Clinico-pathological characteristics and outcomes in adult patients with thin basement membrane nephropathy

Wang Shaofan, Zhang Wen, Xu Feng, Cheng Zhen, Chen Xin, Wang Qingwen

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Chinese Journal of Nephrology ›› 2021, Vol. 37 ›› Issue (5) : 400-406. DOI: 10.3760/cma.j.cn441217-20200616-00059
Clinical Study

Clinico-pathological characteristics and outcomes in adult patients with thin basement membrane nephropathy

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Abstract

Objective To investigate the clinico-pathological characteristics and outcomes of adult patients with thin basement membrane nephropathy (TBMN). Methods Patients with biopsy-proven TBMN in National Clinical Research Center of Kidney Diseases, Jinling Hospital during Jan 1, 2008 to Dec 31, 2017 were collected. The clinico-pathological characteristics, prognosis, the influencing factors of proteinuria and renal chronic lesions were retrospectively analyzed. Results Among 135 adult patients included, 116 cases (85.9%) were female, and 19 cases were males. The age was (40.56±10.30) years old. There were 30 cases (22.2%) with hypertension and 32 cases (23.7%) with overweight or obesity. Proteinuria was found in 41 patients (30.4%) with (0.65±0.19) g/24 h of urine protein, and microscopic hematuria was found in all 135 patients. Serum creatinine was normal in all patients. Glomerulosclerosis was observed in 102 cases (75.6%), in which 51 cases (37.8%) had glomerulosclerosis>10%. There were 79 cases (58.5%) with mild chronic tubulointerstitial lesions, and 53 patients (39.3%) with vascular hyalinosis. The proportions of proteinuria, chronic tubular interstitial lesion and renal vascular lesion in patients with overweight/obesity and/or hypertension were higher than those without complications (all P<0.05). Multivariate logistic regression results showed that overweight/obesity (OR=7.550, 95%CI 2.091-27.257, P=0.002) and hypertension (OR=4.424, 95%CI 1.091-17.935, P=0.037) were independent influencing factors for proteinuria, while proteinuria was the independent influencing factor for chronic tubular interstitial lesion (OR=3.151, 95%CI 1.046-9.491, P=0.041). Four patients were lost to follow-up, and the median follow-up time of the remaining patients was 64.0(24.0, 96.5) months. At the end of the follow-up, urine protein increased in 10 patients (7.4%) and estimated glomerular filtration rate decreased in 3 patients (2.2%). The above 13 cases were all complicated with overweight/obesity and 4 cases with hypertension. The urine test and renal function in the remaining 118 patients didn't change significantly from baseline. Conclusions The incidences of proteinuria and renal chronic lesion are high in adult TBMN patients. Overweight/obesity and hypertension may cause a poor prognosis, and TBMN patients without metabolic abnormalities probably have good prognosis, but need long-term follow-up.

Key words

Glomerular basement membrane / Pathology, clinical / Prognosis / Thin basement membrane nephropathy / Type Ⅳ collagen

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Wang Shaofan. , Zhang Wen. , Xu Feng. , Cheng Zhen. , Chen Xin. , Wang Qingwen. Clinico-pathological characteristics and outcomes in adult patients with thin basement membrane nephropathy[J]. Chinese Journal of Nephrology, 2021, 37(5): 400-406. DOI: 10.3760/cma.j.cn441217-20200616-00059.
薄基底膜肾小球病(thin basement membrane nephropathy,TBMN)是由Ⅳ型胶原α3/α4链(COL4A3/COL4A4)基因突变导致的一种遗传性肾病[1],最显著的特征为肾组织病理电镜下观察到肾小球基底膜弥漫性变薄[2],是儿童和成人无症状镜下血尿的最常见原因[3-4]。TBMN通常被认为远期预后良好,但相关研究结果多来自于儿童病例,对成人病例研究较少。近年有研究显示TBMN患者蛋白尿发生率并不低,28.6%的患者可出现估算肾小球滤过率(estimated glomerular filtration rate,eGFR)下降,原因可能与老年血管硬化有关[5],但研究样本量过小,且包括部分儿童病例。因此,成人典型TBMN的特点及预后尚无定论。本研究对成人典型TBMN病例进行了回顾性分析,旨在探讨成人TBMN的临床、病理特点及其对预后的影响。

对象和方法

1. 研究对象: 选取2008年1月1日至2017年12月31日在东部战区总医院肾脏科经肾活检确诊为TBMN的成年患者。入选标准:(1)年龄≥18岁;(2)无高频听力下降,无双眼晶状体、眼底特征性改变;(3)肾活检电镜检查可见肾小球基底膜广泛、均匀性变薄(基底膜厚度<250 nm)[6],变薄范围≥80%,无电子致密物沉积,无厚薄不一、基底膜分层、撕裂等改变;(4)肾组织Ⅳ型胶原荧光染色正常;(5)排除合并其他肾小球肾炎,如IgA肾病、微小病变性肾小球病、糖尿病肾病、狼疮肾炎等。本研究获得东部战区总医院伦理委员会批准(2021NZKY-016-01)。
2. 临床资料 :包括年龄、性别、体重指数(BMI)、高血压、肾脏表现、肾外合并症等一般情况及家族史调查(范围为三级亲属)。
3. 实验室检查: (1)尿液检查:包括24 h尿蛋白量(双缩脲法)、尿沉渣、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、尿视黄醇结合蛋白(RBP);(2)血液检查:包括血清肌酐(Scr)、血浆白蛋白、血脂、血糖(空腹、餐后2 h血糖及OGTT试验)以及肝功能、血常规、免疫学指标(免疫球蛋白、补体、抗核抗体、抗dsDNA抗体、抗核抗体谱);(3)其他:双耳纯音测听,双眼晶状体、眼底检查。
4. 肾组织病理: 患者均在B超引导下行经皮肾穿刺活检,肾组织标本经石蜡包埋,切片厚度1.5~2.0 μm,HE、PAS、PASM-Masson和Masson三色染色行光镜检查。采用冰冻切片直接法行免疫荧光检查,观察免疫球蛋白(IgG、IgA、IgM、IgE)及补体(C3、C4、C1q)沉积的部位及强度;采用间接法(抗体来源:日本COSMO公司)行Ⅳ型胶原染色,观察α3、α5链分布强度及连续性。电镜检查所取肾组织,以3.75%的冷戊二醛固定,1%四氧化锇后固定,超薄切片厚50 nm,醋酸铀、柠檬酸铅双重染色,透射电镜下观察,随机选取至少3个血管袢,至少10个点测量内皮细胞外侧缘到肾小球基底膜上足细胞足突细胞膜底部之间的距离,计算肾小球基底膜变薄范围。取PAS染色正切的肾小球,采用NIS Element BR软件计算直径、面积。肾小管间质慢性病变分为轻度(肾小管萎缩/间质纤维化比例<25%)、中度(肾小管萎缩/间质纤维化比例25%~49%)和重度(肾小管萎缩和间质纤维化比例≥50%)。
5. 相关定义: BMI≥25 kg/m2定义为超重,BMI≥28 kg/m2定义为肥胖。高血压定义为收缩压≥140 mmHg和/或舒张压≥90 mmHg。蛋白尿定义为尿蛋白量>0.4 g/24 h。镜下血尿定义为尿沉渣红细胞计数>10万/ml。尿NAG酶升高定义为尿NAG酶≥9.7 U/g·Cr,尿RBP升高定义为尿RBP≥0.7 mg/L。高脂血症定义为血清总胆固醇>6.0 mmol/L,或三酰甘油>2.2 mmol/L,或低密度脂蛋白胆固醇>3.63 mmol/L,或高密度脂蛋白胆固醇<1.04 mmol/L。糖耐量异常定义为餐后2 h血糖≥7.8 mmol/L且<11.1 mmol/L,或空腹血糖≥6.2 mmol/L且<7.0 mmol/L。
6. 统计学方法: 采用SPSS 16.0软件进行统计分析。正态分布计量资料以x¯±s形式表示,组间比较用t检验;非正态分布计量资料以MP25P75)形式表示,组间比较用Mann-Whitney U检验;计数资料以例数(百分率)表示,组间比较采用卡方检验。采用Logistic回归分析进行单因素分析,以单因素分析中P<0.2的变量为候选变量,进入多因素Logistic回归模型进一步分析。所有检验均为双侧检验,P<0.05视为差异具有统计学意义。

结果

1. 一般资料: 共纳入135例TBMN患者,女性116例(85.9%),男性19例(14.1%),年龄(40.56±10.30)岁,中位病程24(8,60)个月。63例(46.7%)有血尿家族史;30例(22.2%)合并高血压,中位高血压病程为24(2,39)个月;32例(23.7%)合并超重/肥胖,其中18例合并高血压,5例合并高脂血症或糖耐量异常,无糖尿病病例。135例患者均有镜下血尿,41例(30.4%)存在蛋白尿[(0.65±0.19)g/24 h],所有患者不伴低蛋白血症,Scr、免疫学指标均正常。尿NAG、RBP升高的患者分别为20例(17.9%)和23例(20.4%)。见表1
表1 薄基底膜肾小球病患者的临床病理特征(n=135)
项目 数值
男/女(例) 19/116
年龄(岁,x¯±s) 40.56±10.30
病程[月,M(P25P75)] 24(8,60)
血尿家族史[例(%)] 63(46.7)
高血压[例(%)] 30(22.2)
超重/肥胖[例(%)] 32(23.7)
尿沉渣红细胞计数[万/ml,M(P25P75)] 105(35,200)
尿蛋白量(g/24 h,x¯±s) 0.33±0.24
蛋白尿[例(%)] 41(30.4)
血清肌酐(μmol/L,x¯±s) 56.58±11.49
尿NAG酶[U/g·Cr,M(P25P75)] 8.80(5.65,14.65)
尿RBP[mg/L,M(P25P75)] 0.2(0.1,0.4)
肾小球球性硬化比例[%,M(P25P75)] 6.3(2.2,13.6)
球性硬化>10%[例(%)] 51(37.8)
肾小管间质病变[例(%)] 79(58.5)
肾血管病变[例(%)] 53(39.3)
注:NAG:尿N-乙酰-β-D-氨基葡萄糖苷酶;RBP:尿视黄醇结合蛋白
2. 肾脏病理改变: 所有病例Ⅳ型胶原α3、α5链染色均正常。免疫荧光检查27例可见IgM沉积于系膜区,无补体沉积,余108例免疫球蛋白、补体均阴性。光镜下肾小球病变轻微或存在轻度系膜增生,102例(75.6%)存在肾小球硬化,中位球性硬化比例为6.3%(2.2%,13.6%),其中51例(37.8%)球性硬化比例>10%。3例(2.2%)可见节段硬化(硬化比例分别为3.3%、4.2%、11.1%)。合并高血压的病例未观察到肾小球缺血性改变,合并超重/肥胖病例的平均肾小球面积[n=32,(22 310.3±1 940.0)μm2]与其他病例[n=103,(20 637.3±3 723.3)μm2]比较差异无统计学意义(t值=2.314,P=0.141)。79例(58.5%)存在轻度肾小管间质慢性病变,表现为灶性肾小管萎缩及间质纤维化,无中、重度肾小管间质病变。53例(39.3%)有肾血管病变,表现为节段透明变性。见表1。所有病例电镜下均可见肾小球基底膜广泛、均一性变薄(90~240 nm),无电子致密物沉积,无明显足细胞病变。见图1
图1 薄基底膜肾小球病患者肾脏病理改变
注:A:肾小球轻微病变伴灶性肾小管萎缩、间质纤维化(PAS ×400);B:肾小球轻微病变伴球性硬化(PASM-Masson ×400);C:肾小球基底膜弥漫变薄(电镜 ×8 000);D:Ⅳ型胶原α3、α5链沉积正常(免疫荧光 ×400)

Full size|PPT slide

3. TBMN患者蛋白尿的影响因素: 单因素Logistic回归分析结果显示,高血压、超重/肥胖、肾小球硬化>10%和肾小管间质慢性病变是蛋白尿的影响因素,进一步的多因素Logistic回归分析结果显示,超重/肥胖(OR=7.550,95%CI 2.091~27.257,P=0.002)和高血压(OR=4.424,95%CI 1.091~17.935,P=0.037)是蛋白尿的独立影响因素,见表2
表2 薄基底膜肾小球病患者蛋白尿的影响因素(Logistic回归分析,n=135)
影响因素 单因素 多因素
OR(95%CI) P OR(95%CI) P
年龄(岁) 1.021(0.985~1.059) 0.253
病程(月) 1.000(0.995~1.005) 0.951
超重/肥胖(有/无) 15.176(5.844~39.415) <0.001 7.550(2.091~27.257) 0.002
高血压(有/无) 11.287(4.371~29.145) <0.001 4.424(1.091~17.935) 0.037
超重/肥胖伴高血压(有/无) 29.440(6.343~136.641) <0.001 1.041(0.102~10.575) 0.973
肾小球硬化>10%(有/无) 3.028(1.413~6.490) 0.004 1.828(0.655~5.100) 0.249
肾小管间质慢性病变(有/无) 6.629(2.548~17.245) <0.001 2.399(0.739~7.784) 0.145
4. TBMN患者肾脏慢性病变的影响因素: 单因素Logistic回归分析结果显示,年龄、高血压、超重/肥胖伴高血压和蛋白尿是肾小球硬化>10%的影响因素,见表3。而年龄、高血压、超重/肥胖、超重/肥胖伴高血压、蛋白尿和肾血管病变是肾小管间质慢性病变的影响因素,进一步的多因素Logistic回归分析结果显示,蛋白尿是肾小管间质慢性病变的独立影响因素(OR=3.151,95%CI 1.046~9.491,P=0.041),见表4
表3 薄基底膜肾小球病患者肾小球慢性病变(肾小球球性硬化>10%)的影响因素(Logistic回归分析,n=135)
影响因素 单因素 多因素
OR(95%CI) P OR(95%CI) P
年龄(岁) 1.036(1.000~1.074) 0.048 1.035(0.996~1.075) 0.080
病程(月) 1.001(0.997~1.006) 0.571
高血压(有/无) 2.370(1.027~5.470) 0.043 0.578(0.133~2.523) 0.466
超重/肥胖(有/无) 2.219(0.988~4.982) 0.053 0.655(0.174~2.470) 0.532
超重/肥胖伴高血压(有/无) 3.398(1.220~9.466) 0.019 3.855(0.479~30.991) 0.205
蛋白尿(有/无) 3.028(1.413~6.490) 0.004 2.569(0.980~6.734) 0.055
肾血管病变(有/无) 2.000(0.973~4.110) 0.059 1.700(0.771~3.749) 0.188
表4 薄基底膜肾小球病患者肾小管间质慢性病变的影响因素(Logistic回归分析,n=135)
影响因素 单因素 多因素
OR(95%CI) P OR(95%CI) P
年龄(岁) 1.050(1.013~1.088) 0.008 1.040(0.999~1.082) 0.056
病程(月) 1.002(0.997~1.007) 0.469
高血压(有/无) 8.667(2.472~30.379) 0.001 2.496(0.452~13.775) 0.294
超重/肥胖(有/无) 7.137(2.337~21.800) 0.001 2.321(0.547~9.856) 0.254
超重/肥胖伴高血压(有/无) 15.081(1.943~117.051) 0.009 1.283(0.067~24.658) 0.869
蛋白尿(有/无) 6.629(2.548~17.245) <0.001 3.151(1.046~9.491) 0.041
肾血管病变(有/无) 2.533(1.211~5.299) 0.014 1.666(0.712~3.899) 0.239
将合并超重/肥胖和(或)高血压的患者与无合并症者进行比较,结果显示有合并症组的年龄、尿蛋白量、蛋白尿发生率、肾小管间质慢性病变及肾血管病变发生率均高于无合并症组(均P<0.05),见表5
表5 合并超重/肥胖和(或)高血压患者与无合并症患者肾脏损害比较
项目 有合并症(n=44) 无合并症(n=91) 统计值(t/Z/χ2) P
年龄(岁,x¯±s) 43.5±9.6 39.1±10.3 5.578 0.020
尿蛋白量(g/24 h,x¯±s) 0.49±0.26 0.26±0.19 36.190 <0.001
蛋白尿[例(%)] 29(65.9) 12(13.2) 38.986 <0.001
NAG[U/g·Cr,M(P25P75)] 12.00(6.90,17.50) 7.40(4.95,12.15) -1.783 0.075
RBP[mg/L,M(P25P75)] 0.21(0.14,0.40) 0.15(0.10,0.39) -0.669 0.792
血清肌酐(μmol/L,x¯±s) 59.2±12.4 55.7±11.5 2.608 0.109
肾小球硬化比例[%,M(P25P75)] 8.00(3.15,16.38) 5.90(0,11.10) -1.409 0.159
肾小球硬化>10%[例(%)] 20(45.5) 31(34.1) 1.637 0.201
肾小管间质慢性病变[例(%)] 38(86.4) 42(46.2) 19.863 <0.001
肾血管病变[例(%)] 15(34.1) 10(11.0) 10.490 0.001
注:NAG:尿N-乙酰-β-D-氨基葡萄糖苷酶;RBP:尿视黄醇结合蛋白
5. 随访结果: 135例患者中有4例失访,余患者中位随访时间为64.0(24.0,96.5)个月,随访末有5例基线无蛋白尿患者出现蛋白尿,5例基线有蛋白尿患者出现尿蛋白增加(1.50~2.15 g/24 h),此10例患者均合并超重/肥胖,其中3例合并高血压。共3例(2.2%)在随访末[年龄(51.0±7.9)岁,随访时间分别为92、176、48个月]出现肾小球滤过率下降[eGFR分别为49.9、56.0、67.8 ml·min-1·(1.73 m2)-1],此3例患者均合并超重,其中1例合并高血压,基线均存在少量蛋白尿。余118例患者随访末仍表现为镜下血尿伴或不伴少量蛋白尿,肾功能正常。

讨论

TBMN又被称为良性家族性血尿,为常染色体显性遗传疾病[2],临床上常常仅表现为孤立镜下血尿,蛋白尿、高血压少见,肾脏病理改变轻微,因此既往认为病程为非进展性,很多患者未接受治疗,也未进行规律随访。本研究观察了135例成人典型TBMN患者,分析了其临床、病理表现及预后,结果发现高血压、蛋白尿的发生率分别高达22.2%和30.4%,肾脏病理肾小球球性硬化>10%的患者比例达37.8%,肾小管间质及血管慢性病变发生率高,随访末3例(2.2%)出现eGFR下降,提示成人TBMN的特点和预后与传统观念并不一致。
既往研究显示63.8%的TBMN患者可合并其他肾小球肾炎[7],而合并其他肾小球肾炎增加了高血压、蛋白尿的风险,肾功能不全的发生率可达34.2%,其中10.5%的患者在随访中进入终末期肾病[8]。一项对19例TBMN患者平均随访12年的前瞻性研究观察到,5例患者存在蛋白尿,6例在随访中出现高血压,1例出现血清肌酐升高[9];另有单中心研究显示TBMN患者中蛋白尿的发生率为21/92(22.8%),而在表现为孤立镜下血尿的71例患者中有22例(31.0%)合并高血压 [10],但两项研究病例均未排除TBMN合并其他肾脏疾病的可能。另一方面,同属Ⅳ型胶原相关肾病的Alport综合征早期可能无典型的肾小球基底膜结构改变,少数患者也可有α3、α4胶原链较弱甚至正常表达[11-14],常难以与TBMN相鉴别,但预后则与TBMN不同。因此,本研究首先通过肾活检病理、家族史调查和临床检查排除了TBMN合并其他肾小球肾炎或者典型Alport综合征的可能,避免了合并疾病或误诊对纳入病例临床特点及预后的影响。
本研究观察的135例患者具有TBMN的典型临床特征,起病隐匿,尿检以单纯镜下血尿为主,不伴肾功能损害,但高血压、蛋白尿发生率较高。在30例合并高血压的患者中有16例同时合并超重/肥胖,5例有高血压家族史,余患者年龄为46~64岁。BMI、家族史、年龄均与高血压的发生密切相关,因此本研究中高血压发生率高并不能简单归因于TBMN的进展,而考虑与以上多种因素相关。本研究中41例合并蛋白尿的患者均表现为少量、非肾病性蛋白尿,合并超重/肥胖和(或)高血压患者中蛋白尿的比例明显高于无合并症者。Logistic回归分析发现,蛋白尿与年龄、病程无明显相关性,超重/肥胖和高血压是蛋白尿的独立影响因素,提示TBMN患者的蛋白尿并非随年龄增长而增加,而是与所合并的异常代谢相关,合并超重/肥胖、高血压会增加TBMN患者发生蛋白尿的风险。
文献报道约5%~25%的TBMN病例可随年龄增长而出现局灶节段性肾小球硬化症(focal segmental glomerulosclerosis,FSGS)以及肾小管间质纤维化[2,15]。有研究认为肾小球硬化和肾小管间质的慢性病变可能与老年患者普遍存在的血管硬化有关[5]。但也有研究显示COL4A3/COL4A4基因杂合子突变可导致TBMN患者出现肾小球FSGS样病变[16]。本组病例肾活检病理光镜下仅3例(2.2%)存在FSGS,但球性硬化、肾小管间质及血管慢性病变发生率较高。因正常肾脏随着年龄增长可出现不同程度的肾小球硬化及肾小球滤过率下降[15],本研究主要观察了肾小球球性硬化>10%的病例,分析发现年龄、超重/肥胖、高血压、蛋白尿和肾血管病变是肾脏慢性病变的影响因素,可能影响肾小球硬化和肾小管间质慢性病变,而蛋白尿是肾小管间质慢性病变的独立影响因素,与肾小球硬化的相关性较其他因素也更为突出,证实尿蛋白会加重TBMN患者的肾脏慢性病变的进展。
肥胖、高血压、蛋白尿及肾脏慢性病变都是肾脏远期预后的影响因素。日本的1项单中心研究显示代谢综合征与慢性肾脏病患者尿蛋白水平呈正相关,代谢综合征和蛋白尿均与慢性肾脏病进展至终末期肾病独立相关[17]。近年有个案报道,合并肥胖的TBMN患者随访中出现高血压、蛋白尿和肾小球FSGS样病变[18]。本研究中合并高血压、超重/肥胖的病例肾活检病理并未观察到高血压肾损害或肥胖相关性肾病的典型病理改变,多数病例也未达到代谢综合征的诊断标准,但临床上蛋白尿及肾脏慢性病变发生率已明显升高。随访末有10例患者尿蛋白增加,3例出现eGFR下降,且均合并超重/肥胖伴或不伴高血压,其他患者在随访末则仍表现为轻度尿检异常,再次提示合并代谢异常的病例可能远期预后不良,而未合并代谢异常的患者则预后良好。因此,代谢异常是TBMN患者随访过程中不可忽视的重要因素。
本研究以较大样本量对成人TBMN的临床及病理特点进行了分析,但也存在以下不足:首先,基因检测是家族性血尿疾病的诊断金标准[19],但本组患者多数未进行基因检测,且女性患者比例较高,因此不能完全排除不典型的女性Alport综合征患者;其次,本研究为国内单中心回顾性研究,结论有待多中心前瞻性研究进一步验证。
总之,成人TBMN患者蛋白尿、肾脏慢性病变发生率较高,与合并超重/肥胖、高血压密切相关,可能预后不良,需要长期随访;而未合并代谢异常的TBMN患者远期预后良好。

References

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Familial benign hematuria (FBH) is a common autosomal dominant disorder characterized by the presence of persistent or recurrent hematuria. The clinical and pathologic features of this syndrome resemble those of early Alport syndrome (AS), and for this reason a common molecular defect has been proposed. The COL4A3/4 genes seem to be involved in both autosomal AS and FBH. This study involves a linkage analysis for the COL4A3/4 loci and a search for mutations within these genes in 11 biopsy-proven FBH families. Haplotype analysis showed that linkage to the COL4A3/4 locus could not be excluded in eight of nine families. One family was not linked to this locus; however, it included three affected women who could be X-linked AS carriers. Two families were too small to perform linkage analysis. COL4A3 and COL4A4 mutation screening disclosed six new pathogenic mutations, two in the COL4A3 gene (G985V and G1015E) and four in the COL4A4 gene (3222insA, IVS23-1G>C, 31del11, and G960R). It is the first time that mutations within the COL4A3 gene are described in families with FBH. This study clearly demonstrates the main role of the COL4A4 and COL4A3 genes in the pathogenesis of FBH.
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Thin basement membrane nephropathy (TBMN) is a glomerular disorder characterized clinically by isolated hematuria and pathologically by diffuse thinning of the glomerular basement membrane (GBM) on ultrastructural examination. The pathologic diagnosis of TBMN is problematic, in part because of the wide range of GBM thicknesses in the normal population. GBM thickness varies with age, sex, and the different methods of tissue preparation and measurement. In addition, there are no standardized diagnostic criteria defining the degree or extent of GBM thinning required for the diagnosis of TBMN. GBM thinning is often seen in other glomerulopathies, where it may represent an overlap with TBMN or may be secondary to GBM damage and remodeling. Importantly, TBMN must be differentiated from the GBM thinning seen in some renal biopsy specimens from boys and female heterozygotes with X-linked Alport syndrome because of the very different prognoses of these two conditions.
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Savige J, Rana K, Tonna S, et al. Thin basement membrane nephropathy[J]. Kidney Int, 2003, 64(4): 1169-1178. DOI: 10.1046/j.1523-1755.2003.00234.x.
Thin basement membrane nephropathy. Thin basement membrane nephropathy (TBMN) is the most common cause of persistent glomerular bleeding in children and adults, and occurs in at least 1% of the population. Most affected individuals have, in addition to the hematuria, minimal proteinuria, normal renal function, a uniformly thinned glomerular basement membrane (GBM) and a family history of hematuria. Their clinical course is usually benign. However, some adults with TBMN have proteinuria >500 mg/day or renal impairment. This is more likely in hospital-based series of biopsied patients than in the uninvestigated, but affected, family members. The cause of renal impairment in TBMN is usually not known, but may be due to secondary focal segmental glomerulosclerosis (FSGS) or immunoglobulin A (IgA) glomerulonephritis, to misdiagnosed IgA disease or X-linked Alport syndrome, or because of coincidental disease. About 40% families with TBMN have hematuria that segregates with the COL4A3/COL4A4 locus, and many COL4A3 and COL4A4 mutations have now been described. These genes are also affected in autosomal-recessive Alport syndrome, and at least some cases of TBMN represent the carrier state for this condition. Families with TBMN in whom hematuria does not segregate with the COL4A3/COL4A4 locus can be explained by de novo mutations, incomplete penetrance of hematuria, coincidental hematuria in family members without COL4A3 or COL4A4 mutations, and by a novel gene locus for TBMN. A renal biopsy is warranted in TBMN only if there are atypical features, or if IgA disease or X-linked Alport syndrome cannot be excluded clinically. In IgA disease, there is usually no family history of hematuria. X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen alpha3(IV), alpha4(IV), and alpha5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation. Technical difficulties in the demonstration and interpretation of COL4A3 and COL4A4 mutations mean that mutation detection is not used routinely in the diagnosis of TBMN.
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Gregory MC. The clinical features of thin basement membrane nephropathy[J]. Semin Nephrol, 2005, 25(3): 140-145. DOI: 10.1016/j.semnephrol.2005.01.004.
Thin basement membrane nephropathy (TBMN) is a common, lifelong condition affecting the kidneys that is characterized by microscopic glomerular hematuria, minimal or no proteinuria, and normal renal function. It often is discovered incidentally, and usually has an excellent prognosis. Many cases are familial and show autosomal-dominant inheritance. The defining characteristic is a glomerular basement membrane (GBM) that is thinned to about half its normal thickness on ultrastructural examination of the renal biopsy specimen. However, occasionally patients with TBMN develop marked proteinuria or renal impairment. It is unclear whether individuals with TBMN and impaired renal function represent part of the spectrum of TBMN associated with heterozygous COL4A3 or COL4A4 mutations, or if their disease is caused by mutations of other genes, or whether it is caused by a second coexistent renal lesion or is misdiagnosed Alport syndrome.
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Kajimoto Y, Endo Y, Terasaki M, et al. Pathologic glomerular characteristics and glomerular basement membrane alterations in biopsy-proven thin basement membrane nephropathy[J]. Clin Exp Nephrol, 2019, 23(5): 638-649. DOI: 10.1007/s10157-018-01687-1.
Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease.In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction.All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis.Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.
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Sue YM, Huang JJ, Hsieh RY, et al. Clinical features of thin basement membrane disease and associated glomerulopathies[J]. Nephrology (Carlton), 2004, 9(1): 14-18. DOI: 10.1111/j.1440-1797.2003.00223.x.
Background:  Thin basement membrane disease (TBMD) occurs in 5–11% of renal biopsy series, and can be associated with other glomerulopathies (GNs). Data on the prevalence, clinical features, and prognosis of TBMD with other GNs are limited.
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Nieuwhof CM, de Heer F, de Leeuw P, et al. Thin GBM nephropathy: premature glomerular obsolescence is associated with hypertension and late onset renal failure[J]. Kidney Int, 1997, 51(5): 1596-1601. DOI: 10.1038/ki.1997.219.
Thin glomerular basement membrane (GBM) nephropathy, also called familial benign hematuria, is characterized by chronic hematuria and uniform thinning of the lamina densa of the glomerular basement membrane. It generally holds an excellent renal prognosis. Alport syndrome in early stages can also show attenuation of the GBM; conversely, renal insufficiency has been reported in familial benign hematuria. To discern early Alport syndrome from thin GBM nephropathy, we carried out a prospective epidemiological study in which 19 normotensive and non-azotemic adult patients with chronic microscopic (18 of 19) and macroscopic (1 of 19) hematuria and biopsy-proven thin GBM nephropathy were followed for a median of 12 years (range 9 to 15 years). Renal biopsies of thin GBM patients at entry showed an increased incidence of focal global glomerulosclerosis when compared to disease controls as IgA nephropathy (P = 0.047) and normal renal tissue (P = 0.0075). All renal biopsies showed the presence of the Goodpasture antigen when tested immunohistochemically. Presence of Alport syndrome was excluded clinically as none of the patients had complaints of hearing loss or abnormalities by audiography and ophthalmology. At the end of follow-up, the incidence of hypertension in thin GBM nephropathy (35%) exceeded that of healthy clinical controls (P = 0.048), and one hypertensive patient developed mild renal failure. In the normotensive patients, the glomerular filtration rate at follow-up as measured by inulin clearance was reduced in three out of seven; these were over 50 years of age. Although no family members were known to have renal disease at inclusion, within four families six elderly first degree relatives had developed unexplained renal insufficiency at the end of follow-up. Thus, thin GBM nephropathy predisposes to premature glomerular obsolescence, leading in time to increased incidences of hypertension and late onset renal insufficiency.
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van Paassen P, van Breda Vriesman PJ, van Rie H, et al. Signs and symptoms of thin basement membrane nephropathy: a prospective regional study on primary glomerular disease-The Limburg Renal Registry[J]. Kidney Int, 2004, 66(3): 909-913. DOI: 10.1111/j.1523-1755.2004.00835.x.
To chart the epidemiology of primary glomerular disease by means of a prospective regional study in the southern part of The Netherlands.Experienced renal technicians collected renal biopsies, blood, and 24-hour urine samples at the bed site in each of the participating hospitals. The material was processed and analyzed at the University Hospital Maastricht. Analysis included light microscopy, immunohistochemistry, and electron microscopy of the biopsies as well as serologic and chemical analysis.Primary IgA nephropathy (IgAN), membranous glomerulopathy, antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and thin basement membrane nephropathy (TBMN) are the most common primary glomerular diseases in this order of sequence. Our data show the clinical and histologic phenotype of TBMN to be diverse: the vast majority of TBMN has chronic microscopic hematuria, frequently associated with hypertension in late middle age; about 15% of TBMN has in addition substantial proteinuria which is associated in the majority of cases with the lesions of focal segmental glomerulosclerosis (FSGS). In 5% of TBMN a nephrotic syndrome is observed, occasionally associated with FSGS tip lesions.These results support the notion that TBMN is a disease of genetic heterogeneity; it is not a benign renal condition in a substantial number of patients, particularly those in late middle age.
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Kamiyoshi N, Nozu K, Fu XJ, et al. Genetic, clinical, and pathologic backgrounds of patients with autosomal dominant Alport syndrome[J]. Clin J Am Soc Nephrol, 2016, 11(8): 1441-1449. DOI: 10.2215/CJN.01000116.
Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for &lt;5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear.
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Pescucci C, Mari F, Longo I, et al. Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene[J]. Kidney Int, 2004, 65(5): 1598-1603. DOI: 10.1111/j.1523-1755.2004.00560.x.
Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown.Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation.Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic.This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.
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Pirson Y. Making the diagnosis of Alport's syndrome[J]. Kidney Int, 1999, 56(2): 760-775. DOI: 10.1046/j.1523-1755.1999.00601.x.
[14]
Gubler MC, Knebelmann B, Beziau A, et al. Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution[J]. Kidney Int, 1995, 47(4): 1142-1147. DOI: 10.1038/ki.1995.163.
Alport syndrome (AS) is an hereditary disease of basement membrane collagen. It is mainly transmitted as a dominant X-linked trait and caused by mutations in the COL4A5 gene encoding the alpha 5 chain of type IV collagen. However, autosomal recessive AS due to mutations in the COL4A3 or COL4A4 genes could represent up to 15% of AS. Using the immunofluorescence technique, we analyzed the distribution of the different chains of type IV collagen in renal (12 specimens) and skin (4 specimens) basement membranes of 12 AS patients belonging to 11 unrelated kindreds in which autosomal recessive inheritance had been demonstrated (3 kindreds) or was suggested by clinical and genealogic data (8 kindreds). The renal and skin distribution was normal in one patient with COL4A4 mutations. A peculiar pattern of distribution of the alpha 3-alpha 5(IV) chains was observed in the other patients. It was characterized the co-absence of the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains in the glomerular basement membrane, and the presence of the alpha 5(IV) chain in a series of extraglomerular basement membranes including capsular, collecting ducts and epidermal basement membranes, a combination never observed in X-linked AS. This immunohistochemical pattern is correlated with the specific distribution of the alpha 3-alpha 5 chains of type IV collagen chains within extraglomerular basement membranes. It could be a useful marker for the identification of autosomal recessive AS.
[15]
Glassock RJ, Winearls C. Ageing and the glomerular filtration rate: truths and consequences[J]. Trans Am Clin Climatol Assoc, 2009, 120: 419-428.
The process of glomerular filtration of plasma fluid has been known for over 160 years and the measurement of the rate of its formation (glomerular filtration rate, GFR) has been possible for over 80 years. Studies conducted in the 1930's to the 1950's clearly established that GFR declines, perhaps inexorably, with normal ageing, usually beginning after 30-40 years of age. The rate of decline may accelerate after age 50-60 years. This decline appears to be a part of the normal physiologic process of cellular and organ senescence and is associated with structural changes in the kidneys. In the last decade a new paradigm has been introduced in which the true or measured GFR is estimated (eGFR) by formulas based on serum creatinine levels and in which these estimates are applied to the diagnoses of chronic kidney disease (CKD) in the general population. These criteria for diagnosis of CKD include an absolute threshold for eGFR, unadjusted for the effects of age on the normal values for eGFR. A consequence of these criteria has been to overstate the frequency of CKD in the general population and to generate many "false positive" diagnoses of CKD. This paper discusses the known effects of ageing on GFR and the consequences of using a classification system for defining CKD that does not take into account the normal decline of GFR with ageing.
[16]
Pierides A, Voskarides K, Athanasiou Y, et al. Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis[J]. Nephrol Dial Transplant, 2009, 24(9): 2721-2729. DOI: 10.1093/ndt/gfp158.
[17]
Saito T, Mochizuki T, Uchida K, et al. Metabolic syndrome and risk of progression of chronic kidney disease: a single-center cohort study in Japan[J]. Heart Vessels, 2013, 28(3): 323-329. DOI: 10.1007/s00380-012-0254-5.
Metabolic syndrome (MetS) is a risk factor for the development of diabetes and cardiovascular disease, and recently was linked to incident chronic kidney disease (CKD). The purpose of this study is to examine whether MetS is associated with CKD progression in Japanese at a single center. Outcome variables were a decrease in estimated glomerular filtration rate (eGFR) of 50 % or 25 ml/min/1.73 m(2), end-stage renal disease (ESRD), death, or a composite outcome of all three. There were 213 subjects in the analysis, 40.4 % of whom met the criteria for MetS. The group of subjects with MetS had higher urinary albumin-to-creatinine (UACR) levels. Survival curves stratified by MetS status showed early separation of the curves and a significantly higher survival rate in the group without MetS (P = 0.0086). Comparisons with normoalbuminuria and microalbuminuria showed that macroalbuminuria was equally associated with predicted composite outcome (GFR, ESRD, or death) both in the presence and absence of MetS. Multivariate analyses for all covariates showed that eGFR (hazard ratio (HR) 8.286, 95 % confidence interval (CI) 2.360-28.044, P = 0.0012) and the UACR (HR 2.338, 95 % CI 1.442-3.861, P = 0.0005) at baseline were independently associated with the composite outcomes. The results show that MetS was associated with albuminuria in a cohort of Japanese CKD patients, and both MetS and albuminuria were independently associated with CKD progression.
[18]
Togashi R, Nemoto Y, Waki K, et al. Clinicopathological implications of proteinuria after long-term isolated hematuria due to thin basement membrane nephropathy and focal segmental glomerulosclerosis[J]. Case Rep Nephrol, 2019, 2019: 1627392. DOI: 10.1155/2019/1627392.
[19]
Savige J, Gregory M, Gross O, et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy[J]. J Am Soc Nephrol, 2013, 24(3): 364-375. DOI: 10.1681/ASN.2012020148.
Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.
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