ORIGINAL ARTICLE
Restless legs syndrome is associated with cardio/cerebrovascular events and mortality in end-stage renal disease C.-H. Lina, H.-N. Syb, H.-W. Changc,d, H.-H. Lioue, C.-Y. Linf, V.-C. Wud, S.-L. Wub, C.-C. Changg, P.-F. Chiug, W.-Y. Lih, S.-Y. Lini, K.-D. Wud, Y.-M. Chend and R.-M. Wua
EUROPEAN JOURNAL OF NEUROLOGY
a Department of Neurology, College of Medicine, National Taiwan University Hospital, Taipei; bDepartment of Neurology, Changhua Christian Hospital, Changhua; cFar Eastern Polyclinic, Taipei; dDepartment of Internal Medicine, College of Medicine, National Taiwan University Hospital, Taipei; eDepartment of Internal Medicine, Hsin Jen Hospital, Taipei; fDepartment of Internal Medicine, En Chu Kong Hospital, Taipei; gDepartment of Internal Medicine, Changhua Christian Hospital, Changhua; hDepartment of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou; and iDepartment of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
Keywords:
cardiovascular disease, cerebrovascular disease, end-stage renal disease, mortality, restless legs syndrome, stroke Received 27 April 2014 Accepted 2 July 2014 European Journal of Neurology 2015, 22: 142–149 doi:10.1111/ene.12545
Background and purpose: Earlier studies suggested an association between idiopathic restless legs syndrome (RLS) and cardiovascular diseases. However, the risk of cardiovascular events in patients with secondary RLS due to endstage renal disease (ESRD) is unclear. Our aim was to examine whether ESRD patients with RLS had an increased risk of cardio/cerebrovascular events and mortality. Methods: In all, 1093 ESRD patients were recruited between 2009 and 2010. The diagnosis and severity of RLS were assessed in a face-to-face interview. The occurrence of cardio/cerebrovascular events and death were confirmed by medical record review. The association between RLS and the outcomes of interest was examined using an adjusted multivariate Cox regression model. Results: After a mean follow-up period of 3.7 0.8 years, ESRD patients with RLS had a significantly higher risk of developing cardiovascular events and strokes [adjusted hazard ratio (aHR) 2.82, 95% confidence interval (CI) 2.02–4.11, and aHR 2.41, 95% CI 1.55–3.75, respectively] compared with patients without RLS. Increasing RLS severity was associated with an increasing likelihood of cardiovascular events [mild RLS severity, aHR 1.71 (95% CI 1.02–2.87); moderate, 2.79 (1.64–4.66); severe, 2.85 (1.99–4.46)] and strokes [mild, 1.89 (0.87–4.16); moderate, 2.42 (1.50–3.90); severe, 2.64 (1.49–4.91)] in a dose-dependent manner. RLS also increased the risk of total mortality in patients with ESRD [aHR 1.53 (95% CI 1.07–2.18), P = 0.02]; this association attenuated slightly after stratification by individual RLS severity category [mild RLS severity, aHR 1.44 (95% CI 0.78–2.67); moderate, 1.49 (0.98–2.55); severe, 2.03 (0.93–4.45)]. Conclusions: ESRD patients with RLS demonstrated an increased likelihood of cardio/cerebrovascular events and mortality.
Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs that is Correspondence: R.-M. Wu, Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan (tel.: +886-2-23123456, ext. 65337; fax: +886-2-23418395; e-mail: [email protected]).
142
exacerbated by rest and relieved by motor activity [1,2]. RLS affects 5%–10% of adults in the general population and is associated with various medical conditions [3]. End-stage renal disease (ESRD) is one of the most commonly reported conditions associated with RLS, and the prevalence of RLS amongst dialysis patients is significantly higher than that of the general population [3,4]. It has been postulated that
© 2014 EAN
CVD RISK AND MORTALITY IN UREMIC RLS
symptoms of primary RLS arise from decreasing dopamine release from the dorso-posterior hypothalamus on the spinal cord, which leads to augmentation of sensory input information during leg movement [2]. However, the pathophysiology of uremic RLS in ESRD condition remains largely elusive. Dialysisrelated clinical and biochemical parameters, such as duration of dialysis, anemia and low serum iron status, have been shown to correlate with the risk and severity of uremic RLS in ESRD patients [3]. Recently, studies have observed a relatively high mortality rate and cardiovascular disorders (CVD) associated with either primary RLS or uremic RLS, although inconsistent results exist [5–10]. It is suggested that RLS may increase the risk for CVD via chronic activation of the sympathetic nervous system and hypothalamic pituitary adrenal axis [11]. However, whether uremic RLS follows the same mechanism as primary RLS in associating with the risk of CVD remains unclear. Furthermore, most of these studies were conducted in a relatively small sample size, with a retrospective design or with outcome measurements based on questionnaires which are vulnerable to recall bias. Given that CVD is a major cause of mortality in ESRD patients [11], a large prospective cohort study is needed to clarify the risk of CVD and related vascular disorders in ESRD patients with RLS. According to the US Renal Data System, Taiwan has the highest incidence and prevalence of ESRD worldwide [12,13]. It was observed previously that the prevalence of RLS was 25.3% amongst Taiwanese ESRD patients [4]. Information regarding the risk of cardio/cerebrovascular events has not been examined in a large cohort of ESRD patients with a prospective follow-up design and studies using medical records to confirm the outcomes of interest rather than selfreported questionnaires are lacking. The aim of the current study was to prospectively examine whether patients with uremic RLS have an increased risk of cardio/cerebrovascular events and mortality in a cohort of dialysis patients.
Methods Study population
From October 2009 to 2010, ESRD patients undergoing long-term hemodialysis at 17 hemodialysis centers in Taiwan were consecutively recruited. The study was approved by institutional ethics board committees and all participants provided written informed consent. The epidemiological data of this ESRD patient cohort have been reported previously [4] and the cohort was
© 2014 EAN
143
followed up to examine the outcomes of interest. The inclusion criterion was the adult population under hemodialysis treatment for at least 3 months. The exclusion criteria were subjects with type 1 diabetes mellitus, pregnancy, Parkinson’s disease, patients with unclear consciousness or unresponsiveness to the questionnaire, and patients who did not have a continuous dialysis record for at least 3 months. Diagnosis of medical comorbidities, e.g. diabetes mellitus and hypertension, during the 12-month period before the index date (the date entering the study) was used to ascertain patients’ demographic data. The study consisted of a standardized face-to-face interview followed by the collection of clinical demographic data and a blood sample for biochemical analysis. Because there has been a single-payer and compulsory National Health Insurance (NHI) program implemented in Taiwan since 1995 and there was 99% enrollment by 2010, all the ESRD related therapy such as dialysis regimen, erythropoiesis-stimulating agent and iron supplement therapy are paid by the NHI; therefore the same guides were applied to all the dialysis centers in Taiwan. A questionnaire pertaining to the four essential International RLS Study (IRLSS) group diagnostic criteria [1] and the severity of RLS [14] was administered by a single trained interviewer to avoid inter-rater variability and then referred to movement disorder specialists (CHL and HNS) when RLS was suspected. For the Chinese version of the questionnaire, please refer to Data S1. The four essential criteria [1] are all required to make the diagnosis of RLS. This single interviewer was trained in the movement disorder special clinic of the tertiary referral medical center in Taiwan (National Taiwan University Hospital). Individuals with RLS were classified as mild (IRLSS score 30). Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) [15]. Ascertainment of cardio/cerebrovascular events and death
Medical records of all participants were obtained for all CVD and stroke events and reviewed by clinicians (CCC, LHH and LCY) or neurologists (LCH and SHN). Stroke was confirmed if the participant had a new focal-neurological deficit of sudden onset that persisted for more than 24 h and had been admitted to the hospital with available medical records. Myocardial infarction alone was defined as the main outcome of cardiovascular events. The occurrence of myocardial infarction was confirmed if symptoms met World Health Organization criteria and the event was
144
C.-H. LIN ET AL.
associated with abnormal levels of cardiac enzymes or diagnostic electrocardiogram results with or without coronary revascularization [16]. Stable/unstable angina or acute heart failure was not included without evidence of cardiac enzyme or electrocardiogram abnormality to avoid heterogeneity of the outcome of interest. Deaths were confirmed by review of medical records, death certificates or information obtained from next of kin or family members. Statistical analysis
A total of 1884 participants were initially surveyed. Patients were excluded who did not meet the inclusion criteria (n = 315), declined participation because they refused blood sampling (n = 350), lacked regular follow-up laboratory data (n = 89), lacked a continuous dialysis record or were lost to follow-up for more than 3 months (n = 37). After these exclusions, a total of 1093 individuals participated in this analysis (Fig. S1). Baseline characteristics according to RLS status were compared using the chi-squared test for categorical variables and the t test for continuous variables. The crude incidence rates and 95% confidence intervals for cardio/cerebrovascular events and mortality were estimated on a Poisson distribution in each category. The association between RLS and outcomes of interest was examined by comparing the occurrence of cardio/cerebrovascular events and death amongst ESRD patients with RLS versus the occurrence amongst participants without RLS, using an adjusted multivariate Cox regression model to calculate hazard ratios. The multivariate models were adjusted for age, sex, comorbidities of diabetes mellitus and hypertension, duration of hemodialysis, serum level of hemoglobin, serum level of iron and transferrin saturation. For the outcome of mortality, in addition to the above-mentioned covariates, the numbers of cardio/ cerebrovascular events were also adjusted in the multivariate model of mortality. The proportional hazards assumption was tested by including an interaction term for RLS status and logarithm of follow-up time for all three outcomes of interest separately in ageadjusted models. No statistically significant violation was found. The association between different RLS severity levels and the risk of cardio/cerebrovascular events and mortality was also examined by comparing the occurrence of outcomes of interest across different RLS severity subgroups with the occurrence amongst participants without RLS. Given that RLS is difficult to diagnose in the ESRD condition and false-positive results mostly come from the presence of other leg symptoms suggesting periph-
eral neuropathy [17], whether the effect estimates changed substantially was investigated on excluding individuals with concomitant uremic or diabetic polyneuropathy in the sensitivity analysis. Kaplan–Meier curves were also used to compare the cumulative probability risk of cardio/cerebrovascular events and mortality during the follow-up period between ESRD patients with and without RLS. For the Kaplan–Meier curve of mortality, observations were censored due to death or loss of follow-up for more than 2 months. For the Kaplan–Meier curve of cardio/cerebrovascular events, observations were censored due to having new cardio/cerebrovascular events during the follow-up period. The log-rank test was used to determine the differences in survival between groups. All statistical analyses were performed using STATA 8.0 (STATA Corp., Lakeway, TX, USA).
Results Of the 1093 patients with ESRD, 275 (25.2%) met the criteria of RLS at baseline. ESRD patients with RLS were more likely to have lower serum level of iron, lower serum transferrin saturation, a higher prevalence of diabetes mellitus and hypertension, a longer duration of these comorbidities and poorer sleep quality scores than patients without RLS (Table 1). With a mean follow-up period of 3.7 0.8 years, 158 cardiovascular events, 112 strokes and 132 deaths were documented. The crude incidence rate of cardiovascular events per 100 000 person-days was 8.14 (7.97–8.93) for dialysis patients without RLS and 33.06 (32.89–33.91) for those with RLS (Table 2). In the adjusted multivariate analysis, patients with RLS had a greater risk of cardiovascular events than those without RLS, with an adjusted hazard ratio (aHR) (95% confidence interval) of 2.82 (2.02–4.11) (Table S1). In the survival analysis, the group with RLS had lower cardiovascular-event-free survival than the group without RLS (Fig. 1a, log-rank test P < 0.001). Participants with mild, moderate or severe RLS at the beginning of the study were significantly more likely to have cardiovascular events than patients without RLS (P < 0.01, Table 3), suggesting a dose response manner. This positive association between RLS severity and cardiovascular events decreased slightly, but remained significant, in the regression analysis adjusted for the baseline multivariate differences; the aHR was 1.71 (1.02–2.87) for mild RLS, 2.79 (1.64– 4.66) for moderate RLS and 2.85 (1.99–4.46) for severe RLS (Table 3). Results were similar in the sensitivity analysis (Table 3). Regarding the outcome of strokes, the adjusted multivariate analysis showed that patients with RLS
© 2014 EAN
CVD RISK AND MORTALITY IN UREMIC RLS
145
Table 1 Baseline clinical and laboratory characteristics of ESRD patients according to RLS status
All (N = 1093) Basic characteristics Age (years) Male, n (%) Years on dialysis (years) Laboratory characteristics Hemoglobin (g/dl) Predialysis creatinine (mg/dl) Predialysis BUN (mg/dl) Albumin (g/dl) GOT (mg/dl) GPT (mg/dl) Calcium (mg/dl) Phosphate (mg/dl) Iron (mg/dl) Ferritin (mg/dl) TIBC (mg/dl) Transferrin saturation (%) Comorbidity Diabetes mellitus, n (%) Duration of diabetes (years) Hypertension, n (%) Duration of HTN (years) PSQI sleep score
63.6 3.4 620 (56.72) 5.9 3.1 10.7 10.2 70.9 3.7 22.3 22.0 9.0 5.1 65.9 409.8 237.9 28.1 410 4.9 548 5.4 9.5
RLS (+) (N = 275) 64.2 3.7 147 (53.45) 6.0 3.2
1.3 2.3 18.6 0.7 13.2 14.3 2.2 1.4 23.0 34.4 44.5 9.3
10.6 10.2 71.5 3.6 22.6 21.7 8.9 5.1 62.9 422.1 234.4 27.1
(37.51) 4.2 (50.14) 4.4 3.6
138 6.5 158 6.1 10.8
Mild (N = 191) 63.7 3.3 107 (56.0) 5.8 3.1
1.6 2.4 17.0 0.8 11.6 12.8 2.5 1.8 21.4 68.5 45.0 7.9
10.8 10.8 72.1 3.6 22.4 22.6 8.8 5.0 63.5 423.8 232.9 27.5
(50.18) 4.5 (57.45) 4.4 3.7
92 6.2 106 5.8 9.9
1.3 7.5 17.6 0.8 10.8 11.6 3.2 1.3 20.8 51.2 42.3 8.2
(48.2) 4.2 (55.5) 4.5 3.8
Moderate (N = 61) 64.9 3.42 28 (45.9) 6.3 3.5 10.2 9.9 69.8 3.6 22.8 22.6 8.9 5.1 61.9 415.8 237.2 27.1 32 6.3 37 6.4 12.5
1.3 1.9 18.3 0.8 11.0 11.6 3.1 1.2 22.1 50.9 43.8 7.7
(52.5) 4.4 (60.6) 4.6 3.3
Severe (N = 23)
RLS ( ) (N = 818)
67.5 3.4 12 (52.2) 7.1 3.1 10.4 9.8 71.6 3.5 23.1 22.6 9.1 5.2 64.6 421.8 238.4 26.1 14 7.9 15 7.4 12.7
1.3 1.7 18.5 1.2 10.8 11.6 1.5 1.4 22.7 52.1 44.9 7.5
(60.8) 4.4 (65.2) 4.7 3.7
Pa
63.4 3.4 473 (57.82) 5.9 3.1
0.37 0.21 0.79
1.3 2.3 16.8 0.2 12.8 17.1 1.7 1.3 23.5 62.2 44.3 9.7
0.15 0.77 0.32 0.79 0.89 0.88 0.75 0.80 0.01 0.51 0.12 0.03
(33.25) 3.2 (47.67) 4.9 3.5
Restless legs syndrome is associated with cardio/cerebrovascular events and mortality in end-stage renal disease C.-H. Lina, H.-N. Syb, H.-W. Changc,d, H.-H. Lioue, C.-Y. Linf, V.-C. Wud, S.-L. Wub, C.-C. Changg, P.-F. Chiug, W.-Y. Lih, S.-Y. Lini, K.-D. Wud, Y.-M. Chend and R.-M. Wua
EUROPEAN JOURNAL OF NEUROLOGY
a Department of Neurology, College of Medicine, National Taiwan University Hospital, Taipei; bDepartment of Neurology, Changhua Christian Hospital, Changhua; cFar Eastern Polyclinic, Taipei; dDepartment of Internal Medicine, College of Medicine, National Taiwan University Hospital, Taipei; eDepartment of Internal Medicine, Hsin Jen Hospital, Taipei; fDepartment of Internal Medicine, En Chu Kong Hospital, Taipei; gDepartment of Internal Medicine, Changhua Christian Hospital, Changhua; hDepartment of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou; and iDepartment of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
Keywords:
cardiovascular disease, cerebrovascular disease, end-stage renal disease, mortality, restless legs syndrome, stroke Received 27 April 2014 Accepted 2 July 2014 European Journal of Neurology 2015, 22: 142–149 doi:10.1111/ene.12545
Background and purpose: Earlier studies suggested an association between idiopathic restless legs syndrome (RLS) and cardiovascular diseases. However, the risk of cardiovascular events in patients with secondary RLS due to endstage renal disease (ESRD) is unclear. Our aim was to examine whether ESRD patients with RLS had an increased risk of cardio/cerebrovascular events and mortality. Methods: In all, 1093 ESRD patients were recruited between 2009 and 2010. The diagnosis and severity of RLS were assessed in a face-to-face interview. The occurrence of cardio/cerebrovascular events and death were confirmed by medical record review. The association between RLS and the outcomes of interest was examined using an adjusted multivariate Cox regression model. Results: After a mean follow-up period of 3.7 0.8 years, ESRD patients with RLS had a significantly higher risk of developing cardiovascular events and strokes [adjusted hazard ratio (aHR) 2.82, 95% confidence interval (CI) 2.02–4.11, and aHR 2.41, 95% CI 1.55–3.75, respectively] compared with patients without RLS. Increasing RLS severity was associated with an increasing likelihood of cardiovascular events [mild RLS severity, aHR 1.71 (95% CI 1.02–2.87); moderate, 2.79 (1.64–4.66); severe, 2.85 (1.99–4.46)] and strokes [mild, 1.89 (0.87–4.16); moderate, 2.42 (1.50–3.90); severe, 2.64 (1.49–4.91)] in a dose-dependent manner. RLS also increased the risk of total mortality in patients with ESRD [aHR 1.53 (95% CI 1.07–2.18), P = 0.02]; this association attenuated slightly after stratification by individual RLS severity category [mild RLS severity, aHR 1.44 (95% CI 0.78–2.67); moderate, 1.49 (0.98–2.55); severe, 2.03 (0.93–4.45)]. Conclusions: ESRD patients with RLS demonstrated an increased likelihood of cardio/cerebrovascular events and mortality.
Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs that is Correspondence: R.-M. Wu, Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan (tel.: +886-2-23123456, ext. 65337; fax: +886-2-23418395; e-mail: [email protected]).
142
exacerbated by rest and relieved by motor activity [1,2]. RLS affects 5%–10% of adults in the general population and is associated with various medical conditions [3]. End-stage renal disease (ESRD) is one of the most commonly reported conditions associated with RLS, and the prevalence of RLS amongst dialysis patients is significantly higher than that of the general population [3,4]. It has been postulated that
© 2014 EAN
CVD RISK AND MORTALITY IN UREMIC RLS
symptoms of primary RLS arise from decreasing dopamine release from the dorso-posterior hypothalamus on the spinal cord, which leads to augmentation of sensory input information during leg movement [2]. However, the pathophysiology of uremic RLS in ESRD condition remains largely elusive. Dialysisrelated clinical and biochemical parameters, such as duration of dialysis, anemia and low serum iron status, have been shown to correlate with the risk and severity of uremic RLS in ESRD patients [3]. Recently, studies have observed a relatively high mortality rate and cardiovascular disorders (CVD) associated with either primary RLS or uremic RLS, although inconsistent results exist [5–10]. It is suggested that RLS may increase the risk for CVD via chronic activation of the sympathetic nervous system and hypothalamic pituitary adrenal axis [11]. However, whether uremic RLS follows the same mechanism as primary RLS in associating with the risk of CVD remains unclear. Furthermore, most of these studies were conducted in a relatively small sample size, with a retrospective design or with outcome measurements based on questionnaires which are vulnerable to recall bias. Given that CVD is a major cause of mortality in ESRD patients [11], a large prospective cohort study is needed to clarify the risk of CVD and related vascular disorders in ESRD patients with RLS. According to the US Renal Data System, Taiwan has the highest incidence and prevalence of ESRD worldwide [12,13]. It was observed previously that the prevalence of RLS was 25.3% amongst Taiwanese ESRD patients [4]. Information regarding the risk of cardio/cerebrovascular events has not been examined in a large cohort of ESRD patients with a prospective follow-up design and studies using medical records to confirm the outcomes of interest rather than selfreported questionnaires are lacking. The aim of the current study was to prospectively examine whether patients with uremic RLS have an increased risk of cardio/cerebrovascular events and mortality in a cohort of dialysis patients.
Methods Study population
From October 2009 to 2010, ESRD patients undergoing long-term hemodialysis at 17 hemodialysis centers in Taiwan were consecutively recruited. The study was approved by institutional ethics board committees and all participants provided written informed consent. The epidemiological data of this ESRD patient cohort have been reported previously [4] and the cohort was
© 2014 EAN
143
followed up to examine the outcomes of interest. The inclusion criterion was the adult population under hemodialysis treatment for at least 3 months. The exclusion criteria were subjects with type 1 diabetes mellitus, pregnancy, Parkinson’s disease, patients with unclear consciousness or unresponsiveness to the questionnaire, and patients who did not have a continuous dialysis record for at least 3 months. Diagnosis of medical comorbidities, e.g. diabetes mellitus and hypertension, during the 12-month period before the index date (the date entering the study) was used to ascertain patients’ demographic data. The study consisted of a standardized face-to-face interview followed by the collection of clinical demographic data and a blood sample for biochemical analysis. Because there has been a single-payer and compulsory National Health Insurance (NHI) program implemented in Taiwan since 1995 and there was 99% enrollment by 2010, all the ESRD related therapy such as dialysis regimen, erythropoiesis-stimulating agent and iron supplement therapy are paid by the NHI; therefore the same guides were applied to all the dialysis centers in Taiwan. A questionnaire pertaining to the four essential International RLS Study (IRLSS) group diagnostic criteria [1] and the severity of RLS [14] was administered by a single trained interviewer to avoid inter-rater variability and then referred to movement disorder specialists (CHL and HNS) when RLS was suspected. For the Chinese version of the questionnaire, please refer to Data S1. The four essential criteria [1] are all required to make the diagnosis of RLS. This single interviewer was trained in the movement disorder special clinic of the tertiary referral medical center in Taiwan (National Taiwan University Hospital). Individuals with RLS were classified as mild (IRLSS score 30). Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) [15]. Ascertainment of cardio/cerebrovascular events and death
Medical records of all participants were obtained for all CVD and stroke events and reviewed by clinicians (CCC, LHH and LCY) or neurologists (LCH and SHN). Stroke was confirmed if the participant had a new focal-neurological deficit of sudden onset that persisted for more than 24 h and had been admitted to the hospital with available medical records. Myocardial infarction alone was defined as the main outcome of cardiovascular events. The occurrence of myocardial infarction was confirmed if symptoms met World Health Organization criteria and the event was
144
C.-H. LIN ET AL.
associated with abnormal levels of cardiac enzymes or diagnostic electrocardiogram results with or without coronary revascularization [16]. Stable/unstable angina or acute heart failure was not included without evidence of cardiac enzyme or electrocardiogram abnormality to avoid heterogeneity of the outcome of interest. Deaths were confirmed by review of medical records, death certificates or information obtained from next of kin or family members. Statistical analysis
A total of 1884 participants were initially surveyed. Patients were excluded who did not meet the inclusion criteria (n = 315), declined participation because they refused blood sampling (n = 350), lacked regular follow-up laboratory data (n = 89), lacked a continuous dialysis record or were lost to follow-up for more than 3 months (n = 37). After these exclusions, a total of 1093 individuals participated in this analysis (Fig. S1). Baseline characteristics according to RLS status were compared using the chi-squared test for categorical variables and the t test for continuous variables. The crude incidence rates and 95% confidence intervals for cardio/cerebrovascular events and mortality were estimated on a Poisson distribution in each category. The association between RLS and outcomes of interest was examined by comparing the occurrence of cardio/cerebrovascular events and death amongst ESRD patients with RLS versus the occurrence amongst participants without RLS, using an adjusted multivariate Cox regression model to calculate hazard ratios. The multivariate models were adjusted for age, sex, comorbidities of diabetes mellitus and hypertension, duration of hemodialysis, serum level of hemoglobin, serum level of iron and transferrin saturation. For the outcome of mortality, in addition to the above-mentioned covariates, the numbers of cardio/ cerebrovascular events were also adjusted in the multivariate model of mortality. The proportional hazards assumption was tested by including an interaction term for RLS status and logarithm of follow-up time for all three outcomes of interest separately in ageadjusted models. No statistically significant violation was found. The association between different RLS severity levels and the risk of cardio/cerebrovascular events and mortality was also examined by comparing the occurrence of outcomes of interest across different RLS severity subgroups with the occurrence amongst participants without RLS. Given that RLS is difficult to diagnose in the ESRD condition and false-positive results mostly come from the presence of other leg symptoms suggesting periph-
eral neuropathy [17], whether the effect estimates changed substantially was investigated on excluding individuals with concomitant uremic or diabetic polyneuropathy in the sensitivity analysis. Kaplan–Meier curves were also used to compare the cumulative probability risk of cardio/cerebrovascular events and mortality during the follow-up period between ESRD patients with and without RLS. For the Kaplan–Meier curve of mortality, observations were censored due to death or loss of follow-up for more than 2 months. For the Kaplan–Meier curve of cardio/cerebrovascular events, observations were censored due to having new cardio/cerebrovascular events during the follow-up period. The log-rank test was used to determine the differences in survival between groups. All statistical analyses were performed using STATA 8.0 (STATA Corp., Lakeway, TX, USA).
Results Of the 1093 patients with ESRD, 275 (25.2%) met the criteria of RLS at baseline. ESRD patients with RLS were more likely to have lower serum level of iron, lower serum transferrin saturation, a higher prevalence of diabetes mellitus and hypertension, a longer duration of these comorbidities and poorer sleep quality scores than patients without RLS (Table 1). With a mean follow-up period of 3.7 0.8 years, 158 cardiovascular events, 112 strokes and 132 deaths were documented. The crude incidence rate of cardiovascular events per 100 000 person-days was 8.14 (7.97–8.93) for dialysis patients without RLS and 33.06 (32.89–33.91) for those with RLS (Table 2). In the adjusted multivariate analysis, patients with RLS had a greater risk of cardiovascular events than those without RLS, with an adjusted hazard ratio (aHR) (95% confidence interval) of 2.82 (2.02–4.11) (Table S1). In the survival analysis, the group with RLS had lower cardiovascular-event-free survival than the group without RLS (Fig. 1a, log-rank test P < 0.001). Participants with mild, moderate or severe RLS at the beginning of the study were significantly more likely to have cardiovascular events than patients without RLS (P < 0.01, Table 3), suggesting a dose response manner. This positive association between RLS severity and cardiovascular events decreased slightly, but remained significant, in the regression analysis adjusted for the baseline multivariate differences; the aHR was 1.71 (1.02–2.87) for mild RLS, 2.79 (1.64– 4.66) for moderate RLS and 2.85 (1.99–4.46) for severe RLS (Table 3). Results were similar in the sensitivity analysis (Table 3). Regarding the outcome of strokes, the adjusted multivariate analysis showed that patients with RLS
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CVD RISK AND MORTALITY IN UREMIC RLS
145
Table 1 Baseline clinical and laboratory characteristics of ESRD patients according to RLS status
All (N = 1093) Basic characteristics Age (years) Male, n (%) Years on dialysis (years) Laboratory characteristics Hemoglobin (g/dl) Predialysis creatinine (mg/dl) Predialysis BUN (mg/dl) Albumin (g/dl) GOT (mg/dl) GPT (mg/dl) Calcium (mg/dl) Phosphate (mg/dl) Iron (mg/dl) Ferritin (mg/dl) TIBC (mg/dl) Transferrin saturation (%) Comorbidity Diabetes mellitus, n (%) Duration of diabetes (years) Hypertension, n (%) Duration of HTN (years) PSQI sleep score
63.6 3.4 620 (56.72) 5.9 3.1 10.7 10.2 70.9 3.7 22.3 22.0 9.0 5.1 65.9 409.8 237.9 28.1 410 4.9 548 5.4 9.5
RLS (+) (N = 275) 64.2 3.7 147 (53.45) 6.0 3.2
1.3 2.3 18.6 0.7 13.2 14.3 2.2 1.4 23.0 34.4 44.5 9.3
10.6 10.2 71.5 3.6 22.6 21.7 8.9 5.1 62.9 422.1 234.4 27.1
(37.51) 4.2 (50.14) 4.4 3.6
138 6.5 158 6.1 10.8
Mild (N = 191) 63.7 3.3 107 (56.0) 5.8 3.1
1.6 2.4 17.0 0.8 11.6 12.8 2.5 1.8 21.4 68.5 45.0 7.9
10.8 10.8 72.1 3.6 22.4 22.6 8.8 5.0 63.5 423.8 232.9 27.5
(50.18) 4.5 (57.45) 4.4 3.7
92 6.2 106 5.8 9.9
1.3 7.5 17.6 0.8 10.8 11.6 3.2 1.3 20.8 51.2 42.3 8.2
(48.2) 4.2 (55.5) 4.5 3.8
Moderate (N = 61) 64.9 3.42 28 (45.9) 6.3 3.5 10.2 9.9 69.8 3.6 22.8 22.6 8.9 5.1 61.9 415.8 237.2 27.1 32 6.3 37 6.4 12.5
1.3 1.9 18.3 0.8 11.0 11.6 3.1 1.2 22.1 50.9 43.8 7.7
(52.5) 4.4 (60.6) 4.6 3.3
Severe (N = 23)
RLS ( ) (N = 818)
67.5 3.4 12 (52.2) 7.1 3.1 10.4 9.8 71.6 3.5 23.1 22.6 9.1 5.2 64.6 421.8 238.4 26.1 14 7.9 15 7.4 12.7
1.3 1.7 18.5 1.2 10.8 11.6 1.5 1.4 22.7 52.1 44.9 7.5
(60.8) 4.4 (65.2) 4.7 3.7
Pa
63.4 3.4 473 (57.82) 5.9 3.1
0.37 0.21 0.79
1.3 2.3 16.8 0.2 12.8 17.1 1.7 1.3 23.5 62.2 44.3 9.7
0.15 0.77 0.32 0.79 0.89 0.88 0.75 0.80 0.01 0.51 0.12 0.03
(33.25) 3.2 (47.67) 4.9 3.5
