 patients were divided into HBsAg-negative group(49 cases)and HBsAg-positive group(47 cases)according to their serological HBsAg status.HBV-MN was the main pathological type in both groups,and the distribution of HBV-MPGN in HBsAg-positive group was higher than that in HBsAg-negative group(P<0.05).All 6 patients with HBV-MPGN were serologically positive for HBsAg,HBeAg and anti-HBc and had high viral load.Compared with the HBsAg-positive group,HBsAg-negative group had lower serum IgG level(P<0.01),higher C4 level(P<0.01),higher C3 level(P<0.05),lower renal IgM,C1 q deposition rate and lower proportion of renal tissue “full-house” immunofluorescent staining(P<0.01),and lower renal IgA and C4 deposition rate(P<0.05).Compared with HBsAg-positive group,HBsAg-negative group had lower level of serum indirect bilirubin(P<0.05),lower proportion of patients with high viral load and lower level of AST,ALT,total protein,globulin,total bilirubin,direct bilirubin and total bile acid(P<0.01),higher level of 24-hour urinary protein quantitative,24-hour urine trace albumin,cholinesterase and triglyceride(P<0.05).There were no statistically significant differences in the level of serum creatinine,serum uric acid,eGFR,albumin,cholesterol,LDL and HDL between the two groups(P>0.05).Conclusions:1.In this study,the patients with HBV-GN were mostly males.Membranous nephropathy was the main pathological type.Immunofluorescence showed the deposition of various immunoglobulin and complement,and the deposition rate of IgG was the highest,the “full house” can be observed.In some patients,all serological HBV markers were negative,but HBV markers could be detected in renal tissue.Routine staining of HBV markers was recommended for renal biopsy.2.In this study,the pathological type of HBV-GN was correlated with clinical manifestations and serological HBsAg status.The main clinical manifestation of HBV-GN patients with IgA nephropathy was nephritis syndrome.Serological HBsAg positive patients,especially patients with serological HBsAg,HBeAg and anti-HBc positive were more likely to develop HBV-MPGN.3.Serological HBsAg,HBeAg positive rate and liver inflammation activity are lower in HBV-GN patients presenting with NS than those presenting with nephritis syndrome.Considering the actual long course of HBV infection in HBV-GN patients presenting with NS,attention should be paid to the presence of proteinuria and hypoproteinemia in HBV-GN patients,even if the NS level has not been reached.4.Compared with serological HBsAg-negative patients,HBsAg-positive patients had lower level of serum complement and urine protein quantification,higher inflammatory activity in liver tissue and a higher proportion of "full house" in renal tissue.更多还原