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Published ahead of print on March 1, 2006
Clin J Am Soc Nephrol 1: 496-504, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.00030505
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Epidemiology and Outcomes

Temporal Relation among Depression Symptoms, Cardiovascular Disease Events, and Mortality in End-Stage Renal Disease: Contribution of Reverse Causality

L. Ebony Boulware*,{dagger},{ddagger}, Yongmei Liu{dagger},{ddagger}, Nancy E. Fink*,{dagger},{ddagger}, Josef Coresh*,{dagger},{ddagger}, Daniel E. Ford*,{dagger},{ddagger},§, Michael J. Klag*,{dagger},{ddagger}, and Neil R. Powe*,{dagger},{ddagger}

* Division of General Internal Medicine, Department of Medicine, and § Department of Psychiatry, Johns Hopkins School of Medicine, {dagger} Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and {ddagger} Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland

Address correspondence to: Dr. L. Ebony Boulware, Department of Medicine and Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, 2024 E. Monument Street, Suite 2-600, Baltimore, MD 21205. Phone: 443-287-2582; Fax: 410-955-0476; E-mail: lboulwa{at}jhmi.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Temporal relationships among depression, medical comorbidity, and death or cardiovascular disease (CVD) events are complex. Clarifying temporal relationships may enhance current insight regarding the nature of the association of depression with poor outcomes. The temporal relation of depression symptoms (DS; score ≤52 on five-item Mental Health Index) assessed at 6-mo intervals for 2 yr to CVD event, all-cause death, cardiovascular disease deaths, and non–cardiovascular disease deaths was studied in 917 incident dialysis patients. Cox regression models were used to assess whether the proximity of DS measurement and DS duration would change observed associations between DS and events. Whether increasing medical comorbidity was associated with worsening DS also was assessed. In time-varying models, DS were strongly associated with all-cause deaths, cardiovascular disease deaths, and CVD events (adjusted relative hazard [95% confidence interval]: 2.22 [1.36 to 3.60], 3.27 [1.57 to 6.81], and 1.68 [1.05 to 2.69], respectively). Persistent and current DS were associated with greater risks for all-cause death. Incorporating a 6-mo time lag between DS and outcomes attenuated risks for all-cause death, non–cardiovascular disease deaths, and CVD events. In a subgroup analysis, patients with worsening medical comorbidity (n = 32) during the first year of follow-up experienced a 2.42-point greater decline in mental health scores at 2 yr of follow-up compared with patients with no worsening in medical comorbidity (n = 123), but findings were not statistically significant. DS are strongly related to death and CVD events, with persistent/current DS most strongly associated with poor outcomes. Attenuated risks from time-lag analyses indicate a partial role for reverse causality, suggesting that medical comorbidity may precede DS.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Depression symptoms (DS) have been linked to poor quality of life (1,2) and increased rates of hospitalization (3) and mortality (2–4) among patients with ESRD, with one study demonstrating added risk for mortality with declining mental health scores beyond poor baseline scores (2). Proposed mechanisms for this association include decreased adherence to medical recommendations and changes in endocrine, neurologic, hemostatic, and immune function, which may enhance susceptibility to comorbid illness (5–9). However, not all studies in patients with ESRD confirm associations between depression and poor clinical outcomes. Studies that used multiple measurements of depression over time yielded more powerful positive associations than studies with a single baseline assessment (4). Differences in results might be attributable to variations in the populations studied, statistical methods, or reverse causality (declining health leading to depression) (10). Therefore, both the magnitude of association and the temporal (duration and proximity) association between DS and events remain unclear. Clarifying temporal relationships may enhance insight regarding the nature of the association of depression with outcomes. In addition, whereas the relation between depression and incident cardiovascular disease has been explored among the general public (11–13), it has been less well explored in ESRD. In a national study of incident dialysis patients, we explored the temporal relation between DS, medical comorbidity, and risk for death or cardiovascular disease (CVD) events.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Study Design and Participants
The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study is a national prospective cohort study of 1041 incident dialysis patients, aged 19 to 95 yr, from 81 dialysis clinics associated with Dialysis Clinics, Inc. (Nashville, TN; n = 923), New Haven CAPD (New Haven, CT; n = 88), or St. Raphael’s Hospital (New Haven, CT; n = 30) (14–16). Participants were enrolled from October 1995 to June 1998 a median of 45 d after dialysis initiation. To be eligible, patients had to be initiating outpatient hemodialysis or peritoneal dialysis for ESRD, to be 18 yr or older, and to speak English or Spanish. The protocol was approved by Institutional Review Boards, and patients gave written consent to participate. This analysis was limited to 917 (88%) participants with assessments of DS available at enrollment.

Data Collection
Baseline demographics, clinical data (including coexistent medical comorbidity assessed using the Index of Coexistent Disease [ICED] [17]), and antidepressant use were obtained from medical records and questionnaires. Baseline and follow-up assessments of DS (18–20) and laboratory studies, including creatinine, albumin, calcium, phosphorus, total cholesterol, hematocrit, C-reactive protein (CRP), IL-6, and white blood cell (WBC) counts, also were obtained.

Clinical and Laboratory Assessments
Baseline systolic and diastolic BP included the average of all predialysis sessions’ measures during the first 3 mo after enrollment (median 31 readings). Presence of diabetes, CVD (history of myocardial infarction, cardiac revascularization, stroke, carotid endarterectomy, peripheral vascular disease or revascularization, angina, or positive stress test), and heart failure was determined from medical record review.

Nonfasting serum specimens were drawn before dialysis a median of 5 mo from dialysis initiation, shipped overnight on dry ice to a central laboratory, and stored at –80°C. Total cholesterol was measured using colorimetric methods (coefficient of variation [CV] 5.3%), albumin using the Bromocresol Green method (CV 1.1%), creatinine using a modified Jaffe method, hematocrit and WBC count with the AVIA-120 Bayer autoanalyzer (Tarrytown, NY), CRP using a colorimetric competitive ELISA (CV 8.9%), and IL-6 by an ultrasensitive ELISA method (CV 7%). Albumin, calcium, phosphorus, hematocrit, and WBC count were obtained predialysis and were averaged over each 6-mo follow-up period (median three to four measurements per 6 mo).

Assessment of DS
DS were assessed at baseline and at three intervals (6, 12, and 18 mo) using the self-administered five-item mental health subscale of the Medical Outcomes Study Short Form-36 (MHI-5) (16,18–20). MHI-5 items ask respondents how often during the past month they have felt "nervous," "down in the dumps," "calm and peaceful," "downhearted and blue," and "happy." Items were scored on a scale of 0 to 100, with greater scores indicating better mental health and well-being (19). MHI-5 items have concurrent validity in identifying DS in ESRD measured using the Beck Depression Symptoms Index (21). DS were assessed in dichotomous (considered present when MHI scores were ≤52) and continuous manners. Scores ≤52 have good specificity and sensitivity for the detection of DS in chronic illness (20,22–25).

Outcome Assessment
Deaths from all causes were ascertained by active surveillance through dialysis clinics and passive surveillance using Centers for Medicare and Medicaid Services data. Of 324 deaths, 126 (59% of 214 in-hospital deaths) terminal hospitalization medical records were available and were reviewed for underlying cause of death using an algorithm modified from the Cardiovascular Health Study (26,27).

A composite CVD outcome was composed of the first fatal (death secondary to coronary artery disease, stroke, and peripheral vascular disease) or nonfatal (abdominal aortic aneurysm, extremity amputation, peripheral arterial bypass, coronary artery bypass grafting, carotid endarterectomy, stroke including intracranial hemorrhage, myocardial infarction, and coronary angioplasty) cardiovascular event during follow-up (28). Events coders were unaware of MHI-5 responses.

Statistical Analyses
We performed bivariate ({chi}2 and t test) analysis to ascertain associations between patient characteristics or date of study enrollment and DS at baseline. In survival analysis, we assessed differences in time to death and CVD events up to 2 yr after enrollment. Individuals were censored as a result of leaving a CHOICE clinic (n = 226 [22%]), transplant (n = 151 [15%]), or end of follow-up (n = 386 [37%]).

To ascertain temporal relations, we assessed (1) the association of presence and duration of DS with outcomes and (2) a possible reverse causal association (medical comorbidity preceding onset of DS). We used Cox proportional hazards models to incorporate DS assessed (1) at baseline only, (2) in a time-varying manner (baseline and follow-up at 6, 12, and 18 mo), or (3) in a time-varying manner with a 6-mo time lag in which only DS that were assessed at least 6 mo before the event were related to outcomes.

In baseline only multivariable analyses, covariates were demographics, comorbidity, modality, antidepressant use, creatinine, CVD risk factors, BP, inflammation, hematocrit, albumin, calcium, and phosphorus. For time-varying models, follow-up measures of BP, hematocrit, creatinine, albumin, calcium, phosphorus, and WBC count also were covariates. We performed stratified analyses and overall multivariable analyses using interaction terms to assess differences in the magnitude or direction of associations according to demographics, diabetes status, modality, comorbid disease status, and smoking status. We performed a sensitivity analysis to assess whether controlling for other aspects of quality of life (physical health and vitality, social function, and role emotional function) would change results.

To investigate further the association of the proximity of measurement and the persistence of DS with outcomes, we categorized patients as having had "distant" DS (at least 6 to 12 mo before event occurrence) or "current" DS (within 6 mo of event occurrence), and we created four mutually exclusive categories for patients with (1) distant and current DS (persistent symptoms), (2) current symptoms only, (3) distant symptoms only, and (4) neither distant nor current symptoms (reference group).

We used ICED scores at baseline and 1 yr of follow-up to determine changes in medical comorbidity during the first year of dialysis and to explore further a possible reverse causal relationship between poor health and DS (29). In the subgroup of participants who had no DS at 1 yr of follow-up and who also had measurement available at 2 yr of follow-up (n = 283), we used generalized estimating equation models for repeated measures to ascertain the relation of a change in ICED score during the first year of dialysis to changes in DS scores at 2 yr of follow-up (16,30–33). All analyses accounted for clustering within clinics using robust variance methods in STATA (release 8.0; StataCorp, College Station, TX) statistical software (34).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Prevalence of DS and Participant Baseline Characteristics
DS were prevalent among 24% of participants at baseline, 23% at 6 mo, 19% at 12 mo, and 21% at 18 mo. The incidence of DS was 14% at 6 mo, 9% at 12 mo, and 13% at 18 mo. Patients who were enrolled within 30 d of dialysis initiation (n = 294) were no more likely than patients who were enrolled later to report DS at baseline (23 versus 25%, respectively; P = 0.64). Black patients, those with less than a high school education, those taking antidepressants, and current smokers were more likely to have prevalent DS. Systolic BP and WBC count were greater among patients with DS versus their counterparts without symptoms (Table 1).


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  		Table 1. Baseline characteristics and prevalence of DS at baseline in 917 incident dialysis patientsa

 
Timing of DS Measurement and Relation with Outcomes
During 1468 person-years of follow-up (mean follow-up 1.5 yr; range 67 d to 2 yr), 189 deaths (51% CVD deaths) and 272 CVD events occurred. Crude cumulative mortality from any cause in Kaplan-Meier plots was no different between patients with and without baseline DS, greater in patients with symptoms assessed in a time-varying manner, and greater in patients with symptoms assessed in a time-varying manner with incorporation of a 6-mo time lag between symptom measurement and mortality (Figure 1).


Figure 1
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  		Figure 1. All-cause mortality (unadjusted) according to presence of depression symptoms (DS) measured at baseline (A), in time-varying 6-mo intervals (B), and time-varying 6-mo intervals with 6-mo time lag between measurement of DS and death (C). (A) Crude cumulative deaths over follow-up by presence of DS. (B) Crude cumulative deaths over follow-up by presence of DS assessed in a time-varying manner. (C) Crude cumulative deaths over follow-up by DS assessed in time-varying manner with 6-mo time lag. All events in the time-lag analysis are classified with respect to whether DS were present 6 mo before that event. A time lag between the measurement of DS at baseline and the occurrence of events after 6 mo of follow-up is represented by a flat line.

 
Baseline DS scores ≤52 were associated with only death from non-CVD causes after adjustment (Table 2). In contrast, DS scores ≤52 assessed as a time-varying measure showed a 60% to three-fold increased hazard of death from all causes, death from CVD causes, and CVD events when compared with patients without DS in both unadjusted and adjusted analyses. In subgroup analyses of DS scores ≤52 assessed as a time-varying measure, DS seemed more strongly related to all-cause deaths in patients without diabetes and more strongly related to CVD events in white versus black patients. Although stratified analyses could not be performed by dialysis modality (because of few events among peritoneal dialysis patients), analyses that used an interaction term demonstrated that patients who were on peritoneal dialysis and had DS had a hazard of CVD events 2.36 times (95% confidence interval [CI] 1.05 to 5.32) greater than that for similar patients who were on hemodialysis (Table 3). Results were similar when symptom scores were analyzed as a continuous variable (data not shown).


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  		Table 2. Association of DS with all-cause mortality, CVD mortality, non-CVD mortality, and CVD events at 2 yr using dichotomous definition for DS (MHI-5 ≤52)a

 

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  		Table 3. Association of DS (MHI-5 ≤ 52) with risk for death from all causes and CVD events by patient subgroups

 
Relation of Proximity of DS Measurement and Duration of DS to Outcomes
Among patients who were depressed at baseline, symptoms persisted in 13% at 6 mo, 12% at 12 mo, and 11% at 18 mo of follow-up. Current symptoms were present in 11% of participants at 6 mo, 7% at 12 mo, and 10% at 18 mo of follow-up. Distant but not current symptoms were present in 11% of participants at 6 mo, 9% at 12 mo, and 8% at 18 mo of follow-up. Persistent and current symptoms were associated with four-fold greater adjusted risks for death from all causes and two-fold greater adjusted risk for CVD events when compared with patients with no symptoms in the previous 12 mo (Table 4).


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  		Table 4. Association of persistence of DS (MHI-5 ≤52) with all-cause mortality and CVD events at 2 yr using dichotomous definition for DSa (MHI-5 ≤52)

 
Investigation of Reverse-Causal Relation between DS and Comorbid Disease
DS scores ≤52 assessed as a time-varying measure with incorporation of a 6-mo time lag were crudely associated with a 50 to 70% increased hazard of all deaths, non-CVD deaths, and CVD events, representing an attenuation of findings in models that did not incorporate a 6-mo time lag. After adjustment, the magnitude of risk was similar and not statistically significant (Table 2).

Of 711 participants with ICED scores at baseline and 1 yr follow-up, 59% experienced no change in ICED score, 17% experienced improvement, and 22% experienced a decline. Of 572 participants with depression scores at baseline and 1 yr, mean (SD) symptom scores at 1 yr of follow-up were 79.5 (13.0) for patients with no depression at baseline or at 1 yr (n = 393), 43.9 (8.8) for no depression at baseline but depression at 1 yr (n = 48), 69.9 (11.5) for depression at baseline but no depression at 1 yr (n = 69), and 38.7 (11.4) for depression at both baseline and 1 yr (n = 62). Patients with DS at either baseline or follow-up were no more likely than the 22% of patients with no symptoms at baseline or 1 yr to experience a decline in ICED score: Patients with no symptoms at baseline but symptoms at 1 yr (23 versus 22%; P = 0.8), patients with symptoms at baseline but no symptoms at 1 yr (17 versus 22% P = 0.4), and patients with symptoms at both baseline and 1 yr (30 versus 22%; P = 0.2). In a subgroup analysis of 155 participants who had no DS at baseline or 1 yr (with ICED scores present at baseline and 1 yr and depression scores also present at baseline, 1 yr, 18 mo, and 2 yr), 21% experienced a decline in ICED during the first year of follow-up. Among patients who experienced a decline in ICED, 25% experienced incident DS at 18 mo or 1 yr versus 19% in patients who did not experience a decline in ICED (P = 0.43, adjusted odds ratio [95% CI] for incident depression 1.39 [0.53 to 3.64]).

Patients with no change or an improvement in their ICED scores during the first year experienced a decline in their DS scores between the first and second years of follow-up after adjustment for age, gender, race, education, and dialysis modality (mean change [95% CI] –2.06 points [–0.33 to –3.79]). Patients with worsening ICED scores during the first year of dialysis did experience greater declines in symptom scores when compared with patients with no change or improved ICED scores during the first year of dialysis, but the results were not statistically significant (difference [95% CI] in change –2.42 points [1.36 to –6.21]).

Sensitivity Analysis on Health-Related Quality of Life
Results of analyses that incorporated measures of physical and mental health–related quality of life as covariates were consistent with main results (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In this national study of incident dialysis patients, we found a positive association of DS measured in a time-varying manner (using multiple measures of symptoms over time) with all-cause mortality, CVD mortality, and CVD events at 2 yr of follow-up, but we found no association when symptoms were measured only a single time at baseline. In contrast, we found a positive association of DS measured a single time at baseline with non-CVD deaths. Persistent and current (versus distant) DS were most strongly associated with mortality and CVD events. The strength and statistical significance of the relation between DS and deaths or CVD events was diminished in analyses that incorporated a 6-mo time lag, suggesting that relations between depression and CVD outcomes are partially due to reverse causality (medical comorbidity leading to depression rather than vice versa). Complementary analyses in a small number of patients demonstrated a decrease in DS scores after an increase in medical comorbidity, but results were not statistically significant.

This study confirms and builds on earlier results from a single regional study in 295 patients with ESRD by extending observations in a larger, national sample and by documenting a powerful association between DS measured over multiple time periods and CVD while controlling for traditional and novel risk factors (e.g., inflammation) (4,35,36). Other studies that were performed in individuals in the general public also found an association between change in (and not baseline) DS and outcomes (12).

Much of the observed association between DS measured in a time-varying manner and all-cause mortality was driven by the strong association between symptoms and CVD deaths. A variety of potential mechanisms have been proposed, including changes in platelet aggregation, changes in autonomic function (37,38), neurohormonal alterations (39), and increased endothelial activation (40,41). Few studies have been performed among peritoneal dialysis patients (10). Our findings of greater risk for CVD events in peritoneal dialysis patients with DS may reflect greater activation of these mechanistic factors in patients who were demonstrated to have greater risk for poor CVD outcomes (42). The association of baseline depression with non-CVD death did not become statistically significant until we controlled for WBC count, IL-6, and CRP. Because infection is a leading cause of non-CVD death (43), measures of inflammation may represent important confounders that were not controlled for in previous studies (3,4).

Two possible explanations for our findings of no association between baseline DS and outcomes as well as attenuation of results when a 6-mo time lag between the measurement of time-varying symptoms and outcomes was incorporated include (1) reverse causality and (2) a short-lived effect of depression on health outcomes. If depression is caused by worsening comorbid illness, then measurement near or at the same time of death or CVD event could explain the observed strong, positive association. Our finding that separation of the time of DS measurement and the time of outcomes measurement weakens the associations confirms the possibility of reverse causality. However, it is also possible that mechanisms for the relation between symptoms and CVD outcomes may be short lived in nature and that increased risk for adverse health outcomes occurs only when symptoms have been present within 6 mo of outcome measurement. Our findings that persistent and current symptoms are more strongly associated with death and CVD events than are distant symptoms support this theory.

If declining medical health does lead to depression, then treatment of depression may not have as large an impact on CVD outcomes as might be expected. However, treatment of depression improves other important outcomes, such as nutrition (in patients with ESRD) (44), physical symptoms (45), and quality of life (in patients without ESRD) (46,47). Our subgroup analyses indicate that those with persistent depression may be at greatest risk for poor outcomes. Therefore, clinicians who identify patients with depression should be aware of depressed patients’ increased risk for poor outcomes, particularly when depression persists for longer than 6 mo.

Previous studies have demonstrated that patients experience an acute decline in DS scores at the initiation of dialysis, and symptoms are worse for patients who initiate dialysis when compared with patients who are on chronic dialysis (16,48). Our subgroup analyses demonstrated that 89% of those with DS at baseline were free of symptoms at 18 mo of follow-up, supporting this hypothesis. Although some participants enrolled as late as 6 mo after dialysis initiation, we did not observe any trend of higher or lower scores in relation to proximity of symptom measurement and the time of dialysis initiation.

Depression is strongly related to prevalent medical comorbidity, including risk factors for the development of cardiovascular morbidity in ESRD (49,50) and non-ESRD populations (51–53). However, the potential for worsening comorbid medical disease to cause depression in patients with chronic illnesses has been less well studied. In small studies of other chronic illnesses, the presence of disability (54) and other medical conditions (55) has been associated with incident depression. Patients with ESRD have greater prevalence of medical comorbidity, disability, and poor quality of life compared with other populations (4,29,35,36,56–59). In addition, dialysis therapy and ESRD may lead to biologic changes (e.g., increases in oxidative stress [60], alterations in calcium metabolism, differences in inflammatory mediators [61]) that alter the pathogenic pathways that give rise to CVD and death (62). As incident ESRD patients begin dialysis, they may have a temporary increase in physical well-being, which is not the usual pattern for individuals with other chronic diseases.

Limitations of this study deserve mention. First, although the MHI-5 has been validated in other chronic illnesses, it has not been used widely in ESRD (20,22,24,25). However, our estimates of symptom prevalence and incidence track closely to those reported in other studies (3,4), and our detection of greater prevalence of symptoms among patients who take antidepressant medications is reassuring. MHI-5 items have been shown to have concurrent validity for diagnosing DS when compared with other measures used in patients with ESRD (21). The lack of a single disease-specific instrument for measurement of depression in ESRD has led to use of various measures (4). A strength of the MHI-5 is that it does not measure somatic components that commonly are experienced in patients with ESRD. Second, we did not have reliable longitudinal measures of dialysis adequacy for patients who were receiving peritoneal dialysis. However, when we incorporated average (over follow-up) KT/V in models of patients who were receiving hemodialysis, findings were similar to our main analyses. Finally, 88 (32%) peritoneal dialysis patients were recruited from one center, potentially limiting generalizability.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We found an association between DS assessed within 6 mo before death and CVD events. Persistent and current DS were more powerful in predicting events than symptoms that were diagnosed in the distant past. Our findings suggest that some of the association of depression with health outcomes is due to medical comorbid illness leading to depression, rather than depression preceding death or CVD events. While we await more definitive studies, providers should be aware of the increased risk for death and CVD events in patients with DS, particularly patients whose symptoms persist longer than 1 yr.


   Acknowledgments
 
CHOICE is supported by RO1-HL-62985 (National Heart, Lung, and Blood Institute) and RO1-DK-59616 (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]). L.E.B. is supported by the Harold Amos Medical Faculty Development Program (Robert Wood Johnson Foundation) and grant RO1-DK59616-02S1 (NIDDK), J.C. is supported in part as an American Heart Association established investigator (01-4019-7N), M.J.K. is supported by K24-DK-02856 (NIDDK), and N.R.P. is supported in part by K24-DK-02643 (NIDDK).

Data were presented in abstract form at the National Meeting of the American Society of Nephrology; October 28 to November 1, 2004; St. Louis, MO.

We thank the patients, staff, laboratory, and medical directors of the participating clinics at Dialysis Clinic, Inc., New Haven CAPD, and St. Raphael 's Hospital who contributed to the study. We also thank the CHOICE study Cardiovascular Endpoint Committee. Current members are Bernard G. Jaar, MD, MPH; Yongmei Liu, MD, PhD; Joseph A. Eustace, MD, MHS; Richard M. Ugarte, MD; Melanie H. Katzman, MD, MHS; J. Craig Longenecker, MD, PhD; and Josef Coresh, MD, PhD. Former members of the committee include Michael Klag, MD, MPH; Neil R. Powe, MD, MPH, MBA; Michael J. Choi, MD; Renuka Sothinathan, MD, MHS; and Caroline Fox, MD, MPH. Cardiovascular events adjudicators are Nancy E. Fink, MPH; and Laura C. Plantinga, ScM.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received May 26, 2005. Accepted January 18, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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