The correlation between C1q, MBL, C5a and the progression of type 2 diabetes nephropathy and tubular injury

doi:10.11958/20250671

Abstract

Abstract:

Objective To explore the clinical value of complement 1q (C1q), mannose-binding lectin (MBL) and complement 5a (C5a) in the early diagnosis and disease monitoring of diabetic kidney disease (DKD), as well as their relationship with renal tubular injury. Methods A total of 232 patients with type 2 diabetes mellitus admitted to the Endocrinology Department of Kailuan General Hospital from December 2020 to December 2021 were selected in this study. Patients were divided into the simple diabetes mellitus (SDM) group (n=50) and the DKD group (n=182) based on urinary albumin/creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The DKD group was further divided into the low-risk diabetic nephropathy (LDKD) group (n=90), the moderate-risk diabetic nephropathy (MDKD) group (n=55) and the high-risk diabetic nephropathy (HDKD) group (n=37) according to the risk of chronic kidney disease progression. Forty healthy individuals who underwent physical examinations in our hospital during the same period were selected as the healthy control group (NC group). The DKD group was divided into the Q1-Q4 groups based on the quartile levels of NAG/Ucr according to the severity of renal tubular injury from mild to severe. General biochemical indicators, as well as the levels of C1q, MBL and C5a in each group were detected. Spearman correlation analysis was used to analyze the correlation between C1q, MBL, C5a and glomerular and tubular injury indexes. Multivariate ordinal Logistic regression analysis was used to analyze the influencing factors of the progression risk of DKD and the degree of renal tubular injury. Results The levels of systolic blood pressure, diastolic blood pressure, triglycerides (TG), serum creatinine (Scr), uric acid (UA), UACR, NAG/Ucr, C1q, MBL and C5a were higher in the DKD group than those in the SDM group and the NC group. The levels of TC, LDL-C, ApoB and HbA1c were higher than those in the NC group, while the level of HDL-C was lower than that in the NC group. The levels of TC, LDL-C, HbA1c and NAG/Ucr were higher in the SDM group than those in the NC group, while the level of HDL-C was lower than that in the NC group (P<0.05). Among different progression risk groups of DKD, the levels of C1q were higher in the HDKD group than those in the SDM group and the LDKD group. The levels of MBL and C5a were higher in the MDKD group than those in the SDM group and the LDKD group, and the level of MBL was higher in the LDKD group than that in the SDM group (P<0.05). After grouping according to the quartile levels of NAG/Ucr, the levels of TC, ApoB, HbA1c, Scr, UACR, C1q and C5a were significantly higher in the Q4 group than those in the Q1 group. The levels of TC, ApoB, Scr, UACR, C1q and C5a were significantly higher than those in the Q2 group, and the levels of UACR and C5a were significantly higher than those in the Q3 group. The levels of HbA1c, Scr, UACR, C1q and C5a were significantly higher in the Q3 group than those in the Q1 group. The level of UACR was higher in the Q2 group than that in the Q1 group (all P<0.05). The Spearman correlation analysis showed that C1q, MBL and C5a were positively correlated with UACR and NAG/Ucr, and negatively correlated with eGFR (all P<0.05). The ordinal Logistic regression analysis showed that elevated levels of MBL, C5a, NAG/Ucr, Scr and systolic blood pressure were independent influencing factors of progression risk in DKD patients. Elevated levels of C5a, HbA1c and UACR were independent influencing factors of renal tubular injury in DKD patients. Conclusion C1q and C5a can be used to monitor middle and late DKD and tubular injury, and C5a is an independent risk factor for DKD progression and tubular injury. MBL can be used to screen for early DKD and is also an independent risk factor for its progression.

Key words: diabetes mellitus, type 2, diabetic nephropathies, complement C1q, complement pathway, mannose-binding lectin, complement C5a, renal tubules

CLC Number:

R587.2

Figures/Tables 5

References 27

[1]	中华医学会糖尿病学分会微血管并发症学组. 中国糖尿病肾脏病防治指南(2021年版)[J]. 中华糖尿病杂志, 2021, 13(8):762-784.
	Microvascular Complications Group of Chinese Diabetes Society. Clinical guideline for the prevention and treatment of diabetic kidney disease in China(2021 edition)[J]. Chinese Journal of Diabetes Mellitus, 2021, 13(8):762-784. doi:10.3760/cma.j.cn115791-20210706-00369.
[2]	BUDGE K, DELLEPIANE S, YU S M, et al. Complement,a therapeutic target in diabetic kidney disease[J]. Front Med(Lausanne), 2020,7:599236. doi:10.3389/fmed.2020.599236.
[3]	TAN S M, SNELSON M, ØSTERGAARD J A, et al. The complement pathway:New insights into immunometabolic signaling in diabetic kidney disease[J]. Antioxid Redox Signal, 2022, 37(10/11/12):781-801. doi:10.1089/ars.2021.0125.
[4]	TAMPE D, HAKROUSH S, TAMPE B. Molecular signatures of intrarenal complement receptors C3AR1 and C5AR1 correlate with renal outcome in human lupus nephritis[J]. Lupus Sci Med, 2022, 9(1):e000831. doi:10.1136/lupus-2022-000831.
[5]	TANG S, YIU W H. Innate immunity in diabetic kidney disease[J]. Nat Rev Nephrol, 2020, 16(4):206-222. doi:10.1038/s41581-019-0234-4.
[6]	JIAO Y, JIANG S, WANG Y, et al. Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy:Evidence from transcriptomic data and renal histopathology[J]. J Diabetes Investig, 2022, 13(5):839-849. doi:10.1111/jdi.13739.
[7]	WANG Y, ZHAO M, ZHANG Y. Identification of fibronectin 1(FN1)and complement component 3(C3)as immune infiltration-related biomarkers for diabetic nephropathy using integrated bioinformatic analysis[J]. Bioengineered, 2021, 12(1):5386-5401. doi:10.1080/21655979.2021.1960766.
[8]	VIVARELLI M, BARRATT J, BECKLH J R, et al. The role of complement in kidney disease:Conclusions from a kidney disease:Improving Global Outcomes (KDIGO)Controversies Conference[J]. Kidney Int, 2024, 106(3):369-391. doi:10.1016/j.kint.2024.05.015.
[9]	YAN X, ZHANG X, LI H, et al. Application of proteomics and machine learning methods to study the pathogenesis of diabetic nephropathy and screen urinary biomarkers[J]. J Proteome Res, 2024, 23(8):3612-3625. doi:10.1021/acs.jproteome.4c00267.
[10]	YANG Y, ZHANG Y, LI Y, et al. Complement classical and alternative pathway activation contributes to diabetic kidney disease progression:a glomerular proteomics on kidney biopsies[J]. Sci Rep, 2025, 15(1):495. doi:10.1038/s41598-024-84900-4.
[11]	中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版)(上)[J]. 中国实用内科杂志, 2021, 41(8):668-695.
	Chinese Diabetes Society. Guideline for the prevention and treatment of type 2 diabetes mellitus in China(2020 edition)(Part 1)[J]. Chinese Journal of Practical Internal Medicine, 2021, 41(8):668-695. doi:10.19538/j.nk2021080106.
[12]	李静, 梁田田, 王文健. 糖尿病肾病的早期诊断[J]. 中华肾脏病杂志, 2017, 33(6):470-475.
	LI J, LIANG T T, WANG W J. Early diagnosis of diabetic nephropathy[J]. Chinese Journal of Nephrology, 2017, 33(6):470-475. doi:10.3760/cma.j.issn.1001-7097.2017.06.013.
[13]	SHIM K, BEGUM R, YANG C, et al. Complement activation in obesity,insulin resistance,and type 2 diabetes mellitus[J]. World J Diabetes, 2020, 11(1):1-12. doi:10.4239/wjd.v11.i1.1.
[14]	慕静然, 骆延, 梁璇, 等. 补体系统激活参与阿尔茨海默病的研究进展[J]. 天津医药, 2024, 52(6):663-668.
	MU J R, LUO Y, LIANG X, et al. Research progress on the activation of complement system is involved in the pathogenesis of Alzheimer′s disease[J]. Tianjin Med J, 2024, 52(6):663-668. doi:10.11958/20231554.
[15]	樊玲英, 俸家富. 血清C1q和NGAL及CysC联合检测对早期糖尿病肾病辅助诊断的临床评价[J]. 中华检验医学杂志, 2018, 41(11):847-852.
	FAN L Y, FENG J F. Clinical evaluation of assisted diagnosis of early diabetic kidney disease by serum C1q, NGAL and CysC[J]. Chinese Journal of Laboratory Medicine, 2018, 41(11):847-852. doi:10.3760/cma.j.issn.1009-9158.2018.11.012.
[16]	聂广燕, 孙连芹, 钱军, 等. 肾小球补体C1q及C3c沉积与糖尿病肾病进展的相关性分析[J]. 中华糖尿病杂志, 2020, 12(12):999-1005.
	NIE G Y, SUN L Q, QIAN J, et al. Association of complement C3c and C1q deposition in glomeruli with the progression of diabetic kidney disease[J]. Chinese Journal of Diabetes, 2020, 12(12):999-1005. doi:10.3760/cma.j.cn115791-20200309-00138.
[17]	DØRFLINGER G H, HOLT C B, THIEL S, et al. Mannan-binding lectin is associated with inflammation and kidney damage in a mouse model of type 2 diabetes[J]. Int J Mol Sci, 2024, 25(13):7204. doi:10.3390/ijms25137204.
[18]	MA Y, CAI F, HUANG X, et al. Mannose-binding lectin activates the nuclear factor-κB and renal inflammation in the progression of diabetic nephropathy[J]. FASEB J, 2022, 36(3):e22227. doi:10.1096/fj.202101852R.
[19]	LI X X, LEE J D, KEMPER C, et al. The Complement receptor C5aR2:A powerful modulator of innate and adaptive immunity[J]. J Immunol, 2019, 202(12):3339-3348. doi:10.4049/jimmunol.1900371.
[20]	TAN S M, ZIEMANN M, THALLAS-BONKE V, et al. Complement C5a induces renal injury in diabetic kidney disease by disrupting mitochondrial metabolic agility[J]. Diabetes, 2020, 69(1):83-98. doi:10.2337/db19-0043.
[21]	LI L, CHEN L, ZANG J, et al. C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease[J]. Metabolism, 2015, 64(5):597-610. doi:10.1016/j.metabol.2015.01.014.
[22]	ZHENG J M, JIANG Z H, CHEN D J, et al. Pathological significance of urinary complement activation in diabetic nephropathy:A full view from the development of the disease[J]. J Diabetes Investig, 2019, 10(3):738-744. doi:10.1111/jdi.12934.
[23]	陈莉明. 聚焦肾小管损伤在糖尿病肾脏病诊治中的价值[J]. 中华糖尿病杂志, 2021, 13(10):921-925.
	CHEN L M. Insight into the value of renal tubular injury in diagnosis and treatment of diabetic kidney disease[J]. Chinese Journal of Diabetes, 2021, 13(10):921-925. doi:10.3760/cma.j.cn115791-20210524-00283.
[24]	KIM H K, LEE M, LEE Y H, et al. Renal tubular damage marker,urinary N-acetyl-β-D-glucosaminidase,as a predictive marker of hepatic fibrosis in type 2 diabetes mellitus[J]. Diabetes Metab J, 2022, 46(1):104-116. doi:10.4093/dmj.2020.0273.
[25]	YIU W H, LI R X, WONG D W L, et al. Complement C5a inhibition moderates lipid metabolism and reduces tubulointerstitial fibrosis in diabetic nephropathy[J]. Nephrol Dial Transplant, 2018, 33(8):1323-1332. doi:10.1093/ndt/gfx336.
[26]	TRAMBAS I A, COUGHLAN M T, TAN S M. Therapeutic potential of targeting complement C5a receptors in diabetic kidney disease[J]. Int J Mol Sci, 2023, 24(10):8758. doi:10.3390/ijms24108758.
[27]	LI D, ZOU L, FENG Y, et al. Complement factor B production in renal tubular cells and its role in sodium transporter expression during polymicrobial sepsis[J]. Crit Care Med, 2016, 44(5):e289-e299. doi:10.1097/CCM.0000000000001566.

组别			n	年龄/岁		性别（男/女）		BMI/（kg/m²）				吸烟史	SBP/mmHg			DBP/mmHg			TG/（mmol/L）			TC/（mmol/L）
NC组	40	56.22±8.27		20/20		24.88（22.85，27.25）				8	121.30±6.35			78.85±3.96			1.18±0.43			3.75±0.71
SDM组			50	58.78±11.53		27/23		25.69（23.09，28.23）				17	125.32±8.32			81.50±6.98			1.73±0.54			5.07±1.33^a
DKD组			182	59.55±11.03		94/88		26.88（23.75，29.45）				47	139.71±10.85^ab			84.00±7.03^ab			2.36±1.11^ab			5.22±1.69^a
F、χ²或H				16.660		0.150		5.635				2.356	82.377^＊＊			10.911^＊＊			7.686^＊＊			15.330^＊＊
组别	HDL-C/（mmol/L）				LDL-C/（mmol/L）				ApoA1/（g/L）	ApoB/（g/L）			HbA1c/%		BUN/（mmol/L）			Scr/（μmol/L）		UA/（μmol/L）
NC组	1.53±0.30				2.33±0.58				1.41±0.11	0.92±0.14			4.94±0.41		5.00±0.77			64.25±11.14		300.03±53.98
SDM组	1.34±0.41^a				3.09±1.40^a				1.37±0.29	1.03±0.29			7.97±2.72^a		5.94±1.61			62.92±8.01		307.08±78.65
DKD组	1.23±0.42^a				3.19±1.22^a				1.33±0.34	1.07±0.37^a			8.28±3.23^a		9.83±4.41			97.23±46.85^ab		348.37±115.44^ab
F	9.226^＊＊				4.487^＊				1.376	3.865^＊			22.054^＊＊		1.122			5.401^＊＊		5.704^＊＊
组别		UACR/ （mg/g）					eGFR/ [mL/（min·1.73 m²）]				NAG/Ucr/ （U/g）			C1q/（g/L）			MBL/ （mg/L）				C5a/ （μg/L）
NC组		5.00（4.00，7.00）					114.92（103.54，128.15）				3.71（3.07，4.97）			0.190±0.035			9.33（5.34，13.53）				136.86±36.27
SDM组		5.00（2.00，10.25）					124.84（112.99，137.34）				5.19（3.90，6.90）^a			0.199±0.044			9.06（4.70，12.48）				157.19±41.58
DKD组		188.00（75.00，721.75）^ab					118.35（74.72，149.39）				10.36（6.50，14.96）^ab			0.215±0.046^ab			12.48（6.80，21.46）^ab				181.70±58.83^ab
F或H		170.793^＊＊					2.106				95.206^＊＊			6.295^＊＊			18.224^＊＊				13.573^＊＊

组别			n	年龄/岁		性别（男/女）		BMI/（kg/m²）				吸烟史	SBP/mmHg			DBP/mmHg			TG/（mmol/L）			TC/（mmol/L）
NC组	40	56.22±8.27		20/20		24.88（22.85，27.25）				8	121.30±6.35			78.85±3.96			1.18±0.43			3.75±0.71
SDM组			50	58.78±11.53		27/23		25.69（23.09，28.23）				17	125.32±8.32			81.50±6.98			1.73±0.54			5.07±1.33^a
DKD组			182	59.55±11.03		94/88		26.88（23.75，29.45）				47	139.71±10.85^ab			84.00±7.03^ab			2.36±1.11^ab			5.22±1.69^a
F、χ²或H				16.660		0.150		5.635				2.356	82.377^＊＊			10.911^＊＊			7.686^＊＊			15.330^＊＊
组别	HDL-C/（mmol/L）				LDL-C/（mmol/L）				ApoA1/（g/L）	ApoB/（g/L）			HbA1c/%		BUN/（mmol/L）			Scr/（μmol/L）		UA/（μmol/L）
NC组	1.53±0.30				2.33±0.58				1.41±0.11	0.92±0.14			4.94±0.41		5.00±0.77			64.25±11.14		300.03±53.98
SDM组	1.34±0.41^a				3.09±1.40^a				1.37±0.29	1.03±0.29			7.97±2.72^a		5.94±1.61			62.92±8.01		307.08±78.65
DKD组	1.23±0.42^a				3.19±1.22^a				1.33±0.34	1.07±0.37^a			8.28±3.23^a		9.83±4.41			97.23±46.85^ab		348.37±115.44^ab
F	9.226^＊＊				4.487^＊				1.376	3.865^＊			22.054^＊＊		1.122			5.401^＊＊		5.704^＊＊
组别		UACR/ （mg/g）					eGFR/ [mL/（min·1.73 m²）]				NAG/Ucr/ （U/g）			C1q/（g/L）			MBL/ （mg/L）				C5a/ （μg/L）
NC组		5.00（4.00，7.00）					114.92（103.54，128.15）				3.71（3.07，4.97）			0.190±0.035			9.33（5.34，13.53）				136.86±36.27
SDM组		5.00（2.00，10.25）					124.84（112.99，137.34）				5.19（3.90，6.90）^a			0.199±0.044			9.06（4.70，12.48）				157.19±41.58
DKD组		188.00（75.00，721.75）^ab					118.35（74.72，149.39）				10.36（6.50，14.96）^ab			0.215±0.046^ab			12.48（6.80，21.46）^ab				181.70±58.83^ab
F或H		170.793^＊＊					2.106				95.206^＊＊			6.295^＊＊			18.224^＊＊				13.573^＊＊

组别	n	C1q/（g/L）	MBL/（mg/L）	C5a/（μg/L）
SDM组	50	0.199±0.044	9.06（4.70，12.48）	157.19±41.58
LDKD组	90	0.203±0.038	11.27（6.15，18.25）^a	159.47±46.44
MDKD组	55	0.204±0.042	14.20（6.84，24.79）^ab	202.30±61.08^ab
HDKD组	37	0.259±0.051^abc	18.49（11.03，25.22）^ab	205.16±63.43^ab
F或H		18.451^＊＊	24.085^＊＊	13.629^＊＊

组别	n	C1q/（g/L）	MBL/（mg/L）	C5a/（μg/L）
SDM组	50	0.199±0.044	9.06（4.70，12.48）	157.19±41.58
LDKD组	90	0.203±0.038	11.27（6.15，18.25）^a	159.47±46.44
MDKD组	55	0.204±0.042	14.20（6.84，24.79）^ab	202.30±61.08^ab
HDKD组	37	0.259±0.051^abc	18.49（11.03，25.22）^ab	205.16±63.43^ab
F或H		18.451^＊＊	24.085^＊＊	13.629^＊＊

组别		n	TG/（mmol/L）		TC/（mmol/L）		HDL-C/（mmol/L）		LDL-C/（mmol/L）		ApoA1/（g/L）		ApoB/（g/L）		HbA1c/%
Q1组		45	1.97±0.72		4.81±1.26		1.20±0.32		3.66±1.92		1.31±0.25		0.99±0.28		7.23±2.66
Q2组		45	1.91±0.83		4.98±1.75		1.27±0.43		3.03±1.18		1.31±0.36		1.02±0.38		8.03±3.32
Q3组		46	2.79±1.83		5.28±1.54		1.21±0.36		3.14±1.00		1.31±0.31		1.06±0.31		8.73±2.78^a
Q4组		46	2.24±1.24		5.67±1.74^ab		1.35±0.50		3.54±1.33		1.41±0.36		1.19±0.40^ab		8.86±3.44^a
F			2.374		3.273^＊		1.656		0.741		1.282		3.896^＊		3.484^＊
组别	BUN/（mmol/L）			Scr/（μmol/L）		UA/（μmol/L）		UACR/（mg/g）		C1q/（g/L）		MBL/（mg/L）		C5a/（μg/L）
Q1组	5.91±1.56			61.55±12.31		337.71±84.55		35.50（5.75，106.50）		0.195±0.036		10.03（5.32，13.14）		152.49±45.02
Q2组	14.02±8.24			82.28±33.03		312.58±98.45		70.50（10.50，230.25）^a		0.206±0.052		11.22（5.57，20.04）		170.27±57.94
Q3组	7.49±3.58			101.17±56.84^a		364.31±130.77		288.50（68.75，566.50）^ab		0.219±0.045^a		13.17（8.11，21.85）		179.86±52.75^a
Q4组	8.55±4.17			114.33±59.48^ab		343.29±116.10		736.50（111.50，1 524.50）^abc		0.225±0.048^ab		12.37（7.52，22.10）		203.05±58.04^abc
F或H	1.220			4.223^＊＊		2.214		56.700^＊＊		4.984^＊＊		8.544		8.924^＊＊