血脂蛋白磷脂酶A2和中性粒细胞明胶酶相关脂质运载蛋白在诊断早期糖尿病肾病中的价值

doi:10.3969/j.issn.1674-8115.2021.06.011

摘要/Abstract

摘要：

目的·探讨血脂蛋白磷脂酶A2（lipoprotein phospholipase A2，Lp-PLA2）和中性粒细胞明胶酶相关脂质运载蛋白（neutrophil gelatinase-associated lipocalin，NGAL）在诊断早期糖尿病肾病（diabetic nephropathy，DN）中的价值。方法·选取2017年1月—2019年4月在泰州市人民医院内分泌科确诊的2型糖尿病患者219例，检测所有患者Lp-PLA2、NGAL、尿白蛋白排泄率（urinary albumin excretion rate，UAER）、尿素氮（blood urea nitrogen，BUN）、血肌酐（serum creatinine，SCr）、尿酸（uric acid， UA）、胱抑素C（cystatin C，Cys-C）、血糖、血脂等水平。按UAER将患者分为3组：正常白蛋白尿（normal albuminuria，NA）组75例，微量白蛋白尿（microalbuminuria，MA）组73例，大量白蛋白尿（heavy albuminuria，HA）组71例。将MA组和HA组归为DN组。比较NA组、MA组和HA组间上述指标的差异，采用Pearson线性相关、多元线性回归、二元Logistic回归及受试者操作特征（receiver operator characteristic，ROC）曲线分析Lp-PLA2、NGAL与DN的关系。结果·与NA组和MA组相比，HA组的Lp-PLA2、NGAL、BUN、SCr、UA、Cys-C的水平均明显升高（均P<0.05）；但与NA组相比，MA组中仅Lp-PLA2和NGAL的水平明显升高（均P<0.05）。相关性分析发现，Lp-PLA2、NGAL水平与UAER（r=0.397，r=0.511）、BUN（r=0.274，r=0.411）、SCr（r=0.237，r=0.419）、Cys-C（r=0.278，r=0.436）均呈正相关（均P=0.000），与肾小球滤过率呈负相关（r=-0.170，r=-0.366；P=0.013，P=0.000）。多元线性回归分析表明，UAER的影响因素为Lp-PLA2、NGAL和Cys-C。二元Logistic回归分析显示，经血压、血脂、糖尿病病程、糖化血红蛋白校正后，Lp-PLA2和NGAL仍是DN的独立风险因子（OR=1.012，OR=1.024；P=0.009，P=0.000）。Lp-PLA2、NGAL及两者联合检测DN的ROC曲线下面积（area under the curve，AUC）依次为0.700、0.855、0.871；单项检测时NGAL的敏感度（81.2%）和特异度（80.0%）均较高，Lp-PLA2和NGAL联合检测时诊断效能最大（AUC=0.871）。结论·血Lp-PLA2和NGAL水平均与DN患者肾脏损害程度密切相关；二者作为DN的独立风险因子在早期DN时已明显升高，相比传统肾脏功能指标能更好地反映早期DN的出现。Lp-PLA2和NGAL联合检测可发挥其最大诊断效能，为早期DN的诊断提供新的方法。

关键词: 脂蛋白磷脂酶A2, 中性粒细胞明胶酶相关脂质运载蛋白, 糖尿病肾病, 2型糖尿病, 尿白蛋白排泄率

Abstract:

Objective·To examine the role of blood lipoprotein phospholipase A2 (Lp-PLA2) and neutrophil gelatinase-associated lipocalin (NGAL) in the diagnosis of early diabetic nephropathy (DN).

Methods·A total of 219 participants with type 2 diabetes mellitus diagnosed in the Department of Endocrinology of Taizhou People's Hospital from January 2017 to April 2019 were enrolled. The levels of Lp-PLA2, NGAL, urinary albumin excretion rate (UAER), blood urea nitrogen (BUN), serum creatinine (Scr), uric acid (UA), cystatin C (Cys-C), blood glucose, and blood lipid in all participants were detected. All diabetics were classified into three groups based on UAER: normal albuminuria (NA) group (n=75), microalbuminuria (MA) group (n=73) and heavy albuminuria (HA) group (n=71). The MA group and HA group were classified as DN group.The differences of the above indicators among each group were compared, and the relationship of Lp-PLA2, NGAL and DN were analyzed by Pearson linear correlation, multiple linear regression, Logistic regression and receiver operator characteristic curve.

Results·Compared with the NA group and MA group, the levels of Lp-PLA2, NGAL, BUN, SCr, UA and Cys-C in the HA group were significantly increased (P<0.05). However, compared with the NA group, only Lp-PLA2 and NGAL levels in the MA group were significantly increased (P<0.05). Correlation analysis found the Lp-PLA2 and NGAL were positively correlated with UAER (r=0.397, r=0.511), BUN (r=0.274, r=0.411), SCr (r=0.237, r=0.419), and Cys-C (r=0.278, r=0.436) (all P=0.000), whereas negatively correlated with the estimate glomerular filtration rate (r=-0.170, r=-0.366; P=0.013, P=0.000). Multiple linear regression analysis showed that Lp-PLA2, NGAL and Cys-C were related factors of UAER. Binary Logistic regression analysis found that Lp-PLA2 and NGAL were still risk factors of kidney injury in DN after adjustment for blood pressure, lipids, glycosylated hemoglobin and duration of diabetes (OR=1.012, OR=1.024; P=0.009, P=0.000). The area under the curve (AUC) of Lp-PLA2, NGAL and their combination in diagnosis of DN were 0.700, 0.855 and 0.871. NGAL demonstrated high sensitivity (81.2%) and specificity (80.0%). Lp-PLA2- and NGAL-combined detection had the highest diagnostic efficiency (AUC=0.871).

Conclusion·Both blood Lp-PLA2 and NGAL levels are closely associated with the renal damage in participants with DN. As independent risk factors of DN, Lp-PLA2 and NGAL have been highly expressed in early DN, which could better reflect the occurrence of early DN, compared with traditional renal function indicators. Lp-PLA2- and NGAL-combined detection could demonstrate its maximum diagnostic efficacy, providing a new method for the diagnosis of early renal injury.

Key words: lipoprotein phospholipase A2, neutrophil gelatinase-associated lipocalin, diabetic nephropathy, type 2 diabetes mellitus, urinary albumin excretion rate

中图分类号:

R587.2

张佳思, 邹春波, 卢宇, 陈茜, 张伟亚, 何姣姣. 血脂蛋白磷脂酶A2和中性粒细胞明胶酶相关脂质运载蛋白在诊断早期糖尿病肾病中的价值[J]. 上海交通大学学报(医学版), 2021, 41(6): 770-775.

Jia-si ZHANG, Chun-bo ZOU, Yu LU, Xi CHEN, Wei-ya ZHANG, Jiao-jiao HE. Value of blood lipoprotein phospholipase A2 and neutrophil gelatinase-associated lipocalin in the diagnosis of early diabetic nephropathy[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(6): 770-775.

图/表 6

参考文献 22

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Index	NA group (n=75)	MA group (n=73)	HA group (n=71)	χ2 value	F value	P value
Gender (male/female)/n	43/32	42/31	41/30	0.003	-	0.999
Age/year	57.67±8.40	57.56±12.49	57.87±11.55	-	0.015	0.985
Duration of diabetes/year	5 (2, 10)	7 (3, 10)	10 (5, 16) ^③⑧	16.961	-	0.000
BMI/(kg·m^-2)	24.97±3.59	24.61±3.13	26.07±3.88^⑨	-	3.270	0.040
Waist circumference/cm	91.90±8.77	92.47±9.20	95.65±9.84^⑤	-	3.066	0.049
Hip circumference/cm	98.07±8.59	97.68±6.55	100.12±6.59	-	2.014	0.136
SBP/mmHg	134.17±17.28	139.19±19.96	147.86±22.71^③⑩	-	8.656	0.000
DBP/mmHg	82.91±9.44	84.90±12.87	85.32±11.19	-	0.974	0.379
DR/n(%)	12 (16.00)	22 (30.14)^①	28 (39.44)^⑥	10.051	-	0.007
GLU/(mmoL·L^-1)	7.45±2.21	8.49±2.91^②	8.95±3.42^⑥	-	5.236	0.006
Fructosamine/(μmoL·L^-1)	331.88±83.84	346.15±72.06	337.71±83.66	-	0.539	0.584
HbA1c/%	8.78±2.58	9.50±2.05	9.72±2.21^⑦	-	3.383	0.036
TC/(mmoL·L^-1)	4.49±1.14	4.59±1.32	4.53±1.26	-	0.142	0.867
TAG/(mmoL·L^-1)	1.43±0.70	2.26±1.14^③	2.21±1.07^③	-	16.394	0.000
HDL-C/(mmoL·L^-1)	2.77±1.03	2.49±0.86	2.16±0.96^③?	-	7.124	0.001
LDL-C/(mmoL·L^-1)	1.00±0.34	1.14±0.37	2.29±1.11^③?	-	73.132	0.000
UAER/(μg·min^-1)	6.20±3.00	57.74±23.21^③	673.96±375.31^③?	-	217.929	0.000
BUN/(mmol·L^-1)	5.25±1.55	5.60±1.27	7.87±2.91^③?	-	35.476	0.000
SCr/(μmol·L^-1)	58.13±14.43	63.82±21.18	93.64±36.28^③?	-	40.461	0.000
eGFR/[mL·(min·1.73 m²)^-1]	134.02 (114.41, 156.13)	126.40 (96.64, 153.57)	77.38 (54.95, 119.94) ^③?	44.094	-	0.000
UA/(μmoL·L^-1)	303.59±75.58	307.37±68.20	373.73±108.57^③?	-	15.244	0.000
Cys-C/(mg·L^-1)	0.94±0.20	1.03±0.29	1.81±0.77^③?	-	66.390	0.000
Lp-PLA2/(μg·mL^-1)	120.20±48.71	140.47±53.46^④	197.07±73.64^③?	-	31.641	0.000
NGAL/(ng·mL^-1)	51.09±30.64	83.37±38.19^③	166.40±70.58^③?	-	105.382	0.000

Index	NA group (n=75)	MA group (n=73)	HA group (n=71)	χ2 value	F value	P value
Gender (male/female)/n	43/32	42/31	41/30	0.003	-	0.999
Age/year	57.67±8.40	57.56±12.49	57.87±11.55	-	0.015	0.985
Duration of diabetes/year	5 (2, 10)	7 (3, 10)	10 (5, 16) ^③⑧	16.961	-	0.000
BMI/(kg·m^-2)	24.97±3.59	24.61±3.13	26.07±3.88^⑨	-	3.270	0.040
Waist circumference/cm	91.90±8.77	92.47±9.20	95.65±9.84^⑤	-	3.066	0.049
Hip circumference/cm	98.07±8.59	97.68±6.55	100.12±6.59	-	2.014	0.136
SBP/mmHg	134.17±17.28	139.19±19.96	147.86±22.71^③⑩	-	8.656	0.000
DBP/mmHg	82.91±9.44	84.90±12.87	85.32±11.19	-	0.974	0.379
DR/n(%)	12 (16.00)	22 (30.14)^①	28 (39.44)^⑥	10.051	-	0.007
GLU/(mmoL·L^-1)	7.45±2.21	8.49±2.91^②	8.95±3.42^⑥	-	5.236	0.006
Fructosamine/(μmoL·L^-1)	331.88±83.84	346.15±72.06	337.71±83.66	-	0.539	0.584
HbA1c/%	8.78±2.58	9.50±2.05	9.72±2.21^⑦	-	3.383	0.036
TC/(mmoL·L^-1)	4.49±1.14	4.59±1.32	4.53±1.26	-	0.142	0.867
TAG/(mmoL·L^-1)	1.43±0.70	2.26±1.14^③	2.21±1.07^③	-	16.394	0.000
HDL-C/(mmoL·L^-1)	2.77±1.03	2.49±0.86	2.16±0.96^③?	-	7.124	0.001
LDL-C/(mmoL·L^-1)	1.00±0.34	1.14±0.37	2.29±1.11^③?	-	73.132	0.000
UAER/(μg·min^-1)	6.20±3.00	57.74±23.21^③	673.96±375.31^③?	-	217.929	0.000
BUN/(mmol·L^-1)	5.25±1.55	5.60±1.27	7.87±2.91^③?	-	35.476	0.000
SCr/(μmol·L^-1)	58.13±14.43	63.82±21.18	93.64±36.28^③?	-	40.461	0.000
eGFR/[mL·(min·1.73 m²)^-1]	134.02 (114.41, 156.13)	126.40 (96.64, 153.57)	77.38 (54.95, 119.94) ^③?	44.094	-	0.000
UA/(μmoL·L^-1)	303.59±75.58	307.37±68.20	373.73±108.57^③?	-	15.244	0.000
Cys-C/(mg·L^-1)	0.94±0.20	1.03±0.29	1.81±0.77^③?	-	66.390	0.000
Lp-PLA2/(μg·mL^-1)	120.20±48.71	140.47±53.46^④	197.07±73.64^③?	-	31.641	0.000
NGAL/(ng·mL^-1)	51.09±30.64	83.37±38.19^③	166.40±70.58^③?	-	105.382	0.000

Index	Non-standardized coefficient		Standardized coefficient	t value	P value	95%CI of β
Index	β	SE	Standardized coefficient	t value	P value	95%CI of β
Constant	-0.207	0.425	-	-0.487	0.627	-1.046?0.632
Lp-PLA2	0.002	0.001	0.186	3.439	0.001	0.001?0.004
NGAL	0.005	0.001	0.431	7.494	0.000	0.004?0.006
Cys-C	0.347	0.077	0.260	4.486	0.000	0.194?0.499

Index	Non-standardized coefficient		Standardized coefficient	t value	P value	95%CI of β
Index	β	SE	Standardized coefficient	t value	P value	95%CI of β
Constant	-0.207	0.425	-	-0.487	0.627	-1.046?0.632
Lp-PLA2	0.002	0.001	0.186	3.439	0.001	0.001?0.004
NGAL	0.005	0.001	0.431	7.494	0.000	0.004?0.006
Cys-C	0.347	0.077	0.260	4.486	0.000	0.194?0.499

Index	β	SE	Wald χ² value	P value	OR	95%CI
Model 1
Lp-PLA2	0.012	0.004	8.059	0.005	1.012	1.004?1.020
NGAL	0.027	0.006	20.774	0.000	1.028	1.016?1.040
Model 2
Lp-PLA2	0.012	0.004	7.988	0.005	1.012	1.004?1.021
NGAL	0.024	0.006	14.332	0.000	1.024	1.012?1.037
Model 3
Lp-PLA2	0.013	0.005	8.102	0.004	1.013	1.004?1.022
NGAL	0.024	0.006	14.226	0.000	1.024	1.012?1.037
Model 4
Lp-PLA2	0.012	0.005	6.737	0.009	1.012	1.003?1.021
NGAL	0.023	0.007	12.782	0.000	1.024	1.011?1.037