Relationship between selection of dosage forms of vitamin D receptor activators and short-term survival of patients on hemodialysis

Figures & data

Figure 1. Participated patients’ flowchart. (A) Definitions of the three main groups and details of follow-up. (B) Definitions of baseline and follow-up period, and changes of VDRA usage status from the time of initiation of dialysis (baseline) to March 2015 (interim report). IV: intravenous VDRA group; OV: oral VDRA group; NV: without VDRA group.

Table 1. Baseline characteristics and laboratory data before commencing dialysis.

Variables	Without VDRAs (NV, n = 177)	Oral VDRAs (OV, n = 447)	Intravenous VDRAs (IV, n = 343)	p value
Age (years old)	70 [58–76]	68 [60–76]	69 [60–78]	0.472
Female Gender (%)	42.9	31.1	35.9	0.018*
Diabetes Mellitus (%)	63.3	58.8	48.1	0.001*
History of CAD (%)	13.0	15.2	13.5	0.680
History of Stroke (%)	15.8	16.1	12.5	0.342
History of CVD (%)	42.4	43.8	37.9	0.234
History of Malignancy (%)	8.5	8.5	8.5	1
BMI (kg/m^2)	23.0 [20.7–26.1]	23.1 [20.8–25.7]	23.5 [21.3–26.3]	0.248
SBP (mmHg)	155 ± 29	154 ± 25	152 ± 26	0.446
DBP (mmHg)	76 [66–88]	78 [68–88]	78 [68–88]	0.566
Aortic Calc (%)	37.5	33.8	36.3	0.618
Aortic Valve Calc (%)	31.8	28.2	30.3	0.672
Period from dialysis initiation to final observation (days)	1386 [1219–1583]	1352 [1218–1571]	1373 [1217–1569]	0.951
Period from initiation of dialysis to 1st March 2015 (days)	859 [719–1058]	846 [699–1045]	851 [691–1047]	0.656
Follow-up period (Period from 1st March 2015 to final observation) (days)	579 [530–579]	579 [579–579]	579 [579–579]	0.0641
Laboratory data
Hemoglobin (g/dL)	8.9 [8.1–9.4]	9.5 [8.6–10.5]	9.3 [8.2–10.2]	0.0309*
Albumin (g/dL)	3.1 [2.7–3.5]	3.2 [2.8–3.6]	3.3 [2.9–3.6]	0.0915
ALP (IU/L)	215 [173–268]	225 [178–279]	249 [201–319]	<0.001*
Uric Acid (mg/dL)	8.5 [7.6–10.3]	8.5 [7.0–9.8]	8.4 [7.1–10.0]	0.202
BUN (mg/dL)	86.1 [73.0–107.0]	88.0 [73.7–102.6]	87.0 [69.6–107.0]	0.912
Creatinine (mg/dL)	8.45 [7.08–10.0]	8.64 [7.28–10.5]	8.71 [7.21–10.2]	0.372
eGFR (mL/min/1.73m^2)	5.0 [4.0–6.0]	4.95 [4.08–6.08]	4.82 [3.89–6.03]	0.509
Adjusted Calcium (mg/dL)	8.9 [8.1–9.4]	8.8 [8.0–9.3]	8.6 [7.8–9.1]	<0.001*
Phosphate (mg/dL)	6.4 [5.3–7.5]	6.2 [5.1–7.1]	6.1 [5.2–7.1]	0.218
Magnesium (mg/dL)	2.2 [1.9–2.5]	2.2 [1.9–2.4]	2.0 [1.8–2.3]	<0.001*
LDL-C (mg/dL)	86 [66–108]	84 [67–107]	84 [65–109]	0.620
HDL-C (mg/dL)	43 [33–55]	43 [33–54]	42 [33–52]	0.625
TG (mg/dL)	111 [86–148]	113 [83–153]	110 [78–149]	0.402
Ferritin (ng/mL)	131 [76–272]	122 [63–207]	121 [59–203]	0.104
Intact PTH (pg/mL)	244 [158–335]	260 [186–381]	407 [281–591]	<0.001*
1,25(OH)2 vitamin D (pg/mL)	10.1 [7.0–13.7]	12.6 [8.0–17.0]	12.3 [8.2–19.0]	0.0073*
Bicarbonate (mmol/L)	19.4 [17.5–22.6]	19.7 [16.9–22.3]	18.6 [15.9–21.8]	0.0116*
CRP (mg/dL)	0.31 [0.10–1.43]	0.26 [0.10–1.14]	0.24 [0.11–1.09]	0.461
Medication
ACEIs / ARBs (%)	67.8	61.0	60.3	0.211
CCBs (%)	74.6	81.2	83.4	0.052
Loop diuretics (%)	67.2	66.9	65.3	0.866
βBs (%)	31.6	33.8	33.5	0.872
Statins (%)	36.7	40.5	41.1	0.603
VDRAs (%)	0.0	33.1	25.1	<0.001*
Phosphate binders (%)	33.9	42.1	34.1	0.037*
NaHCO3 (%)	42.9	46.5	46.9	0.657
ESAs (%)	85.3	87.2	88.9	0.496
Cause of renal failure
Diabetic nephropathy (%)	53.7	49.4	37.0	<0.001*
Nephrosclerosis (%)	22.0	20.1	30.3	0.0035*
Chronic glomerulonephritis (%)	8.47	13.0	18.1	0.0078*

Data: Mean ± standard deviation; Median [1st quartile to 3rd quartile].

Significant p-values are marked with ‘*’.

VDRA: vitamin D receptor activator, IV: intravenous, CAD: coronary artery disease, CVD: cardiovascular disease, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, Calc: calcification, ALP: alkaline phosphatase, BUN: blood urea nitrogen, eGFR: estimated glomerular filtration rate, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglyceride, PTH: parathyroid hormone, CRP: C reactive protein, ACEI: angiotensin converting enzyme, ARB: angiotensin receptor blocker, CCB, calcium channel blocker, βB: β blocker, VDRA: vitamin D receptor activator, ESA: erythropoiesis stimulating agent.

Figure 2. Kaplan–Meier curves for the cumulative survival between the three groups. Significant differences between the cumulative survival rates were observed for the three groups (p = 0.010). IV: intravenous VDRA group; OV: oral VDRA group; NV: without VDRA group.

Figure 3. Kaplan–Meier curves for the cumulative survival for each cause of death between the three groups. (A) Comparison of mortality from cardiovascular diseases, (B) Comparison of mortality from infection, (C) Comparison of mortality from cancer, (D) Comparison of mortality from non-cancer causes. Significant differences between the non-cancer-related mortality were observed for the three groups (p = 0.027). IV: intravenous VDRA group; OV: oral VDRA group; NV: without VDRA group.

Table 2. Associations of variables with all-cause mortality according to the univariate Cox proportional hazard regression analysis.

Variables	Hazard ratio	95% CI	p-Value
IV vs NV	0.44	0.25–0.76	0.003
OV vs NV	0.75	0.47–1.19	0.225
Age (10 years old)	2.06	1.68–2.53	<0.001
Female Gender	0.54	0.34–0.85	0.005
Diabetes Mellitus	1.12	0.76–1.66	0.560
History of CAD	1.46	0.90–2.38	0.129
History of Stroke	1.59	0.99–2.54	0.054
History of CVD	2.07	1.40–3.05	<0.001
BMI (1 kg/m^2)	0.93	0.88–0.98	0.005
SBP (10 mmHg)	0.99	0.93–1.06	0.801
DBP (10 mmHg)	0.90	0.91–1.00	0.050
Aortic Calc	1.87	1.28–2.75	0.001
Aortic Valve Calc	1.39	0.90–2.16	0.143
Hemoglobin (1 g/dL)	1.10	0.97–1.26	0.131
Albumin (1 g/dL)	0.82	0.60–1.12	0.215
ALP (10 IU/L)	1.01	0.99–1.02	0.289
Uric Acid (mg/dL)	1.00	0.93–1.09	0.945
BUN (10 mg/dL)	1.02	0.96–1.09	0.476
Creatinine (1 mg/dL)	0.86	0.80–0.93	<0.001
eGFR (1 mL/min/1.73m^2)	1.09	1.02–1.16	0.010
Adjusted Calcium (1 mg/dL)	1.38	1.14–1.67	0.001
Phosphate (1 mg/dL)	0.83	0.74–0.94	0.003
Magnesium (1 mg/dL)	1.53	1.07–2.19	0.020
LDL-C (10 mg/dL)	0.96	0.90–1.03	0.220
HDL-C (10 mg/dL)	1.11	0.98–1.24	0.101
TG (10 mg/dL)	1.01	0.98–1.03	0.538
Ferritin* (1 ng/mL)	1.00	0.99–1.00	0.917
Intact PTH* (1 pg/mL)	1.00	0.99–1.00	0.180
Bicarbonate (1 mmol/L)	1.03	0.99–1.08	0.193
CRP* (1 mg/dL)	1.03	0.98–1.07	0.229
ACEIs/ARBs	0.64	0.44–0.94	0.023
CCBs	1.09	0.65–1.80	0.754
Loop diuretics	1.15	0.76–1.75	0.503
βBs	1.00	0.66–1.50	0.989
Statins	0.72	0.47–1.08	0.108
Phosphate binders	0.70	0.46–1.07	0.096
NaHCO3	0.97	0.66–1.43	0.882
ESAs	0.96	0.54–1.72	0.901

CI: confidence interval; IV: intravenous VDRA (vitamin D receptor activator) group; OV: oral VDRA group; NV: without VDRA group; CAD: coronary artery disease; CVD: cardiovascular disease; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; Calc: calcification; ALP: alkaline phosphatase; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; TG: triglyceride; PTH: parathyroid hormone; CRP: C reactive protein; ACEI: angiotensin converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; βB: β blocker; ESA: erythropoiesis stimulating agent.

Table 3. Associations of variables with all-cause mortality according to the multivariate Cox proportional hazard regression analysis.

Variables	Hazard ratio	95%CI	p-Value
IV vs NV	0.46	0.24–0.89	0.022
Age (10 years old)	2.04	1.56–2.67	<0.001
Female gender	0.42	0.23–0.77	0.005
Adjusted calcium (1 mg/dL)	1.49	1.13–1.96	0.005

CI: confidence interval; IV: intravenous VDRA (vitamin D receptor activator) group; NV: without VDRA group.

Adjusted for DM: history of CVD: BMI: DBP: aortic calcification: eGFR: serum phosphate: serum magnesium: and use of ACEIs/ARBs.

DM: diabetes mellitus; CVD: cardiovascular disease; BMI: body mass index; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker.

Figure 4. Hazard ratio for all-cause mortality of each subgroup compared to Subgroup 1. Subjects were subdivided into five subgroups according to which form of VDRA was used at both of two points: initiation of dialysis (at baseline) and March 2015 (at interim report). Subgroup a, which did not use VDRA at both points (NV-NV); Subgroup b, which used oral VDRA in March 2015 but not at dialysis initiation (NV-OV); Subgroup c, which used oral VDRA at both points (OV-OV); Subgroup d, which had not used any forms of VDRA at initiation of dialysis but used intravenous VDRA in March 2015 (NV-IV); and Subgroup e, which had used oral VDRA at initiation of dialysis but used intravenous VDRA in March 2015 (OV-IV). Models were adjusted by several factors as follows: Model 1: adjusted for age and gender. Model 2: adjusted for Model 1 plus comorbidity of diabetes, history of cardiovascular disease, BMI, diastolic blood pressure, aortic calcification, eGFR, serum phosphate, serum magnesium, and use of ACEI / ARB. Model 3: adjusted for Model 2 plus serum adjusted calcium. All-cause mortality rates were significantly lower of the Subgroup d than the Subgroup a in model 1 (HR = 0.30, 95% CI = 0.11–0.86, p = 0.024). All-cause mortality rates were significantly lower for the Subgroup e than the Subgroup a in model 1 and 2 (HR = 0.43, 95% CI = 0.24–0.77, p = 0.004, HR = 0.47, 95% CI = 0.23–0.96, p = 0.038, respectively). Details of hazard ratio (CI) and P value of each subgroup in each model were as follows. Significant p values are marked with * in the figure. In unadjusted model, b (HR = 0.74, 95% CI = 0.45–1.22, p = 0.240); c (HR = 0.77, 95% CI = 0.43–1.40, p = 0.396); d (HR = 0.49, 95% CI = 0.28–0.88, p = 0.016); e (HR = 0.28, 95% CI = 0.099–0.81, p = 0.019). In Model 1, b (HR = 0.82, 95% CI = 0.45–1.49, p = 0.520); c (HR = 0.68, 95% CI = 0.41–1.12, p = 0.127); d (HR = 0.30, 95% CI = 0.105–0.856, p = 0.024); e (HR = 0.43, 95% CI = 0.24–0.768, p = 0.004). In Model 2, b (HR = 0.65, 95% CI = 0.30–1.39, p = 0.265); c (HR = 0.69, 95% CI = 0.37–1.28, p = 0.241); d (HR = 0.37, 95% CI = 0.12–1.105, p = 0.075); e (HR = 0.47, 95% CI = 0.23–0.958, p = 0.038). In Model 3, b (HR = 0.68, 95% CI = 0.32–1.47, p = 0.332); c (HR = 0.74, 95% CI = 0.40–1.38, p = 0.337); d (HR = 0.40, 95% CI = 0.13–1.19, p = 0.098); e (HR = 0.53, 95% CI = 0.26–1.09, p = 0.083). IV: intravenous VDRA group; OV: oral VDRA group; NV: without VDRA group.

Data availability statement

The datasets analyzed during the current study are available from the corresponding author on reasonable request.