Serum levels of ET-1 and SDC-1 in children with nephrotic syndrome and their correlation with hormone therapy response

doi:10.11958/20221637

Abstract

Abstract:

Objective To investigate the correlation between serum levels of endothelin-1 (ET-1) and polyligand proteoglynan-1 (SDC-1) with the responsiveness to hormone therapy in children with nephrotic syndrome (NS). Methods A total of 157 children with NS who were expected to receive hormone therapy and 67 healthy children matching the age and sex with NS at the same time were selected (the control group). Clinical data were collected and serum levels of ET-1, SDC-1, 24 h urine protein, urea nitrogen (BUN), serum creatinine (Scr) and other laboratory indexes were detected. According to the response to hormone therapy, NS children were divided into the hormone resistant nephrotic syndrome (SRNS) group (31 cases) and the hormone sensitive nephrotic syndrome (SSNS) group (126 cases). Factors influencing the resistance of NS children to hormone therapy were analyzed by Logistic regression, and the differential diagnositic value of ET-1 and SDC-1 to SRNS and SSNS were analyzed by receiver operating characteristic curve (ROC). Results The levels of body weight, BUN, Scr, 24 h urine protein, ET-1 and SDC-1 were increased successively in the control group, the SSNS group and the SRNS group, while the serum albumin was decreased successively (P<0.05). Serum ET-1 and SDC-1 levels of all the subjects were positively correlated with BUN, Scr and 24 h urinary protein, and negatively correlated with serum albumin level (P<0.05). Multivariate Logistic regression analysis showed that the increased ET-1 and SDC-1 were risk factors for the resistance of NS children to hormone therapy (P<0.05). ROC analysis results showed that the area under the curve for the identification of SRNS and SSNS combined with ET-1 and SDC-1 was 0.943, which was higher than ET-1 and SDC-1 (Z=3.959, 4.364, P<0.05). Conclusion Serum ET-1 and SDC-1 levels are significantly increased in children with SRNS, which are related to renal function injury and resistance to steroid therapy, and can be used as potential indicators for the differential diagnosis of SRNS.

Key words: nephrotic syndrome, hormones, drug tolerance, endothelin-1, syndecan-1

CLC Number:

R692

Figures/Tables 6

References 21

[1]	阳海平, 池欢, 李秋. 儿童激素耐药型肾病综合征治疗进展[J]. 中华实用儿科临床杂志, 2021, 36(17):1290-1295.
	YANG H P, CHI H, LI Q. Treatment progress of pediatric steroid-resistant nephrotic syndrome[J]. Chin J Appl Clin Pediatr, 2021, 36(17):1290-1295. doi:10.3760/cma.j.cn101070-20210716-00834.
[2]	KAMEI K, ISHIKURA K, SAKO M, et al. Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children[J]. Pediatr Nephrol, 2020, 35(1):17-24. doi:10.1007/s00467-018-4166-1.
[3]	LI P, SCHMIDT I M, SABBISETTI V, et al. Plasma endothelin-1 and risk of death and hospitalization in patients undergoing maintenance hemodialysis[J]. Clin J Am Soc Nephrol, 2020, 15(6):784-793. doi:10.2215/CJN.11130919.
[4]	KUSUZAWA K, SUZUKI K, OKADA H, et al. Measuring the concentration of serum syndecan-1 to assess vascular endothelial glycocalyx injury during hemodialysis[J]. Front Med(Lausanne), 2021, 8:791309. doi:10.3389/fmed.2021.791309.
[5]	CHEN X, GENG X, JIN S, et al. The association of syndecan-1,hypercoagulable state and thrombosis and in patients with nephrotic syndrome[J]. Clin Appl Thromb Hemost, 2021, 27:10760296211010256. doi:10.1177/10760296211010256.
[6]	中华医学会儿科学分会肾脏学组. 儿童激素敏感、复发/依赖肾病综合征诊治循证指南(2016)[J]. 中华儿科杂志, 2017, 55(10):729-734.
	Nephrology Group, Pediatrics Society of Chinese Medical Association. Evidence-based guidelines for diagnosis and treatment of hormone-sensitive,relapsed/dependent nephrotic syndrome in children(2016)[J]. Chin J Pediatr, 2017, 55(10):729-734. doi:10.3760/cma.j.issn.0578-1310.2017.10.003.
[7]	中华医学会儿科学分会肾脏学组. 激素耐药型肾病综合征诊治循证指南(2016)[J]. 中华儿科杂志, 2017, 55(11):805-809.
	Nephrology Group, Pediatrics Society of Chinese Medical Association. Evidence-based guidelines for the diagnosis and treatment of hormone resistant nephrotic syndrome(2016)[J]. Chin J Pediatr, 2017, 55(11):805-809. doi:10.3760/cma.j.issn.0578-1310.2017.11.002.
[8]	RUSLIE R H, DARMADI D, SIREGAR G A. Vascular endothelial growth factor(VEGF)and neopterin levels in children with steroid-sensitive and steroid-resistant nephrotic syndrome[J]. Med Arch, 2021, 75(2):133-137. doi:10.5455/medarh.2021.75.133-137.
[9]	DAEHN I S, DUFFIELD J S. The glomerular filtration barrier:A structural target for novel kidney therapies[J]. Nat Rev Drug Discov, 2021, 20(10):770-788. doi:10.1038/s41573-021-00242-0.
[10]	VAN DE LEST N A, BAKKER A E, DIJKSTRA K L, et al. Endothelial endothelin receptor a expression is associated with podocyte injury and oxidative stress in patients with focal segmental glomerulosclerosis[J]. Kidney Int Rep, 2021, 6(7):1939-1948. doi:10.1016/j.ekir.2021.04.013.
[11]	JONES N K, STEWART K, CZOPEK A, et al. Endothelin-1 mediates the systemic and renal hemodynamic effects of GPR81 activation[J]. Hypertension, 2020, 75(5):1213-1222. doi:10.1161/HYPERTENSIONAHA.119.14308.
[12]	KINO J, TSUJI S, KITAO T, et al. Antiproteinuric effect of an endothelin-1 receptor antagonist in puromycin aminonucleoside-induced nephrosis in rat[J]. Pediatr Res, 2018, 83(5):1041-1048. doi:10.1038/pr.2018.11.
[13]	YAHIA S, HAMMAD A, EL-GILANY A H, et al. Genetic variant in the 5' untranslated region of endothelin1(EDN1)gene in children with primary nephrotic syndrome[J]. J Biochem Mol Toxicol, 2022, 36(3):e22963. doi:10.1002/jbt.22963.
[14]	RIZK H, HAMMAD A, EL-SAID A, et al. Endothelin-1 RS5370 gene polymorphism in primary nephrotic syndrome:A case-control study[J]. An Pediatr (Engl Ed), 2021, 95(6):406-412. doi:10.1016/j.anpede.2020.12.001.
[15]	DAEHN I, CASALENA G, ZHANG T, et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis[J]. J Clin Invest, 2014, 124(4):1608-1621. doi:10.1172/JCI71195.
[16]	GARSEN M, LENOIR O, ROPS A L, et al. Endothelin-1 induces proteinuria by heparanase-mediated disruption of the glomerular glycocalyx[J]. J Am Soc Nephrol, 2016, 27(12):3545-3551. doi:10.1681/ASN.2015091070.
[17]	RANGARAJAN S, RICHTER J R, RICHTER R P, et al. Heparanase-enhanced shedding of syndecan-1 and its role in driving disease pathogenesis and progression[J]. J Histochem Cytochem, 2020, 68(12):823-840. doi:10.1369/0022155420937087.
[18]	KIM H B, SOH S, KWAK Y L, et al. High preoperative serum syndecan-1,a marker of endothelial glycocalyx degradation,and severe acute kidney injury after valvular heart surgery[J]. J Clin Med, 2020, 9(6):1803. doi:10.3390/jcm9061803.
[19]	HAHN R G, ZDOLSEK M, ZDOLSEK J. Plasma concentrations of syndecan-1 are dependent on kidney function[J]. Acta Anaesthesiol Scand, 2021, 65(6):809-815. doi:10.1111/aas.13801.
[20]	PADBERG J S, WIESINGER A, DI MARCO G S, et al. Damage of the endothelial glycocalyx in chronic kidney disease[J]. Atherosclerosis, 2014, 234(2):335-343. doi:10.1016/j.atherosclerosis.2014.03.016.
[21]	SALMITO F T, DE OLIVEIRA NEVES F M, MENESES G C, et al. Glycocalyx injury in adults with nephrotic syndrome:Association with endothelial function[J]. Clin Chim Acta, 2015, 447:55-58. doi:10.1016/j.cca.2015.05.013.

组别	n		年龄（岁）	男性		体质量（kg）		身高（cm）	收缩压（mmHg）	舒张压（mmHg）		病理类型
组别	n		年龄（岁）	男性		体质量（kg）		身高（cm）	收缩压（mmHg）	舒张压（mmHg）		微小病变	系膜增生性肾小球肾炎		局灶节段性肾小球硬化		膜增生性肾小球肾炎
对照组	67		7.09±1.36	42（62.69）		20.03±3.67		116.65±21.35	108.03±10.24	64.11±5.85
SSNS组	126		7.16±1.42	81（64.29）		28.45±4.19^a		119.42±26.72	108.11±12.51	64.32±6.03		91（72.22）	18（14.29）		15（11.90）		2（1.59）
SRNS组	31		9.02±2.11^ab	19（61.29）		32.15±5.49^ab		126.24±34.09^ab	109.35±13.42	65.42±6.28		23（74.19）	4（12.90）		3（9.68）		1（3.23）
F或χ²			12.410^**	0.222		142.095^**		7.443^**	2.202	0.559		0.504
组别			NS病程（d）		激素疗程（月）		镜下血尿		双肾增大或弥漫性病变			TC（mmol/L）			TG（mmol/L）		BUN（mmol/L）
对照组												4.16±0.58			1.42±0.23		3.24±0.41
SSNS组			7.24±2.01		2.01±0.36		15（11.90）		38（30.16）			5.69±0.69^a			1.51±0.26		7.32±1.52^a
SRNS组			14.52±3.26		3.95±0.71		18（58.06）		20（64.52）			5.72±0.75^a			2.18±0.32^ab		9.62±2.39^ab
F、t或χ²			17.470^**		18.460^**		31.932^**		12.607^**			136.890^**			123.632^**		273.784^**
组别		Scr（μmol/L）				血钠（mmol/L）		血钾（mmol/L）		24 h尿蛋白（g）	血白蛋白（g/L）			ET-1（ng/L）		SDC-1（μg/L）
对照组		65.46±7.08				141.35±6.03		3.51±0.24		0.12±0.02	40.01±5.32			16.35±3.65		5.32±1.63
SSNS组		116.59±10.15^a				142.45±6.82		3.53±0.21		3.35±0.22^a	23.12±1.35^a			62.12±16.84^a		21.35±8.67^a
SRNS组		123.35±29.32^ab				142.02±6.95		3.56±0.25		4.12±0.35^ab	20.23±2.42^ab			95.42±20.35^ab		35.12±10.42^ab
F		464.564^**				0.605		1.222		5 263.429^**	856.700^**			316.638^**		164.165^**

组别	n		年龄（岁）	男性		体质量（kg）		身高（cm）	收缩压（mmHg）	舒张压（mmHg）		病理类型
组别	n		年龄（岁）	男性		体质量（kg）		身高（cm）	收缩压（mmHg）	舒张压（mmHg）		微小病变	系膜增生性肾小球肾炎		局灶节段性肾小球硬化		膜增生性肾小球肾炎
对照组	67		7.09±1.36	42（62.69）		20.03±3.67		116.65±21.35	108.03±10.24	64.11±5.85
SSNS组	126		7.16±1.42	81（64.29）		28.45±4.19^a		119.42±26.72	108.11±12.51	64.32±6.03		91（72.22）	18（14.29）		15（11.90）		2（1.59）
SRNS组	31		9.02±2.11^ab	19（61.29）		32.15±5.49^ab		126.24±34.09^ab	109.35±13.42	65.42±6.28		23（74.19）	4（12.90）		3（9.68）		1（3.23）
F或χ²			12.410^**	0.222		142.095^**		7.443^**	2.202	0.559		0.504
组别			NS病程（d）		激素疗程（月）		镜下血尿		双肾增大或弥漫性病变			TC（mmol/L）			TG（mmol/L）		BUN（mmol/L）
对照组												4.16±0.58			1.42±0.23		3.24±0.41
SSNS组			7.24±2.01		2.01±0.36		15（11.90）		38（30.16）			5.69±0.69^a			1.51±0.26		7.32±1.52^a
SRNS组			14.52±3.26		3.95±0.71		18（58.06）		20（64.52）			5.72±0.75^a			2.18±0.32^ab		9.62±2.39^ab
F、t或χ²			17.470^**		18.460^**		31.932^**		12.607^**			136.890^**			123.632^**		273.784^**
组别		Scr（μmol/L）				血钠（mmol/L）		血钾（mmol/L）		24 h尿蛋白（g）	血白蛋白（g/L）			ET-1（ng/L）		SDC-1（μg/L）
对照组		65.46±7.08				141.35±6.03		3.51±0.24		0.12±0.02	40.01±5.32			16.35±3.65		5.32±1.63
SSNS组		116.59±10.15^a				142.45±6.82		3.53±0.21		3.35±0.22^a	23.12±1.35^a			62.12±16.84^a		21.35±8.67^a
SRNS组		123.35±29.32^ab				142.02±6.95		3.56±0.25		4.12±0.35^ab	20.23±2.42^ab			95.42±20.35^ab		35.12±10.42^ab
F		464.564^**				0.605		1.222		5 263.429^**	856.700^**			316.638^**		164.165^**

指标	ET-1		SDC-1
指标	r	P	r	P
TC	0.026	0.109	0.036	0.652
TG	0.109	0.153	0.085	0.209
BUN	0.482	<0.001	0.401	<0.001
Scr	0.536	<0.001	0.493	<0.001
血钠	0.103	0.165	0.058	0.415
血钾	0.069	0.351	0.071	0.254
血白蛋白	-0.513	<0.001	-0.485	<0.001
24 h尿蛋白	0.585	<0.001	0.503	<0.001

指标	ET-1		SDC-1
指标	r	P	r	P
TC	0.026	0.109	0.036	0.652
TG	0.109	0.153	0.085	0.209
BUN	0.482	<0.001	0.401	<0.001
Scr	0.536	<0.001	0.493	<0.001
血钠	0.103	0.165	0.058	0.415
血钾	0.069	0.351	0.071	0.254
血白蛋白	-0.513	<0.001	-0.485	<0.001
24 h尿蛋白	0.585	<0.001	0.503	<0.001

因素	β	SE	Wald χ²	OR（95%CI）	P
年龄	-0.055	0.084	0.423	0.947（0.802~1.117）	0.515
体质量	0.162	0.153	1.121	1.176（0.871~1.587）	0.393
TC	0.027	0.133	0.041	1.027（0.791~1.334）	0.839
尿蛋白	0.023	0.087	0.072	1.024（0.863~1.214）	0.788
BUN	0.024	0.049	0.229	1.024（0.930~1.128）	0.632
Scr	0.105	0.098	1.148	1.111（0.917~1.346）	0.979
血白蛋白	-0.008	0.016	0.222	0.992（0.961~1.024）	0.637
NS病程	0.132	0.125	1.115	1.141（0.893~1.458）	0.711
激素疗程	0.129	0.197	0.426	1.137（0.773~1.675）	0.514
双肾增大或弥漫性病变	0.195	0.182	1.148	1.215（0.851~1.736）	0.746
镜下血尿	0.682	0.201	11.513	1.978（1.334~2.933）	<0.001
ET-1	0.533	0.198	7.246	1.704（1.156~2.512）	<0.001
SDC-1	0.402	0.177	5.158	1.495（1.057~2.115）	<0.001