Clin Exp Nephrol DOI 10.1007/s10157-014-0994-x
ORIGINAL ARTICLE
Ability of vitamin D receptor activator to prevent pulmonary congestion in advanced chronic kidney disease Shinichi Sueta • Kunio Morozumi • Asami Takeda • Keiji Horike • Yasuhiro Otsuka • Hibiki Shinjo • Minako Murata • Yuki Kato • Kazunori Goto • Daijo Inaguma • and the Aichi cohort study of prognosis in patients newly initiated into dialysis (AICOPP) study group
Received: 4 March 2014 / Accepted: 24 May 2014 Ó Japanese Society of Nephrology 2014
Abstract Background Vitamin D deficiency is common among patients with chronic kidney disease (CKD). However, the benefits of vitamin D supplementation versus vitamin D receptor activator (VDRA) administration have yet to be established. Recently, an association between activated vitamin D and cardiovascular factors was reported. To evaluate the benefits of VDRA in advanced CKD, we analyzed the association between VDRA administration and the prevalence of pulmonary congestion. Methods This retrospective, cross-sectional analysis included patients initiated on dialysis between October 2011 and September 2013 at 17 Japanese institutions. Data from 952 participants were analyzed using a multivariate logistic regression model and a linear regression model. We also analyzed subgroup data for groups classified by selection of peritoneal dialysis or hemodialysis. Results Of the 952 participants, 303 patients received VDRA. VDRA administration was associated with a low prevalence of pulmonary congestion in the multivariate logistic regression model (odds ratio [OR], 0.64; 95 % confidence interval [CI], 0.44–0.94; P = 0.02). There was no significant association between VDRA administration and systolic blood pressure, diastolic blood pressure, or pulse pressure. Subgroup analysis revealed a tendency that VDRA administration was associated with low prevalence of pulmonary congestion in both groups.
S. Sueta (&) K. Morozumi A. Takeda K. Horike Y. Otsuka H. Shinjo M. Murata Y. Kato K. Goto D. Inaguma Kidney Disease Center, Japanese Red Cross Nagoya Daini Hospital, 2–9, Myoken-cho, Showa-ku, Nagoya 466–8650, Japan e-mail: [email protected]
Conclusions In this study, VDRA administration was associated with a low prevalence of pulmonary congestion in patients initiated on dialysis. Appropriate VDRA administration may prevent pulmonary congestion. Keywords Chronic kidney disease Congestive heart failure Vitamin D receptor activator
Introduction The global prevalence of chronic kidney disease (CKD) is increasing and is currently in the range of 8–16 % [1]. In general, vitamin D deficiency is best assessed by the measurement of serum levels of 25-hydroxyvitamin D. Over the past decades, studies have demonstrated that kidney disease is associated with a high incidence of vitamin D insufficiency or deficiency [2, 3]. Vitamin D plays a central role in calcium and phosphorus homoeostasis and bone metabolism. Over the past several decades, studies have shown that activated vitamin D is a potential contributor to the pathophysiology of extraskeletal conditions involving cellular proliferation and differentiation, inflammation, the immune system, and the endocrine system, including the renin-angiotensin-aldosterone system [4–6]. Cohort studies have shown that vitamin D deficiency is associated with albuminuria and an increased prevalence of cardiovascular disease and mortality [7, 8]. Furthermore, several studies have shown an association between vitamin D deficiency and other traditional cardiovascular risk factors such as hypertension, insulin resistance, diabetes mellitus, and dyslipidemia [4, 5, 9]. An association has also been reported to exist between vitamin D deficiency and a poor prognosis in heart failure [10]. A recent study reported
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that vitamin D deficiency is independently associated with a high risk of renal disease progression in patients with type II diabetic nephropathy [11]. Finally, an association between mortality and vitamin D deficiency has been demonstrated in both dialysis- and non-dialysis-dependent CKD [7, 12]. In the general population, the exogenous administration of vitamin D has been shown to reduce the risk of falls and fractures and to correct calcium- and phosphorus-related abnormalities as well as secondary hyperparathyroidism [13]. A recent systematic review reported that moderate to high dose vitamin D supplementation reduced cardiovascular disease risk [14]. Considering that vitamin D receptor activation and the renin-angiotensin-aldosterone system are related, we hypothesized that the intake of a vitamin D receptor activator (VDRA) could prevent pulmonary congestion in patients initiated on dialysis [15]. We therefore performed a cross-sectional study to examine the association of VDRA administration with the prevalence of pulmonary congestion in patients newly initiated into dialysis across 17 Japanese facilities.
Subjects and methods Study design, size, and subjects This study used a retrospective, multicenter, cross-sectional design. We examined 952 subjects from a total of 1,527 CKD patients who were newly initiated on peritoneal dialysis (PD) or hemodialysis (HD) between the first day of October 2011 and the last day of September 2013 at a center affiliated with our study. Of the total 1,527 patients, 575 patients were excluded from the study for the following reasons: the follow-up period was shorter than three months or unknown (309 patients), the selected renal replacement therapy was transplantation or unknown (10 patients), and data on the timeline of the first dialysis treatment were insufficient (256 patients). Compared to patients who were included in this study, excluded patients had a higher prevalence of pulmonary congestion (37.5 and 26.9 %, respectively; P \ 0.001) and a lower frequency of VDRA use (19.0 and 31.8 %, respectively; P \ 0.001). There was no significant difference at sex and age. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMINCTR) under trial identification no. UMIN C000007096 and was approved and registered by the Institutional Review Board of Japanese Red Cross Nagoya Daini Hospital for Clinical Research (IRB20110823-3). Permission for the use of medical records was obtained from the institutional review board of each institution.
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Data collection Demographic and medical data, including age, sex, medical history, comorbid conditions, the length of nephrology follow-up, and hematological data were obtained from medical records compiled by the participating nephrologists. Pulmonary congestion was assessed by the presence of dyspnea or hypoxia with congestion or radiographic findings of pleural effusion at the time of initiation on dialysis. All participating nephrologists met the requirements for a Board Certified Nephrologist as outlined by the Japanese Society of Nephrology and the Japanese Society of Dialysis Therapy. Predictor variables, outcome variables, and explanatory variables The predictor variable was VDRA administration at the time of the first dialysis treatment. The main outcome variable was the prevalence of pulmonary congestion among patients newly initiated on dialysis. Other outcome variables, systolic and diastolic blood pressure, and pulse pressure, were obtained at the time of dialysis treatment initiation. From our data set, the following were selected as explanatory variables: age; sex; selection of PD as renal replacement therapy; use of a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), an angiotensin-converting enzyme inhibitor, another antihypertensive drug, a loop diuretic, thiazide diuretic, an erythropoiesis-stimulating agent (ESA), or a statin; quintiles of serum-corrected calcium; quintiles of serum phosphorus; quintiles of serum intact parathyroid hormone (iPTH); quintiles of serum total cholesterol concentration; serum uric acid concentration; serum C reactive protein (CRP) concentration; serum albumin concentration; hemoglobin concentration; quintiles of body mass index; medical history of ischemic heart disease (IHD); cause of end-stage renal disease; and length of nephrology follow-up. We divided the length of nephrology follow-up by 30 for use in our analysis. Statistical analyses Statistical analyses were performed using JMPÒ9 software (SAS Institute Inc., Cary, NC, USA). Baseline data are described as mean ± standard deviation, median, or frequency, as appropriate. Between-group differences and the Chi-squared test were used for categorical variables. The t test was used for continuous variables with approximately normal distributions, and the Mann–Whitney U test was used for those with skewed distributions. A multiple logistic regression analysis was used to identify factors influencing pulmonary congestion, and a multiple linear regression analysis was used for systolic and diastolic
Clin Exp Nephrol Table 1 Comparison of baseline characteristics between patients who received and did not receive vitamin D receptor activator treatment
Characteristics
All patients (N = 952)
VDRA? (N = 303)
VDRA(N = 649)
P value
Age (years)
67.7 ± 12.7
65.7 ± 12.5
68.6 ± 12.7
\0.001
Male sex
657 (69.0 %)
198 (65.3 %)
459 (70.7 %)
0.10
Length of follow-up with nephrologist (days)
815 (381–1597)
941 (447–1875)
759 (366–1457)
0.007
Pulmonary congestion
256 (26.9 %)
58 (19.1 %)
198 (30.5 %)
B0.001
Cause of end-stage renal disease
0.003
Glomerulonephritis
159 (16.7 %)
60 (19.8 %)
99 (15.2 %)
Diabetes mellitus nephropathy Hypertension-related renal disease
428 (45.0 %) 243 (25.5 %)
124 (40.9 %) 66 (21.8 %)
304 (46.8 %) 177 (27.3 %)
132 (13.0 %)
56 (17.6 %)
76 (10.9 %)
Peritoneal dialysis
Other
71 (7.5 %)
39 (12.9 %)
32 (4.9 %)
Medical history of ischemic heart disease
155 (16.3 %)
39 (12.9 %)
116 (17.9 %)
\0.001 0.05
Body mass index (kg/m2)
23.6 ± 4.1
23.5 ± 4.3
23.6 ± 4.1
0.77
Systolic blood pressure
152 ± 25
152 ± 25
151 ± 24
0.48
Diastolic blood pressure
78 ± 14
79 ± 14
78 ± 13
0.25
Pulse pressure
74 ± 19
74 ± 19
74 ± 19
0.31
Medications Angiotensin II receptor blocker
597 (62.7 %)
195 (64.4 %)
402 (61.9 %)
0.47
Angiotensin-converting enzyme inhibitor
93 (9.8 %)
29 (9.6 %)
64 (9.9 %)
0.89
Calcium channel blocker
798 (83.8 %)
258 (85.1 %)
540 (83.2 %)
0.45
Other antihypertensive drug
445 (46.7 %)
143 (47.2 %)
302 (46.5 %)
0.85
Loop diuretic
665 (69.9 %)
199 (65.7 %)
466 (71.8 %)
0.06
Thiazide diuretic
237 (24.9 %)
62 (20.5 %)
175 (27.0 %)
0.03
Statin
424 (44.5 %)
128 (42.2 %)
296 (45.6 %)
0.33
Erythropoiesis-stimulating agent
899 (94.4 %)
284 (93.7 %)
615 (94.8 %)
0.52
Laboratory parameters
Data are presented as percentage, mean ± standard deviation, and median (interquartile range) a
Corrected calcium was calculated using the formula: corrected calcium = serum calcium (mmol/l) ? 0.02*(40-albumin)
Hemoglobin (g/L)
95 ± 14
97 ± 17
94 ± 14
0.001
Total protein (g/L)
62 ± 7
62 ± 7
6.1 ± 7
0.04 \0.001
Albumin (g/L)
32 ± 6
34 ± 6
32 ± 6
Total cholesterol (mg/dL) Blood urea nitrogen (mmol/L)
160 ± 42 33 ± 10
158 ± 39 32 ± 9
161 ± 44 34 ± 10
0.37 0.01
Creatinine (lmol/L)
795 ± 252
804 ± 259
791 ± 249
0.46
Sodium (mmol/L)
138 ± 4
138 ± 4
138 ± 4
0.79 0.46
Potassium (mmol/L)
4.5 ± 0.8
4.5 ± 0.7
4.5 ± 0.8
Chlorine (mmol/L)
104 ± 6
105 ± 6
104 ± 6
0.28
Corrected calciuma
2.10 ± 0.25
2.13 ± 0.25
2.09 ± 0.25
0.008
Phosphorous (mmol/L)
2.05 ± 0.74
2.04 ± 1.02
2.05 ± 0.56
0.84
Intact parathyroid hormone (ng/L)
360 ± 264
332 ± 280
374 ± 255
0.02
Uric acid (lmol/L)
507 ± 135
491 ± 109
515 ± 145
0.01
C reactive protein (nmol/L)
1.90 (0.76–9.62)
1.90 (0.67–7.24)
2.29 (0.95–10.38)
0.03
blood pressure and pulse pressure. Significant variables in the unadjusted analysis and other important variables were selected for further multivariate analysis. In this study, subgroups were used to further analyze the data for groups classified by selection of PD or HD. A difference was considered significant if the P value was \5 %.
Results Baseline characteristics The analysis included 303 participants, 31.8 % of whom were administered VDRA (Table 1). Compared to patients
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Clin Exp Nephrol Table 2 Association between vitamin D receptor activator supplementation and the prevalence of pulmonary congestion
Univariate model
Multivariate model
OR (95 % CI)
P value
OR (95 % CI)
P value
Vitamin D receptor activator
0.54 (0.39–0.75)
\0.001
0.64 (0.44–0.94)
Age (10 years)
1.28 (1.13–1.44)
\0.001
1.17 (1.01–1.37)
0.04
Male sex
0.83 (0.61–1.12)
0.23
0.70 (0.49–0.99)
0.04
Length of follow-up with nephrologist
0.99 (0.99–1.00)
0.002
1.00 (0.99–1.00)
0.42
0.02
Cause of end-stage renal disease Glomerulonephritis
1.00 (reference)
Diabetes mellitus nephropathy
2.28 (1.44–3.61)
\0.001
1.00 (reference) 1.45 (0.86–2.46)
Hypertension-related renal disease
2.10 (1.28–3.45)
0.003
1.19 (0.67–2.11)
0.55
Other
0.96 (0.51–1.81)
0.90
0.74 (0.36–1.49)
0.39
Peritoneal dialysis
0.42 (0.21–0.84)
0.01
0.90 (0.42–1.92)
0.79
Medical history of ischemic heart disease Medication
2.22 (1.55–3.17)
\0.001
1.46 (0.96–2.23)
0.08
Angiotensin II receptor blocker
0.60 (0.45–0.81)
\0.001
0.62 (0.44–0.87)
\0.005
Angiotensin-converting enzyme inhibitor
0.67 (0.40–1.14)
0.14
0.76 (0.43–1.92)
0.35
Calcium channel blocker
0.87 (0.60–1.28)
0.48
0.87 (0.56–1.37)
0.55
0.17
Other antihypertensive drug
1.42 (1.07–1.89)
0.02
1.27 (0.91–1.75)
0.16
Loop diuretic
2.59 (1.80–3.71)
\0.001
2.06 (1.38–3.07)
\0.001
Thiazide diuretic
1.65 (1.20–2.26)
0.002
1.34 (0.93–1.93)
0.11
Statin
1.41 (1.06–1.88)
0.20
1.24 (0.89–1.73)
0.21
Erythropoiesis-stimulating agent
0.84 (0.46–1.54)
0.58
0.75 (0.37–1.50)
0.41
Hemoglobin (10 g/L)
0.77 (0.69–0.85)
\0.001
0.81 (0.72–0.91)
\0.001
Albumin (10 g/L)
0.58 (0.45–0.74)
\0.001
0.87 (0.64–1.18)
0.37
Uric acid(10 lmol/L)
1.01 (1.00–1.02)
0.10
1.00 (0.99–1.00)
0.25
C reactive protein (nmol/L)
1.01 (1.01–1.02)
\0.001
1.01 (1.00–1.02)
\0.001
Q1 (\1.91) Q2 (1.91 B \2.08)
0.90 (0.57–1.41) 1.23 (0.79–1.90)
0.63 0.16
1.05 (0.62–1.76) 1.28 (0.79–2.07)
0.86 0.31
Q3 (2.08 B \2.19)
1.00 (reference)
Q4 (2.19 B \2.29)
0.79 (0.50–1.25)
0.31
0.79 (0.47–1.30)
0.35
Q5 (C2.29)
0.69 (0.43–1.09)
0.11
0.69 (0.41–1.19)
0.18
Q1 (\1.61)
1.69 (1.08–2.67)
0.02
1.90 (1.14–3.17)
0.01
Q2 (1.61 B \1.84)
1.53 (0.95–2.45)
0.08
1.55 (0.90–2.66)
0.11
Q3 (1.84 B \2.13)
1.00 (reference)
Q4 (2.13 B \2.49)
1.57 (0.99–2.48)
0.06
1.53 (0.92–2.55)
0.10
Q5 (C2.49)
1.34 (0.83–2.15)
0.23
1.35 (0.79–2.30)
0.27
Laboratory parameters
Quintiles of corrected calciuma
1.00 (reference)
Quintiles of phosphorous (nmol/L)
Analyses were performed using a multivariate logistic regression model OR odds ratio, CI confidence interval a
Corrected calcium was calculated using the formula: corrected calcium = serum calcium(mmol/ l) ? 0.02 9 (40-albumin)
Quintiles of intact parathyroid hormone (10 ng/L) Q1 (\169)
0.90 (0.57–1.43)
0.66
1.01 (0.59–1.73)
0.99
Q2 (169 B \257)
1.05 (0.67–1.66)
0.82
1.00 (0.60–1.65)
0.98
Q3 (257 B \352)
1.00 (reference)
Q4 (352 B \498) Q5 (C498)
1.45 (0.93–2.26) 0.83 (0.52–1.33)
who were not administered VDRA, those administered VDRA were younger (65.7 ± 12.5 and 68.6 ± 12.7 years, respectively; P = 0.001), had a lower frequency of
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1.00 (reference)
1.00 (reference) 0.10 0.44
1.44 (0.88–2.37) 0.85 (0.50–1.45)
0.14 0.55
diabetes mellitus nephropathy (40.9 and 46.8 %), a lower frequency of hypertension-related renal disease (21.8 and 27.3 %), a lower frequency of a medical history of IHD
Clin Exp Nephrol Table 3 Comparison of baseline characteristics between patients who selected hemodialysis and peritoneal dialysis Characteristics
Hemodialysis (N = 881)
Peritoneal dialysis (N = 71)
P value
Male sex
607 (68.9 %)
50 (70.4)
0.79
Age
68.3 ± 12.5
60.5 ± 13.2
\0.001
Vitamin D receptor activator
264 (30.0 %)
39 (54.9 %)
\0.001
Pulmonary congestion
246 (27.9 %)
10 (14.1 %)
0.01
Data are presented as percentage, mean ± standard deviation
Fig. 1 Various medications or medical conditions significantly associated with the prevalence of congestive heart failure. VDRA vitamin D receptor activator, ARB angiotensin II receptor blocker, OR odds ratio values in parentheses are the 95 % confidence intervals
(12.9 and 17.9 %, respectively; P = 0.05), and a longer follow-up period with a nephrologist (median 941; interquartile range 447–1,875 versus median 759; interquartile range 366–1,457; P = 0.007). PD was selected for renal replacement therapy with a higher frequency in the VDRA group (12.9 and 4.9 %, respectively; P \ 0.001). The VDRA group also tended to have higher levels of hemoglobin, total serum protein, serum albumin, and serumcorrected calcium, and lower levels of serum blood urea nitrogen, serum iPTH, serum CRP, and serum uric acid. Association between VDRA administration and the prevalence of pulmonary congestion In our cohort, 256 patients had pulmonary congestion (26.9 %). The patients who received VDRA had a lower prevalence of pulmonary congestion than the group that did not (58 [19.1 %] and 198 [30.5 %], respectively; P \ 0.001). Table 2 shows the unadjusted and multivariable-adjusted associations between VDRA administration and the prevalence of pulmonary congestion. After adjusting for potential confounders, the internal use of VDRA was significantly associated with a lower prevalence of pulmonary congestion (odds ratio [OR], 0.64; 95 % confidence interval [CI], 0.44–0.94; P = 0.02). Figure 1 shows various medications or medical conditions that were significantly associated with the prevalence of pulmonary congestion. In this analysis, male sex, ARB use, and higher hemoglobin levels were associated with a low prevalence of pulmonary congestion. Conversely, the use of loop diuretics, older age, higher serum CRP levels, and first quintile of phosphorus were associated with a high prevalence of pulmonary congestion.
Table 4 Univariate analysis of the association between vitamin D receptor activator supplementation and pulmonary congestion in patients with hemodialysis and peritoneal dialysis OR (95 % CI)
P value
Hemodialysis
0.61 (0.43–0.85)
0.004
Peritoneal dialysis
0.16 (0.03–0.83)
0.03
Analyses were performed using a univariate logistic regression model OR odds ratio, CI confidence interval
Subgroup analysis In this study, we also used subgroup analysis. The patients who selected PD had a lower prevalence of pulmonary congestion (10 [14.1 %] and 246 [27.9 %], respectively; P = 0.01) and a higher frequency of VDRA administration (39 [54.9 %] and 264 [30.0 %], respectively; P \ 0.001) than the group that did not (Table 3). In the group of selection of HD, we used univariate logistic regression model and multivariate logistic regression model (Table 4). However, we used only unadjusted analysis because of the small sample size in the group with PD (Table 4). We detected a significant association between VDRA with pulmonary congestion by unadjusted analysis, in both HD patients (OR 0.61; 95 % CI 0.43–0.85; P = 0.004) and PD patients (OR 0.16; 95 % CI 0.03–0.83; P = 0.03). In this analysis, participants with PD had a lower OR for pulmonary congestion than those with HD. In multivariate analysis for the group with HD, we did not detect a significant association between VDRA and pulmonary congestion (OR 0.69; 95 % CI 0.47–1.01; P = 0.05) (Table 5). Association of VDRA administration with predialysis systolic and diastolic blood pressure and pulse pressure on first dialysis The average systolic blood pressure, diastolic blood pressure, and pulse pressure values were 152, 79, and 74 mmHg, respectively, in the VDRA group and 151, 78,
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Clin Exp Nephrol Table 5 Multivariate analysis of predictors for pulmonary congestion in patients with hemodialysis
Table 5 continued OR (95 % CI)
P value
0.74 (0.43–1.29)
0.29
Q1 (\1.61)
2.00 (1.18–3.37)
0.01
0.10
Q2 (1.61 B \1.84)
1.66 (0.95–2.88)
0.07
0.36
Q3 (1.84 B \2.13)
1.00 (reference)
Q4 (2.13 B \2.49)
1.57 (0.93–2.64)
0.09
Q5 (C2.49)
1.31 (0.76–2.26)
0.34
OR (95 % CI)
P value
Vitamin D receptor activator
0.69 (0.47–1.01)
0.05
Age (10 years)
1.19 (1.02–1.40)
0.03
Male sex
0.74 (0.51–1.06)
Length of follow-up with nephrologist
0.99 (0.99–1.00)
Q5 (C2.29) Quintiles of phosphorous(nmol/L)
Cause of end-stage renal disease Glomerulonephritis Diabetes mellitus nephropathy
1.00 (reference) 1.50 (0.87–2.59)
Hypertension-related renal disease
1.18 (0.65–2.13)
0.56
Q1 (\169)
Other
0.72 (0.35–1.50) 1.32 (0.86–2.04)
0.38
Q2 (169 B \257)
0.21
Q3 (257 B \352)
1.00 (reference)
Q4 (352 B \498)
1.45 (0.88–2.40)
0.15
Angiotensin II receptor blocker
0.63 (0.44–0.88)
0.007
Q5 (C498)
0.90 (0.53–1.56)
0.72
Angiotensin-converting enzyme inhibitor
0.82 (0.45–1.48)
0.51
Calcium channel blocker
1.00 (0.63–1.59)
0.99
Other antihypertensive drug
1.26 (0.91–1.76)
0.17
Loop diuretic
1.88 (1.25–2.82)
0.002
Thiazide diuretic
1.28 (0.88–1.86)
0.19
Statin
1.24 (0.88–1.75)
0.21
Erythropoiesis-stimulating agent
0.82 (0.39–1.72)
0.60
Hemoglobin (10 g/L)
0.79 (0.69–0.89)
\0.001
Albumin (10 g/L)
0.88 (0.65–1.20)
0.43
Uric acid (10 lmol/L)
1.00 (1.00–1.01)
0.24
C reactive protein (nmol/L)
1.01 (1.00–1.02)
\0.001
Q1 (\1.91)
1.13 (0.66–1.93)
0.66
Q2 (1.91 B \2.08)
1.35 (0.82–2.21)
0.24
Q3 (2.08 B \2.19)
1.00 (reference)
Q4 (2.19 B \2.29)
0.87 (0.52–1.46)
Medical history of ischemic heart disease
0.14
Quintiles of intact parathyroid hormone (10 ng/L)
Medication
Laboratory parameters
Quintiles of corrected calciuma
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0.59
1.03 (0.60–1.80) 0.92 (0.55–1.55)
0.90 0.75
Analyses were performed using a multivariate logistic regression model OR odds ratio, CI confidence interval a
Corrected calcium was calculated using the formula: corrected calcium = serum calcium (mmol/l) ? 0.02 9 (40-albumin)
and 74 mmHg, respectively, in the non-VDRA group. VDRA administration was not significantly associated with systolic blood pressure (b value 1.20; 95 % CI -2.00 to 4.42; P = 0.48), diastolic blood pressure (b value 0.08; 95 % CI -3.83 to 3.97; P = 0.98), or pulse pressure (b value 0.44; 95 % CI -3.69 to 4.58; P = 0.85) by multivariate linear regression analysis.
Discussion In this cross-sectional study, we found an association between VDRA administration and a low prevalence of pulmonary congestion in newly initiated dialysis patients in Japan. To the best of our knowledge, this is the first study to investigate the association between VDRA administration and the prevalence of pulmonary congestion in patients initiated on dialysis. In our cohort, the baseline characteristics of patients treated with VDRA reflected a lower risk for pulmonary congestion. Patients administered VDRA were younger, had a lower frequency of diabetes mellitus nephropathy, a
Clin Exp Nephrol
higher frequency of PD, a lower frequency of hypertension-related renal disease, a lower frequency of a medical history of HID, and a longer follow-up period with a nephrologist than those who did not receive VDRA. The VDRA group also tended to have higher hemoglobin and serum albumin levels. However, in a multivariate adjusted analysis using these factors as explanatory variables, our results also showed a significantly lower prevalence of pulmonary congestion in patients who received VDRA (OR 0.64; 95 % CI 0.44–0.94; P = 0.02). We found other significant associations between pulmonary congestion and age, sex, ARB use, loop diuretic use, hemoglobin, serum CRP, and serum phosphorus in the multivariate analysis. The association between CHEF and the use of loop diuretics may imply a medical history of CHEF. These associations are generally known or under consideration. Thus, our result showed that VDRA administration was a strong predictor, equal to known predictors of pulmonary congestion. In subgroup analysis, the univariate analysis showed that administration of VDRA was associated with pulmonary congestion in both groups. Within the group with HD, we were not able to detect significant association by the multivariate analysis. However, we found the tendency that VDRA was associated with low prevalence of pulmonary congestion in the multivariate analysis. Thus, we believe that a significant association could be detected if there were more participants. On the basis of many reports, vitamin D has been newly shown to act as a hormone that negatively regulates the renin-angiotensin-aldosterone system [15]. A national survey in the United States revealed that vitamin D deficiency is associated with a higher prevalence of cardiovascular disease and mortality [7]. In the general population, it was reported that moderate to high dose vitamin D supplementation could reduce cardiovascular disease risk [14]. It is therefore considered that the high risk of cardiovascular disease in CKD patients indicates that there may be significant potential benefits to vitamin D supplementation or VDRA administration in this population [16]. In fact, a cross-sectional study in pediatric CKD patients reported an association of vitamin D deficiency with increased left ventricular mass and diastolic dysfunction [17]. However, no study has concluded whether vitamin D supplementation or VDRA administration improved cardiovascular outcomes in CKD patients [18]. Our study demonstrated the association between VDRA and pulmonary congestion. We suspect our result implies that the potential ability of VDRA to prevent congestive heart failure resulted in the association. In our cohort, the average serum-corrected calcium concentration was significantly higher in the VDRA group than in the other group, but the difference was very small
(2.13 vs. 2.09). In general, clinical symptoms due to hypercalcemia are a well-known adverse effect of VDRA use. We did not observe such a tendency in our cohort. In accordance with our results, we suspect that appropriate VDRA administration can prevent pulmonary congestion without adverse effects in CKD patients. Interestingly, we did not detect any association between VDRA administration and systolic blood pressure, diastolic blood pressure, or pulse pressure. This signifies that the lower prevalence of pulmonary congestion in patients administered VDRA did not depend on these three variables. We hypothesize that there may be a relationship between vitamin D receptor activation and several hemodynamic factors such as the circadian rhythm of blood pressure, but this has yet to be elucidated. There were some limitations to this study. First, we did not measure serum levels of 25-hydroxyvitamin D. Therefore, the benefits of VDRA administration for patients with a vitamin D deficiency were unclear. Second, we had no data on VDRA types and dosage, or on the duration of VDRA administration. The relationship between various vitamin D activators and mortality among hemodialysis patients was demonstrated recently [19, 20]. It is also possible that different dosages of VDRA affect clinical outcomes differently [21]. Third, because of the retrospective nature of this study, we could not analyze the association between VDRA administration and the low prevalence of pulmonary congestion using other important covariates such as ejection fraction or cardiac output. In our study, we cannot deny the presence of some selection bias in classifying patients who did or did not receive VDRA. Finally, owing to the retrospective, cross-sectional design of this study, we can only infer associations, and not causality, from our results. By presenting these results, we conclude that appropriate VDRA administration may prevent pulmonary congestion in patients initiated on dialysis. We hypothesize that there is a possibility that appropriate VDRA administration can provide significant benefits in CKD patients. Acknowledgments We acknowledge the support of the following investigators, members of the Aichi cohort study of prognosis in patients newly initiated into dialysis (AICOPP), who participated in this study: Hirofumi Tamai (Anjo Kosei Hospital), Tomohiko Naruse (Kasugai Municipal Hospital), Kei Kurata (Tosei General Hospital), Hideto Oishi (Komaki City Hospital), Isao Aoyama (Social Insurance Chukyo Hospital), Hiroshi Ogawa (Shinseikai Daiichi Hospital), Hiroko Kushimoto(Chita City Hospital), Hideaki Shimizu (Chubu-Rosai Hospital), Junichiro Yamamoto (Tsushima City Hospital), Hisashi Kurata (Toyota Kosei Hospital), Taishi Yamakawa (Toyohashi Municipal Hospital), Takaaki Yaomura (Nagoya Medical Center), Hirotake Kasuga (Nagoya Kyouritsu Hospital), Shizunori Ichida (Japanese Red Cross Nagoya Daiichi Hospital), Shoichi Maruyama (Nagoya University Graduate School of Medicine), Noritoshi Kato (Nagoya University Graduate School of Medicine), Seiichi Matsuo (Nagoya University Graduate School of Medicine), Shigehisa Koide
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Clin Exp Nephrol (Fujita Health University Hospital), and Yukio Yuzawa (Fujita Health University Hospital). Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:208. 2. LaClair RE, Hellman RN, Karp SL, et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney Dis. 2005;45:1026–33. 3. Bhan I, Burnett-Bowie SA, Ye J, Tonelli M, Thadhani R. Clinical measures identify vitamin D deficiency in dialysis. Clin J Am Soc Nephrol. 2010;5:460–7. 4. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49:1063–9. 5. Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006;9:650–6. 6. Jones G. Expanding role of vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1a-hydroxylase in the classical and nonclassical actions of 1a,25dihydroxyvitamin D3. Semin Dial. 2007;20:316–24. 7. Mehrotra R, Kermah DA, Salusky IB. Chronic kidney disease, hypovitaminosis D, and mortality in the United States. Kidney Int. 2009;76:977–83. 8. De Boer I, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25(OH)D levels and albuminuria in the Third National Health and Nutrition Examination Survey(NHANES III). Am J Kidney Dis. 2007;50:69–77. 9. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;11:1159–65.
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10. Liu LC, Voors AA, Van Veldhuisen DJ, et al. Vitamin D status and outcomes in heart failure patients. Eur J Heart Fail. 2011;13:615–25. 11. Ferna´ndez-Jua´rez G, Lun˜o J, Barrio V, et al. 25 (OH) vitamin D levels and renal disease progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system. Clin J Am Soc Nephrol. 2013;8:1870–6. 12. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004–13. 13. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357: 266–81. 14. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152:315–23. 15. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem. 2003;88:327–31. 16. Kilickesmez KO, Abaci O, Okcun B. Chronic kidney disease as a predictor of coronary lesion morphology. Angiology. 2010;61: 344–9. 17. Patange AR, Valentini RP, Gothe MP, Du W, Pettersen MD. Vitamin D deficiency is associated with increased left ventricular mass and diastolic dysfunction in children with chronic kidney disease. Pediatr Cardiol. 2013;34:536–42. 18. Kandula P, Dobre M, Schold JD, Schreiber MJ Jr, Mehrotra R, Navaneethan SD. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol. 2011;6:50–62. 19. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Eng J Med. 2003;31:446–56. 20. Tentori F, Hunt WC, Stidley CA. For the medical directors of Dialysis Clinic Inc: mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70:1858–65. 21. Miller JE, Molnar MZ, Kovesdy CP, et al. Administered paricalcitol dose and survival in hemodialysis patients: a marginal structural model analysis. Pharmacoepidemiol Drug Saf. 2012;21:1232–9.
ORIGINAL ARTICLE
Ability of vitamin D receptor activator to prevent pulmonary congestion in advanced chronic kidney disease Shinichi Sueta • Kunio Morozumi • Asami Takeda • Keiji Horike • Yasuhiro Otsuka • Hibiki Shinjo • Minako Murata • Yuki Kato • Kazunori Goto • Daijo Inaguma • and the Aichi cohort study of prognosis in patients newly initiated into dialysis (AICOPP) study group
Received: 4 March 2014 / Accepted: 24 May 2014 Ó Japanese Society of Nephrology 2014
Abstract Background Vitamin D deficiency is common among patients with chronic kidney disease (CKD). However, the benefits of vitamin D supplementation versus vitamin D receptor activator (VDRA) administration have yet to be established. Recently, an association between activated vitamin D and cardiovascular factors was reported. To evaluate the benefits of VDRA in advanced CKD, we analyzed the association between VDRA administration and the prevalence of pulmonary congestion. Methods This retrospective, cross-sectional analysis included patients initiated on dialysis between October 2011 and September 2013 at 17 Japanese institutions. Data from 952 participants were analyzed using a multivariate logistic regression model and a linear regression model. We also analyzed subgroup data for groups classified by selection of peritoneal dialysis or hemodialysis. Results Of the 952 participants, 303 patients received VDRA. VDRA administration was associated with a low prevalence of pulmonary congestion in the multivariate logistic regression model (odds ratio [OR], 0.64; 95 % confidence interval [CI], 0.44–0.94; P = 0.02). There was no significant association between VDRA administration and systolic blood pressure, diastolic blood pressure, or pulse pressure. Subgroup analysis revealed a tendency that VDRA administration was associated with low prevalence of pulmonary congestion in both groups.
S. Sueta (&) K. Morozumi A. Takeda K. Horike Y. Otsuka H. Shinjo M. Murata Y. Kato K. Goto D. Inaguma Kidney Disease Center, Japanese Red Cross Nagoya Daini Hospital, 2–9, Myoken-cho, Showa-ku, Nagoya 466–8650, Japan e-mail: [email protected]
Conclusions In this study, VDRA administration was associated with a low prevalence of pulmonary congestion in patients initiated on dialysis. Appropriate VDRA administration may prevent pulmonary congestion. Keywords Chronic kidney disease Congestive heart failure Vitamin D receptor activator
Introduction The global prevalence of chronic kidney disease (CKD) is increasing and is currently in the range of 8–16 % [1]. In general, vitamin D deficiency is best assessed by the measurement of serum levels of 25-hydroxyvitamin D. Over the past decades, studies have demonstrated that kidney disease is associated with a high incidence of vitamin D insufficiency or deficiency [2, 3]. Vitamin D plays a central role in calcium and phosphorus homoeostasis and bone metabolism. Over the past several decades, studies have shown that activated vitamin D is a potential contributor to the pathophysiology of extraskeletal conditions involving cellular proliferation and differentiation, inflammation, the immune system, and the endocrine system, including the renin-angiotensin-aldosterone system [4–6]. Cohort studies have shown that vitamin D deficiency is associated with albuminuria and an increased prevalence of cardiovascular disease and mortality [7, 8]. Furthermore, several studies have shown an association between vitamin D deficiency and other traditional cardiovascular risk factors such as hypertension, insulin resistance, diabetes mellitus, and dyslipidemia [4, 5, 9]. An association has also been reported to exist between vitamin D deficiency and a poor prognosis in heart failure [10]. A recent study reported
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that vitamin D deficiency is independently associated with a high risk of renal disease progression in patients with type II diabetic nephropathy [11]. Finally, an association between mortality and vitamin D deficiency has been demonstrated in both dialysis- and non-dialysis-dependent CKD [7, 12]. In the general population, the exogenous administration of vitamin D has been shown to reduce the risk of falls and fractures and to correct calcium- and phosphorus-related abnormalities as well as secondary hyperparathyroidism [13]. A recent systematic review reported that moderate to high dose vitamin D supplementation reduced cardiovascular disease risk [14]. Considering that vitamin D receptor activation and the renin-angiotensin-aldosterone system are related, we hypothesized that the intake of a vitamin D receptor activator (VDRA) could prevent pulmonary congestion in patients initiated on dialysis [15]. We therefore performed a cross-sectional study to examine the association of VDRA administration with the prevalence of pulmonary congestion in patients newly initiated into dialysis across 17 Japanese facilities.
Subjects and methods Study design, size, and subjects This study used a retrospective, multicenter, cross-sectional design. We examined 952 subjects from a total of 1,527 CKD patients who were newly initiated on peritoneal dialysis (PD) or hemodialysis (HD) between the first day of October 2011 and the last day of September 2013 at a center affiliated with our study. Of the total 1,527 patients, 575 patients were excluded from the study for the following reasons: the follow-up period was shorter than three months or unknown (309 patients), the selected renal replacement therapy was transplantation or unknown (10 patients), and data on the timeline of the first dialysis treatment were insufficient (256 patients). Compared to patients who were included in this study, excluded patients had a higher prevalence of pulmonary congestion (37.5 and 26.9 %, respectively; P \ 0.001) and a lower frequency of VDRA use (19.0 and 31.8 %, respectively; P \ 0.001). There was no significant difference at sex and age. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMINCTR) under trial identification no. UMIN C000007096 and was approved and registered by the Institutional Review Board of Japanese Red Cross Nagoya Daini Hospital for Clinical Research (IRB20110823-3). Permission for the use of medical records was obtained from the institutional review board of each institution.
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Data collection Demographic and medical data, including age, sex, medical history, comorbid conditions, the length of nephrology follow-up, and hematological data were obtained from medical records compiled by the participating nephrologists. Pulmonary congestion was assessed by the presence of dyspnea or hypoxia with congestion or radiographic findings of pleural effusion at the time of initiation on dialysis. All participating nephrologists met the requirements for a Board Certified Nephrologist as outlined by the Japanese Society of Nephrology and the Japanese Society of Dialysis Therapy. Predictor variables, outcome variables, and explanatory variables The predictor variable was VDRA administration at the time of the first dialysis treatment. The main outcome variable was the prevalence of pulmonary congestion among patients newly initiated on dialysis. Other outcome variables, systolic and diastolic blood pressure, and pulse pressure, were obtained at the time of dialysis treatment initiation. From our data set, the following were selected as explanatory variables: age; sex; selection of PD as renal replacement therapy; use of a calcium channel blocker (CCB), an angiotensin II receptor blocker (ARB), an angiotensin-converting enzyme inhibitor, another antihypertensive drug, a loop diuretic, thiazide diuretic, an erythropoiesis-stimulating agent (ESA), or a statin; quintiles of serum-corrected calcium; quintiles of serum phosphorus; quintiles of serum intact parathyroid hormone (iPTH); quintiles of serum total cholesterol concentration; serum uric acid concentration; serum C reactive protein (CRP) concentration; serum albumin concentration; hemoglobin concentration; quintiles of body mass index; medical history of ischemic heart disease (IHD); cause of end-stage renal disease; and length of nephrology follow-up. We divided the length of nephrology follow-up by 30 for use in our analysis. Statistical analyses Statistical analyses were performed using JMPÒ9 software (SAS Institute Inc., Cary, NC, USA). Baseline data are described as mean ± standard deviation, median, or frequency, as appropriate. Between-group differences and the Chi-squared test were used for categorical variables. The t test was used for continuous variables with approximately normal distributions, and the Mann–Whitney U test was used for those with skewed distributions. A multiple logistic regression analysis was used to identify factors influencing pulmonary congestion, and a multiple linear regression analysis was used for systolic and diastolic
Clin Exp Nephrol Table 1 Comparison of baseline characteristics between patients who received and did not receive vitamin D receptor activator treatment
Characteristics
All patients (N = 952)
VDRA? (N = 303)
VDRA(N = 649)
P value
Age (years)
67.7 ± 12.7
65.7 ± 12.5
68.6 ± 12.7
\0.001
Male sex
657 (69.0 %)
198 (65.3 %)
459 (70.7 %)
0.10
Length of follow-up with nephrologist (days)
815 (381–1597)
941 (447–1875)
759 (366–1457)
0.007
Pulmonary congestion
256 (26.9 %)
58 (19.1 %)
198 (30.5 %)
B0.001
Cause of end-stage renal disease
0.003
Glomerulonephritis
159 (16.7 %)
60 (19.8 %)
99 (15.2 %)
Diabetes mellitus nephropathy Hypertension-related renal disease
428 (45.0 %) 243 (25.5 %)
124 (40.9 %) 66 (21.8 %)
304 (46.8 %) 177 (27.3 %)
132 (13.0 %)
56 (17.6 %)
76 (10.9 %)
Peritoneal dialysis
Other
71 (7.5 %)
39 (12.9 %)
32 (4.9 %)
Medical history of ischemic heart disease
155 (16.3 %)
39 (12.9 %)
116 (17.9 %)
\0.001 0.05
Body mass index (kg/m2)
23.6 ± 4.1
23.5 ± 4.3
23.6 ± 4.1
0.77
Systolic blood pressure
152 ± 25
152 ± 25
151 ± 24
0.48
Diastolic blood pressure
78 ± 14
79 ± 14
78 ± 13
0.25
Pulse pressure
74 ± 19
74 ± 19
74 ± 19
0.31
Medications Angiotensin II receptor blocker
597 (62.7 %)
195 (64.4 %)
402 (61.9 %)
0.47
Angiotensin-converting enzyme inhibitor
93 (9.8 %)
29 (9.6 %)
64 (9.9 %)
0.89
Calcium channel blocker
798 (83.8 %)
258 (85.1 %)
540 (83.2 %)
0.45
Other antihypertensive drug
445 (46.7 %)
143 (47.2 %)
302 (46.5 %)
0.85
Loop diuretic
665 (69.9 %)
199 (65.7 %)
466 (71.8 %)
0.06
Thiazide diuretic
237 (24.9 %)
62 (20.5 %)
175 (27.0 %)
0.03
Statin
424 (44.5 %)
128 (42.2 %)
296 (45.6 %)
0.33
Erythropoiesis-stimulating agent
899 (94.4 %)
284 (93.7 %)
615 (94.8 %)
0.52
Laboratory parameters
Data are presented as percentage, mean ± standard deviation, and median (interquartile range) a
Corrected calcium was calculated using the formula: corrected calcium = serum calcium (mmol/l) ? 0.02*(40-albumin)
Hemoglobin (g/L)
95 ± 14
97 ± 17
94 ± 14
0.001
Total protein (g/L)
62 ± 7
62 ± 7
6.1 ± 7
0.04 \0.001
Albumin (g/L)
32 ± 6
34 ± 6
32 ± 6
Total cholesterol (mg/dL) Blood urea nitrogen (mmol/L)
160 ± 42 33 ± 10
158 ± 39 32 ± 9
161 ± 44 34 ± 10
0.37 0.01
Creatinine (lmol/L)
795 ± 252
804 ± 259
791 ± 249
0.46
Sodium (mmol/L)
138 ± 4
138 ± 4
138 ± 4
0.79 0.46
Potassium (mmol/L)
4.5 ± 0.8
4.5 ± 0.7
4.5 ± 0.8
Chlorine (mmol/L)
104 ± 6
105 ± 6
104 ± 6
0.28
Corrected calciuma
2.10 ± 0.25
2.13 ± 0.25
2.09 ± 0.25
0.008
Phosphorous (mmol/L)
2.05 ± 0.74
2.04 ± 1.02
2.05 ± 0.56
0.84
Intact parathyroid hormone (ng/L)
360 ± 264
332 ± 280
374 ± 255
0.02
Uric acid (lmol/L)
507 ± 135
491 ± 109
515 ± 145
0.01
C reactive protein (nmol/L)
1.90 (0.76–9.62)
1.90 (0.67–7.24)
2.29 (0.95–10.38)
0.03
blood pressure and pulse pressure. Significant variables in the unadjusted analysis and other important variables were selected for further multivariate analysis. In this study, subgroups were used to further analyze the data for groups classified by selection of PD or HD. A difference was considered significant if the P value was \5 %.
Results Baseline characteristics The analysis included 303 participants, 31.8 % of whom were administered VDRA (Table 1). Compared to patients
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Clin Exp Nephrol Table 2 Association between vitamin D receptor activator supplementation and the prevalence of pulmonary congestion
Univariate model
Multivariate model
OR (95 % CI)
P value
OR (95 % CI)
P value
Vitamin D receptor activator
0.54 (0.39–0.75)
\0.001
0.64 (0.44–0.94)
Age (10 years)
1.28 (1.13–1.44)
\0.001
1.17 (1.01–1.37)
0.04
Male sex
0.83 (0.61–1.12)
0.23
0.70 (0.49–0.99)
0.04
Length of follow-up with nephrologist
0.99 (0.99–1.00)
0.002
1.00 (0.99–1.00)
0.42
0.02
Cause of end-stage renal disease Glomerulonephritis
1.00 (reference)
Diabetes mellitus nephropathy
2.28 (1.44–3.61)
\0.001
1.00 (reference) 1.45 (0.86–2.46)
Hypertension-related renal disease
2.10 (1.28–3.45)
0.003
1.19 (0.67–2.11)
0.55
Other
0.96 (0.51–1.81)
0.90
0.74 (0.36–1.49)
0.39
Peritoneal dialysis
0.42 (0.21–0.84)
0.01
0.90 (0.42–1.92)
0.79
Medical history of ischemic heart disease Medication
2.22 (1.55–3.17)
\0.001
1.46 (0.96–2.23)
0.08
Angiotensin II receptor blocker
0.60 (0.45–0.81)
\0.001
0.62 (0.44–0.87)
\0.005
Angiotensin-converting enzyme inhibitor
0.67 (0.40–1.14)
0.14
0.76 (0.43–1.92)
0.35
Calcium channel blocker
0.87 (0.60–1.28)
0.48
0.87 (0.56–1.37)
0.55
0.17
Other antihypertensive drug
1.42 (1.07–1.89)
0.02
1.27 (0.91–1.75)
0.16
Loop diuretic
2.59 (1.80–3.71)
\0.001
2.06 (1.38–3.07)
\0.001
Thiazide diuretic
1.65 (1.20–2.26)
0.002
1.34 (0.93–1.93)
0.11
Statin
1.41 (1.06–1.88)
0.20
1.24 (0.89–1.73)
0.21
Erythropoiesis-stimulating agent
0.84 (0.46–1.54)
0.58
0.75 (0.37–1.50)
0.41
Hemoglobin (10 g/L)
0.77 (0.69–0.85)
\0.001
0.81 (0.72–0.91)
\0.001
Albumin (10 g/L)
0.58 (0.45–0.74)
\0.001
0.87 (0.64–1.18)
0.37
Uric acid(10 lmol/L)
1.01 (1.00–1.02)
0.10
1.00 (0.99–1.00)
0.25
C reactive protein (nmol/L)
1.01 (1.01–1.02)
\0.001
1.01 (1.00–1.02)
\0.001
Q1 (\1.91) Q2 (1.91 B \2.08)
0.90 (0.57–1.41) 1.23 (0.79–1.90)
0.63 0.16
1.05 (0.62–1.76) 1.28 (0.79–2.07)
0.86 0.31
Q3 (2.08 B \2.19)
1.00 (reference)
Q4 (2.19 B \2.29)
0.79 (0.50–1.25)
0.31
0.79 (0.47–1.30)
0.35
Q5 (C2.29)
0.69 (0.43–1.09)
0.11
0.69 (0.41–1.19)
0.18
Q1 (\1.61)
1.69 (1.08–2.67)
0.02
1.90 (1.14–3.17)
0.01
Q2 (1.61 B \1.84)
1.53 (0.95–2.45)
0.08
1.55 (0.90–2.66)
0.11
Q3 (1.84 B \2.13)
1.00 (reference)
Q4 (2.13 B \2.49)
1.57 (0.99–2.48)
0.06
1.53 (0.92–2.55)
0.10
Q5 (C2.49)
1.34 (0.83–2.15)
0.23
1.35 (0.79–2.30)
0.27
Laboratory parameters
Quintiles of corrected calciuma
1.00 (reference)
Quintiles of phosphorous (nmol/L)
Analyses were performed using a multivariate logistic regression model OR odds ratio, CI confidence interval a
Corrected calcium was calculated using the formula: corrected calcium = serum calcium(mmol/ l) ? 0.02 9 (40-albumin)
Quintiles of intact parathyroid hormone (10 ng/L) Q1 (\169)
0.90 (0.57–1.43)
0.66
1.01 (0.59–1.73)
0.99
Q2 (169 B \257)
1.05 (0.67–1.66)
0.82
1.00 (0.60–1.65)
0.98
Q3 (257 B \352)
1.00 (reference)
Q4 (352 B \498) Q5 (C498)
1.45 (0.93–2.26) 0.83 (0.52–1.33)
who were not administered VDRA, those administered VDRA were younger (65.7 ± 12.5 and 68.6 ± 12.7 years, respectively; P = 0.001), had a lower frequency of
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1.00 (reference)
1.00 (reference) 0.10 0.44
1.44 (0.88–2.37) 0.85 (0.50–1.45)
0.14 0.55
diabetes mellitus nephropathy (40.9 and 46.8 %), a lower frequency of hypertension-related renal disease (21.8 and 27.3 %), a lower frequency of a medical history of IHD
Clin Exp Nephrol Table 3 Comparison of baseline characteristics between patients who selected hemodialysis and peritoneal dialysis Characteristics
Hemodialysis (N = 881)
Peritoneal dialysis (N = 71)
P value
Male sex
607 (68.9 %)
50 (70.4)
0.79
Age
68.3 ± 12.5
60.5 ± 13.2
\0.001
Vitamin D receptor activator
264 (30.0 %)
39 (54.9 %)
\0.001
Pulmonary congestion
246 (27.9 %)
10 (14.1 %)
0.01
Data are presented as percentage, mean ± standard deviation
Fig. 1 Various medications or medical conditions significantly associated with the prevalence of congestive heart failure. VDRA vitamin D receptor activator, ARB angiotensin II receptor blocker, OR odds ratio values in parentheses are the 95 % confidence intervals
(12.9 and 17.9 %, respectively; P = 0.05), and a longer follow-up period with a nephrologist (median 941; interquartile range 447–1,875 versus median 759; interquartile range 366–1,457; P = 0.007). PD was selected for renal replacement therapy with a higher frequency in the VDRA group (12.9 and 4.9 %, respectively; P \ 0.001). The VDRA group also tended to have higher levels of hemoglobin, total serum protein, serum albumin, and serumcorrected calcium, and lower levels of serum blood urea nitrogen, serum iPTH, serum CRP, and serum uric acid. Association between VDRA administration and the prevalence of pulmonary congestion In our cohort, 256 patients had pulmonary congestion (26.9 %). The patients who received VDRA had a lower prevalence of pulmonary congestion than the group that did not (58 [19.1 %] and 198 [30.5 %], respectively; P \ 0.001). Table 2 shows the unadjusted and multivariable-adjusted associations between VDRA administration and the prevalence of pulmonary congestion. After adjusting for potential confounders, the internal use of VDRA was significantly associated with a lower prevalence of pulmonary congestion (odds ratio [OR], 0.64; 95 % confidence interval [CI], 0.44–0.94; P = 0.02). Figure 1 shows various medications or medical conditions that were significantly associated with the prevalence of pulmonary congestion. In this analysis, male sex, ARB use, and higher hemoglobin levels were associated with a low prevalence of pulmonary congestion. Conversely, the use of loop diuretics, older age, higher serum CRP levels, and first quintile of phosphorus were associated with a high prevalence of pulmonary congestion.
Table 4 Univariate analysis of the association between vitamin D receptor activator supplementation and pulmonary congestion in patients with hemodialysis and peritoneal dialysis OR (95 % CI)
P value
Hemodialysis
0.61 (0.43–0.85)
0.004
Peritoneal dialysis
0.16 (0.03–0.83)
0.03
Analyses were performed using a univariate logistic regression model OR odds ratio, CI confidence interval
Subgroup analysis In this study, we also used subgroup analysis. The patients who selected PD had a lower prevalence of pulmonary congestion (10 [14.1 %] and 246 [27.9 %], respectively; P = 0.01) and a higher frequency of VDRA administration (39 [54.9 %] and 264 [30.0 %], respectively; P \ 0.001) than the group that did not (Table 3). In the group of selection of HD, we used univariate logistic regression model and multivariate logistic regression model (Table 4). However, we used only unadjusted analysis because of the small sample size in the group with PD (Table 4). We detected a significant association between VDRA with pulmonary congestion by unadjusted analysis, in both HD patients (OR 0.61; 95 % CI 0.43–0.85; P = 0.004) and PD patients (OR 0.16; 95 % CI 0.03–0.83; P = 0.03). In this analysis, participants with PD had a lower OR for pulmonary congestion than those with HD. In multivariate analysis for the group with HD, we did not detect a significant association between VDRA and pulmonary congestion (OR 0.69; 95 % CI 0.47–1.01; P = 0.05) (Table 5). Association of VDRA administration with predialysis systolic and diastolic blood pressure and pulse pressure on first dialysis The average systolic blood pressure, diastolic blood pressure, and pulse pressure values were 152, 79, and 74 mmHg, respectively, in the VDRA group and 151, 78,
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Clin Exp Nephrol Table 5 Multivariate analysis of predictors for pulmonary congestion in patients with hemodialysis
Table 5 continued OR (95 % CI)
P value
0.74 (0.43–1.29)
0.29
Q1 (\1.61)
2.00 (1.18–3.37)
0.01
0.10
Q2 (1.61 B \1.84)
1.66 (0.95–2.88)
0.07
0.36
Q3 (1.84 B \2.13)
1.00 (reference)
Q4 (2.13 B \2.49)
1.57 (0.93–2.64)
0.09
Q5 (C2.49)
1.31 (0.76–2.26)
0.34
OR (95 % CI)
P value
Vitamin D receptor activator
0.69 (0.47–1.01)
0.05
Age (10 years)
1.19 (1.02–1.40)
0.03
Male sex
0.74 (0.51–1.06)
Length of follow-up with nephrologist
0.99 (0.99–1.00)
Q5 (C2.29) Quintiles of phosphorous(nmol/L)
Cause of end-stage renal disease Glomerulonephritis Diabetes mellitus nephropathy
1.00 (reference) 1.50 (0.87–2.59)
Hypertension-related renal disease
1.18 (0.65–2.13)
0.56
Q1 (\169)
Other
0.72 (0.35–1.50) 1.32 (0.86–2.04)
0.38
Q2 (169 B \257)
0.21
Q3 (257 B \352)
1.00 (reference)
Q4 (352 B \498)
1.45 (0.88–2.40)
0.15
Angiotensin II receptor blocker
0.63 (0.44–0.88)
0.007
Q5 (C498)
0.90 (0.53–1.56)
0.72
Angiotensin-converting enzyme inhibitor
0.82 (0.45–1.48)
0.51
Calcium channel blocker
1.00 (0.63–1.59)
0.99
Other antihypertensive drug
1.26 (0.91–1.76)
0.17
Loop diuretic
1.88 (1.25–2.82)
0.002
Thiazide diuretic
1.28 (0.88–1.86)
0.19
Statin
1.24 (0.88–1.75)
0.21
Erythropoiesis-stimulating agent
0.82 (0.39–1.72)
0.60
Hemoglobin (10 g/L)
0.79 (0.69–0.89)
\0.001
Albumin (10 g/L)
0.88 (0.65–1.20)
0.43
Uric acid (10 lmol/L)
1.00 (1.00–1.01)
0.24
C reactive protein (nmol/L)
1.01 (1.00–1.02)
\0.001
Q1 (\1.91)
1.13 (0.66–1.93)
0.66
Q2 (1.91 B \2.08)
1.35 (0.82–2.21)
0.24
Q3 (2.08 B \2.19)
1.00 (reference)
Q4 (2.19 B \2.29)
0.87 (0.52–1.46)
Medical history of ischemic heart disease
0.14
Quintiles of intact parathyroid hormone (10 ng/L)
Medication
Laboratory parameters
Quintiles of corrected calciuma
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0.59
1.03 (0.60–1.80) 0.92 (0.55–1.55)
0.90 0.75
Analyses were performed using a multivariate logistic regression model OR odds ratio, CI confidence interval a
Corrected calcium was calculated using the formula: corrected calcium = serum calcium (mmol/l) ? 0.02 9 (40-albumin)
and 74 mmHg, respectively, in the non-VDRA group. VDRA administration was not significantly associated with systolic blood pressure (b value 1.20; 95 % CI -2.00 to 4.42; P = 0.48), diastolic blood pressure (b value 0.08; 95 % CI -3.83 to 3.97; P = 0.98), or pulse pressure (b value 0.44; 95 % CI -3.69 to 4.58; P = 0.85) by multivariate linear regression analysis.
Discussion In this cross-sectional study, we found an association between VDRA administration and a low prevalence of pulmonary congestion in newly initiated dialysis patients in Japan. To the best of our knowledge, this is the first study to investigate the association between VDRA administration and the prevalence of pulmonary congestion in patients initiated on dialysis. In our cohort, the baseline characteristics of patients treated with VDRA reflected a lower risk for pulmonary congestion. Patients administered VDRA were younger, had a lower frequency of diabetes mellitus nephropathy, a
Clin Exp Nephrol
higher frequency of PD, a lower frequency of hypertension-related renal disease, a lower frequency of a medical history of HID, and a longer follow-up period with a nephrologist than those who did not receive VDRA. The VDRA group also tended to have higher hemoglobin and serum albumin levels. However, in a multivariate adjusted analysis using these factors as explanatory variables, our results also showed a significantly lower prevalence of pulmonary congestion in patients who received VDRA (OR 0.64; 95 % CI 0.44–0.94; P = 0.02). We found other significant associations between pulmonary congestion and age, sex, ARB use, loop diuretic use, hemoglobin, serum CRP, and serum phosphorus in the multivariate analysis. The association between CHEF and the use of loop diuretics may imply a medical history of CHEF. These associations are generally known or under consideration. Thus, our result showed that VDRA administration was a strong predictor, equal to known predictors of pulmonary congestion. In subgroup analysis, the univariate analysis showed that administration of VDRA was associated with pulmonary congestion in both groups. Within the group with HD, we were not able to detect significant association by the multivariate analysis. However, we found the tendency that VDRA was associated with low prevalence of pulmonary congestion in the multivariate analysis. Thus, we believe that a significant association could be detected if there were more participants. On the basis of many reports, vitamin D has been newly shown to act as a hormone that negatively regulates the renin-angiotensin-aldosterone system [15]. A national survey in the United States revealed that vitamin D deficiency is associated with a higher prevalence of cardiovascular disease and mortality [7]. In the general population, it was reported that moderate to high dose vitamin D supplementation could reduce cardiovascular disease risk [14]. It is therefore considered that the high risk of cardiovascular disease in CKD patients indicates that there may be significant potential benefits to vitamin D supplementation or VDRA administration in this population [16]. In fact, a cross-sectional study in pediatric CKD patients reported an association of vitamin D deficiency with increased left ventricular mass and diastolic dysfunction [17]. However, no study has concluded whether vitamin D supplementation or VDRA administration improved cardiovascular outcomes in CKD patients [18]. Our study demonstrated the association between VDRA and pulmonary congestion. We suspect our result implies that the potential ability of VDRA to prevent congestive heart failure resulted in the association. In our cohort, the average serum-corrected calcium concentration was significantly higher in the VDRA group than in the other group, but the difference was very small
(2.13 vs. 2.09). In general, clinical symptoms due to hypercalcemia are a well-known adverse effect of VDRA use. We did not observe such a tendency in our cohort. In accordance with our results, we suspect that appropriate VDRA administration can prevent pulmonary congestion without adverse effects in CKD patients. Interestingly, we did not detect any association between VDRA administration and systolic blood pressure, diastolic blood pressure, or pulse pressure. This signifies that the lower prevalence of pulmonary congestion in patients administered VDRA did not depend on these three variables. We hypothesize that there may be a relationship between vitamin D receptor activation and several hemodynamic factors such as the circadian rhythm of blood pressure, but this has yet to be elucidated. There were some limitations to this study. First, we did not measure serum levels of 25-hydroxyvitamin D. Therefore, the benefits of VDRA administration for patients with a vitamin D deficiency were unclear. Second, we had no data on VDRA types and dosage, or on the duration of VDRA administration. The relationship between various vitamin D activators and mortality among hemodialysis patients was demonstrated recently [19, 20]. It is also possible that different dosages of VDRA affect clinical outcomes differently [21]. Third, because of the retrospective nature of this study, we could not analyze the association between VDRA administration and the low prevalence of pulmonary congestion using other important covariates such as ejection fraction or cardiac output. In our study, we cannot deny the presence of some selection bias in classifying patients who did or did not receive VDRA. Finally, owing to the retrospective, cross-sectional design of this study, we can only infer associations, and not causality, from our results. By presenting these results, we conclude that appropriate VDRA administration may prevent pulmonary congestion in patients initiated on dialysis. We hypothesize that there is a possibility that appropriate VDRA administration can provide significant benefits in CKD patients. Acknowledgments We acknowledge the support of the following investigators, members of the Aichi cohort study of prognosis in patients newly initiated into dialysis (AICOPP), who participated in this study: Hirofumi Tamai (Anjo Kosei Hospital), Tomohiko Naruse (Kasugai Municipal Hospital), Kei Kurata (Tosei General Hospital), Hideto Oishi (Komaki City Hospital), Isao Aoyama (Social Insurance Chukyo Hospital), Hiroshi Ogawa (Shinseikai Daiichi Hospital), Hiroko Kushimoto(Chita City Hospital), Hideaki Shimizu (Chubu-Rosai Hospital), Junichiro Yamamoto (Tsushima City Hospital), Hisashi Kurata (Toyota Kosei Hospital), Taishi Yamakawa (Toyohashi Municipal Hospital), Takaaki Yaomura (Nagoya Medical Center), Hirotake Kasuga (Nagoya Kyouritsu Hospital), Shizunori Ichida (Japanese Red Cross Nagoya Daiichi Hospital), Shoichi Maruyama (Nagoya University Graduate School of Medicine), Noritoshi Kato (Nagoya University Graduate School of Medicine), Seiichi Matsuo (Nagoya University Graduate School of Medicine), Shigehisa Koide
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Clin Exp Nephrol (Fujita Health University Hospital), and Yukio Yuzawa (Fujita Health University Hospital). Conflict of interest interest exists.
The authors have declared that no conflict of
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