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American Journal of Clinical Nutrition, Vol. 87, No. 6, 1631-1638, June 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Serum 25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis patients: a 3-y prospective cohort study1,2,3

Angela Yee-Moon Wang, Christopher Wai-Kei Lam, John E Sanderson, Mei Wang, Iris Hiu-Shuen Chan, Siu-Fai Lui, Mandy Man-Mei Sea and Jean Woo

1 From the Departments of Medicine and Therapeutics (AY-MW, JES, MW, S-FL, MM-MS, and JW) and Chemical Pathology (CW-KL and IH-SC), The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

2 Supported by the Hong Kong Health Service Research Fund.

3 Reprints not available. Address correspondence to AY-M Wang, University Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong. E-mail: aymwang{at}hku.hk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUJBECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background:Patients with kidney disease are at high risk of developing 25-hydroxyvitamin D [25(OH)D] deficiency.

Objective:We studied the association between serum 25(OH)D status and clinical outcomes of chronic peritoneal dialysis patients.

Design:We measured serum 25(OH)D concentrations in 230 prevalent peritoneal dialysis patients and then followed these patients prospectively for 3 y or until death.

Results:Serum 25(OH)D was deficient or insufficient (ie, <75nmol/L) in 87% of the patients. Adjusting for clinical and demographic factors, every 1-unit increase in log-transformed serum 25(OH)D was associated with a 44% reduction in the hazard of fatal or nonfatal cardiovascular events (95% CI: 0.35, 0.91; P = 0.018). However, the association was gradually lost when additional adjustment was made in a stepwise fashion for residual glomerular filtration rate (P = 0.078) and echocardiographic measures (P = 0.39). Kaplan-Meier estimates showed a significantly greater fatal or nonfatal cardiovascular event-free survival probability among patients with serum 25(OH)D > 45.7 nmol/L (median) than among patients with concentrations ≤ 45.7 nmol/L (P = 0.004). In addition, patients with 25(OH)D > 45.7 nmol/L had a significantly higher cardiovascular event-free survival probability than did patients with 25(OH)D ≤ 45.7 nmol/L in the stratified analysis for patients with left ventricular mass index less than the median (P = 0.013) or normal systolic function (P = 0.005).

Conclusions:A lower serum 25(OH)D concentration was associated with an increased risk of cardiovascular events in chronic peritoneal dialysis patients. Furthermore, serum 25(OH)D status appeared to show a differential influence on the cardiovascular outcomes of peritoneal dialysis patients depending on the degree of left ventricular hypertrophy and systolic dysfunction.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUJBECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD). Apart from considering traditional risk factors such as age, hypertension, diabetes, and hypercholesterolemia, there is increasing evidence that abnormalities in mineral metabolism have important contributions to increased cardiovascular morbidity and mortality in patients receiving dialysis (1, 2). In a recent 2-y cohort study of 58 058 patients receiving maintenance hemodialysis, Kalantar-Zadeh et al (3) showed that both hypercalcemia and hypocalcemia were associated with increased mortality risks. This helps balance the risk and benefit of treatment with vitamin D compound, because it can normalize serum calcium and improve survival, but it can also lower survival by inducing hypercalcemia. However, the Kidney Disease Outcome Quality Initiative (K/DOQI) has recently raised concerns of a high prevalence of vitamin D deficiency in patients with chronic kidney disease (4). Patients with stage 5 chronic kidney disease receiving long-term peritoneal dialysis (PD) or hemodialysis treatment or patients with stage 3–4 chronic kidney disease not yet requiring dialysis treatment were all consistently reported to have a high prevalence of vitamin D deficiency, as characterized by low serum 25-hydroxyvitamin D [25(OH)D] (5-11).

Abnormal vitamin D metabolism with resulting active vitamin D deficiency is well known to play an important role in the pathogenesis of secondary hyperparathyroidism in patients with chronic kidney disease (12, 13). An increasing body of evidence suggests that vitamin D plays a role in cardiovascular disease (14, 15). Studies in the general population have shown an association between low concentrations of vitamin D and hypertension (16, 17), as well as higher prevalence of chronic heart failure (18, 19). Vitamin D supplementation was shown to reduce the inflammatory profile in patients with chronic heart failure (20). In addition, there are emerging data to support a beneficial effect of vitamin D supplementation on the survival and cardiovascular outcome of patients receiving hemodialysis (21, 22). A number of studies in patients receiving hemodialysis also observed regression of myocardial hypertrophy with calcitriol therapy (23-25). Therefore, vitamin D deficiency may indeed be an important cardiovascular risk factor in the dialysis population.

Given this background, we conducted this study to determine the prevalence of vitamin D deficiency and to evaluate factors relating to serum 25(OH)D concentration in a prevalent cohort of Chinese chronic PD patients. More importantly, we investigated the relation between serum 25(OH)D concentrations and clinical outcome of these patients.


   SUJBECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUJBECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study protocol and study subjects
We conducted a prospective cohort study in a single dialysis center of a university teaching hospital in Hong Kong. The study protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Patients were considered eligible for study inclusion if they had ESRD and had been on continuous ambulatory PD therapy for ≥3 mo. All patients used the conventional lactate-buffered glucose-based PD solutions. Exclusion criteria included patients with underlying malignancy, chronic liver disease, chronic obstructive airway disease, systemic lupus erythematosus, chronic rheumatic heart disease, congenital heart disease; patients who refused to give consent; and patients with missing data. There were 270 patients receiving PD in total, of which 40 patients were excluded by the criteria listed above. The remaining 230 (85%) patients were included in the current study with informed consent.

At study entry, all patients underwent measurement of serum 25(OH)D together with other biochemical measures. In addition, echocardiography was performed, nutrition status was assessed, and residual renal function and dialysis indexes were measured. In patients who developed acute coronary syndrome, congestive heart failure, peritonitis, exit site infections, other infective complications, or any other complications that required hospitalization, all the above assessments were deferred for ≥1 mo after complete resolution of the complication.

Biochemical analysis
Fasting clotted, EDTA, and heparinized blood samples were collected for measurement of serum or plasma 25(OH)D, high-sensitivity C-reactive protein (hs-CRP), albumin, intact parathyroid hormone (iPTH), hemoglobin, urea, creatinine, calcium, phosphorus, and lipid profile. Serum 25(OH)D was measured by an enzyme-linked immunosorbent assay (Immunodiagnostic Systems Inc, Fountain Hills, AZ) that detects both vitamin D2 and D3 with a detection limit of 5.0 nmol/L and a CV of 4.7% at 43.4 nmol/L. hs-CRP and albumin in heparin plasma were measured, respectively, with the use of the Tina-quant C-reactive protein latex ultrasensitive assay (detection limit of 0.01 mg/L and CV of 1.6% at 2.0 mg/L) and the bromcresol purple method (CV of 2.8% at 45 g/L) on the Roche modular analyzer (Roche Diagnostics Corp, Indianapolis, IN). Plasma iPTH was measured by chemiluminescence immunoassay with the use of the IMMULITE 1000 Analyzer (Diagnostic Products Corporation, Los Angeles, CA) with a detection limit of 3 µg/L and a CV of 7.6% at 43 µg/L. Plasma urea, creatinine, calcium, phosphorus, and lipid profile were measured by spectrophotometric methods on the Roche DP Modular Analyser (Roche Diagnostics Corp). Hemoglobin was measured by the GEN-S blood cell counter (Beckman-Coulter Inc, Miami, FL).

Echocardiography
Two-dimensional echocardiography was performed with the use of a GE-VingMed System 5 echocardiographic machine (GE-VingMed Sound AB, Horten, Norway) with a 3.3-mHz multiphase array probe in subjects lying in the left decubitus position by a single experienced cardiologist blinded to all clinical details of patients. All echocardiographic data were recorded according to the guidelines of the American Society of Echocardiography (26). Mitral inflow velocities and diastolic filling pattern were assessed by Doppler echocardiography as previously described, namely normal filling, abnormal relaxation pattern, restrictive filling pattern, and pseudonormal pattern (27). Left ventricular (LV) mass and volume were indexed by body surface area. The ejection fraction (EF) was obtained with the use of a modified biplane Simpson's method from apical 2- and 4-chamber views (28).

Assessment of nutrition status
Subjective global assessment (SGA) was used to evaluate the overall protein-energy nutritional status of the PD patients (29, 30). It was performed by experienced research staff, blinded to all clinical and biochemical data of patients. The SGA includes 6 subjective assessments, 3 based on the patient's history of weight loss, presence of anorexia, and vomiting and 3 based on the physician's grading of muscle wasting, presence of edema, and loss of subcutaneous fat. On the basis of these assessments, each patient was graded as normal nutrition status or as mild, moderate, or severe malnutrition. Edema is not an index of malnutrition (30). However, its presence or absence had to be taken into account when assessing changes in body weight. Dry weight was measured with the abdomen drained dry of peritoneal fluid with the use of a weighing scale without shoes and in light clothing to the nearest 0.1 kg, and height was measured to the nearest 0.5 cm. Body mass index (in kg/m2) was calculated.

Indexes of dialysis adequacy
Residual glomerular filtration rate (GFR) was calculated as the average of the 24-h urine urea and creatinine clearance (31). Adequacy of dialysis was determined by measurement of total weekly urea clearance (Kt/V) and creatinine clearance with the use of standard methods (32). Creatinine concentration in dialysate was corrected for interference by glucose according to the reference formula determined in our laboratory (33). The contribution of PD and the renal component to the total Kt/V was estimated separately.

Study outcome
All patients were prospectively followed for 3 y after the baseline assessments or until death or the first fatal or nonfatal cardiovascular event (CVE). Patients who underwent kidney transplantation were censored at the time of kidney transplantation. The clinical outcomes evaluated were death from all causes and first fatal or nonfatal CVE. For patients who had multiple CVEs, survival analysis in relation to CVE was limited to the first CVE. The causes of death and the nature of the first CVE were determined by the attending physicians who had no knowledge of the baseline serum 25(OH)D results. This information was retrieved from the computerized Clinical Management System of the Hong Kong Hospital Authority and the Renal Registry Database that keeps detailed records of all hospitalization episodes. In case of death out of the hospital, family members were interviewed by telephone to ascertain the circumstances surrounding the patient's death. Fatal or nonfatal CVE included acute myocardial ischemia or infarction, electrocardiographically documented arrhythmia, transient ischemic attack, thromboembolic or hemorrhagic stroke, peripheral vascular disease, all of which were defined according to standard clinical criteria, circulatory congestion, and sudden cardiac death. Circulatory congestion was defined clinically by the presence of symptoms and signs of heart failure, including dyspnea, raised jugular venous pressure, and basal crepitations together with radiologic evidence of pulmonary venous congestion or interstitial edema and resolution of symptoms, signs, and radiologic changes with hypertonic PD exchanges (34). Sudden cardiac death was defined as unexpected natural death within 1 h from the symptom onset and without any prior condition that would appear fatal (35, 36).

Statistical analysis
We tested continuous data for normality by the Kolmogorov-Smirnov test, and we expressed data as mean ± SD or median [interquartile range (IQR)], depending on the distribution. Comparisons between groups were done by the t test or the Mann-Whitney U test for continuous data when appropriate or by the chi-square test for categorical data. In view that serum 25(OH)D was not normally distributed, patients were stratified in 2 groups according to the median 25(OH)D concentration, namely those with serum 25(OH)D > 45.7 nmol/L and those with serum 25(OH)D ≤ 45.7 nmol/L for the logistic regression analysis described above and ln-transformed when used as a covariate in the Cox proportional hazards regression models. Multiple logistic regression analysis was performed to identify factors that were independently correlated with serum 25(OH)D concentrations ≤ 45.7 nmol/L (median). We generated survival curves stratified by the median of serum 25(OH)D concentrations with the use of the Kaplan-Meier's method, and between-group survival was compared by the log-rank test. We used the Cox proportional hazards model to estimate the hazard ratios of all-cause mortality and fatal or nonfatal CVE in relation to log-transformed serum 25(OH)D, and adjustment for potential confounding covariates was performed in a stepwise fashion. We considered P values < 0.05 to be statistically significant, and all tests were 2 sided. All statistical analyses were performed with the use of SPSS software, version 14.0 (SPSS Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUJBECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The baseline characteristics of the study population are shown in Table 1Go. The median serum 25(OH)D concentration was 45.7 nmol/L (IQR: 35.7–60.7 nmol/L). Serum 25(OH)D concentration was below the K/DOQI recommended sufficient value for stage 3–4 chronic kidney disease (ie, ≤75 nmol/L) in 200 patients (87%) of which 69 patients (30%) had mild vitamin D deficiency [defined as serum 25(OH)D between 12.5 and 37.4 nmol/L] and 131 patients (57%) had vitamin D insufficiency [defined as serum 25(OH)D between 39.9 and 75 nmol/L]. None of our patients had severe vitamin D deficiency [defined as serum 25(OH)D < 12.5 nmol/L]. Significant sex difference was observed in the degree of vitamin D deficiency in that 47 (42.0%) and 57 (50.9%) female patients compared with 22 (18.6%) and 74 (62.7%) male patients had mild vitamin D deficiency and vitamin D insufficiency, respectively (P < 0.001). The distribution of serum 25(OH)D in the male and female PD patients is shown in Figure 1Go.


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  		TABLE 1. Baseline characteristics1

 

Figure 1
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  		FIGURE 1.. Distribution of serum 25-hydroxyvitamin D in a population of 118 male and 112 female patients receiving peritoneal dialysis.

 
The causes of kidney disease were chronic glomerulonephritis in 75 patients (32.6%), diabetic nephropathy in 55 patients (23.9%), hypertensive nephrosclerosis in 30 patients (13.0%), tubulointerstitial nephritis in 6 patients (2.6%), polycystic kidney disease in 12 patients (5.2%), obstructive uropathy in 13 patients (5.7%), and not identified in 39 patients (17%). The baseline characteristics of patients with serum 25(OH)D ≤ 45.7 nmol/L (median) compared with patients with serum 25(OH)D > 45.7 nmol/L are presented in Table 1Go.

On univariate logistic regression analysis, the odds ratios for serum 25(OH)D ≤ 45.7 nmol/L of blood samples obtained in the spring (n = 40), summer (n = 41), and autumn (n = 77) months were 1.17 (95% CI: 0.54, 2.53; P = 0.69), 1.83 (95% CI: 0.84, 4.02; P = 0.13), and 0.71 (95% CI: 0.31, 1.36; P = 0.31), respectively, compared with those obtained in the winter months (n = 72). Multiple logistic regression analysis showed that diabetes mellitus was the most significant factor associated with serum 25(OH)D ≤ 45.7 nmol/L followed by female sex and loss of residual renal function. Other factors, including increasing age and LV volume index, were marginally insignificant (Table 2Go). Entering the variable "the season of blood collection" in the multiple logistic regression analysis for serum 25(OH)D ≤ 45.7 nmol/L did not alter the significance of association of other factors in the final model (Table 2Go), indicating no significant confounding effect of the season of blood collection on serum 25(OH)D.


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  		TABLE 2. Multiple logistic regression analysis of factors associated with serum 25-hydroxyvitamin D ≤ 45.7 nmol/L (median)1

 
During the 3-y follow-up, 70 patients (30.4%) had died and 25 patients (10.9%) received transplants. Of the 70 fatalities, there were 31 (13.5%) death from cardiac causes, 12 (5.2%) deaths from cerebrovascular causes, 8 (3.5%) deaths from peritonitis, 13 (5.7%) deaths from other infections, 1 (0.4%) death from malignancy, and 5 (2.2%) deaths from termination of dialysis. The 31 cardiac deaths included acute myocardial ischemia or infarction in 6 (2.6%) patients, sudden cardiac death in 18 (7.8%) patients, circulatory congestion in 2 (0.9%) patients, peripheral vascular disease in 4 (1.7%) patients, and arrhythmia in 1 (0.4%) patients. The baseline median serum 25(OH)D was 46.7 nmol/L (IQR: 34.9–61.4 nmol/L) for patients who died compared with 45.7 nmol/L (IQR: 35.7 –58.7 nmol/L) for patients who survived the period of follow-up (P = 0.95).

During follow-up, 129 patients developed ≥1 fatal or nonfatal CVEs. Patients who had ≥1 CVEs had lower baseline median serum 25(OH)D (42.9 nmol/L; IQR: 32.9–57.9 nmol/L) than those without a CVE (49.4 nmol/L; IQR: 38.9–66.4 nmol/L; P = 0.006). The nature of CVE was acute myocardial ischemia or infarction in 14 patients (6.1%), cerebrovascular event in 19 patients (8.3%), circulatory congestion in 78 patients (33.9%), arrhythmia in 6 patients (2.6%), peripheral vascular disease in 6 patients (2.6%), and sudden cardiac death in 6 patients (2.6%). The Kaplan-Meier survival curves in relation to all-cause mortality and first fatal or nonfatal CVE in patients stratified by the median concentration of serum 25(OH)D are shown in Figure 2AGo and B.


Figure 2
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  		FIGURE 2.. (A) Kaplan-Meier estimates of overall survival probability of patients in relation to serum 25-hydroxyvitamin D [25(OH)D] ≤ 45.7 nmol/L (median) or > 45.7 nmol/L. (B) Kaplan-Meier estimates of cardiovascular event-free survival probability of patients in relation to serum 25(OH)D ≤ 45.7 nmol/L (median) or > 45.7 nmol/L.

 
On univariate Cox regression analysis, the hazard ratios (HRs) in relation to all-cause mortality and first fatal or nonfatal CVE were 1.06 (95% CI: 0.59, 1.89; P = 0.84) and 0.57 (95% CI: 0.37, 0.87; P = 0.010), respectively, for log-transformed serum 25(OH)D. The univariate Cox regression analysis for other factors in relation to fatal or nonfatal CVE is detailed in Table 3Go. Adjusting for demographic and clinical factors, log-transformed serum 25(OH)D showed a significant association with fatal or nonfatal CVE. However, the association was lost when further controlling for residual GFR and echocardiographic measures in a stepwise fashion (Table 4Go). LV volume index but not EF was considered in the multivariable Cox regression analysis because LV volume index and EF were correlated (Spearman's r = –0.34, P < 0.001) and both LV volume index (HR: 1.025; 95% CI: 1.018, 1.033; P < 0.001) and EF (HR: 0.95; 95% CI: 0.93, 0.96; P < 0.001) were significant factors in predicting CVE in the univariate Cox regression analysis. However, EF marginally lost its significance (HR: 0.98; 95% CI: 0.95, 1.00; P = 0.052) in the Cox regression model for CVE when both LV volume index and EF were considered together.


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  		TABLE 3. Univariate Cox regression analysis in relation to fatal or nonfatal cardiovascular events in patients receiving peritoneal dialysis1

 

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  		TABLE 4. Adjusted hazard ratios (HRs) of log-transformed serum 25-hydroxyvitamin D in relation to fatal or nonfatal cardiovascular events with adjustment for confounding covariates in the stepwise multivariable Cox regression analysis1

 
The Kaplan-Meier estimates of fatal or nonfatal CVE-free survival probability for patients stratified into 4 groups on the basis of LV EF ≥ 50% and < 50% and serum 25(OH)D ≤ 45.7 nmol/L (median) and > 45.7 nmol/L are shown in Figure 3AGo. Adjusting for age, sex, diabetes, coronary artery disease, duration of dialysis, residual GFR, hemoglobin, serum albumin, LDL cholesterol, hs-CRP, iPTH, SGA, and LV mass index, the HRs in relation to the first fatal or nonfatal CVE were 1.79 (95% CI: 1.08, 2.96; P = 0.024), 3.16 (95% CI: 1.74, 5.74; P < 0.001), and 2.39 (95% CI: 1.40, 4.11; P = 0.002), respectively, for patients with LV EF ≥ 50% but serum 25(OH)D ≤ 45.7 nmol/L, patients with LV EF < 50% but serum 25(OH)D > 45.7 nmol/L, and patients with LV EF < 50% and serum 25(OH)D ≤ 45.7 nmol/L compared with those with LV EF ≥ 50% and serum 25(OH)D > 45.7 nmol/L (reference group).


Figure 3
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  		FIGURE 3.. A: Kaplan-Meier estimates of cardiovascular event-free survival rate in patients stratified on the basis of serum 25-hydroxyvitamin D [25(OH)D] ≤ 45.7 nmol/L (median) or > 45.7 nmol/L and ejection fraction (EF) ≥ 50% or < 50%. B: Kaplan-Meier estimates of cardiovascular event-free survival rate in patients stratified on the basis of serum 25(OH)D ≤ 45.7 nmol/L (median) or > 45.7 nmol/L and left ventricular mass index (LVMi) ≤ 206 g/m2 (median) or > 206 g/m2.

 
The Kaplan-Meier estimates of fatal or nonfatal CVE-free survival probability for patients stratified into 4 groups on the basis of LV mass index ≥ 206 g/m2 (median) and < 206 g/m2 and serum 25(OH)D concentrations ≤ 45.7 nmol/L (median) and > 45.7 nmol/L are shown in Figure 3BGo. Adjusting for age, sex, diabetes, coronary artery disease, duration of dialysis, residual GFR, hemoglobin, serum albumin, LDL cholesterol, hs-CRP, iPTH, SGA, and LV EF, the HRs in relation to fatal or nonfatal CVE were 2.08 (95% CI: 1.01, 3.91; P = 0.024), 2.55 (95% CI: 1.40, 4.63; P = 0.002), and 2.36 (95% CI: 1.32, 4.23; P = 0.004), respectively, for patients with LV mass index < 206 g/m2 but serum 25(OH)D ≤ 45.7 nmol/L, patients with LV mass index ≥ 206 g/m2 but serum 25(OH)D > 45.7 nmol/L, and patients with LV mass index ≥ 206 g/m2 and serum 25(OH)D ≤ 45.7 nmol/L compared with patients with LV mass index < 206 g/m2 and serum 25(OH)D > 45.7 nmol/L (reference group).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUJBECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The principal finding of this study was that a low serum 25(OH)D concentration was associated with a greater risk of developing fatal or nonfatal CVE but not overall mortality in long-term PD patients. Of importance was that the association with CVE was marginally lost when additional adjustment was made for residual GFR and most profoundly dropped when controlling for LV factors. This suggests that 25(OH)D deficiency may partly mediate an increased risk of CVE by the loss of residual renal function and the presence of LV hypertrophy and dilatation. Patients with lower serum concentrations of 25(OH)D had marginally more LV dilatation than did patients with higher serum concentrations of 25(OH)D, although the difference in LV mass failed to reach statistical significance. There is experimental evidence that vitamin D deficiency may induce myocardial hypertrophy and fibrosis (25, 37) and that treatment with 1,25-dihydroxyvitamin D3 inhibits myocardial hypertrophy (38). Studies have also reported regression of myocardial hypertrophy with 1,25-dihydroxyvitamin D3 therapy in patients receiving hemodialysis (23, 24). More recent data showed that an activated vitamin D compound, 19-nor-1,25(OH)2D2, attenuated LV abnormalities in Dahl salt-sensitive rats exposed to a high-salt diet. A further retrospective analysis also suggested comparable findings in patients receiving hemodialysis treated with the same compound (39).

Two recent epidemiologic studies showing an improved survival and reduced cardiovascular mortality with activated injectable vitamin D therapy in patients receiving hemodialysis provide additional evidence that vitamin D deficiency may be an important cardiovascular risk in patients with chronic kidney disease (21, 22). More recently, Wolf et al (40) reported an important association between serum 25(OH)D status and early mortality in incident hemodialysis patients. In their study, low serum 25(OH)D was associated with an increased risk of cardiovascular mortality when adjusting for age, sex, and race but lost significance when adjusting for other covariates. Thus, our current data add to the existing data that suggest an important link between serum 25(OH)D deficiency and increased risk of CVE in chronic PD patients.

Note that nearly 60% of the CVE in our PD patients was due to circulatory congestion. A previous study in subjects with nonrenal failure with severe heart failure reported a high prevalence of vitamin D deficiency and hyperparathyroidism (19). Low vitamin D status was shown to contribute to the pathogenesis of heart failure in the general population (18). The exact relation between low vitamin D status and heart failure is currently not known. However, vitamin D is a negative hormone regulator of the renin-angiotensin system (41-43), which plays an important role in hypertension and cardiovascular disease. There was some suggestion that inflammatory cytokines such as tumor necrosis factor may suppress 1,25(OH)2D3 synthesis (44). The finding that vitamin D treatment normalized impaired myocardial contractility in experimental models of vitamin D deficiency was important evidence to support a pivotal role of vitamin D on cardiac function (37, 45). London et al (6) recently showed that deficient vitamin D status was associated with more arterial stiffening in hemodialysis patients. This is in keeping with our current data showing a trend toward greater diastolic dysfunction, more restrictive filling, and pseudonormal filling pattern among those with lower serum 25(OH)D.

In this study, we observed a differential influence of 25(OH)D status on the cardiovascular outcomes of PD patients in that low serum 25(OH)D was associated with an increased risk of CVE among PD patients with preserved LV systolic function or less severe LV hypertrophy. Yet, low serum 25(OH)D status did not seem to have additional influence on the cardiovascular outcomes of PD patients with established systolic dysfunction or more severe LV hypertrophy. The explanation for this observation is currently not known. However, this data seemed to suggest that deficient 25(OH)D status may play a more important role in the early but not the advanced stage of cardiac disease in ESRD and that deficient vitamin D may influence more the adverse cardiovascular outcome among PD patients with less severe LV hypertrophy and normal LV systolic function.

In keeping with other studies showing a high prevalence of vitamin D deficiency in patients with stage 5 chronic kidney disease receiving either PD or hemodialysis therapy (6-11, 40), a majority of the Chinese PD patients were deficient of 25(OH)D with the use of the cutoff defined by K/DOQI. Our results were similar to the observations by Elder et al (5) and Taskapan et al (9), showing that 25(OH)D deficiency was more prevalent in diabetic as well as in female PD patients. The exact relation between diabetes and 25(OH)D deficiency is currently not known. However, recent data suggest that calcium and vitamin D supplementation may attenuate an increase in glycemia and insulin resistance in adult elderly subjects with impaired fasting glucose (46). Furthermore, our results showed that 25(OH)D deficiency was more common in PD patients with loss of residual renal function. This finding was somewhat not surprising, given that kidney-specific 1{alpha}-hydroxylase activity parallels the decline in residual renal function (47). However, it raises the question whether vitamin D supplementation should be considered in anuric PD patients.

Contrary to studies in patients receiving hemodialysis that show a positive survival benefit with activated injectable vitamin D therapy (21, 22), we did not observe any effect of oral calcitriol or alfacalcidol treatment on the outcomes of our PD patients. Several reasons may explain this difference. First, our study may not be powered enough, given that studies showing a survival advantage with injectable vitamin D therapy had a population of nearly 50 000 (21, 22). Second, a relatively low usage of oral calcitriol or alfacalcidol was observed in our population. In addition, the average daily oral vitamin D dose was low in the magnitude of only 10 IU/d in contrast to the recommended daily intake of 1000–2000 IU/d. Third, given that the treatment was recorded at study baseline, some of the patients may have started on oral calcitriol or alfacalcidol subsequently during the 3-y follow-up and was not accounted for in the analysis.

Our study has several limitations that need considering. First, only serum 25(OH)D but not 1,25-dihydroxyvitamin D was measured because serum 25(OH)D was currently used by the K/DOQI to define vitamin D deficiency. Second, serum 25(OH)D and most other clinical factors were measured at a single time and did not reflect changes over time. The use of a single serum 25(OH)D concentration probably understates the predictive power of 25(OH)D and may partly explain the lack of association between serum 25(OH)D and overall survival of our PD patients. Third, our study had a relatively small sample size and may not be adequately powered to detect a significance difference in LV mass, volume, and EF between patients with high and low concentrations of serum 25(OH)D. Nevertheless, our study represents the first and the largest prospective outcome study that addresses this important issue in the PD population.

In conclusion, this study provides important novel evidence that low serum 25(OH)D status may contribute to an increased risk of CVEs in chronic PD patients and its influence on cardiovascular outcomes appears to be closely related to residual renal function and the severity of cardiac hypertrophy and dysfunction. A prospective randomized controlled study will be needed to evaluate whether correction of vitamin D insufficiency or deficiency will improve cardiovascular outcomes of PD patients.


   ACKNOWLEDGMENTS
 
The author's responsibilities were as follows—AY-MW: contributed to the concept of the study, study design and data collection, data analysis, and writing and final review of the manuscript; CW-KL: contributed to the laboratory investigations, data analysis, and critical review of the manuscript; MW and JES: contributed to the echocardiographic assessments in the study, data collection, and critical review of the manuscript; MM-MS: contributed to the nutrition assessment, data collection, and review of the manuscript; IH-SC: contributed to the laboratory investigations, data analysis, and review of the manuscript; S-FL: contributed to the critical review of the manuscript; JW: contributed to the nutrition assessment and critical review of the manuscript. None of the authors had a financial or personal interest in any company or organization sponsoring the research.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUJBECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607–17.[Medline]
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Received for publication October 22, 2007. Accepted for publication January 27, 2008.




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