高血清胱抑素C水平是IgA肾病不良预后的独立危险因素

doi:10.12122/j.issn.1673-4254.2025.02.19

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (2): 379-386.doi: 10.12122/j.issn.1673-4254.2025.02.19

• • 上一篇

高血清胱抑素C水平是IgA肾病不良预后的独立危险因素

唐天威¹(), 李路安², 陈源汉², 张丽², 徐丽霞², 李志莲², 冯仲林², 张辉林³, 华瑞芳³, 叶智明², 梁馨苓², 李锐钊¹()

^1.广东省心血管病研究所//广东省人民医院//广东省医学科学院，广东广州 510080
^2.南方医科大学附属广东省人民医院（广东省医学科学院）肾内科，广东广州 510080
^3.广东省人民医院赣州医院（赣州市立医院）肾内科，江西赣州 341000

收稿日期:2024-08-17 出版日期:2025-02-20 发布日期:2025-03-03
通讯作者: 李锐钊 E-mail:tw122666@163.com;liruizhao1979@126.com
作者简介:唐天威，在读硕士研究生，E-mail: tw122666@163.com
基金资助:
广东省基础与应用基础研究项目(2024A1515010424);广东省人民医院登峰计划(KJ012019440);广东省科技厅项目(2019B121205005);广州市科技基础与应用基础研究项目(202102080608)

High serum cystatin C is an independent risk factor for poor renal prognosis in IgA nephropathy

Tianwei TANG¹(), Luan LI², Yuanhan CHEN², Li ZHANG², Lixia XU², Zhilian LI², Zhonglin FENG², Huilin ZHANG³, Ruifang HUA³, Zhiming YE², Xinling LIANG², Ruizhao LI¹()

^1.Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
^2.Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
^3.Department of Nephrology, Ganzhou Hospital of Guangdong Provincial People's Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, China

Received:2024-08-17 Online:2025-02-20 Published:2025-03-03
Contact: Ruizhao LI E-mail:tw122666@163.com;liruizhao1979@126.com

摘要/Abstract

摘要：

目的探讨血清胱抑素C（CysC）水平评估IgA肾病（IgAN）患者肾脏预后的价值。方法回顾性收集2014年1月~2018年12月在广东省人民医院通过肾穿刺活检诊断为IgAN患者的临床资料。根据基线血清CysC值将患者分为高血清CysC组（CysC>1.03 mg/L）和正常血清CysC组（CysC≤1.03 mg/L）。估算肾小球滤过率（eGFR）下降≥50%，和/或进入终末期肾病（ESRD）作为肾脏不良预后的随访复合终点事件。采用lasso回归和多因素Cox回归筛选独立危险因素，并基于这些独立危险因素构建多因素Cox回归预测模型。采用Kaplan⁃Meier生存分析比较两组之间的肾脏生存率差异。平滑曲线拟合及阈值效应探究血清CysC水平与结局之间的关系。通过Bootstrap法内部验证预测模型并使用一致性指数、校正曲线、受试者工作特征（ROC）曲线及其曲线下面积（AUC）对模型预测效能进行评价，并通过列线图可视化。结果本研究共纳入356例IgAN患者，平均随访时间为（4.65±0.93）年，74例发生肾脏不良预后的复合终点事件。高血清CysC被筛选为IgAN肾脏不良预后的独立危险因素（HR=2.142，95% CI：1.222~3.755），且血清CysC水平高的患者肾脏生存率较低（Log-rank检验χ²=47.970，P<0.001）。阈值效应分析显示，当患者血清CysC≤2.12 mg/L时，血清CysC水平越高，肾脏不良预后风险越大（β=3.487，95% CI：2.561~4.413，P<0.001）；当患者的血清CysC>2.12 mg/L时，肾脏不良预后的发生风险仍有上升但差异无统计学意义（β=0.676，95% CI：-0.642~1.995，P=0.315）。基于血清 CysC及其他3个独立危险因素构建的多因素Cox回归预测模型经内部验证表现良好，其一致性指数为0.873（95% CI：0.839~0.907），AUC为0.909（95% CI：0.873~0.945）。结论血清CysC水平与IgAN患者肾脏预后相关，高血清CysC是IgA肾病不良预后的独立危险因素。

关键词: 血清胱抑素C, IgA肾病, 预后

Abstract:

Objective To explore the value of serum cystatin C (CysC) levels in evaluating renal prognosis in IgA nephropathy (IgAN) patients. Methods We retrospectively collected the clinical data of IgAN patients diagnosed by renal biopsy at Guangdong Provincial People's Hospital from January, 2014 to December, 2018. Based on baseline serum CysC levels, the patients were divided into high serum CysC (>1.03 mg/L) group and normal serum CysC (≤1.03 mg/L) group. The composite endpoint for poor renal prognosis was defined as ≥50% decline in estimated glomerular filtration rate (eGFR) and/or progression to end-stage renal disease (ESRD). Lasso regression, multivariate Cox regression and Kaplan-Meier survival analysis were used to identify the risk factors and compare renal survival rates between the two groups. Smooth curves fitting and threshold effect analysis were used to explore the relationship between serum CysC levels and the outcomes. A nomogram model was constructed and its predictive performance was evaluated using concordance index, calibration curve, receiver operating characteristic (ROC) curve and the area under curve (AUC). Results A total of 356 IgAN patients were enrolled, who were followed up for 4.65±0.93 years. The composite endpoint occurred in 74 patients. High serum CysC was identified as an independent risk factor for poor renal prognosis in IgAN (HR=2.142, 95% CI 1.222 to 3.755), and the patients with high serum CysC levels had a lower renal survival rate (Log-rank χ²=47.970, P<0.001). In patients with serum CysC below 2.12 mg/L, a higher CysC level was associated with an increased risk of poor renal prognosis (β=3.487, 95% CI: 2.561-4.413, P<0.001), while above this level, the increase of the risk was not significant (β=0.676, 95% CI: -0.642-1.995, P=0.315). The nomogram model based on serum CysC and 3 other independent risk factors demonstrated good internal validity with a concordance index of 0.873 (95% CI: 0.839-0.907) and an AUC of 0.909 (95% CI: 0.873-0.945). Conclusion Serum CysC levels are associated with renal prognosis in IgAN patients, and high serum CysC an independent risk factor for poor renal prognosis.

Key words: serum cystatin C, IgA nephropathy, prognosis

唐天威, 李路安, 陈源汉, 张丽, 徐丽霞, 李志莲, 冯仲林, 张辉林, 华瑞芳, 叶智明, 梁馨苓, 李锐钊. 高血清胱抑素C水平是IgA肾病不良预后的独立危险因素[J]. 南方医科大学学报, 2025, 45(2): 379-386.

Tianwei TANG, Luan LI, Yuanhan CHEN, Li ZHANG, Lixia XU, Zhilian LI, Zhonglin FENG, Huilin ZHANG, Ruifang HUA, Zhiming YE, Xinling LIANG, Ruizhao LI. High serum cystatin C is an independent risk factor for poor renal prognosis in IgA nephropathy[J]. Journal of Southern Medical University, 2025, 45(2): 379-386.

图/表 10

参考文献 32

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Pathological parameters and score	Content
Mesangial hypercellularity (M)
M0	Mesangial score ≤0.5
M1	Mesangial score >0.5
Endocapillary hypercellularity (E)
E0	Absent
E1	Present
Segmental glomerulosclerosis (S)
S0	Absent
S1	Present
Tubular atrophy/interstitial fibrosis (T)
T0	0-25%
T1	26%-50%
T2	>50%
Cellular/fibrocellular crescents (C)
C0	Absent
C1	Crescents in a least 1 glomerulus and <25% of glomeruli
C2	Crescents in ≥25% of glomeruli

Pathological parameters and score	Content
Mesangial hypercellularity (M)
M0	Mesangial score ≤0.5
M1	Mesangial score >0.5
Endocapillary hypercellularity (E)
E0	Absent
E1	Present
Segmental glomerulosclerosis (S)
S0	Absent
S1	Present
Tubular atrophy/interstitial fibrosis (T)
T0	0-25%
T1	26%-50%
T2	>50%
Cellular/fibrocellular crescents (C)
C0	Absent
C1	Crescents in a least 1 glomerulus and <25% of glomeruli
C2	Crescents in ≥25% of glomeruli

Variables	Overall (n=356)	Normal serum CysC group (n=130)	High serum CysC group (n=226)	t/Z/χ²	P
Age (year)	36 (29, 45)	32 (26, 39)	39 (32, 47)	-5.245	<0.001
Male [n (%)]	149 (41.9)	33(25.4)	116 (51.3)	21.770	<0.001
Hypertension [n (%)]	139 (39.0)	28 (21.5)	111 (49.1)	25.224	<0.001
Hyperuricaemia [n (%)]	31 ( 8.7)	5 (3.8)	26 (11.5)	5.163	0.023
Mean arterial pressure (mmHg)	100.34 (91, 112.34)	94.67 (87.33, 104.33)	105 (94.67, 115.25)	-5.989	<0.001
Weight (kg)	59.8 (52.39, 68)	58 (51, 65.81)	61.48 (53.78, 69.48)	-2.766	0.006
Serum uric acid (μmol/L)	423.5 (342, 517.5)	345 (293, 409)	470.1 (392.25, 565)	-9.559	<0.001
Serum sodium (mmol/L)	139 (137.7, 140.5)	138.9 (137.7, 140.2)	139.1 (137.8, 140.7)	-0.794	0.427
Serum potassium (mmol/L)	3.72 (3.49, 3.95)	3.58 (3.4, 3.77)	3.84 (3.58, 4.07)	-6.489	<0.001
Serum albumin (g/L)	36.7 (33.78, 39.8)	37.35 (34.53, 40.78)	36.3 (32.4, 39.1)	3.049	0.002
Triglyceride (mmol/L)	1.59 (1.11, 2.49)	1.38 (0.98, 2.02)	1.78 (1.25, 2.57)	-3.577	<0.001
Cholesterol (mmol/L)	5.3 (4.4, 6.04)	5.15 (4.25, 5.68)	5.36 (4.56, 6.29)	-2.544	0.011
Low density lipoprotein cholesterol (mmol/L)	3.19 (2.62, 3.89)	3.1 (2.49, 3.53)	3.27 (2.65, 4.04)	-2.777	0.005
High density lipoprotein cholesterol (mmol/L)	1.15 (0.96, 1.41)	1.23 (1.01, 1.48)	1.13 (0.93, 1.38)	2.306	0.021
Transferrin (g/L)	1.96 (1.76, 2.25)	2.11 (1.85, 2.36)	1.91 (1.73, 2.17)	4.300	<0.001
Serum IgA (g/L)	3.4 (2.5, 4.09)	3.23 (2.49, 3.79)	3.47 (2.55, 4.45)	-1.908	0.056
Serum IgM (g/L)	1.16 (0.83, 1.68)	1.21 (0.88, 1.67)	1.14 (0.8, 1.68)	1.154	0.249
Serum IgG (g/L)	11.5 (9.74, 13.1)	11.4 (10.1, 12.6)	11.55 (9.6, 13.5)	-0.551	0.582
Complement C3 (mg/L)	878 (773.75, 1010)	889 (769.25, 1010)	868 (776.5, 1000)	0.592	0.555
Complement C4 (mg/L)	226 (178, 275)	215.5 (166.25, 250.5)	233 (184.5, 284)	-2.971	0.003
Hemoglobin (g/L)	124.56±18.02	126.68±16.16	123.34±18.92	1.765	0.079
White blood cell (×10⁹/L)	7.48 (6.41, 8.69)	7.37 (6.31, 8.59)	7.59 (6.51, 8.75)	-1.049	0.295
Platelet (×10⁹/L)	251 (209, 289.25)	256.5 (218, 296)	249 (204, 285.75)	1.685	0.092
Fibrinogen (g/L)	3.56 (3.08, 4.31)	3.31 (2.91, 3.85)	3.73 (3.16, 4.54)	-4.052	<0.001
D-Dimer(ng/mL)	330 (270, 472.5)	290 (270, 390)	350 (270, 520)	-3.168	0.001
Hematuria [n (%)]	151 (42.4)	78 (60.0)	73 (32.3)	24.802	<0.001
24 h urine protein (g)	1.14 (0.51, 2.16)	0.70 (0.33, 1.40)	1.38 (0.69, 2.67)	-5.977	<0.001
eGFR[mL·min^-1·(1.73 m²)^-1]	65.62 (39.43, 100.51)	106.39 (88.53, 119.9)	44.84 (31.57, 64.36)	13.664	<0.001
Serum IgA/Complement C3	3.68 (2.83, 4.76)	3.61 (2.75, 4.34)	3.8 (2.86, 5.09)	-1.785	0.074
RAAS-inhibitor [n (%)]	294 (82.6)	125 (96.2)	169 (74.8)	24.752	<0.001
Immunosuppressive agents [n (%)]	217 (61.0)	64 (49.2)	153 (67.7)	11.064	0.001
Percentage of global glomerulosclerosis	0.23 (0.09, 0.46)	0.1 (0.03, 0.18)	0.36 (0.17, 0.55)	-9.405	<0.001
M1 [n (%)]	291 (81.7)	110 (84.6)	181 (80.1)	0.850	0.357
E1 [n (%)]	54 (15.2)	22 (16.9)	32 (14.2)	0.299	0.585
S1 [n (%)]	167 (46.9)	49 (37.7)	118 (52.2)	6.416	0.011
T [n (%)]				92.316	<0.001
0	209 (58.7)	119 (91.5)	90 (39.8)
1	91 (25.6)	10 (7.7)	81 (35.8)
2	56 (15.7)	1 (0.8)	55 (24.3)
C [n (%)]				7.860	0.020
0	152 (42.7)	49 (37.7)	103 (45.6)
1	168 (47.2)	73 (56.2)	95 (42.0)
2	36 (10.1)	8 (6.2)	28 (12.4)

Variables	Overall (n=356)	Normal serum CysC group (n=130)	High serum CysC group (n=226)	t/Z/χ²	P
Age (year)	36 (29, 45)	32 (26, 39)	39 (32, 47)	-5.245	<0.001
Male [n (%)]	149 (41.9)	33(25.4)	116 (51.3)	21.770	<0.001
Hypertension [n (%)]	139 (39.0)	28 (21.5)	111 (49.1)	25.224	<0.001
Hyperuricaemia [n (%)]	31 ( 8.7)	5 (3.8)	26 (11.5)	5.163	0.023
Mean arterial pressure (mmHg)	100.34 (91, 112.34)	94.67 (87.33, 104.33)	105 (94.67, 115.25)	-5.989	<0.001
Weight (kg)	59.8 (52.39, 68)	58 (51, 65.81)	61.48 (53.78, 69.48)	-2.766	0.006
Serum uric acid (μmol/L)	423.5 (342, 517.5)	345 (293, 409)	470.1 (392.25, 565)	-9.559	<0.001
Serum sodium (mmol/L)	139 (137.7, 140.5)	138.9 (137.7, 140.2)	139.1 (137.8, 140.7)	-0.794	0.427
Serum potassium (mmol/L)	3.72 (3.49, 3.95)	3.58 (3.4, 3.77)	3.84 (3.58, 4.07)	-6.489	<0.001
Serum albumin (g/L)	36.7 (33.78, 39.8)	37.35 (34.53, 40.78)	36.3 (32.4, 39.1)	3.049	0.002
Triglyceride (mmol/L)	1.59 (1.11, 2.49)	1.38 (0.98, 2.02)	1.78 (1.25, 2.57)	-3.577	<0.001
Cholesterol (mmol/L)	5.3 (4.4, 6.04)	5.15 (4.25, 5.68)	5.36 (4.56, 6.29)	-2.544	0.011
Low density lipoprotein cholesterol (mmol/L)	3.19 (2.62, 3.89)	3.1 (2.49, 3.53)	3.27 (2.65, 4.04)	-2.777	0.005
High density lipoprotein cholesterol (mmol/L)	1.15 (0.96, 1.41)	1.23 (1.01, 1.48)	1.13 (0.93, 1.38)	2.306	0.021
Transferrin (g/L)	1.96 (1.76, 2.25)	2.11 (1.85, 2.36)	1.91 (1.73, 2.17)	4.300	<0.001
Serum IgA (g/L)	3.4 (2.5, 4.09)	3.23 (2.49, 3.79)	3.47 (2.55, 4.45)	-1.908	0.056
Serum IgM (g/L)	1.16 (0.83, 1.68)	1.21 (0.88, 1.67)	1.14 (0.8, 1.68)	1.154	0.249
Serum IgG (g/L)	11.5 (9.74, 13.1)	11.4 (10.1, 12.6)	11.55 (9.6, 13.5)	-0.551	0.582
Complement C3 (mg/L)	878 (773.75, 1010)	889 (769.25, 1010)	868 (776.5, 1000)	0.592	0.555
Complement C4 (mg/L)	226 (178, 275)	215.5 (166.25, 250.5)	233 (184.5, 284)	-2.971	0.003
Hemoglobin (g/L)	124.56±18.02	126.68±16.16	123.34±18.92	1.765	0.079
White blood cell (×10⁹/L)	7.48 (6.41, 8.69)	7.37 (6.31, 8.59)	7.59 (6.51, 8.75)	-1.049	0.295
Platelet (×10⁹/L)	251 (209, 289.25)	256.5 (218, 296)	249 (204, 285.75)	1.685	0.092
Fibrinogen (g/L)	3.56 (3.08, 4.31)	3.31 (2.91, 3.85)	3.73 (3.16, 4.54)	-4.052	<0.001
D-Dimer(ng/mL)	330 (270, 472.5)	290 (270, 390)	350 (270, 520)	-3.168	0.001
Hematuria [n (%)]	151 (42.4)	78 (60.0)	73 (32.3)	24.802	<0.001
24 h urine protein (g)	1.14 (0.51, 2.16)	0.70 (0.33, 1.40)	1.38 (0.69, 2.67)	-5.977	<0.001
eGFR[mL·min^-1·(1.73 m²)^-1]	65.62 (39.43, 100.51)	106.39 (88.53, 119.9)	44.84 (31.57, 64.36)	13.664	<0.001
Serum IgA/Complement C3	3.68 (2.83, 4.76)	3.61 (2.75, 4.34)	3.8 (2.86, 5.09)	-1.785	0.074
RAAS-inhibitor [n (%)]	294 (82.6)	125 (96.2)	169 (74.8)	24.752	<0.001
Immunosuppressive agents [n (%)]	217 (61.0)	64 (49.2)	153 (67.7)	11.064	0.001
Percentage of global glomerulosclerosis	0.23 (0.09, 0.46)	0.1 (0.03, 0.18)	0.36 (0.17, 0.55)	-9.405	<0.001
M1 [n (%)]	291 (81.7)	110 (84.6)	181 (80.1)	0.850	0.357
E1 [n (%)]	54 (15.2)	22 (16.9)	32 (14.2)	0.299	0.585
S1 [n (%)]	167 (46.9)	49 (37.7)	118 (52.2)	6.416	0.011
T [n (%)]				92.316	<0.001
0	209 (58.7)	119 (91.5)	90 (39.8)
1	91 (25.6)	10 (7.7)	81 (35.8)
2	56 (15.7)	1 (0.8)	55 (24.3)
C [n (%)]				7.860	0.020
0	152 (42.7)	49 (37.7)	103 (45.6)
1	168 (47.2)	73 (56.2)	95 (42.0)
2	36 (10.1)	8 (6.2)	28 (12.4)

Variables	Lasso regression coefficients	Multivariate Cox regression
Variables	Lasso regression coefficients	HR (95% CI)	P
Mean arterial pressure (mmHg)	4.23×10^-3	1.015 (1.000-1.031)	0.048
Serum CysC (mg/L)	6.10×10^-1	2.142 (1.222-3.755)	0.008
Serum albumin (g/L)	-4.57×10^-3	0.934 (0.892-0.977)	0.003
24-hour urine protein (g)	2.88×10^-5	1.000 (0.999-1.000)	0.638
eGFR[mL·min^-1·(1.73 m²)^-1]	-5.43×10^-3	0.984 (0.965-1.003)	0.107
Percentage of global glomerulosclerosis	1.81×10^-2	2.077 (0.518-8.327)	0.302
T [n (%)]	5.10×10^-1	1.000 (Ref)
T1		3.416 (1.424-8.192)	0.006
T2		3.408 (1.144-10.150)	0.028

高血清胱抑素C水平是IgA肾病不良预后的独立危险因素

High serum cystatin C is an independent risk factor for poor renal prognosis in IgA nephropathy

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Threshold effect	β (95% CI)	P
Fitting by GAMs
Serum CysC	2.637 (2.034, 3.240)	<0.001
Fitting by two-piecewise GAMs
Inflection point	2.12
Serum CysC≤2.12	3.487 (2.561, 4.413)	<0.001
Serum CysC>2.12	0.676 (-0.642, 1.995)	0.315
Log likelihood ratio		0.008

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