Role of fibroblast growth factor-23 in renal disease activity and bone density involvement in patients with lupus nephritis

Table 1 Baseline characteristics of the studied groups, n (%)/mean ± SD

Variables	Inactive LN group (n = 50)	Active LN group (n = 50)	P value
Age (years)	28.88 ± 5.83	30.56 ± 8.08	0.23
Sex			0.18
Male	17 (34)	12 (24)
Female	33 (66)	38 (76)
Body mass index (kg/m2)	24.57 ± 6.78	23.09 ± 4.48	0.78
Duration of disease (years)	7.68 ± 2.98	9.87 ± 3.45	0.02
Number of relapses	3 (6)	5 (10)	0.48

LN: Lupus nephritis.

Table 2 Laboratory characteristics of the studied groups, n (%)/mean ± SD

Variables	Inactive LN group (n = 50)	Active LN group (n = 50)	P value
Random blood sugar (mg/dL)	97.42 ± 15.38	108.80 ± 14.31	< 0.001
Complete blood count
Hemoglobin (g/dL)	9.11 ± 1.67	8.86 ± 1.63	0.45
Leucocytes (103/μL)	6.69 ± 2.32	6.98 ± 2.87	0.60
Platelets (103/μL)	233.86 ± 85.29	265.66 ± 106.99	0.97
Neutrophil/Lymphocyte ratio	2.09 ± 0.78	3.11 ± 1.01	< 0.001
Platelets/Lymphocytes ratio	198.11 ± 34.98	256.98 ± 67.89	< 0.001
Kidney function tests
Blood urea nitrogen (mg/dL)	17.90 ± 3.79	19.06 ± 1.90	0.78
Creatinine (μmol/L)	89.36 ± 8.62	232.72 ± 27.50	< 0.001
Proteinuria (mg/day)	1795.30 ± 154.37	3778.14 ± 407.98	< 0.001
Glomerular filtration rate (mL/minute/1.73 m2)	87.41 ± 4.81	57.10 ± 5.26	< 0.001
Urine analysis
Hematuria (HPF)	13.96 ± 3.73	10.07 ± 4.44	0.15
Pyuria (HPF)	10.18 ± 1.56	13.58 ± 2.38	0.93
Albuminuria			0.39
0	6 (1)	4 (8)
+	19 (38)	15 (30)
++	22 (44)	25 (50)
+++	2 (4)	6 (12)
++++	1 (2)	0
Coagulation profile
International normalized ratio	1.04 ± 0.11	1.02 ± 0.17	0.63
Bone parameters
Calcium (mg/dL)	8.07 ± 0.62	7.88 ± 0.66	0.14
Phosphorus (mg/dL)	4.12 ± 1.29	4.71 ± 1.97	0.07
Parathormone (pg/mL)	65.93 ± 17.49	110.24 ± 19.81	0.02
Vitamin D (ng/mL)	37.93 ± 8.52	27.52 ± 7.13	0.22
Alkaline phosphatase (U/L)	95.16 ± 6.33	84.60 ± 9.57	0.36
Complement
C3 (mg/dL)	95.60 ± 12.09	40.18 ± 7.80	< 0.001
C4 (mg/dL)	19.90 ± 3.33	5.55 ± 1.65	< 0.001
Positive antinuclear antibody	50 (100)	50 (100)	-
Positive anti-double-stranded DNA	50 (100)	50 (100)	-

HPF: High-power field; LN: Lupus nephritis.

Table 3 Radiological characteristics of the studied groups, n (%)/mean ± SD

Variables	Inactive LN group (n = 50)	Active LN group (n = 50)	P value
Renal echogenicity			0.04
Normal	42 (84)	26 (52)
Echogenic-I	4 (85)	12 (24)
Echogenic I/II	3 (6)	2 (4)
Echogenic-II	1 (2)	6 (12)
Echogenic-II/III	0	4 (8)
Chest radiograph			< 0.001
Normal findings	49 (98)	38 (76)
Pleural effusion	1 (2)	12 (24)
Echocardiography
Ejection fraction (%)	60.10 ± 10.57	63.24 ± 8.21	0.13
Left ventricular end diastolic diameter (cm)	5.26 ± 1.17	5.13 ± 0.99	0.56
Left ventricular end systolic diameter (cm)	3.50 ± 0.99	3.46 ± 0.73	0.18
Pulmonary artery systolic pressure (mmHg)	34.85 ± 11.93	32.91 ± 6.04	0.09
Left ventricular diastolic dysfunction	3 (8.6)	4 (11.4)	0.40
Renal biopsy LN classes			< 0.001
Class-I	18 (36)	1 (2)
Class-II	28 (56)	9 (18)
Class-III	0	2 (4)
Class-IV	3 (6)	21 (42)
Class-V	1 (2)	17 (34)

LN: Lupus nephritis.

Table 4 Bone mineral density among the studied groups, n (%)/mean ± SD

Variables	Inactive LN group (n = 50)	Active LN group (n = 50)	P value
Dual-energy X-ray absorptiometry scan (g/cm2)	0.56 ± 0.16	0.42 ± 0.19	< 0.001
T score	- 0.36 ± 0.15	-1.53 ± 0.18	< 0.001
Z score	- 0.28 ± 0.14	-1.49 ± 0.22	< 0.001
Class of BMD			< 0.001
Normal BMD	37 (74)	10 (20)
Low BMD	13 (26)	40 (80)

BMD: Bone mineral density; LN: Lupus nephritis.

Table 5 Characteristics of the studied patients based on bone mineral density status, n (%)/mean ± SD

Variables	Normal BMD (n = 47)	Low BMD (n = 53)	P value
Age (years)	28.72 ± 6.58	30.60 ± 7.40	0.18
Sex			0.47
Male	13 (27.7)	16 (30.2)
Female	34 (72.3)	37 (69.8)
Body mass index (kg/m2)	25.91 ± 6.11	21.09 ± 6.89	< 0.001
Duration of disease (years)	5.67 ± 2.67	10.46 ± 3.11	< 0.001
Frothy urine	5 (10.6)	20 (37.7)	0.002
Oliguria/anuria	4 (8.5)	10 (18.9)	0.11
Lower limb edema	6 (12.8)	20 (37.7)	0.002
New-onset hypertension	2 (4.3)	7 (13.2)	0.11
Pulmonary congestion	1 (2.1)	5 (9.4)	0.13
Raised renal chemistry	1 (2.1)	4 (7.5)	0.22
Anasarca	1 (2.1)	1 (1.9)	0.72
Volume overload	1 (2.1)	0 (0.0)	0.47
Renal biopsy lupus nephritis classes			< 0.001
Class-I	16 (34)	3 (5.7)
Class-II	23 (48.9)	14 (26.4)
Class-III	0	2 (3.8)
Class-IV	3 (6.4)	21 (39.6)
Class-V	5 (10.6)	13 (24.5)

BMD: Bone mineral density.

Table 6 Laboratory characteristics of the studied patients based on bone mineral density status, n (%)/mean ± SD

Variables	Normal BMD (n = 47)	Low BMD (n = 53)	P value
Random blood sugar (mg/dL)	98.26 ± 15.06	107.42 ± 15.41	< 0.001
Complete blood count
Hemoglobin (g/dL)	9.25 ± 1.84	8.75 ± 1.41	0.13
Leucocytes (103/μl)	7.14 ± 2.40	6.54 ± 2.76	0.25
Platelets (103/μL)	293.74 ± 87.80	248.49 ± 104.66	0.02
Neutrophil/Lymphocyte ratio	1.22 ± 0.38	2.67 ± 0.56	< 0.001
Platelets/Lymphocytes ratio	156.89 ± 34.90	245.09 ± 56.90	< 0.001
Kidney function tests
Blood urea nitrogen (mg/dL)	19.14 ± 4.03	17.89 ± 1.76	0.78
Creatinine (μmol/L)	100.37 ± 13.97	214.60 ± 25.65	< 0.001
Proteinuria (mg/day)	2158.98 ± 276	3343.40 ± 362.98	0.01
Glomerular filtration rate (mL/minute/1.73 m2)	81.92 ± 32.64	63.68 ± 41.67	0.01
Urine analysis
Hematuria (HPF)	13.26 ± 3.64	9.23 ± 1.98	0.31
Pyuria (HPF)	10.11 ± 3.47	13.46 ± 2.31	0.24
Albuminuria			0.62
0	6 (12.8)	4 (7.5)
+	17 (36.2)	17 (32.1)
++	20 (42.6)	27 (50.9)
+++	3 (6.4)	5 (9.4)
++++	1 (2.1)	0 (0.0)
Coagulation profile
Prothrombin time (seconds)	11.88 ± 1.53	12.21 ± 176	0.43
Prothrombin concentration (%)	93.15 ± 13.93	94.11 ± 17.87	0.81
International normalized ratio	1.03 ± 0.17	1.03 ± 0.09	0.97
Bone parameters
Calcium (mg/dL)	8.01 ± 0.64	7.94 ± 0.65	0.55
Phosphorus (mg/dL)	4.07 ± 1.19	4.23 ± 1.98	0.56
Parathormone (pg/mL)	72.64 ± 33.56	101.22 ± 18.61	0.16
Vitamin D (ng/mL)	39.90 ± 9.05	22.36 ± 4.84	0.01
Alkaline phosphatase (U/L)	94.47 ± 6.45	85.81 ± 9.26	0.45
Complement
C3 (mg/dL)	100.98 ± 13.99	50.56 ± 12.98	< 0.001
C4 (mg/dL)	23.89 ± 6.78	9.05 ± 1.90	< 0.001

BMD: Bone mineral density; HPF: High-power field.

Table 7 Correlation of fibroblast growth factor-23 with the other variables, n (%)

Variables	Fibroblast growth factor-23
Age (years)	-0.01 (0.90)
Body mass index (kg/m2)	0.03 (0.75)
Duration	-0.14 (0.20)
Random blood sugar (mg/dL)	-0.10 (0.34)
Hemoglobin (g/dL)	-0.03 (0.79)
Leucocytes (103/μL)	0.13 (0.13)
Platelets (103/μL)	0.12 (0.82)
Neutrophil/Lymphocyte ratio	-0.15 (0.17)
Platelets/Lymphocytes ratio	-0.19 (0.20)
Blood urea nitrogen (mg/dL)	0.10 (0.34)
Creatinine (μmol/L)	0.21 (0.06)
Proteinuria (mg/day)	0.01 (0.26)
Glomerular filtration rate (mL/minute/1.73 m2)	0.09 (0.51)
Urine analysis
Hematuria (HPF)	0.06 (0.53)
Pyuria (HPF)	-0.04 (0.77)
Albuminuria	-0.18 (0.48)
Coagulation profile
Prothrombin time (seconds)	-0.02 (0.86)
Prothrombin concentration (%)	-0.15 (0.17)
International randomized ratio	0.10 (0.34)
Bone parameters
Calcium (mg/dL)	0.14 (0.26)
Phosphorus (mg/dL)	0.12 (0.51)
Parathormone (pg/mL)	-0.11 (0.08)
Vitamin D (ng/mL)	0.12 (0.53)
Alkaline phosphatase (U/L)	-0.19 (0.17)
Complement
C3 (mg/dL)	-0.14 (0.92)
C4 (mg/dL)	-0.08 (0.48)
Echocardiography
Ejection fraction (%)	0.10 (0.38)
Left ventricular end diastolic diameter (cm)	0.03 (0.76)
Left ventricular end systolic diameter (cm)	-0.18 (0.10)
Pulmonary artery systolic pressure (mmHg)	-0.05 (0.62)
Dual-energy X-ray absorptiometry scan (g/cm2)	-0.67 (0.001)

HPF: High-power field.

Table 8 Regression analysis for prediction of low bone mineral density in patients with lupus nephritis

Predictor	Odds ratio	95%CI	P value
Age	0.47	0.33-1.68	0.56
Sex	1.12	0.78-2.22	0.08
Low body mass index	1.42	0.18-1.88	0.68
Disease duration (years)	1.36	0.67-1.69	0.77
Active LN	6.95	1.89-14.21	< 0.001
Serum creatinine (μmol/L)	1.04	0.56-1.08	0.66
Glomerular filtration rate (per 10 mL/minute decrease)	0.69	0.12-2.09	0.90
Proteinuria (per 1 g/day)	1.88	0.59-3.10	0.58
Neutrophil/Lymphocyte ratio	0.41	0.36-4.92	0.71
Platelets/Lymphocytes ratio	0.68	0.71-1.04	0.89
Low C3	0.72	0.38-7.95	0.18
Low C4	0.21	0.17-2.42	0.46
Advanced LN class (III-V)	3.69	2.11-10.34	< 0.001
Fibroblast growth factor-23 (per 10 pg/mL increase)	4.18	1.49-9.90	< 0.001

LN: Lupus nephritis.

Table 9 Receiver operating characteristic curve analysis of fibroblast growth factor-23 for the prediction of low bone mineral density

Parameter	Value
Area under the curve	0.83
95%CI	0.75-0.91
P value	< 0.001
Optimal cutoff value, pg/mL	≥ 135
Sensitivity (%)	81
Specificity (%)	78
Positive predictive value (%)	80
Negative predictive value (%)	79
Accuracy (%)	79.5

Table 10 Regression analysis for the prediction of active lupus nephritis

Predictor	Odds ratio	95%CI	P value
Age	1.13	0.34-1.67	0.44
Sex	1.01	0.88-2.01	0.12
Low body mass index	0.67	0.34-1.34	0.40
Disease duration (years)	0.98	0.22-1.45	0.60
Serum creatinine (μmol/L)	0.67	0.11-1.68	0.76
Glomerular filtration rate (per 10 mL/minute decrease)	1.30	0.59-2.11	0.21
Proteinuria (per 1 g/day)	1.22	0.70-2.44	0.89
Neutrophil/Lymphocyte ratio	0.78	0.54-2.18	0.46
Platelets/Lymphocytes ratio	1.47	1.11-1.89	0.01
Low C3	1.69	1.49-1.19	0.01
Low C4	1.10	0.70-2.32	0.09
Fibroblast growth factor-23 (per 10 pg/mL increase)	2.18	1.22-4.45	< 0.001

Table 11 Receiver operating characteristic curve analysis of fibroblast growth factor-23 for the prediction of active lupus nephritis

Parameter	Value
Area under the curve	0.86
95%CI	0.78-0.94
P value	< 0.001
Optimal cutoff value, pg/mL	≥ 121.10
Sensitivity (%)	79
Specificity (%)	81
Positive predictive value (%)	80.6
Negative predictive value (%)	79.4
Accuracy (%)	80.0
Disease frequency (%)	50