Value of blood lipoprotein phospholipase A2 and neutrophil gelatinase-associated lipocalin in the diagnosis of early diabetic nephropathy

doi:10.3969/j.issn.1674-8115.2021.06.011

Abstract

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

CLC Number:

R587.2

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.

Figures/Tables 6

TrendMD

References 22

1	Wang Y, Zheng ZJ, Jia YJ, et al. Role of p53/miR-155-5p/sirt1 loop in renal tubular injury of diabetic kidney disease[J]. J Transl Med, 2018, 16(1): 146.
2	Thethi TK, Batuman V. Challenging the conventional wisdom on diabetic nephropathy: is microalbuminuria the earliest event?[J]. J Diabetes Complications, 2019, 33(3): 191-192.
3	Ling Y, Tang SX, Cao YH, et al. Relationship between plasma lipoprotein-associated phospholipase A2 concentrations and apolipoprotein in stable coronary artery disease patients[J]. Dis Markers, 2020, 2020: 8818358.
4	Younus A, Humayun C, Ahmad R, et al. Lipoprotein-associated phospholipase A2 and its relationship with markers of subclinical cardiovascular disease: a systematic review[J]. J Clin Lipidol, 2017, 11(2): 328-337.
5	Jourde-Chiche N, Fakhouri F, Dou L, et al. Endothelium structure and function in kidney health and disease[J]. Nat Rev Nephrol, 2019, 15(2): 87-108.
6	Ahmad T, Jackson K, Rao VS, et al. Worsening renal function in patients with acute heart failure undergoing aggressive diuresis is not associated with tubular injury[J]. Circulation, 2018, 137(19): 2016-2028.
7	Kim SY, Jeong TD, Lee W, et al. Plasma neutrophil gelatinase-associated lipocalin as a marker of tubular damage in diabetic nephropathy[J]. Ann Lab Med, 2018, 38(6): 524-529.
8	Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation[J]. Diabet Med, 1998, 15(7): 539-553.
9	顾乡, 方向华. 三种GFR计算公式在中老年人群中心血管事件预测价值的比较[J]. 中国中西医结合肾病杂志, 2018, 19(11): 974-978.
10	Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018[J]. Am J Kidney Dis, 2018, 71(6): 884-895.
11	Hosny SS, Bekhet MM, Hebah HA, et al. Urinary neutrophil gelatinase-associated lipocalin in type 2 diabetes: relation to nephropathy and retinopathy[J]. Diabetes Metab Syndr, 2018, 12(6): 1019-1024.
12	Perkins BA, Ficociello LH, Roshan B, et al. In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria[J]. Kidney Int, 2010, 77(1): 57-64.
13	Santoso A, Heriansyah T, Rohman MS. Phospholipase A2 is an inflammatory predictor in cardiovascular diseases: is there any spacious room to prove the causation?[J]. Curr Cardiol Rev, 2020, 16(1): 3-10.
14	Huang F, Wang K, Shen J. Lipoprotein-associated phospholipase A2: the story continues[J]. Med Res Rev, 2020, 40(1): 79-134.
15	Zhang H, Gao Y, Wu D, et al. The relationship of lipoprotein-associated phospholipase A2 activity with the seriousness of coronary artery disease[J]. BMC Cardiovasc Disord, 2020, 20(1): 295.
16	Svarovskaya AV, Teplyakov AT, Gusakova AM, et al. Role of markers of inflammation and endothelial dysfunction in the prognosis of the development of cardiovascular complications in patients with coronary artery disease and metabolic syndrome after coronary stenting[J]. Kardiologiia, 2020, 60(8): 98-105.
17	Canning P, Kenny BA, Prise V, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes[J]. Proc Natl Acad Sci USA, 2016, 113(26): 7213-7218.
18	Abbasi F, Moosaie F, Khaloo P, et al. Neutrophil gelatinase-associated lipocalin and retinol-binding protein-4 as biomarkers for diabetic kidney disease[J]. Kidney Blood Press Res, 2020, 45(2): 222-232.
19	Beker BM, Corleto MG, Fieiras C, et al. Novel acute kidney injury biomarkers: their characteristics, utility and concerns[J]. Int Urol Nephrol, 2018, 50(4): 705-713.
20	Satirapoj B. Tubulointerstitial biomarkers for diabetic nephropathy[J]. J Diabetes Res, 2018, 2018: 2852398.
21	Eguchi K, Izumi Y, Nakayama Y, et al. Insufficiency of urinary acid excretion of overweight or obese patients with chronic kidney disease and its involvement with renal tubular injury[J]. Nephrology (Carlton), 2019, 24(11): 1131-1141.
22	张会芬, 杨宏秀, 刘丽, 等. 血清中性粒细胞明胶酶相关脂质运载蛋白、胱抑素C及尿白蛋白肌酐比值、N-乙酰-β-D-氨基葡萄糖苷酶检测在早期糖尿病肾脏疾病中的应用价值[J]. 中国糖尿病杂志, 2018, 26(4): 309-315.

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