特发性膜性肾病患者血栓栓塞事件发病率及危险因素的队列研究

doi:10.24920/11809

摘要/Abstract

摘要：

目的评估特发性膜性肾病（IMN）患者队列中动脉血栓栓塞事件（ATEs）和静脉血栓栓塞事件（VTEs）的发生率及其特点,并探索其相关危险因素。方法回顾性研究队列共纳入766名连续中国人IMN患者,以Kaplan-Meier模型统计新发的ATEs和VTEs的累积发病率,以单因素和多因素风险回归分析其可能的危险因素。结果在肾活检诊断为IMN后的第0.5、1、2、3、5年中,ATEs的累积发病率分别为4.3%、5.7%、6.3%、7.1%和8.0%,VTEs的累积发病率分别为5.9%、6.8%、6.9%、7.0%和7.2%。在78起ATE事件（71例）中,心血管疾病、血栓性缺血性脑卒中和外周动脉性疾病分别占比50%、45%和5%;在60起VTE事件（53例）中,深静脉血栓、肾静脉血栓和肺栓塞分别占比60%、13%和27%。ATE和VTE事件发生时,分别有42.1%和81.5%的患者处于肾病综合征（NS）状态（χ ²=18.1,P < 0.001）。ATEs与大量蛋白尿、年龄、吸烟史、高血压和既往ATE史相关,其中年龄是ATEs的独立危险因素（P=0.001）,低白蛋白血症为VTEs主要独立危险因素(P=0.03)。结论 IMN患者ATEs和VTEs发病率高,尤其在病程的前6个月内。ATEs中IS占比高。大量蛋白尿和动脉粥样硬化经典危险因素与ATEs的发生相关,低白蛋白血症为VTEs的独立预测因素。肾病综合征状态时ATEs和VTEs的发生风险增高,特别是VTEs。

关键词: 特发性膜性肾病, 血栓栓塞事件, 动脉, 静脉

Abstract:

Objective The aims of this study were to assess incidences and characteristics of arterial thromboembolic events (ATEs) and venous thromboembolic events (VTEs) in Chinese patients with idiopathic membranous nephropathy (IMN), and to identify the predisposing risk factors of them.Methods A total of 766 consecutive Chinese patients with IMN were enrolled in this retrospective cohort study. The cumulative incidences of newly diagnosed ATEs and VTEs were calculated using Kaplan-Meier methods. Univariable risk prediction model analysis followed by multivariable survival analysis was used to evaluate the potential risk factors of ATE and VTE.Results At 0.5, 1, 2, 3, and 5 years after biopsy diagnosis of IMN, the cumulative incidence of newly diagnosed ATEs were 4.3%, 5.7%, 6.3%, 7.1%, and 8.0%, and of newly diagnosed VTEs were 5.9%, 6.8%, 6.9%, 7.0%, and 7.2%, respectively. In 78 ATEs events (71 patients), cardiovascular diseases, thrombotic ischemic stroke (IS) and peripheral artery disease accounted for 50%, 45% and 5% respectively; in 60 VTEs events(53 patients), the deep vein thrombosis, renal vein thrombosis and pulmonary embolism accounted for 60%, 13% and 27% respectively. At the time of event, 42.1% patients with ATEs and 81.5% patients with VTEs were at nephrotic syndrome(NS) status (χ ²=18.1, P<0.001). Severe proteinuria, aging, smoking, hypertension and prior ATE history were associated with ATEs. Aging was demonstrated as the independent risk factor for ATEs (P=0.001), and hypoalbuminemia was the dominant independent risk factor for VTEs (P=0.03). Conclusions Patients with IMN have increased incidences of ATEs and VTEs, and most of events occurred within the first 6 months of the disease. IS was very common in ATEs in our cohort. Severe proteinuria and classic risk factors for atherosclerosis were associated with onset of ATEs. Hypoalbuminemia independently predicted VTEs. Risks of both ATEs and VTEs were particularly high in the status of NS, particularly VTEs.

Key words: idiopathic membranous nephropathy, thromboembolic events, arterial, venous

Zou Peimei, Li Hang, Cai Jianfang, Chen Zhenjie, Li Chao, Xu Ping, Li Mingxi, Chen Limeng, Li Xuemei, Li Xuewang. A Cohort Study of Incidences and Risk Factors for Thromboembolic Events in Patients with Idiopathic Membranous Nephropathy[J].Chinese Medical Sciences Journal, 2018, 33(2): 91-99.

图/表 7

Table 1

Table 2

Table 3

Table 4

参考文献 23.

1.	Cattran D . Management of membranous nephropathy: when and what for treatment. J Am Soc Nephrol 2005; 16(5):1188-94. doi: 10.1681/ASN.2005010028. doi: 10.1681/ASN.2005010028 pmid: 15800117
2.	Pan X, Xu J, Ren H , et al. Changing spectrum of biopsy-proven primary glomerular diseases over the past 15 years: a single-center study in China. Contrib Nephrol 2013; 181:22-30. doi: 10.1159/000348638. doi: 10.1159/000348638
3.	Barbour SJ, Greenwald A, Djurdjev O , et al. Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis. Kidney Int 2012; 81(2):190-5. doi: 10.1038/ki.2011.312. doi: 10.1038/ki.2011.312 pmid: 21918501
4.	Glassock RJ . Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum. J Am Soc Nephrol 2007; 18(8):2221-5. doi: 10.1681/ASN.2006111300. doi: 10.1681/ASN.2006111300 pmid: 17599972
5.	Kayali F, Najjar R, Aswad F , et al. Venous thromboembolism in patients hospitalized with nephrotic syndrome. Am J Med 2008; 121(3):226-30. doi: 10.1016/j.amjmed.2007.08.042. doi: 10.1016/j.amjmed.2007.08.042 pmid: 18328307
6.	Gilboa N . Letter: Incidence of coronary heart disease associated with nephrotic syndrome. Med J Aust 1976; 1(7):207-8. pmid: 1272153
7.	Ordo?ez JD, Hiatt RA, Killebrew EJ , et al. The increased risk of coronary heart disease associated with nephrotic syndrome. Kidney Int 1993; 44(3):638-42. doi: 10.1038/ki.1993.292. doi: 10.1038/ki.1993.292 pmid: 8231039
8.	Wass VJ, Jarrett RJ, Chilvers C , et al. Does the nephrotic syndrome increase the risk of cardiovascular disease? Lancet 1979; 2(8144):664-7. doi: 10.1016/s0140-6736(79)92067-1. doi: 10.1016/s0140-6736(79)92067-1 pmid: 90759
9.	Mahmoodi BK, ten Kate MK, Waanders F , et al. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study. Circulation 2008; 117(2):224-30. doi: 10.1161/CIRCULATIONAHA.107.716951. doi: 10.1161/CIRCULATIONAHA.107.716951 pmid: 18158362
10.	Lee T, Derebail VK, Kshirsagar AV , et al. Patients with primary membranous nephropathy are at high risk of cardiovascular events. Kidney Int 2016; 89(5):1111-8. doi: 10.1016/j.kint.2015.12.041. doi: 10.1016/j.kint.2015.12.041 pmid: 26924046
11.	Levey AS, Stevens LA, Schmid CH , et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150(9):604-12. doi: 10.7326/0003-4819-150-9-200905050-00006 pmid: 2763564
12.	Troyanov S, Wall CA, Scholey J W , et al. Idiopathic membranous nephropathy: definition and relevance of a partial remission. Kidney Int 2004; 66(3):1199-205. doi: 10.1111/j.1523-1755.2004.00873.x doi: 10.1111/j.1523-1755.2004.00873.x pmid: 15327418
13.	Radhakrishnan J, Appel AS, Valeri A , et al. The nephrotic syndrome, lipids, and risk factors for cardiovascular disease. Am J Kidney Dis 1993; 22(1):135-42. doi: 10.1016/s0272-6386(12)70179-8. doi: 10.1016/s0272-6386(12)70179-8 pmid: 8322776
14.	Vaziri ND . Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int 2016; 90(1):41-52. doi: 10.1016/j.kint.2016.02.026. doi: 10.1016/j.kint.2016.02.026 pmid: 27165836
15.	Nandwani A, Pathania D, Jha PK , et al. Renal artery thrombosis with renal infarction: a rare cause of acute abdomen. Indian J Nephrol 2017; 27(4):313-5. doi: 10.4103/0971-4065.183581. doi: 10.4103/0971-4065.183581 pmid: 5514829
16.	Parag KB, Somers SR, Seedat YK , et al. Arterial thrombosis in nephrotic syndrome. Am J Kidney Dis 1990; 15(2):176-7. doi: 10.1016/s0272-6386(12) 80516-6. doi: 10.1016/s0272-6386(12) 80516-6 pmid: 609917
17.	Sasaki Y, Raita Y, Uehara G , et al. Carotid thromboembolism associated with nephrotic syndrome treated with dabigatran. Case Rep Nephrol Urol 2014; 4(1):42-52. doi: 10.1159/000362162. doi: 10.1159/000362162 pmid: 24803917
18.	Singhal R, Brimble KS . Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management. Thromb Res 2006; 118(3):397-407. doi: 10.1016/j.thromres.2005.03.030. doi: 10.1016/j.thromres.2005.03.030 pmid: 15990160
19.	Li SJ, Guo JZ, Zuo K , et al. Thromboembolic complications in membranous nephropathy patients with nephrotic syndrome-a prospective study. Thromb Res 2012; 130(3):501-5. doi: 10.1016/j.thromres.2012.04.015. doi: 10.1016/j.thromres.2012.04.015 pmid: 22633211
20.	Lionaki S, Derebail VK, Hogan SL , et al. Venous thromboembolism in patients with membranous nephropathy. Clin J Am Soc Nephrol 2012; 7(1):43-51. doi: 10.2215/CJN.04250511. doi: 10.2215/CJN.04250511 pmid: 22076873
21.	Llach F . Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int 1985; 28(3):429-39. doi: 10.1038/ki.1985.149. doi: 10.1038/ki.1985.149 pmid: 3906225
22.	Bellomo R, Atkins RC . Membranous nephropathy and thromboembolism: is prophylactic anticoagulation warranted? Nephron 1993; 63(3):249-54. doi: 10.1159/000187205. doi: 10.1159/000187205 pmid: 8446259
23.	Ponticelli C, Glassock RJ . Glomerular diseases: membranous nephropathy-a modern view. Clin J Am Soc Nephrol 2014; 9(3):609-16. doi: 10.2215/CJN.04160413. doi: 10.2215/CJN.04160413

	ATEs (n=71)	VTEs (n=53)	Pvalue
Sex, n (%)			0.84
Male	44(62.0)	34(64.2)
Female	27(38.0)	19(35.8)
Age, year	57.0±11.9	49.6±14.8	0.003
History of
Smoking, n(%)	31 (43.7)	15 (28.3)	0.08
Hypertension, n (%)	46 (64.8)	26 (49.1)	0.08
Diabetes, n(%)	16 (22.5)	14 (26.4)	0.62
Prior ATE, n(%)	4 (5.6)	2 (3.8)	0.63
Observation time, month	43.2 (5.4, 145.1)	43.6 (21.5, 62.0)	0.41
Proteinuria, g/24 h	6.38 (3.79, 10.16)	7.30 (4.88, 10.54)	0.15
Serum albumin, g/L	26.7±6.3	25.8±6.6	0.45
eGFR, ml/min/1.73 m²	88.65±22.27	97.22±18.86	0.03
Total cholesterol, mmol/L	7.98±2.42	8.87±2.84	0.11
Triglycerides, mmol/L	2.43 (1.81, 3.60)	3.32 (1.96, 4.71)	0.10
LDL-C, mmol/L	5.41±2.19	5.63±2.48	0.68
NS, n (%)	49 (69.0)	38 (71.7)	0.75

Characteristics	ATEs (n=58)				VTEs (n=56)				P value^?
Characteristics	Mean/ Median	Early onset (n=27)	Delayed onset (n=31)	P value*	Mean/ Median	Early onset (n=48)	Delayed onset (n=8)	P value*	P value^?
Age, year	59.0±11.4	59.4±11.8	58.7±11.2	0.81	50.0±15.4	49.0±16.0	56.4±9.5	0.21	0.001
Proteinuria, g/24 h	3.5(1.05, 7.12)	4.5(2.0, 6.7)	2.8(0.7, 7.8)	0.33	6.2(4.5, 9.6)	6.2(4.5, 9.8)	6.7(4.4, 9.2)	0.76	0.002
Serum albumin, g/L	29.8±8.0	26.8±7.6	32.4±7.5	0.01	25.1±7.7	25.1±8.1	25.1±5.8	1.00	0.002
eGFR, ml/min/ 1.73m²	84.2±22.1	87.5±20.8	81.6±23.1	0.35	94.8±22.3	96.6±21.4	84.0±26.3	0.14	0.02
Total cholesterol, mmol/L	7.4(5.1, 8.9)	7.8(6.5, 8.9)	6.1(4.9, 9.3)	0.11	8.0(6.3, 9.3)	8.4±2.7	7.9±1.4	0.66	0.21
Triglycerides, mmol/L	2.1(1.7, 3.0)	2.1(1.7, 4.3)	2.6(1.1, 2.9)	0.75	3.4(1.9, 4.4)	3.4(2.0, 4.0)	1.9(1.6, 4.8)	0.63	0.04
LDL-C, mmol/L	4.3(2.7, 6.5)	5.5(2.7, 6.7)	3.8(2.6, 6.4)	0.27	4.5(3.4, 7.0)	4.5(3.3, 7.2)	4.51(3.45, -)	0.87	0.54
NS, n (%)									< 0.001
NS status	24 (42.1)	16 (59.3)	8 (26.7)	0.01	44 (81.5)	38 (79.2)	6 (75.0)	N/A
Sub-NS	22 (38.6)	10 (37.0)	12 (38.7)		8 (14.8)	8 (16.7)	0 (0.0)
CR	11 (19.3)	1 (3.7)	10 (35.5)		2 (3.7)	2 (4.2)	0 (0.0)

Variables	n	ATE			VTE
Variables	n	HR	95% CI	Pvalue	HR	95% CI	P value
Sex, male	449	1.2	0.8-2.0	0.39	1.6	0.8-2.4	0.29
Age, years	766			< 0.001			0.35
<35	167	1.0	reference		1.0	reference
35-54	323	5.1	1.2-21.7		0.8	0.4-1.7
≥55	276	13.0	3.1-53.3		1.3	0.6-2.6
History of	766
Smoking	228	1.7	1.0-2.7	0.03	0.9	0.5-1.7	0.81
Hypertension	360	1.8	1.1-3.0	0.02	0.9	0.5-1.6	0.77
Diabetes	90	1.5	0.8-2.8	0.24	1.3	0.6-2.9	0.44
ATE	35	2.4	1.1-5.2	0.03	0.8	0.2-3.4	0.79
Proteinuria, g/24 h	712			0.04			0.03
<3.5	191	1.0	reference		1.0	reference
3.5-8.0	313	1.3	0.7-2.7		3.6	1.3-10.5
>8.0	208	2.2	1.1-4.4		4.3	1.5-12.8
Serum albumin, g/L	710			0.64			0.01
<20	73	1.6	0.6-4.4		5.5	1.5-19.9
20-35	198	1.4	0.6-3.0		2.3	0.7-7.6
≥35	246	1.0	reference		1.0	reference
eGFR, ml/min/1.73 m²	760			0.10			0.27
≥90	517	1.0	reference		1.0	reference
60-89	195	1.4	0.8-2.4		1.4	0.8-2.5
<60	48	2.2	1.0-4.8		0.3	0.1-2.4
Total cholesterol, mmol/L	543			0.97			0.14
<5.18	43	1.0	reference		1.0	reference
5.18-7.76	240	0.9	0.3-2.4		2.4	0.3-18.3
>7.76	260	0.9	0.3-2.3		4.1	0.6-30.5

ATE				VTE
Variables	HR	95% CI	Pvalue	Variables	HR	95% CI	Pvalue
History of				Serum albumin, g/L			0.03
Smoker	1.4	0.8-2.4	0.19	<20	3.2	0.8-12.5
ATE	1.6	0.7-3.5	0.28	20-35	1.3	0.4-4.5
Hypertension	1.1	0.6-1.8	0.84	≥35	1.0	reference
Age, years			0.001
<35	1.0	reference
35-54	4.4	1.0-19.1
≥55	9.2	2.2-39.5
Proteinuria, g/24 h			0.11	Proteinuria, g/24 h			0.13
<3.5	1.0	reference		<3.5	1.0	reference
3.5-8.0	1.1	0.6-2.3		3.5-8.0	3.0	1.0-8.9
>8.0	1.9	0.9-3.8		>8.0	3.2	1.0-10.1

[1]	廖中华, 冯俊涛, 唐家乐, 罗丽颖, 李晓照. 1例严重肺及下肢血管栓塞并轻微肾损害的髓过氧化物酶阳性的抗中性粒细胞胞浆抗体相关性血管炎：病例报告[J]. Chinese Medical Sciences Journal, 2021, 36(4): 342-345.
[2]	李慧利, 林陪双, 姚允泰. 海德综合征与主动脉瓣置换术：已发表文献回顾[J]. Chinese Medical Sciences Journal, 2021, 36(4): 307-315.
[3]	王轶, 张竹花, 连伟. 垂体瘤切除术后突发感音神经性聋—病例系列报告及文献复习[J]. Chinese Medical Sciences Journal, 2021, 36(2): 120-126.
[4]	王维嘉, 申乐, 拉巴次仁, 李晗歌, 张越伦, 黄宇光. 西藏地区麻醉医师职业耗竭现状及相关因素分析[J]. Chinese Medical Sciences Journal, 2021, 36(2): 97-102.
[5]	祖红林,侯骊坤,刘洪伟,詹渊博,何菊. 应用BITOLA系统筛选腹主动脉瘤与2型糖尿病相互作用的候选基因[J]. Chinese Medical Sciences Journal, 2021, 36(1): 50-56.
[6]	尹俊雄, 余诚, 魏丽霞, 余传勇, 刘红星, 杜明洋, 孙丰, 王崇骏, 王小姗. 基于机器学习的脑卒中高危人群无症状性颈动脉狭窄的检测研究[J]. Chinese Medical Sciences Journal, 2020, 35(4): 297-305.
[7]	章旭,吉磊,陈梦寅,王威,郑月宏. 腹主动脉瘤腔内隔绝术后经动脉栓塞与经腰栓塞治疗Ⅱ型内漏效果对比的meta分析[J]. Chinese Medical Sciences Journal, 2020, 35(2): 135-141.
[8]	张兴华, 李涛, 杨立, 金鑫, 吴坚, 常瑞萍, 张晶. 主动脉壁内血肿CT血管成像形态学特征与C反应蛋白的相关性研究[J]. Chinese Medical Sciences Journal, 2019, 34(4): 241-247.
[9]	陈强, 张丽伟, 黄党生, 张春红, 王秋霜, 沈东, 熊敏俊, 杨菲菲. 冠状动脉疾病合并糖尿病患者经StentBoost技术指导的经皮冠状动脉介入治疗后5年的随访分析[J]. Chinese Medical Sciences Journal, 2019, 34(3): 177-183.
[10]	黄河, 林颖, 姚荣欣, 何牧卿, 林晓骥. 静脉丙种球蛋白联合血小板输注、利伐沙班治疗肝素诱导的危重血小板减少症1例[J]. Chinese Medical Sciences Journal, 2019, 34(1): 60-64.
[11]	陈伟健, 乔宏宇, 方桂婷, 钟兴. 1例可能由按摩引起的椎动脉夹层[J]. Chinese Medical Sciences Journal, 2019, 34(1): 65-68.
[12]	马瑾, 陈婷, 王一玮, 赵潺, 李东辉, 王萌, 干霖洋, 钟勇. 纵向测量大鼠非动脉炎性前部缺血性视神经病变模型中后部视乳头血流变化的研究[J]. Chinese Medical Sciences Journal, 2018, 33(4): 252-259.
[13]	张雪芳,张震宇,李楠. 一例妊娠早期合并脑静脉窦血栓女性成功中期引产的报道[J]. Chinese Medical Sciences Journal, 2018, 33(4): 267-271.
[14]	张宏民, 王小亭, 张青, 刘大为. 应用“目标与目的”方案进行脓毒症患者的复苏：来自一个中国三级甲等医院ICU的回顾性研究[J]. Chinese Medical Sciences Journal, 2018, 33(3): 135-142.
[15]	李涛, 杨立, 张卫国, 罗春才, 黄自立, 李金锋, 李欣. 6 4层多排CT对冠状动脉旁路移植术后的中期随访：影响桥血管通畅性的危险因素研究[J]. Chinese Medical Sciences Journal, 2018, 33(2): 69-76.

优先出版

当期目次

过刊浏览

虚拟专题

作者中心

评阅者中心