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

doi:10.12122/j.issn.1673-4254.2025.02.19

Abstract

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

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.

Figures/Tables 10

References 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