伴血尿特发性膜性肾病中医证候、临床病理特点研究

【作者】 王丽颖；

【导师】 占永立；

【作者基本信息】 北京中医药大学 ， 中西医结合临床（专业学位）， 2018， 硕士

【摘要】 背景膜性肾病(MN)是临床上导致成人肾病综合征(NS)或无症状蛋白尿的主要病理类型之一,其典型的病理特征是弥漫性肾小球基底膜(GBM)增厚伴上皮细胞下免疫复合物沉积。根据病因,MN可分为特发性膜性肾病(IMN)和继发性膜性肾病(SMN)两大类,继发性者多由自身免疫性疾病、感染、肿瘤、药物等引起,病因未明者称为IMN。国外报道IMN占成人原发NS的20%～40%,国内流行病学报道,IMN占原发性肾小球疾病的10%以上,近年来发病率显著升高。IMN多在40岁后发病,男性居多,男性患病率高于女性约1倍以上。本病起病缓慢,以蛋白尿为主要表现,60%～80%%呈现NS,约40%患者伴随镜下血尿,无并发症时不出现肉眼血尿。IMN的自然病史是可变的,25%的患者可能在5年内出现蛋白尿的完全自发缓解,而35%可能在10年内发展为终末期肾病(ESRD)。回顾文献,目前影响膜性肾病预后的因素包括高龄、男性、伴随高血压、大量蛋白尿、肾功能不全及病理表现上较多肾小球硬化、较重肾小管间质病变等。作为IMN中较常见的临床表现——血尿,尤其是镜下血尿,其与IMN中医证侯、临床表现、肾脏病理的相关性尚有待研究。目的初步探讨伴血尿特发性膜性肾病(IMN)的中医证候、临床及病理特征。方法采用回顾性研究方法,选取2006年1月至2016年12月在中国中医科学院广安门医院肾内科就诊,经病理诊断为IMN且符合纳入标准的患者,根据是否伴血尿(高倍镜下尿红细胞计数≥3/HP,且异形红细胞>70%),将纳入患者分为伴血尿的IMN组(A组)(185例)和不伴血尿的IMN组(B组)(82例)。比较两组中医症状、辨证分型、临床表现、肾脏病理资料等,初步探讨血尿与IMN中医证候、临床病理的相关性。结果1 一般资料1.1性别伴血尿组患者中,男性106例(57.3%),女性79例(42.7%),男女比例1.34:1;不伴血尿组患者中,男性48例(58.5%),女性34例(41.5%),男女比例1.41:1;两组患者性别比较差异无统计学意义(P=0.850,>0.05)。1.2年龄伴血尿组患者中,接受肾活检年龄中位数52.84(42.90,59.78)岁,不伴血尿组接受肾活检年龄中位数49.57(41.46,62.62)岁;两组接受肾活检年龄比较差异无统计学意义(P=0.921,>0.05)。1.3病程伴血尿组患者中,接受肾活检时病程中位数伴血尿组5.0(2.0,11.0)月,不伴血尿组6.0(3.0,12.0)月;两组接受肾活检时病程比较差异有统计学意义(P=0.016,<0.05)。2 中医证候2.1中医症状比较两组发生率大于100%的中医症状显示,两组主要中医症状按发生率从大到小排列依次为:下肢水肿、小便有泡沫、腰酸腰痛、口干、夜尿频多、咳嗽、眠差、头晕、颜面浮肿、大便偏稀、小便色黄、口苦、纳差;其中伴血尿组在咳嗽、口苦症状中分布较不伴血尿组多,咳嗽(22.2%vs 11.0%)(P=0.031,<0.05);口苦(15.1%vs 6.1%)(P=0.038,<0.05);其余中医症状分布两组间差异无统计学意义(P均>0.05)。2.2中医辨证分型2.2.1总体情况伴血尿组与不伴血尿组中医辨证分型对比:本虚证(93.5%vs 91.5%),P=0.548;标实证(97.8%vs 97.6%),P=0.888;两组中医辨证均以虚实夹杂为主,差异无统计学意义(P均>0.05)。2.2.2本虚证伴血尿组与不伴血尿组本虚证占比情况按从大到小排列依次为:脾肾气虚证(42.2%vs 46.3%)、气阴两虚证(23.8%vs 22.0%)、肝肾阴虚证(16.8%vs 13.4%)、肺肾气虚证(10.3%vs 11.0%)、脾肾阳虚证(4.9%vs 4.9%%);(P均>0.05)。2.2.3标实证伴血尿组与不伴血尿组标实证占比情况按从大到小排列依次为:水湿证(81.1%vs 79.3%)、血瘀证(58.4%vs 59.8%)、湿热证(42.2%vs 41.5%)、湿浊证(0.5%vs 0.0%);(P均>0.05)。3临床资料3.1合并症伴血尿组与不伴血尿组合并症比较:高血压(62.7%vs 64.6%,P=0.763),血脂异常(72.4%vs 68.3%,P=0.491),高尿酸血症(18.4%vs 17.1%,P=0.798),2 型糖尿病(14.1%vs 23.2%,P=0.066),动脉硬化(11.9%vs 13.4%,P=0.727);两组间合并症差异均无统计学意义(P均>0.05)。3.2 eGFR伴血尿组与不伴血尿组估算肾小球率过滤(eGFR)中位数比较:(100 vs 96)mL · min-· 1.73m-2,两组间差异无统计学意义(P=0.066,<0.05)。3.3 CKD分期伴血尿组与不伴血尿组患者CKD分期比较:CKD1期(73.0%vs 58.5%)、CKD2期(21.1%vs 35.4%)、CKD3 期(4.9%vs 2.4%)、CKD4 期(0.5%vs 3.7%)、CKD5 期(0.4%vs 0.0%);伴血尿组CKD1期、CKD3期、CKD5期占比更多,不伴血尿组CKD2期、CKD4期占比更多;两组间差异有统计学意义(P=0.024,<0.05)。3.4实验室指标3.4.1尿蛋白定量伴血尿组与不伴血尿组肾病范围蛋白尿占比比较:(48.1%vs 39.0%),差异无统计学意义(P=0.169,>0.05)。伴血尿组与不伴血尿组24小时尿蛋白定量中位数比较:(3799.50mg/24h vs 3036.00mg/24h),差异无统计学意义(P=0.585,>0.05)。3.4.2白蛋白伴血尿组血白蛋白(ALB)中位数24.90(19.08,30.53)g/L低于不伴血尿组26.90(20.85,31.5)g/L,差异有统计学意义(P=0.045,<0.05)。3.4.3肾功能伴血尿组与不伴血尿组肾功能各项中位数比较:血肌酐(Scr)(68.90 umol/Lvs 74.00umol/L),P=0.091;血尿素氮(BUN)(4.80mmol/Lvs5.16 mmol/L),P=.406;血尿酸(UA)(359.00 umol/L vs 375.00 umol/L),P=0.287。伴血尿组 Scr、BUN、UA均较不伴血尿组低,但差异无统计学意义(P均>0.05)。3.4.4肝功能伴血尿组与不伴血尿组肝功能各项中位数比较:谷草转氨酶(AST)(19.90 U/Lvs 19.70U/L),P=0.486;谷丙转氨酶(ALT)(16.00U/Lvs 16.00U/L),P=0.107;γ谷氨酰转氨酶(γ GT)(18.00 U/L vs 22.80 U/L),P=0.001。伴血尿组γGT低于不伴血尿组,具有显著统计学差异(P<0.01);AST、ALT两组间差异无统计学意义(P>0.05)。3.4.5血脂伴血尿组与不伴血尿组血脂各项中位数比较:血浆胆固醇(CH0)(6.97mmol/Lvs 6.97 mmol/L),P=0.854;血浆甘油三酯(TG)(2.09 mmol/L vs 2.25 mmol/L),P=0.585;高密度脂蛋白(HDL-C)(4.42mmol/L vs 4.22 mmol/L),P=0.363;低密度脂蛋白(LDL-C)(4.22 mmol/L vs 4.43 mmol/L),P=0.363。两组间差异均无统计学意义(P均>0.05)。4病理资料4.1肾脏病理分期伴血尿组与不伴血尿组患者肾脏病理分期占比比较:Ⅰ期膜性肾病(43.1%vs 46.99%),Ⅰ-Ⅱ期膜性肾病(24.9%vs 19.8%),Ⅱ期膜性肾病(23.8%vs 28.4%),Ⅱ-Ⅲ期膜性肾病(6.1%vs 3.7%),Ⅲ期膜性肾病(2.2%vs 1.2%);两组间差异无统计学意义(P=0.707,>0.05)。4.2肾小球系膜病变情况伴血尿组与不伴血尿组患者系膜细胞病变占比比较:系膜区免疫复合物多样(45.9%vs 58.2%,P=0.067),系膜细胞增生(49.7%vs 40.2%,P=0.152);两组间差异无统计学意义(P>0.05)。4.3肾小球硬化情况伴血尿组与不伴血尿组患者肾小球硬化占比比较:缺血性硬化(31.4%vs 40.2%,P=0.157),新月体形成(11.4%vs 6.1%,P=0.182),球性硬化(13.5%%vs 13.4%,P=0.983),节段性硬化(3.8%vs 4.9%,P=0.678);两组间差异均无统计学意义(P>0.05)。4.4肾小管及间质病变情况伴血尿组与不伴血尿组患者肾小管及间质病变占比比较:无明显病变(30.5%vs 26.6%,P=0.517),肾间质炎性细胞浸润(66.8%vs 64.6%,P=0.725),肾间质纤维化(54.7%vs 17.6%,P=0.375);两组间差异均无统计学意义(P>0.05)。4.5肾小动脉病变情况伴血尿组与不伴血尿组患者肾小动脉病变占比比较:无名显病变(20.7%vs 12.2%,P=0.098),小动脉玻璃样变(11.0%vs 2.2%,P=0.006),小动脉管腔狭窄(3.7%vs 0%,P=0.029),小动脉管腔增厚(79.9%vs 88.9%,P=0.075);伴血尿组较不伴血尿组小动脉玻璃样变占比低,具有显著统计学差异(P<0.01);伴血尿组较不伴血尿组小动脉管腔狭窄占比低,具有统计学差异(P<0.05);其余病理改变两组间差异无统计学意义(P>0.05)。结论1伴血尿IMN中医症状、辨证分型与无血尿者基本一致。2伴血尿IMN性别、年龄、临床表现与无血尿者基本相同3与不伴血尿IMN相比,伴血尿IMN肾小球、肾小管间质病变无差异,但肾小动脉病变较轻。更多还原

【Abstract】 Research BackgroundMembranous nephropathy(MN)is one of the main pathological types leading to adult nephrotic syndrome(NS)or asymptomatic proteinuria.Its typical pathological features are diffusing glomerular basement membrane(GBM)thickening with immune complex deposition under epithelial cells.According to the etiology,MN can be divided into two categories of idiopathic membranous nephropathy(IMN)and secondary membranous nephropathy(SMN),and secondary cases are caused by autoimmune diseases,infections,tumors,drugs,etc.The cases with unknown causes are called IMN.Foreign research reports that IMN accounted for 20%to 40%of adult primary NS,domestic epidemiological journals report that IMN accounted for more than 10%of primary glomerular disease and the incidence rate in recent years is significantly increased.The incidence of IMN is mostly after the age of 40,with the majority of males,and the prevalence of males is more than about 1 times higher than that of females.The onset of this disease is slow.As proteinuria is the main clinical manifestation,60%to 80%of IMN patients present NS,about 40%of them can be found microscopic hematuria and no gross hematuria in the absence of complications.The natural history of IMN is variable.25%of patients may have complete spontaneous remission of proteinuria within 5 years,while 35%may develop end-stage renal disease(ESRD)within 10 years.Reviewing the literature,the factors affecting the prognosis of membranous nephropathy include advanced age,male gender,concomitant hypertension,massive albuminuria,renal insufficiency,and pathological findings with more glomerulosclerosis and heavier tubulointerstitial lesions.As a more common clinical manifestation in IMN-hematuria,especially microscopic hematuria;,its impact on other clinical manifestations,pathological features and the TCM syndrome features of IMN remains to be studied.ObjectivesTo investigate the TCM syndrome,clinical and pathological features of idiopathic membranous nephropathy(IMN)associated with hematuria.MethodsA retrospective study was conducted to select patients who were diagnosed with renal disease in the China Academy of Chinese Medical Sciences Guang’ anmen Hospital from January 2006 to December 2016.The patients were diagnosed with IMN and met the inclusion criteria.The patients will be devided into two groups according to whether they were associated with hematuria(High magnification red blood cell count ≥3/HP and abnormal red blood cell>70%):the IMN group with hematuria(Group A)(185 cases)and the IMN group without hematuria(Group B)(82 cases).The TCM symptoms,syndrome differentiation,clinical manifestations,and renal pathological data were compared between the two groups to initially investigate the relationship between hematuria and TCM syndromes and clinical pathology within IMN patients.Results1 General information1.1 GenderAmong the patients with hematuria group,106 were males(57.3%),79 were females(42.7%),male to female ratio was 1.34:1;In patients without hematuria,males were 48(58.5%)and females were 34(41.5%).The ratio of male to female was 1.41:1.There was no significant difference in gender between the two groups(P=0.850,>0.05).1.2 AgeIn the hematuria group,the median age of renal biopsy was 52.84(42.90,59.78)years,which was greater than the median age of 49.57(41.46,62.62)years of renal biopsy without hematuria(group B).The difference in age was not statistically significant(P=0.921,>0.05).1.3 Disease courseIn the group with hematuria,the median duration of disease during renal biopsy with hematuria was 5.0(2.0,11.0)months,which was less than that of the group without hematuria(6.0,3.0,12.0 months).The differences in the course of disease between the two groups when receiving renal biopsy were statistically significant(P=0.016;<0.05).2 TCM Symptoms and Syndrome Differentiation2.1 TCM SymtomsComparing the symptoms of TCM with the incidence rate of more than 10%in the two groups,the main symptoms of the two groups ranking in descending order of incidence are as follows:lower extremity edema,urine foam,lumbar acid and back pain,dry mouth,frequent nocturia,cough,poor sleep,dizziness,facial edema,thin stool,yellow urine,bitter mouth and anorexia;in the group with hematuria,the symptom distribution of cough,bitter mouth is less than the group without hematuria:cough(22.2%vs 11.0%),(P= 0.031;<0.05);bitter mouth(15.1%vs 6.1%),(P=0.038,<0.05).The rest of the TCM symptom distribution was not statistically significant(P>0.05).2.2 TCM Syndrome Differentiation2.2.1 General StatisticsThe syndrome differentiation between hematuria group and non-hematuria group:the deficiency syndrome(93.5%vs.91.5%),P=0.548;sthenia syndrome(97.8%vs 97.6%),P=0.888.The two groups of TCM syndrome differentiation were mainly deficiency-excess complex.There was no statistical difference in distribution of syndrome differentiation between the two groups(P>0.05).2.2.2 Deficiency SyndromeThe proportions of deficiency syndrome in hematuria group and non-hematuria group ranking from highest to lowest is:spleen and kidney Qi deficiency syndrome(42.2%vs 46.3%),Qi and Yin deficiency syndrome(23.8%vs 22.0%),liver and kidney Yin deficiency syndrome(16.8%vs 13.4%),lung-kidney Qi deficiency syndrome(10.3%vs 11.0%),spleen-kidney Yang deficiency syndrome(4.9%vs 4.9%);(P all>0.05).2.2.3 Sthenia SyndromeThe proportions of sthenia syndrome in hematuria group and non-hematuria group ranking from highest to lowest is:wetness syndrome(81.1%vs 79.3%),blood stasis syndrome(58.4%vs 59.8%),damp heat syndrome(42.2%vs.41.5%),wet cloud syndrome(0.5%vs 0.0%);(P all>0.05).3 Clinical Information3.1 ComplicationsComparing complications between hematuria group and non-hematuria group:patients with hypertension(62.7%vs 64.6%,P=0.763),patients with dyslipidemia(72.4%vs 68.3%,P=0.491),patients with hyperuricemia(18.4%vs 17.1%,P=0:798),patients with type 2 diabetes(14.1%vs 23.2%,P=0.066),and patients with arteriosclerosis(11.9%vs 13.4%,P=0.727).There was no significt difference in comorbidities between the two groups(P all>0.05).3.2 eGFREstimated glomerular filtration rate(eGFR)medians in patients with hematuria versus those without hematuria:(100 vs 96)mL·min-1·1.73m-2.There was no significant difference between the two groups(P=0.066,<0.05).3.3 CKD stagingComparison of staging of CKD in patients with hematuria and without hematuria:CKD stage 1(73.0%vs 58.5%),CKD stage 2(21.1%vs 35.4%),CKD stage 3(4.9%vs 2.4%),CKD stage 4(0.5%vs 3.7%),CKD stage 5(0.4%vs 0.0%);The proportions of CKD1,CKD3,and CKD5 in the hematuria group were more than those in the non-hematuria group.The proportions of CKD2 and CKD4 were less in the hematuria group.The difference between the two groups was statistically significant(P=0.024,<0.05).3.4 Laboratory datas3.4.1 Urine protein quantificationThe comparison of the proportion of proteinuria in nephrotic area between the hematuria group and non-hematuria group is:(48.1%vs 39.0%),the difference was not statistically significant(P=0.169,>0.05);The 24-hour urinary protein quantification of the hematuria group and non-hematuria group is:(3799.50mg/24h vs 3036.00mg/24h).There was no significant difference between the two groups(P=0.585，>0.05).3.4.2 Serum albuminThe median serum albumin in the group with hematuria:24.90(19.08,30.53)g/L was lower than that in the group without hematuria:26.90(20.85,31.5)g/L.The difference was statistically significant(P=0.045,<0.05).3.4.3 Kidney function testsMedian comparison of renal function in patients with hematuria and without hematuria;Serum creatinine(Scr)(68.90 umol/L vs 74.00 umol/L),P=0.091,blood urea nitrogen(BUN)(4.80 mmol/L vs 5.16 mmol/L,P=0.406,serum uric acid(UA)(359.00 umol/L vs 375.00 umol/L),P=0.287;Scr;BUN,and UA were lower in the hematuria group than in the hematuria group,but the difference was not statistically significant(P>0.05).3.4.4 Liver function testMedian comparison of liver function in patients with hematuria and without hematuria:Aspartate aminotransferase(AST)(19.90 U/L vs 19.70 U/L),P=0.486,alanine aminotransferase(ALT)(16.00 U/L vs 16.00 U/L)，P=0.107,and gamma glutamyl transaminase(y-GT)(18.00 U/L vs 22.80 U/L),P=0.001.The y-GT with hematuria group was lower than that without hematuria group,with significant statistical difference(P=0.001,<0.01).There was no significant difference between AST and ALT groups(P>0.05).3.4.5 Lipid test Comparing the median blood lipids in the hematuria group and the without hematuria group:Plasma cholesterol(CHO)(6.97 mmol/L vs 6.97 mmoll/L),P=0.854,plasma triglyceride(TG)(2.09 mmol/L vs 2.25 mmol/L),P=0.585,high-density lipoprotein(HDL-C)(4.42 mmol/L vs 4.22 mmol/L),P=0.363.Low density lipoprotein(LDL-C)(4.22 mmol/L vs 4.43 mmol/L),P=0.363.There was no significant difference between the two groups(P>0.05).4 Pathological data4.1 Kidney pathological stagingComparing the proportion of renal pathological stages in patients with hematuria and without hematuria:Stage I membranous nephropathy(43.1%vs 46.9%),stage Ⅰ-Ⅱmembranous nephropathy(24.9%vs 19.8%),stage II membranous nephropathy(23.8%vs 28.4%),stage Ⅱ-Ⅲ membranous nephropathy(6.1%vs 3.7%),stage Ⅲ membranous nephropathy(2.2%vs 1.2%).The difference between the two groups was not statistically significant(P=0.707,>0.05).4.2 Glomerular mesangial lesionsComparing the proportion of mesangial cytopathies in patients with hematuria and those without hematuria:Mesangial area immune complex diversity(45.9%vs 58.2%,P=0.067),mesangial cell proliferation(49.7%vs 40.2%,P=0.152).There was no significant difference between the two groups(P>0.05).4.3 Glomerular sclerosisComparing the proportion of glomerulosclerosis in patients with hematuria and without hematuria:Ischemia(31.4%vs.40.2%,P=0.157),crescent formation(11.4%vs 6.1%,P=0.182),sclerosing(13.5%vs 13.4%,P=0.983),segmental sclerosis(3.8%vs 4.9%,P=0.678).There was no significant difference between the two groups(P>0.05).4.4 Tubular and interstitial lesionsComparing the proportion of tubular and interstitial lesions in patients with hematuria and without hematuria:No obvious lesions(30.5%vs 26.6%,P=0.517),interstitial inflammatory cell infiltration(66.8%vs 64.6%,P=0.725),renal interstitial fibrosis(54.7%vs 17.6%,P = 0.375).There was no significant difference between the two groups(P>0.05).4.5 Renal artery lesionsComparing the proportion of renal arteriopathy in patients with hematuria and without hematuria:No obvious lesions(20.7%vs 12.2%,P=0.098)，small arterial hyalinosis(11.0%vs 2.2%,P=0.006),arteriolar lumen stenosis(3.7%vs 0%,P=0.029)%lumen thickening of small arteries(79.9%vs 88.9%,P=0.075);The proportion of small arterial hyalinosis in the hematuria group was lower than that in the non-hematuria group,with significant statistical differences(P<0.01).The proportion of small arterial stenosis in the hematuria group was lower than that in the non-hematuria group,with statistical difference(P<0.05).There was no significant difference in other renal arteriopathy between the two groups(P>0.05).Conclusion1 Symptoms of TCM and syndrome differentiation of patients with hematuria are basically the same as those without hematuria.2 The gender,age,and clinical manifestations of IMN with hematuria are basically the same as those without hematuria3 Compared with non-hematuria IMN,there was no difference in glomerular and tubulointerstitial lesions with hematuria,but renal arteriole lesions were lighter.更多还原