Lipocalin-2, Soluble Transferrin Receptor, and Erythropoietin in Anemia During Mild Renal Dysfunction

Figures & data

Table 1 Clinical and Laboratory Characteristics of Subjects

Parameters	Patients with MRD (n = 235)	Healthy Individuals (n = 92)	p value
Clinical characteristics
Age (year)	60.3 ± 7.5	59.4 ± 6.8	0.317
Sex (male; n, %)	132 (56.2)	49 (53.3)	0.631
BMI (kg/m^2)	23.4 ± 3.6	22.9 ± 3.2	0.243
SBP (mmHg)	125.3 ± 12.1	121.2 ± 9.5	0.004
Current smoking (n, %)	54 (22.9)	20 (21.7)	0.815
Lipocalin
LCN2 (ng/mL)	165.3 (92.5–241.0)	67.5 (57.3–132.8)	< 0.001
Elevated LCN2 (n, %)	137 (58.3)	0 (0.0)	< 0.001
cLCN2 (ng/mL)	146.2 (71.3–192.5)	67.5 (57.3–132.8)	< 0.001
Percent difference (%)*	12.5 ± 8.4	0.0 ± 0.0	< 0.001
Iron profiles
sTfR (mg/L)	2.54 ± 1.86	1.32 ± 0.65	< 0.001
Serum iron (µg/dL)	36.9 ± 28.1	64.3 ± 41.2	< 0.001
TS (%)	19.7 ± 13.6	28.1 ± 17.4	< 0.001
Serum ferritin (ng/mL)	51.4 (20.1–187.2)	65.3 (41.7–152.8)	0.047
Renal parameters
EPO (IU/L)	10.5 (4.2–16.3)	14.3 (5.6–19.1)	0.015
Estimated CrCl (mL/min)	70.1 ± 8.6	93.2 ± 4.5	< 0.001
Hematologic parameters
Hemoglobin (g/dL)	13.4 ± 1.8	14.9 ± 1.1	< 0.001
Anemia (n, %)	51 (21.7)	0 (0.0)	< 0.001
Inflammatory parameters
hsCRP (mg/dL)	0.26 (0.13–2.14)	0.09 (0.04–0.25)	< 0.001
Elevated hsCRP (n, %)	82 (34.9)	0 (0.0)	< 0.001
cESR (mm/h)	14.3 ± 12.1	8.7 ± 5.2	< 0.001

Notes: Data are expressed as mean ± SD, median (IQR), or frequency (%). *Percent difference between LCN2 and cLCN2.

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; LCN2, lipocalin-2; cLCN2, corrected lipocalin-2; sTfR, soluble transferrin receptor; TS, transferrin saturation; EPO, erythropoietin; CrCl, creatinine clearance; hsCRP, high-sensitivity C-reactive protein; cESR, corrected erythrocyte sedimentation rate; MRD, mild renal dysfunction.

Table 2 RMI, sTfR, and Serum Iron Levels and the Prevalence of Anemia According to LCN2 Levels

Parameters	LCN2 Levels		p value
	Elevated (n = 137)	Non-Elevated (n = 98)
Age (year)	59.8 ± 7.2	60.7 ± 7.9	0.365
Sex (male; n, %)	78 (56.9)	54 (55.1)	0.784
BMI (kg/m^2)	23.1 ± 3.4	23.6 ± 3.7	0.285
SBP (mmHg)	127.3 ± 12.2	124.3 ± 12.0	0.062
Current smoking (n, %)	30 (21.9)	24 (24.5)	0.641
sTfR (mg/L)	3.04 ± 2.15	2.01 ± 1.36	< 0.001
RMI (%)	1.02 ± 0.49	1.28 ± 0.54	< 0.001
EPO (IU/L)	9.8 (3.6–15.4)	11.1 (5.2–17.5)	0.214
Serum iron (µg/dL)	31.9 ± 18.2	42.6 ± 23.1	< 0.001
Erythrocytes (× 10^12/L)	4.12 ± 0.75	4.58 ± 0.96	< 0.001
Anemia (n, %)	38 (27.7)	13 (13.3)	0.008
Estimated CrCl (mL/min)	67.4 ± 7.1	73.8 ± 9.2	< 0.001
hsCRP (mg/dL)	0.34 (0.21–2.59)	0.19 (0.12–1.83)	< 0.001

Notes: Data are expressed as mean ± SD, median (IQR), or frequency (%).

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; sTfR, soluble transferrin receptor; RMI, reticulocyte maturity index; EPO, erythropoietin; CrCl, creatinine clearance; hsCRP, high-sensitivity C-reactive protein; LCN2, lipocalin-2.

Figure 1 Hemoglobin levels according to LCN2 levels in patients with mild renal dysfunction. Hemoglobin levels are significantly lower in patients with elevated LCN2 levels than in those without elevated LCN2 levels (12.9 ± 1.6 g/dL vs 14.0 ± 1.7 g/dL). *p < 0.001.

Table 3 LCN2, sTfR, and EPO Levels in Patients with and without Anemia

Parameters	Patients		p value
	With Anemia (n = 51)	Without Anemia (n = 184)
Age (year)	61.2 ± 7.4	59.6 ± 7.8	0.192
Sex (male; n, %)	27 (52.9)	105 (57.1)	0.593
LCN2 (ng/mL)	195.8 (97.2–278.5)	142.0 (63.5–205.3)	< 0.001
cLCN2 (ng/mL)	176.3 (82.1–214.6)	123.2 (56.4–172.8)	< 0.001
EPO (IU/L)	8.9 (3.4–15.1)	10.7 (4.5–18.9)	0.145
sTfR (mg/L)	3.61 ± 2.43	2.18 ± 1.67	< 0.001
Serum iron (µg/dL)	24.5 ± 16.2	43.2 ± 21.5	< 0.001
Estimated CrCl (mL/min)	67.2 ± 7.4	71.5 ± 8.9	0.002
hsCRP (mg/dL)	0.29 (0.24–2.35)	0.24 (0.19–2.17)	0.417

Notes: Data are expressed as mean ± SD, median (IQR), or frequency (%).

Abbreviations: LCN2, lipocalin-2; cLCN2, corrected lipocalin-2; EPO, erythropoietin; sTfR, soluble transferrin receptor; CrCl, creatinine clearance; hsCRP, high-sensitivity C-reactive protein.

Table 4 Relationship Between LCN2 and sTfR, RMI, EPO, Serum Iron, and Hemoglobin Levels

Parameters	Univariate		Multivariate*
	Standardized β	p value	Standardized β	p value
sTfR	0.275	< 0.001	0.232	< 0.001
Serum iron	−0.242	< 0.001	−0.201	< 0.001
Hemoglobin	−0.318	< 0.001	−0.245	< 0.001
EPO	−0.126	0.041	−0.097	0.101
RMI	−0.273	< 0.001	−0.229	< 0.001

Notes: *Adjusted for age, sex, body mass index, systolic blood pressure, current smoking, and high-sensitivity C-reactive protein.

Abbreviations: sTfR, soluble transferrin receptor; RMI, reticulocyte maturity index; EPO, erythropoietin; LCN2, lipocalin-2.

Figure 2 Scatter plots of the relationship between LCN2 and hemoglobin levels in patients with mild renal dysfunction. The LCN2 levels are negatively correlated with hemoglobin levels (y = −0.011x + 13.907; r² = 0.101; p < 0.001).

Table 5 Association Between LCN2 Elevation and the Presence of Anemia in Subjects with MRD

LCN2 Elevation (> 150 ng/mL)	Presence of Anemia
	Odds Ratio (95% CI)	p value
Unadjusted	2.386 (1.102–4.541)	< 0.001
Adjusted for
Age, sex, and BMI	2.147 (1.057–4.262)	< 0.001
Age, sex, BMI, and SBP	1.843 (1.049–3.673)	< 0.001
Age, sex, BMI, SBP, and current smoking	1.651 (1.025–3.221)	< 0.001
Age, sex, BMI, SBP, current smoking, and hsCRP	1.302 (1.012–2.527)	< 0.001

Abbreviations: LCN2, lipocalin-2; BMI, body mass index; SBP, systolic blood pressure; hsCRP, high-sensitivity C-reactive protein; CI, confidence interval.