Relationships between blood bone metabolic biomarkers and anemia in patients with chronic kidney disease

Figures & data

Figure 1. Flow diagram of the study.

Table 1. Demographic data and laboratory values of controls and CKD patients.

Variables	Controls (n = 100)	CKD patients (n = 239)	p Value^a	CKD patients
				No anemia (n = 38)	Mild anemia (n = 70)	Moderate anemia (n = 68)	Severe anemia (n = 63)	p Value^b
Demographics
Age (years)	48.97 ± 13.54	49.25 ± 13.22	0.859	45.24 ± 13.04	51.07 ± 12.31	49.91 ± 12.90	48.94 ± 14.39	0.169
Male/female	51/49	130/109	0.568	22/16	41/29	34/34	33/30	0.726
Body mass index (kg/m^2)	23.56 ± 2.75	23.19 ± 3.63	0.314	24.60 ± 3.79	23.84 ± 3.60	22.47 ± 3.55	22.41 ± 3.32	0.003
Systolic pressure (mmHg)	122.63 ± 16.36	146.00 ± 25.92	<0.001	132.24 ± 16.92	144.96 ± 25.16	149.87 ± 22.44	153.51 ± 30.99	<0.001
Diastolic pressure (mmHg)	77.88 ± 10.91	86.83 ± 13.94	<0.001	85.71 ± 12.24	85.79 ± 14.81	86.85 ± 11.73	88.65 ± 16.09	0.637
Cause of CKD, n (%)
Glomerulonephritis	/	185(77.41)	/	33(86.84)	51(72.86)	52(76.47)	49(77.78)	0.423
Diabetic nephropathy	/	24(10.04)	/	2(5.26)	9(12.86)	7(10.29)	6(9.52)	0.629
Hypertensive nephropathy	/	9(3.77)	/	1(2.63)	3(4.29)	3(4.41)	2(3.17)	0.967
Polycystic kidney disease	/	9(3.77)	/	0(0)	2(2.86)	3(4.41)	4(6.35)	/
Other	/	12(5.02)	/	2(5.26)	5(7.14)	3(4.41)	2(3.17)	0.419
Dialysis mode, n (%)
Non-dialysis	/	140(58.58)	/	34(89.47)	45(64.29)	29(42.65)	32(50.79)	<0.001
Hemodialysis	/	77(32.22)	/	4(10.53)	19(27.14)	32(47.06)	34(47.06)	0.001
Peritoneal dialysis	/	22(9.21)	/	0(0)	6(8.57)	7(10.29)	9(14.29)	0.027
Dialysis vintage(m)	/	60.00(12.00–84.00)	/	102.00(30.00–168.00)	60.00(17.00–108.50)	60.00(24.00–96.00)	36.00(5.00–72.00)	0.066
Medication history, n (%)
CCB	/	126(52.72)	/	13(34.21)	34(48.57)	42(61.76)	37(58.73)	0.031
ACEI/ARB	/	73(30.54)	/	16(42.11)	22(31.43)	22(32.35)	13(20.63)	0.142
β-receptor blocker	/	53(22.18)	/	5(13.16)	16(22.86)	17(25.00)	15(23.81)	0.528
Active vitamin D sterols	/	74(30.96)	/	4(10.53)	18(25.71)	33(48.53)	19(30.16)	<0.001
Calcimimetics	/	8(3.35)	/	1(2.63)	4(5.71)	3(4.41)	0(0.00)	0.264
Laboratory values
Hemoglobin (g/L)	144.40 ± 15.52	98.76 ± 25.62	<0.001	139.39 ± 13.63	110.86 ± 5.99	92.71 ± 5.96	67.38 ± 10.56	<0.001
Hematocrit (%)	43.26 ± 4.24	30.19 ± 7.66	<0.001	41.93 ± 3.98	33.96 ± 2.12	28.41 ± 2.18	20.83 ± 3.56	<0.001
Glucose (mmol/L)	5.41 ± 0.77	5.28 ± 2.33	0.442	5.58 ± 2.82	5.64 ± 2.92	4.87 ± 1.30	5.14 ± 2.10	0.202
Albumin (g/L)	47.76 ± 2.87	35.74 ± 6.63	<0.001	37.14 ± 7.59	36.36 ± 6.92	34.57 ± 7.13	35.50 ± 4.78	0.212
Creatinine (µmol/L)	71.75 ± 15.61	625.65 ± 462.33	<0.001	206.51 ± 257.33	471.02 ± 400.79	705.20 ± 375.35	964.40 ± 437.92	<0.001
Urea (mmol/L)	5.56 ± 1.42	20.16 ± 11.90	<0.001	9.14 ± 7.15	15.68 ± 8.07	21.39 ± 8.55	30.45 ± 12.47	<0.001
Total cholesterol (mmol/L)	5.01 ± 0.83	4.98 ± 1.89	0.816	5.92 ± 2.90	5.33 ± 1.77	4.76 ± 1.51	4.27 ± 1.25	<0.001
Triglyceride (mmol/L)	1.44 ± 1.45	1.92 ± 1.33	0.003	2.02 ± 1.02	2.22 ± 1.49	1.90 ± 1.39	1.53 ± 1.16	0.024
eGFR (ml/min/1.73 m^2)	97.8 ± 18.3	25.7 ± 36.0	<0.001	65.5 ± 45.1	34.7 ± 40.5	12.5 ± 15.6	6.2 ± 4.1	<0.001
Calcium (mmol/L)	2.36 ± 0.11	2.23 ± 0.28	<0.001	2.28 ± 0.17	2.25 ± 0.30	2.26 ± 0.27	2.13 ± 0.32	0.021
Adjusted Ca (mmol/L)	2.20 ± 0.11	2.31 ± 0.27	<0.001	2.34 ± 0.15	2.32 ± 0.26	2.37 ± 0.23	2.22 ± 0.31	0.013
Phosphorus (mmol/L)	1.17 ± 0.15	1.72 ± 0.60	<0.001	1.26 ± 0.38	1.55 ± 0.48	1.86 ± 0.54	2.04 ± 0.66	<0.001
lnALP	4.31 ± 0.26	4.63 ± 0.81	<0.001	4.40 ± 0.69	4.56 ± 0.72	4.81 ± 0.94	4.64 ± 0.80	0.076
lniPTH	3.58 ± 0.39	5.18 ± 1.61	<0.001	4.04 ± 1.36	4.59 ± 1.58	5.72 ± 1.56	5.94 ± 1.14	<0.001
lnFGF23	4.15 ± 0.31	7.29 ± 2.36	<0.001	5.29 ± 1.72	6.79 ± 2.29	8.20 ± 2.40	8.07 ± 1.82	<0.001
lnKlotho	6.50 ± 0.27	5.82 ± 0.49	<0.001	6.05 ± 0.44	5.78 ± 0.50	5.80 ± 0.52	5.74 ± 0.43	0.012

Data were presented as means ± SD or median (interquartile range) for continuous variables and as n (%) for categorical variables. Bold values were statistically significant at p < 0.05.

Abbreviations: CKD: chronic kidney disease; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; CCB: dihydropyridine Ca channel blocker; ACEI/ARB: angiotensin converting enzyme inhibitors/angiotensin receptor blocker; Ca: calcium; TC: total cholesterol; TG: triglyceride; eGFR: estimated glomerular filtration rate; ALP: alkaline phosphatase; iPTH: intact parathyroid hormone; FGF23: fibroblast growth factor 23.

^aControls vs. CKD patients.

^bAnalysis of variance of 4 subgroups in CKD patients.

Figure 2. Baseline blood bone metabolism indices in different subgroups of CKD patients. The CKD patients were divided into four subgroups according to the tertiles of hemoglobin levels: 1: no anemia(male: Hb ≥ 130g/L; female: Hb ≥ 120g/L, n = 38), 2: mild anemia(male: 102 ≤ Hb < 130g/L; female: 102 ≤ Hb < 120g/L, n = 70), 3: moderate anemia(83 ≤ Hb < 102g/L, n = 68), 4: severe anemia(30 ≤ Hb < 83g/L, n = 63). P: analysis of variance of 4 subgroups in CKD patients. Abbreviations: Ca: calcium; P: phosphorus; ALP: alkaline phosphatase; iPTH: intact parathyroid hormone; FGF23: fibroblast growth factor 23.

Figure 3. Correlations between blood bone metabolism indices and Hb levels in CKD patients. Abbreviations: Hb: hemoglobin; Ca: calcium; P: phosphorus; ALP: alkaline phosphatase; iPTH: intact parathyroid hormone; FGF23: fibroblast growth factor 23.

Table 2. Influencing factors of Hb levels in CKD patients analyzed by multiple linear stepwise regression.

Independent Variable	Unstandardized Coefficient	Standardized Coefficient	95% CI		p Value
			Lower	Upper
Female	−11.690	−0.224	−17.117	−6.263	<0.001
BMI	0.955	0.130	0.200	1.710	0.013
SBP	−0.170	−0.170	−0.275	−0.064	0.002
Alb	1.400	0.355	0.957	1.844	<0.001
TC	3.990	0.296	2.423	5.558	<0.001
Adjusted Ca	12.903	0.134	3.019	22.786	0.011
P	−11.505	−0.264	−17.216	−5.794	<0.001
lniPTH	−2.574	−0.157	−4.840	−0.307	0.026
lnklotho	5.622	0.105	0.151	11.093	0.044

Multiple stepwise regression model with adjustment for age, sex, BMI, SBP, DBP, and Glu, Alb, TC, TG, adjusted Ca, P, lniPTH, lnFGF23, lnklotho and CCB, ACEI/ARB, β-receptor blocker, calcimimetics and active vitamin D sterols.

Abbreviations: Hb: hemoglobin; CKD: chronic kidney disease; BMI: body mass index; SBP: systolic blood pressure; Alb: albumin; TC: total cholesterol; Ca: calcium; P: phosphorus; iPTH: intact parathyroid hormone; CI: confidence interval.

Figure 4. Multiple ordered logistic regression analysis of factors associated with anemia in CKD patients. Abbreviations: BMI: body mass index; SBP: systolic blood pressure; Alb: albumin; TC: total cholesterol; Ca: calcium; P: phosphorus; iPTH: intact parathyroid hormone; OR: odds ratio; CI: confidence interval.

Figure 5. Comparisons of pre- and post-operative laboratory values in severe SHPT patients with PTX. Circulating levels of Hb (A), Hct (B), Alb (C), adjusted Ca (D), P (E), lnALP (F), lniPTH(G), lnFGF23(H), and lnklotho(I) (pre-PTX versus post-PTX), Data were expressed as 95% CIs. Abbreviations: PTX: parathyroidectomy; SHPT: secondary hyperparathyroidism; Hb: hemoglobin; Hct: hematocrit; Alb: albumin; Ca: calcium; P, phosphorus; ALP: alkaline phosphatase; iPTH: intact parathyroid hormone; FGF23: fibroblast growth factor 23.

Table 3. Associations between the changes of bone metabolism indices and Hb levels in PTX patients before and after operation analyzed by univariate linear regression.

Independent Variable	Unstandardized Coefficient	Standardized Coefficient	95% CI		p Value
			Lower	Upper
ΔAdjusted Ca	7.992	0.166	−11.194	27.177	0.400
ΔP	1.134	0.048	−8.282	10.549	0.806
lnΔALP	1.000	0.074	−4.846	6.846	0.727
lnΔiPTH	−5.908	−0.199	−20.791	8.974	0.414
lnΔFGF23	0.074	0.005	−5.736	5.883	0.979
ln(|Δklotho|)	−2.425	−0.123	−12.44	7.589	0.616

Abbreviations: Hb: hemoglobin; Ca, calcium; P: phosphorus; ALP: alkaline phosphatase; iPTH: intact parathyroid hormone; FGF23: fibroblast growth factor 23; Δ: subtracting the values of bone markers after PTX from baseline values; |Δ|: absolute value.