Evaluating new biomarkers for diabetic nephropathy: Role of α2-macroglobulin, podocalyxin, α-L-fucosidase, retinol-binding protein-4, and cystatin C

doi:10.4239/wjd.v15.i6.1212

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World Journal of Diabetes

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Retrospective Cohort Study

World J Diabetes. Jun 15, 2024; 15(6): 1212-1225
Published online Jun 15, 2024. doi: 10.4239/wjd.v15.i6.1212

Table 1 Diagnostic criteria for diabetes (World Health Organization, 1999)

Diagnostic criteria	Venous plasma glucose levels (mmol/L)
Diabetic symptoms and random blood glucose	≥ 11.1 mmol/L
Fasting plasma glucose	≥ 7.0 mmol/L
Plasma glucose 2 h after oral glucose tolerance test	≥ 11.1 mmol/L

At least one of the three diagnostic criteria needs to be met. If there is no typical “three more and one less”, it needs another test to confirm the diagnosis.

Table 2 Comparison of clinical and laboratory parameters between diabetic nephropathy and non-diabetic nephropathy patients

Parameters	NDN (n = 88)	DN (n = 115)	F/Z value	P value
Age, yr	57.03 ± 10.34	60.57 ± 11.05^a	0.680	0.021
Sex, male, n (%)	58 (65.90)	75 (65.20)	0.011	0.918
BMI, kg/m²	25.69 ± 2.67	26.35 ± 3.72	7.695	0.192
Hypertension, present, n (%)	41 (46.60)	97 (84.30)^a	32.650	< 0.001
Course, yr	8 (3.75, 15.00)	12 (8.00, 20.00)^a	3.666	< 0.001
FPG, mmol/L	6.80 (5.60, 8.10)	6.80 (5.68, 8.70)	0.469	0.639
HbA1c, %	8.82 ± 1.77	8.70 ± 2.39	6.676	0.681
NLR	1.72 (1.34, 2.14)	2.19 (1.70, 3.19)^a	4.547	< 0.001
hs-CRP, mg/L	1.55 (0.72, 3.37)	2.60 (0.95, 7.20)^a	2.293	0.022
TC, mmol/L	4.35 ± 1.03	4.71 ± 1.53^a	8.009	0.045
TG, mmol/L	1.64 (1.08, 2.26)	1.65 (1.12, 2.66)	1.064	0.287
LDL-C, mmol/L	2.53 ± 0.77	2.61 ± 0.96	3.181	0.544
HDL-C, mmol/L	0.99 ± 0.20	0.96 ± 0.23	1.228	0.265
Urea, mmol/L	5.50 (4.63, 6.30)	7.60 (5.80, 11.93)^a	6.726	< 0.001
CysC, mg/L	0.53 (0.45, 0.72)	1.18 (0.65, 1.99)^a	7.419	< 0.001
RBP-4, mg/L	39.99 (30.69, 46.30)	53.20 (41.00, 73.00)^a	6.284	< 0.001
Scr, μmol/L	68.00 (59.00, 79.75)	105.00 (70.00, 199.00)^a	6.525	< 0.001
eGFR, mL·min^-1·1.73 m^-2	95.99 (90.11, 104.82)	57.01 (27.22, 93.84)^a	6.561	< 0.001
UACR, mg/g	6.30 (3.70, 15.45)	446.20 (114.10, 1086.20)^a	11.542	< 0.001
UTP/24 h, g/24 h	0.04 (0.02, 0.08)	1.31 (0.34, 4.07)^a	11.624	< 0.001
U-α2-MG/UCr, mg/g	1.20 (0.86, 2.02)	5.78 (2.00, 17.31)^a	8.110	< 0.001
U-PCX/UCr, μg/g	2.91 (1.48, 5.04)	12.83 (6.25, 42.27)^a	8.817	< 0.001
U-AFU/UCr, nmol/g	0.04 (0.03, 0.07)	0.34 (0.05, 2.14)^a	7.105	< 0.001

^aCompared with the group of NDN, P < 0.05.

DN: Diabetic nephropathy; α2-MG: α2-macroglobulin; PCX: Podocalysin; AFU: α-L-fucosidase; RBP-4: Retinol binding protein-4; CysC: Cystatin C; NDN: Nondiabetic nephropathy; CKD: Chronic kidney disease; UACR: Urinary albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; hs-CRP: Hypersensitive C-reactive protein; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TG: Triglyceride; TC: Total cholesterol; FPG: Asting plasma glucose; HbA1c: Glycosylated hemoglobin; Urea: Urea nitrogen; SCr: Serum creatinine; UTP/24 h: Urinary total protein/24 h; NLR: Neutrophilic-to-lymphoid ratio; BMI: Body mass index.

Table 3 Partial correlation analysis between cystatin C, retinol-binding protein-4, U-α2- macroglobulin, U-podocalyxin, U-α-L-fucosidase, and clinical indicators

Indicator	CysC		RBP-4		U-α2-MG/UCr		U-PCX/UCr		U-AFU/UCr
Indicator	r	P value	r	P value	r	P value	r	P value	r	P value
UACR	0.730	< 0.001	0.625	< 0.001	0.805	< 0.001	0.639	< 0.001	0.780	< 0.001
eGFR	-0.816	< 0.001	-0.702	< 0.001	-0.711	< 0.001	-0.604	< 0.001	-0.742	< 0.001
CysC	1.000	-	0.693	< 0.001	0.710	< 0.001	0.645	< 0.001	0.692	< 0.001
RBP-4	0.693	< 0.001	1.000	-	0.530	< 0.001	0.432	< 0.001	0.588	< 0.001
U-α2-MG/UCr	0.710	< 0.001	0.530	< 0.001	1.000	-	0.820	< 0.001	0.874	< 0.001
U-PCX/UCr	0.645	< 0.001	0.432	< 0.001	0.820	< 0.001	1.000	-	0.746	< 0.001
U-AFU/UCr	0.692	< 0.001	0.588	< 0.001	0.874	< 0.001	0.746	< 0.001	1.000	-
Scr	0.953	< 0.001	0.680	< 0.001	0.755	< 0.001	0.645	< 0.001	0.715	< 0.001
Urea	0.799	< 0.001	0.651	< 0.001	0.657	< 0.001	0.568	< 0.001	0.703	< 0.001
UTP/24 h	0.665	< 0.001	0.506	< 0.001	0.740	< 0.001	0.523	< 0.001	0.743	< 0.001
NLR	0.417	< 0.001	0.167	0.018	0.311	< 0.001	0.299	< 0.001	0.313	< 0.001
hs-CRP	0.067	0.343	0.079	0.267	0.094	0.186	0.111	0.118	0.087	0.222

Gender and age were adjusted. α2-MG: α2-macroglobulin; PCX: Podocalysin; AFU: α-L-fucosidase; RBP-4: Retinol binding protein-4; CysC: Cystatin C; UACR: Urinary albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; hs-CRP: Hypersensitive c-reactive protein; Urea: Urea nitrogen; SCr: Serum creatinine; UTP/24 h: Urinary total protein/24 h; NLR: Neutrophilic-to-lymphoid ratio.

Table 4 Evaluation of area under the curve and its 95% confidence interval for various indicators

Indicators waiting to be measured	AUC	Standard error	P value	95% confidence interval
UACR	0.97	0.01	< 0.001	(0.95, 1.00)
eGFR	0.77	0.03	< 0.001	(0.70, 0.84)
CysC	0.80	0.03	< 0.001	(0.75, 0.86)
RBP-4	0.76	0.03	< 0.001	(0.69, 0.82)
U-α2-MG/UCr	0.83	0.03	< 0.001	(0.78, 0.89)
U-PCX/UCr	0.86	0.03	< 0.001	(0.81, 0.91)
U-AFU/UCr	0.79	0.03	< 0.001	(0.73, 0.85)
U-α2-MG/UCr + U-PCX/UCr	0.88	0.03	< 0.001	(0.83, 0.93)
U-PCX/UCr + U-AFU/UCr	0.88	0.03	< 0.001	(0.84, 0.93)
U-α2-MG/UCr + U-AFU/UCr	0.86	0.03	< 0.001	(0.80, 0.91)
U-α2-MG/UCr + U-PCX/UCr + U-AFU/UCr	0.89	0.03	< 0.001	(0.85, 0.94)

α2-MG: α2-macroglobulin; PCX: Podocalysin; AFU: α-L-fucosidase; RBP-4: Retinol binding protein-4; CysC: Cystatin C; UACR: Urinary albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; AUC: Area under the receiver operating characteristic curve.

Table 5 Optimal diagnostic cut-off points and their sensitivity and specificity for various indicators

Indicators	Optimal diagnostic cut-off points	Sensitivity	Specificity	Youden index
UACR	29.50	0.95	0.98	0.93
eGFR	74.41	0.96	0.58	0.54
CysC	1.11	0.54	0.99	0.53
RBP-4	56.90	0.45	0.98	0.43
U-α2-MG/UCr	3.90	0.55	0.99	0.54
U-PCX/UCr	4.81	0.84	0.75	0.59
U-AFU/UCr	0.18	0.63	0.92	0.55
U-α2-MG/UCr + U-PCX/UCr	-	0.86	0.76	0.62
U-PCX/UCr + U-AFU/UCr	-	0.75	0.86	0.61
U-α2-MG/UCr + U-AFU/UCr	-	0.68	0.90	0.58
U-α2-MG/UCr + U-PCX/UCr + U-AFU/UCr	-	0.89	0.75	0.64

Citation: Li JJ, Sa RL, Zhang Y, Yan ZL. Evaluating new biomarkers for diabetic nephropathy: Role of α2-macroglobulin, podocalyxin, α-L-fucosidase, retinol-binding protein-4, and cystatin C. World J Diabetes 2024; 15(6): 1212-1225
URL: https://www.wjgnet.com/1948-9358/full/v15/i6/1212.htm
DOI: https://dx.doi.org/10.4239/wjd.v15.i6.1212