Independent prognostic value of lipocalin-2 in congenital heart disease-associated pulmonary artery hypertension

Table 1 Baseline characteristics of the nonpulmonary arterial hypertension and pulmonary arterial hypertension patients

Variables	Total number	nonPAH	PAH	P value
Number	69	18	51	-
Sex, number of males	69	7 (38.9)	21 (41.2)	0.866
Age in months	69	8.5 (5.4, 12.0)	11.0 (7.0,19.0)	0.094
BMI	68	15.4 (13.8, 17.4)	15.1 (14.1, 16.6)	0.451
Creatinine in μmol/L	68	21.8 (18.0, 26.5)	27.8 (24.3, 33.6)	< 0.001
BUN in mmol/L	68	3.0 (2.1, 3.7)	4.2 (2.8, 5.1)	0.015
Albumin in g/L	67	42.6 (39.6, 43.7)	43.5 (41.4, 45.3)	0.243
Glucose in mmol/L	65	4.6 (4.1, 5.0)	4.1 (3.8, 4.4)	0.036
Hemoglobin in g/L	69	116 (101, 123)	118 (108, 128)	0.448
Platelets as 109/L	69	276 (247, 314)	267 (221, 344)	0.995
White blood cells as 109/L	46	8.3 (5.7, 9.7)	8.7 (7.5, 11.0)	0.140
SBP in mmHg	66	93.0 (84.5, 95.0)	95.0 (86.5, 101.5)	0.144
DBP in mmHg	66	55.0 (48.5, 60.0)	55.0 (45.0, 60.0)	0.860
EF as %	67	65.0 (62.0, 66.3)	65.0 (65.0, 69.5)	0.072
Diameter in mm	66	10.0 (7.5, 13.0)	10.0 (8.0, 14.8)	0.219
mPAP in mmHg	69	17.7 (16.7, 18.8)	29.4 (24.6, 40.1)	< 0.001
LCN2 in ng/mL	69	19.3 (16.9, 27.6)	33.4 (23.9, 46.3)	< 0.001
ET1 in μg/mL	69	0.14 (0.07, 0.31)	0.30 (0.10, 0.72)	0.049

Data are n (%). Sex is expressed as a proportion; continuous variables are expressed as median (Q1, Q3). Diameter means the diameter of the defect, which was measured during surgery. BMI: Body mass index; BUN: Blood urea nitrogen; DBP: Diastolic blood pressure; EF: Ejection fraction; ET-1: Endothelin-1; LCN2: Lipocalin-2; mPAP: Mean pulmonary artery pressure; PAH: Pulmonary arterial hypertension; SBP: Systolic blood pressure.

Table 2 Correlations of mean pulmonary artery pressure, lipocalin-2 and endothelin-1 with clinical variables

Variables	mPAP		LCN2		ET-1
	r	P value	r	P value	r	P value
Sex	0.087	0.475	0.031	0.800	-0.115	0.347
Age in months	0.298	0.013	0.319	0.008	0.048	0.698
BMI	-0.089	0.483	-0.128	0.310	-0.248	0.046
Creatinine in μmol/L	0.389	0.001	0.094	0.446	-0.156	0.205
BUN in mmol/L	0.328	0.006	-0.040	0.747	-0.070	0.568
Albumin in g/L	0.066	0.594	-0.072	0.563	-0.238	0.052
Glucose in mmol/L	-0.174	0.166	0.021	0.869	-0.004	0.973
Hemoglobin in g/L	0.217	0.074	0.080	0.514	-0.173	0.156
Platelets as 109/L	0.007	0.958	-0.128	0.293	-0.098	0.422
White blood cells as 109/L	0.345	0.019	0.291	0.050	0.107	0.480
SBP in mmHg	0.135	0.280	0.074	0.554	0.033	0.795
DBP in mmHg	0.097	0.438	0.106	0.399	0.003	0.983
EF as %	-0.107	0.388	-0.176	0.155	-0.021	0.864
Diameter in mm	0.371	0.002	0.081	0.516	0.230	0.063
mPAP in mmHg	-	-	0.544	< 0.001	0.508	< 0.001
LCN2 in ng/mL	0.544	< 0.001	-	-	0.427	< 0.001
ET1 in μg/mL	0.508	< 0.001	0.427	< 0.001	-	-

BMI: Body mass index; BUN: Blood urea nitrogen; DBP: Diastolic blood pressure; EF: Ejection fraction; ET-1: Endothelin-1; LCN2: Lipocalin-2; mPAP: Mean pulmonary artery pressure; SBP: Systolic blood pressure.

Table 3 Multivariate logistic regression analysis to define the correlation between lipocalin-2 and renal function in ventricular septal defect patients

Variables	Creatinine1			BUN1
	OR	95%CI	P value	OR	95%CI	P value
Age in months	1.077	1.006-1.153	0.034	1.117	1.010-1.235	0.031
BMI	1.226	0.913-1.648	0.175	-	-	-
Albumin in g/L	1.089	0.901-1.315	0.378	1.016	0.837-1.232	0.875
Glucose in mmol/L	-	-	-	0.635	0.294-1.371	0.248
Hemoglobin in g/L	-	-	-	1.042	0.992-1.094	0.102
mPAP in mmHg	1.065	0.992-1.142	0.082	1.086	1.008-1.170	0.030
LCN2 in ng/mL	0.962	0.914-1.014	0.147	0.972	0.922-1.025	0.294

¹Variable was binarized based on its median value.

BMI: Body mass index; BUN: Blood urea nitrogen; LCN2: Lipocalin-2; mPAP: Mean pulmonary artery pressure; OR: Odds ratio.

Table 4 Univariate logistic regression analysis to determine the related factors of pulmonary arterial hypertension and lipocalin-2

Variables	Correlation with PAH			Correlation with LCN21
	OR	95%CI	P value	OR	95%CI	P value
Sex, males	1.1	0.366-3.303	0.865	1.212	0.463 ± 3.172	0.696
Age in months	1.05	0.985-1.119	0.137	1.050	1.002 ± 1.101	0.043
BMI	0.868	0.669-1.127	0.289	0.859	0.676 ± 1.091	0.213
Creatinine in μmol/L	1.204	1.066-1.359	0.003	1.021	0.952 ± 1.094	0.566
BUN in mmol/L	1.684	1.089-2.606	0.019	0.967	0.711 ± 1.316	0.832
Albumin in g/L	1.114	0.942-1.317	0.205	1.050	0.930 ± 1.186	0.432
Glucose in mmol/L	0.648	0.346-1.213	0.175	0.763	0.431 ± 1.350	0.353
Hemoglobin in g/L	1.017	0.982-1.053	0.345	1.006	0.977 ± 1.036	0.686
Platelets as 109/L	1	0.995-1.006	0.887	0.999	0.995 ± 1.004	0.841
White blood cells as 109/L	1.259	0.960-1.651	0.096	1.111	0.908 ± 1.361	0.306
SBP in mmHg	1.036	0.984-1.091	0.176	1.018	0.977 ± 1.060	0.401
DBP in mmHg	0.998	0.955-1.044	0.944	1.027	0.983 ± 1.073	0.239
EF as %	1.099	0.966-1.250	0.152	0.932	0.834 ± 1.040	0.207
Diameter in mm	1.106	0.944-1.296	0.211	1.011	0.883 ± 1.157	0.877
mPAP in mmHg	-	-	-	1.084	1.026 ± 1.145	0.004
LCN2 in ng/mL	1.107	1.033-1.185	0.004	-	-	-
ET-1 in μg/mL	10.028	0.896-112.196	0.061	2.101	0.887 ± 4.979	0.092

¹Variable was binarized based on its median value.

BMI: Body mass index; BUN: Blood urea nitrogen; DBP: Diastolic blood pressure; EF: Ejection fraction; ET-1: Endothelin-1; LCN2: Lipocalin-2; mPAP: Mean pulmonary artery pressure; OR: Odds ratio; PAH: Pulmonary arterial hypertension; SBP: Systolic blood pressure.

Table 5 Multivariate logistic regression analysis to define the correlation between endothelin-1 concentration and risk for pulmonary arterial hypertension

Variables	OR (95%CI)	P value
Age in months	0.994 (0.914-1.081)	0.889
Creatinine in μmol/L	1.232 (1.056-1.436)	0.008
Diameter in mm	0.984 (0.811-1.195)	0.871
ET-1 in μg/mL	9.681 (0.650-144.192)	0.099

ET-1: Endothelin-1; OR: Odds ratio.

Table 6 Predictive values of lipocalin-2 and endothelin-1 for pulmonary arterial hypertension

	AUC	Youden’s index	Sensitivity, %	Specificity, %	Cutoff value
LCN2	0.783	0.4575	90.19	55.56	19.42 ng/mL
ET-1	0.657	0.3954	45.10	94.44	0.39 μg/mL

AUC: Area under the receiver operating characteristic curve; ET-1: Endothelin-1; LCN2: Lipocalin-2.

Table 7 Correlations of post-repair mean pulmonary artery pressure with clinical variables, n = 23

Variables	Post-operative mPAP		mPAP decrease
	r	P value	r	P value
Sex, male	0.404	0.056	0.303	0.161
Age in months	0.347	0.105	0.434	0.039
BMI	-0.141	0.531	-0.050	0.826
Creatinine in μmol/L	-0.150	0.493	0.248	0.255
BUN in mmol/L	0.236	0.278	0.411	0.052
Albumin in g/L	0.313	0.156	0.029	0.897
Glucose in mmol/L	-0.045	0.849	-0.057	0.813
Hemoglobin in g/L	0.223	0.306	0.163	0.458
Platelets as 109/L	-0.066	0.764	0.107	0.628
White blood cells as 109/L	0.186	0.507	0.623	0.013
SBP in mmHg	0.094	0.677	0.043	0.848
DBP in mmHg	0.361	0.099	0.185	0.410
EF as %	-0.311	0.148	-0.037	0.867
Diameter in mm	0.398	0.060	0.552	0.006
Pre-repair mPAP in mmHg	0.471	0.023	0.883	< 0.001
LCN2 in ng/mL	0.532	0.009	0.181	0.407
ET-1 in μg/mL	0.140	0.523	0.298	0.167

BMI: Body mass index; BUN: Blood urea nitrogen; DBP: Diastolic blood pressure; EF: Ejection fraction; ET-1: Endothelin-1; mPAP: Mean pulmonary artery pressure; SBP: Systolic blood pressure; LCN2: Lipocalin-2.