尿转铁蛋白与2型糖尿病人群新发心血管疾病的关系

doi:10.3969/j.issn.1004-583X.2024.08.004

摘要/Abstract

摘要：

目的探索2型糖尿病(type 2 diabetes mellitus,T2DM)人群尿转铁蛋白与尿肌酐比值(uTRF/Cr)和新发心血管疾病(cardiovascular disease,CVD)的关系。方法选择参加开滦第6次健康体检且进行尿转铁蛋白及尿肌酐检测的T2DM患者8 163例。依据基线uTRF/Cr水平将患者按三分位数分为3组,第一分位组2 721例,第二分位组2 721例;第三分位组2 721例。采用多因素Cox回归模型分析uTRF/Cr对CVD发病风险的影响。结果 ①研究人群基线年龄(60.46±9.96)岁,男性占78.30%,基线uTRF/Cr为0.24(0.16~0.47) mg/mmol。②中位随访时间为3.85(3.43~4.22)年,共发生CVD事件411例(6.79%),第一、二、三分位组总CVD事件的累计发病率分别为3.81%、4.65%和7.29%。③校正相关影响因素后,第二、三分位组总CVD事件的风险分别是第一分位组的1.12(95%CI:0.86~1.46)倍和1.52(95%CI:1.18~1.97)倍。结论 uTRF/Cr升高是T2DM 人群CVD的独立危险因素,在出现大量白蛋白尿之前,CVD的发病风险也随着uTRF/Cr升高而增加。

关键词: 糖尿病, 2型, 心血管疾病, 尿转铁蛋白与尿肌酐比值, 蛋白尿

Abstract:

Objective To explore the correlation between urinary transferrin to urinary creatinine ratio (uTRF/Cr) and new onset cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). Methods A total of 8 163 T2DM patients who participated in the 6th health examination in Kailuan and underwent urinary transferrin and urinary creatinine detection were recruited. Subjects were divided into the first group (n=2 721), the second group (n=2 721), and the third group (n=2 721) based on baseline uTRF/Cr. The effects of uTRF/Cr on the risk of CVD were analyzed by multivariate Cox regression model. Results The baseline age of the study population was (60.46±9.96) years, with 78.30% of males, and 0.24(0.16-0.47) mg/mmol of baseline uTRF/Cr. The median follow-up time was 3.85(3.43-4.22) years, with 411(6.79%) of CVD events occurred. The cumulative incidence of total CVD events in the first, second and third groups was 3.81%, 4.65%, and 7.29%, respectively. After adjusting for relevant influencing factors, the risk of total CVD events in the second and third groups of uTRF/Cr was 1.12(95%CI 0.86-1.46) times and 1.52(95%CI 1.18-1.97) times that in the first group, respectively. Conclusion Increased uTRF/Cr is an independent risk factor for CVD in T2DM populations, and the risk of CVD increases with increased uTRF/Cr, even before the onset of macroalbuminuria.

Key words: diabetes mellitus, type 2, cardiovascular diseases, transferrin to urinary creatinine ratio, proteinuria

中图分类号:

R587.1
R54

马剑楠, 陶杰, 桑大森, 吴寿岭, 张旗. 尿转铁蛋白与2型糖尿病人群新发心血管疾病的关系[J]. 临床荟萃, 2024, 39(8): 700-705.

Ma Jiannan, Tao Jie, Sang Dasen, Wu Shouling, Zhang Qi. Association of urinary transferrin with new-onset cardiovascular disease in type 2 diabetes mellitus[J]. Clinical Focus, 2024, 39(8): 700-705.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2024.08.004

https://huicui.hebmu.edu.cn/CN/Y2024/V39/I8/700

图/表 6

表1 3组基线资料比较

Tab.1 Baseline data among the three groups

组别		例数	年龄(岁)		男性 [例(%)]		收缩压 (mmHg)			舒张压 (mmHg)			心率 (次/min)		BMI (kg/m²)
总人群		8 163	60.46±9.96		6 392(78.30)		146.08±20.60			82.92±10.91			77.47± 12.82		25.80±3.47
第一分位组		2 721	58.77±9.93		2 326(85.48)		141.77±19.34			82.07±10.48			58.77±9.93		25.73±3.34
第二分位组		2 721	60.68±9.66		2 063(75.78)		145.42±20.22			82.43±10.57			76.83±12.48		25.64±3.38
第三分位组		2 721	61.92±10.03		2 003(73.65)		151.03±21.15			84.26±11.52			79.06±13.14		26.04±3.66
$F$ / $H$ /χ²值			24.650		24.660		34.987			14.435			49.789		13.897
$P$ 值			<0.001		<0.001		<0.001			<0.001			<0.001		<0.001
组别	uACR (mg/mmol)			uTRF/Cr (mg/mmol)				FBG (mmol/L)		HbA₁c (%)		TG (mmol/L)				LDL-C (mmol/L)
总人群	1.67(0.81~4.50)			0.24(0.16~0.47)				9.11±3.17		7.59±1.66		1.54(1.05~2.34)				3.25±0.96
第一分位组	0.98(0.65~1.54)			0.13(0.11~0.16)				8.38±2.60		7.20±1.44		1.44(1.01~2.16)				3.22±0.94
第二分位组	1.50(0.79~2.71)			0.24(0.21~0.29)				8.82±2.93		7.47±1.59		1.49(1.01~2.28)				3.22±0.93
第三分位组	7.46(3.10~20.00)			0.70(0.47~1.48)				10.12±3.67		8.11±1.81		1.70(1.15~2.63)				3.32±1.01
$F$ / $H$ /χ²值	87.580			33.890				25.340		37.990		1.479				39.380
$P$ 值	<0.001			<0.001				<0.001		<0.001		0.207				<0.001
组别	eGFR [ml/(min·1.73 m²)]					吸烟 [例(%)]			高血压 [例(%)]		降压治疗 [例(%)]			降糖治疗 [例(%)]
总人群	92.20±16.34					2 707(33.16)			4 647(56.93)		3 361(41.17)			3 590(43.98)
第一分位组	93.28±16.62					1 042(38.29)			1 371(50.39)		1 073(39.43)			1 033(37.96)
第二分位组	92.56±14.43					872(32.05)			1 509(55.46)		1 068(39.25)			1 166(42.85)
第三分位组	90.74±17.69					793(29.14)			1 767(64.94)		1 220(44.84)			1 391(51.12)
$F$ / $H$ /χ²值	7.890					20.776			28.980		14.768			29.987
$P$ 值	<0.001					<0.001			<0.001		<0.001			<0.001

表1 3组基线资料比较

Tab.1 Baseline data among the three groups

组别		例数	年龄(岁)		男性 [例(%)]		收缩压 (mmHg)			舒张压 (mmHg)			心率 (次/min)		BMI (kg/m²)
总人群		8 163	60.46±9.96		6 392(78.30)		146.08±20.60			82.92±10.91			77.47± 12.82		25.80±3.47
第一分位组		2 721	58.77±9.93		2 326(85.48)		141.77±19.34			82.07±10.48			58.77±9.93		25.73±3.34
第二分位组		2 721	60.68±9.66		2 063(75.78)		145.42±20.22			82.43±10.57			76.83±12.48		25.64±3.38
第三分位组		2 721	61.92±10.03		2 003(73.65)		151.03±21.15			84.26±11.52			79.06±13.14		26.04±3.66
$F$ / $H$ /χ²值			24.650		24.660		34.987			14.435			49.789		13.897
$P$ 值			<0.001		<0.001		<0.001			<0.001			<0.001		<0.001
组别	uACR (mg/mmol)			uTRF/Cr (mg/mmol)				FBG (mmol/L)		HbA₁c (%)		TG (mmol/L)				LDL-C (mmol/L)
总人群	1.67(0.81~4.50)			0.24(0.16~0.47)				9.11±3.17		7.59±1.66		1.54(1.05~2.34)				3.25±0.96
第一分位组	0.98(0.65~1.54)			0.13(0.11~0.16)				8.38±2.60		7.20±1.44		1.44(1.01~2.16)				3.22±0.94
第二分位组	1.50(0.79~2.71)			0.24(0.21~0.29)				8.82±2.93		7.47±1.59		1.49(1.01~2.28)				3.22±0.93
第三分位组	7.46(3.10~20.00)			0.70(0.47~1.48)				10.12±3.67		8.11±1.81		1.70(1.15~2.63)				3.32±1.01
$F$ / $H$ /χ²值	87.580			33.890				25.340		37.990		1.479				39.380
$P$ 值	<0.001			<0.001				<0.001		<0.001		0.207				<0.001
组别	eGFR [ml/(min·1.73 m²)]					吸烟 [例(%)]			高血压 [例(%)]		降压治疗 [例(%)]			降糖治疗 [例(%)]
总人群	92.20±16.34					2 707(33.16)			4 647(56.93)		3 361(41.17)			3 590(43.98)
第一分位组	93.28±16.62					1 042(38.29)			1 371(50.39)		1 073(39.43)			1 033(37.96)
第二分位组	92.56±14.43					872(32.05)			1 509(55.46)		1 068(39.25)			1 166(42.85)
第三分位组	90.74±17.69					793(29.14)			1 767(64.94)		1 220(44.84)			1 391(51.12)
$F$ / $H$ /χ²值	7.890					20.776			28.980		14.768			29.987
$P$ 值	<0.001					<0.001			<0.001		<0.001			<0.001

图1 3组CVD事件累积发病率

Fig.1 Cumulative incidence rate of CVD events in the three groups

表2 uTRF/Cr与新发CVD的多因素COX回归模型

Tab.2 Multivariate COX regression model for uTRF/Cr and newly occurred CVD

变量	回归系数	标准误	Wald χ²值	$H R$ 值	95% $C I$	$P$ 值
分组
第一分位组	-	-	-	1	-	-
第二分位组	0.112	0.137	0.673	1.12	0.86~1.46	0.412
第三分位组	0.418	0.131	10.250	1.52	1.18~1.97	0.001
年龄	0.030	0.007	20.356	1.03	1.02~1.04	<0.001
性别(男)	0.125	0.138	0.815	1.13	0.86~1.49	0.367
收缩压	0.011	0.002	19.904	1.01	1.01~1.02	<0.001
BMI	-0.013	0.015	0.775	0.99	0.96~1.02	0.379
LDL-C	0.023	0.052	0.192	1.02	0.92~1.13	0.661
FBG	0.061	0.014	18.959	1.06	1.03~1.09	<0.001
eGFR	0.001	0.004	0.165	1.00	0.99~1.01	0.685
吸烟	0.283	0.113	6.291	1.33	1.06~1.66	0.012
使用降压药	0.354	0.100	12.470	1.42	1.17~1.73	<0.001
使用降糖药	0.029	0.103	0.078	1.03	0.84~1.26	0.779

表2 uTRF/Cr与新发CVD的多因素COX回归模型

Tab.2 Multivariate COX regression model for uTRF/Cr and newly occurred CVD

变量	回归系数	标准误	Wald χ²值	$H R$ 值	95% $C I$	$P$ 值
分组
第一分位组	-	-	-	1	-	-
第二分位组	0.112	0.137	0.673	1.12	0.86~1.46	0.412
第三分位组	0.418	0.131	10.250	1.52	1.18~1.97	0.001
年龄	0.030	0.007	20.356	1.03	1.02~1.04	<0.001
性别(男)	0.125	0.138	0.815	1.13	0.86~1.49	0.367
收缩压	0.011	0.002	19.904	1.01	1.01~1.02	<0.001
BMI	-0.013	0.015	0.775	0.99	0.96~1.02	0.379
LDL-C	0.023	0.052	0.192	1.02	0.92~1.13	0.661
FBG	0.061	0.014	18.959	1.06	1.03~1.09	<0.001
eGFR	0.001	0.004	0.165	1.00	0.99~1.01	0.685
吸烟	0.283	0.113	6.291	1.33	1.06~1.66	0.012
使用降压药	0.354	0.100	12.470	1.42	1.17~1.73	<0.001
使用降糖药	0.029	0.103	0.078	1.03	0.84~1.26	0.779

图2 uTRF/Cr与新发CVD的关系

Fig.2 Correlation between uTRF/Cr and newly occurred CVD

图3 uTRF/Cr与新发CVD关系的亚组分析

Fig.3 Subgroup analysis of the correlation between uTRF/Cr and newly occurred CVD

表3 校正相关因素并排除大量白蛋白尿人群后uTRF/Cr与新发CVD的多因素COX回归模型

Tab.3 Multivariate Cox regression model for the correlation between uTRF/Cr and newly occurred CVD after adjusting for relevant factors and excluding a large population of albuminuria

变量	回归系数	标准误	Wald χ²值	$H R$ 值	95% $C I$	$P$ 值
分组
第一分位组	-	-	-	1	-	-
第二分位组	0.033	0.142	0.053	1.03	0.78~1.37	0.818
第三分位组	0.294	0.137	4.643	1.34	1.03~1.76	0.031
年龄	0.029	0.007	15.946	1.03	1.02~1.04	<0.001
性别(男)	0.109	0.150	0.525	1.12	0.83~1.50	0.367
收缩压	0.010	0.003	13.539	1.01	1.01~1.02	<0.001
BMI	-0.020	0.016	1.422	0.98	0.95~1.01	0.223
LDL-C	0.013	0.057	0.054	1.01	0.91~1.13	0.817
FBG	0.056	0.016	12.592	1.06	1.03~1.09	<0.001
eGFR	0.002	0.004	0.323	1.00	0.99~1.01	0.570
吸烟	0.317	0.120	6.926	1.37	1.08~1.740	0.009
使用降压药	0.309	0.108	8.231	1.36	1.10~1.68	0.004
使用降糖药	0.081	0.111	0.530	1.08	0.87~1.35	0.467

表3 校正相关因素并排除大量白蛋白尿人群后uTRF/Cr与新发CVD的多因素COX回归模型

Tab.3 Multivariate Cox regression model for the correlation between uTRF/Cr and newly occurred CVD after adjusting for relevant factors and excluding a large population of albuminuria

变量	回归系数	标准误	Wald χ²值	$H R$ 值	95% $C I$	$P$ 值
分组
第一分位组	-	-	-	1	-	-
第二分位组	0.033	0.142	0.053	1.03	0.78~1.37	0.818
第三分位组	0.294	0.137	4.643	1.34	1.03~1.76	0.031
年龄	0.029	0.007	15.946	1.03	1.02~1.04	<0.001
性别(男)	0.109	0.150	0.525	1.12	0.83~1.50	0.367
收缩压	0.010	0.003	13.539	1.01	1.01~1.02	<0.001
BMI	-0.020	0.016	1.422	0.98	0.95~1.01	0.223
LDL-C	0.013	0.057	0.054	1.01	0.91~1.13	0.817
FBG	0.056	0.016	12.592	1.06	1.03~1.09	<0.001
eGFR	0.002	0.004	0.323	1.00	0.99~1.01	0.570
吸烟	0.317	0.120	6.926	1.37	1.08~1.740	0.009
使用降压药	0.309	0.108	8.231	1.36	1.10~1.68	0.004
使用降糖药	0.081	0.111	0.530	1.08	0.87~1.35	0.467

参考文献 22

[1]	Gregory A, Degu A, Kalkidan H, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet, 2018, 392(10159): 1736-1788. doi: S0140-6736(18)32203-7 pmid: 30496103
[2]	Roth G, Mensah G, Johnson C, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 study[J]. J Am Coll Cardiol, 2020, 76(25): 2982-3021. doi: 10.1016/j.jacc.2020.11.010 pmid: 33309175
[3]	Wang H, Zhang H, Zou Z. Changing profiles of cardiovascular disease and risk factors in China: A secondary analysis for the Global Burden of Disease Study 2019[J]. Chin Med J(Engl), 2023, 136(20): 2431-2441.
[4]	中国心血管健康与疾病报告编写组. 《中国心血管健康与疾病报告2022》概要[J]. 中国介入心脏病学杂志, 2023, 31(7): 485-508.
[5]	Christine G, Bødtker M, Johnny K, et al. 10-year cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus[J]. J Am Coll Cardiol, 2023, 82(16): 1583-1594.
[6]	Wang Y, Neil A, Jiao Y, et al. Sex differences in the association between diabetes and risk of cardiovascular disease, cancer, and all-cause and cause-specific mortality: A systematic review and meta-analysis of 5,162,654 participants[J]. BMC Medicine, 2019, 17(1): 1-18.
[7]	An Y, Zhang P, Wang P, et al. Cardiovascular and all-cause mortality over a 23-year period among Chinese with newly diagnosed diabetes in the Da Qing IGT and diabetes study[J]. Diabetes Care, 2015, 38(7): 1365-1371. doi: 10.2337/dc14-2498 pmid: 25887356
[8]	Festa A, Agostino R. Howard Gronic. Chronic subclinical inflammation as part of the insulin resistance syndrome: The Insulin Resistance Atherosclerosis Study(IRAS)[J]. Circulation, 2000, 102(1): 42-47. doi: 10.1161/01.cir.102.1.42 pmid: 10880413
[9]	Matsushita K, Coresh J, Sang Y, et al. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: A collaborative meta-analysis of individual participant data[J]. Lancet Diabetes Endocrinol, 2015, 3(7): 514-525.
[10]	Bernard A, Amor A, Goemaere-Vanneste J, et al. Microtransferrinuria is a more sensitive indicator of early glomerular damage in diabetes than microalbuminuria[J]. Clin Chem, 1988, 34(9):1920-1921. pmid: 3416456
[11]	Zou L, Wang X, Guo Z, et al. Differential urinary proteomics analysis of myocardial infarction using iTRAQ quantification[J]. Mol Med Rep, 2019, 19(5): 3972-3988. doi: 10.3892/mmr.2019.10088 pmid: 30942401
[12]	Wu S, Huang Z, Yang X, et al. Prevalence of ideal cardiovascular health and its relationship with the 4-year cardiovascular events in a northern Chinese industrial city[J]. Circ Cardiovasc Qual Outcomes, 2012, 5(4): 487-493.
[13]	Association D. Standards of medical care in diabetes-2010[J]. Diabetes Care, 2010, 33 Suppl 1(S1):S11-61.
[14]	Inker L, Schmid C, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C[J]. N Engl J Med, 2012, 367(1):20-29.
[15]	Huang Z, Chen Z, Wang X, et al. Association of cardiovascular health score trajectory with incident myocardial infarction in hypertensive patients[J]. Hypertension, 2022, 79(11):2622-2630. doi: 10.1161/HYPERTENSIONAHA.122.19633 pmid: 36082672
[16]	Wu J, Chen S, Zhou Y, et al. Non-high-density lipoprotein cholesterol on the risks of stroke: A result from the Kailuan study[J]. PLoS One, 2013, 8(9): e74634.
[17]	Takuma N, Mihoko H, Masafumi K, et al. Increased urinary excretions of immunoglobulin G, ceruloplasmin, and transferrin predict development of microalbuminuria in patients with type 2 diabetes[J]. Diabetes Care, 2006, 29(1): 142-144. doi: 10.2337/diacare.29.1.142 pmid: 16373913
[18]	Tao J, Sang D, Zhang X, et al. An elevated urinary albumin-to-creatinine ratio increases the risk of incident cardia-cerebrovascular disease in individuals with type 2 diabetes[J]. Diabetol Metab Syndr, 2024, 16(1): 30. doi: 10.1186/s13098-024-01256-5 pmid: 38291519
[19]	Chen F, Yang W, Weng J, et al. Albuminuria: Prevalence, associated risk factors and relationship with cardiovascular disease[J]. J Diabetes Investig, 2014, 5(4): 464-471.
[20]	Juan J, Antonio J, Juan J, et al. Urine transferrin as an early endothelial dysfunction marker in type 2 diabetic patients without nephropathy: A case control study[J]. Diabetol Metab Syndr, 2021, 13(1): 128.
[21]	Rubler S, Dlugash J, Yuceoglu Y, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis[J]. Am J Cardiol, 1972, 30(6):595-602. doi: 10.1016/0002-9149(72)90595-4 pmid: 4263660
[22]	Fang Z, Prins J, Marwick T. Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications[J]. Endocr Rev, 2004, 25(4): 543-567. doi: 10.1210/er.2003-0012 pmid: 15294881