Introduction
The restless leg syndrome (RLS) is a neuro-logical disorder characterized by sensorimotor symptoms, a type of paresthesia and involuntary initiation of the lower extremities, usually occurring during rest or at night.1 The RLS in patients on dialysis is in all likelihood of the secondary variety. The pathophysiological me-chanisms of symptomatic or secondary forms of RLS include iron deficiency, pregnancy, neuro-logical lesions (polyneuropathy), uremia, rheu-matic disease, venous insufficiency and other causes.2 Epidemiological studies show that the prevalence of RLS in the general population is 5-10%. In patients with terminal renal insuffi-ciency, the prevalence is 12-62%,3 suggesting that renal failure might be a significant risk factor affecting its occurrence. Thus, symptoms of RLS improve after renal transplantation, but deteriorate after graft rejection.1 The RLS affects quality of life and is associated with increased mortality in patients on hemodialysis (HD).45 La Manna et al1 found that the proba-bility of occurrence of new cardiovascular di-sease in patients on HD with RLS was twice as high as that for patients without such symp-toms.
Lately, much research in the general popula-tion has indicated that presence of cardio-vascular and cerebrovascular diseases is asso-ciated with various forms of RLS. Walters et al6 detected a mutual correlation between RLS and stroke.
The aim of this study was to determine the characteristics of patients on chronic HD with RLS, parameters of survivals and impact on the increase in mortality.
Methods
Study design
This prospective, non-randomized, clinical study was conducted at the Clinic of Urology and Nephrology, Clinical Center, Kragujevac, Serbia. The study included 204 patients [71 females (34.8%) and 133 males (65.2%)] with symp-toms of RLS. Most of the patients received HD for 12 h per week using commercially available dialyzers (Fresenius Medical Care, Bad Hom-burg, Germany and Gambro AB, Lund, Sweden) using a bicarbonate dialysate; few patients were on hemodiafiltration.
Procedures were in accordance with the Helsinki Declaration.
Criteria for selection and clinical research
The research population was selected after a clinical interview, which recorded the symp-toms of RLS. Because there is no specific diag-nostic test for RLS, the diagnosis was based on the assessment of subjective symptoms and the clinical picture for each patient. Positive an-swers to the following four questions confirmed the diagnosis of RLS, according to the criteria of the International Restless Legs Syndrome Study Group in 1953 and revised by the Inter-national Diagnostic Workshop at the National Institute of Health in Washington:7
- Do you have an urge to move the legs due to an unpleasant feeling in your legs?
- Does the urge to move your legs, or the unpleasant feelings in your legs, begin or get worse when you are at rest or not moving around frequently?
- Is the urge to move your legs, or the unpleasant feelings in your legs, partly or completely relieved by movement (such as walking or stretching) for as long as the movement continues?
- Is the urge to move your legs, or the unpleasant feelings in your legs, worse in the evening and at night, or does it only occur in the evening or at night?78
After identifying the patients with and without RLS, two groups of respondents were formed and monitored for outcome of clinical treat-ment. Demographic and sex structure, length and type of HD (bicarbonate/hemodiafiltration), information about the existence of insomnia and residual diuresis (at least 250 mL) were recorded for all respondents. We registered smokers, patients on erythropoietin therapy and presence of co-morbidity such as cardiovascular disease and diabetes mellitus. Body mass index was calculated from the ratio between body weight in kilograms and the square of body height in meter squared. Adequacy of HD was estimated by the urea kinetic model Kt/V, according to the formula of Daugirdas.9
Blood flow through the arteriovenous fistula (AVF; mL/L) was measured by Doppler ultra-sound examination in a LOGIQ P5 apparatus (GE Healthcare, Wau-watosa, WI, USA). Also, the intima-media thickness of the posterior wall of the common carotid artery (mm) was determined 2 cm above and below the carotid bifurcation with Doppler study.10
Blood samples for biochemical analysis were obtained in Vacutainer® tubes in the middle of the week before dialysis. All analyses were made by flow cytometry (Beckman Coulter Inc., Fullerton, CA, USA) and spectrophotometrically (ILAB-600, Diamond Diagnostics, Fiske Street Holliston, MA, USA) using the original reagents.
Statistical Analysis
Using the SPSS and INSTAT software pro-grams, descriptive statistical parameters such as arithmetic mean and standard deviation (SD) were obtained and the results were subjected to Student’s t-test, the Mann-Whitney test and the chi-square test for homogeneity and Fisher’s exact test for trends, as appropriate. The median survival was estimated using the Kaplan-Meier survival analysis. The influence of potential predictors of mortality on survival was deter-mined using the Cox regression analysis. Statis-tical significance was set at P <0.05.
Results
The median age of the study patients was 60 years, and they were on treatment with HD for a mean of 4.5 years. The average flow through the AVF in our study patients was 690 mL/min. Over half of the respondents had some form of cardiovascular disease and 16% were diabetic. The mean body mass index in our study sub-jects was 23 kg/m2. Measured values of Kt/V in the patients were unsatisfactory and suggested inadequate dialysis. Intima-media thickness of the carotid artery was 1 mm. Nearly two-thirds of respondents were receiving iron and erythropoietin therapy. Half of the subjects were smokers, 44% had insomnia and 30% of the respondents had preserved diuresis. The median survival of the study patients was 121 months.
When the clinical characteristics of patients who completed the study and those who died were compared, significant differences in body mass index (25 ± 5.8 vs.19 ± 2:17, P <0.0001), intima-media thickness (1 ± 0.2 vs. 1 ± 0.11, P = 0.01) and flow through the AVF (P = 0.01) were observed. The relative number of smokers (P = 0.007) as well as the incidence of cardio-vascular disease (P = 0.005) and diabetes mellitus (P = 0.04) were significantly higher among patients who died. On the other hand, a higher proportion of patients who completed the study used erythropoietin therapy (P = 0.001) and had residual diuresis (P = 0.001) (Table 1).
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Table 1: Gender, demographic, anthropometric and clinical findings in patients with restless leg syndrome who completed the study and those who died.
The group of patients who survived had higher levels of hemoglobin (103 ± 17.1 vs. 93 ± 12.9; P = 0.005), higher serum creatinine (898 ± 315 vs. 858 ± 202; P = 0.03) and higher serum iron (11 ± 12.7 vs. 8 ± 4.6, P = 0.01) as well as transferrin saturation (31 ± 12.6 vs. 21.5 ± 13.7; P = 0.01) (Table 2). Additionally, patients with RLS who had diabetes mellitus (B = 1.802, P = 0.002) or lower Kt/V index (B = -5218; P = 0.001) died earlier (Table 3).
Table 2: Biochemical findings in patients with restless leg syndrome who completed the study and those who died.
Table 3: Survival analysis with the Cox regression model for patients with restless leg syndrome
Discussion
To the best of our knowledge, this is the first study in which the impact of RLS on the sur-vival of patients receiving chronic HD was eva-luated over such a long period. The basic idea was to identify patients with RLS in order to determine their characteristics, survival and pre-dictive parameters for mortality. A significantly higher incidence of diabetes mellitus was found among patients with RLS. This was expected, given that a significant number of studies have indicated a positive association.111213 Also, others have shown that a long duration on dialysis is a significant characteristic of patients with RLS.14 Although the average duration on dialysis in our patients with RLS was longer than six years, in contrast to two years for patients with-out these symptoms, the difference was not statistically significant. In the patients with RLS who died, the median survival after 121 months was 50%. In their 18-months evaluation, La Manna et al1 found that patients with RLS had an increased mortality risk. We found that patients with RLS who died had a significantly lower body mass index, which supports the theory of inverse epidemio-logy, which promulgates an increased survival rate of obese patients on HD.1516171819 In support of this theory is the increased concentration of creatinine, as a nutritional parameter, which was significantly higher in our patients with RLS who did not die.
Among our patients with RLS who died, one-third were smokers, which was significantly higher than in the group of patients who com-pleted the study. This finding concurs with other studies1920 that have reported a similar association with smoking habit.
The presence of cardiovascular diseases cha-racterized our patients who died. An analysis of the cause of death showed that cardiovascular diseases were the cause in almost two-thirds of cases, while stroke was the reason in one-quarter of cases. In the general population with RLS, there are reportedly a significant number of co-morbidities, but cardiovascular disease and stroke are prevalent. One of the pathophysiological mechanisms by which RLS contri-butes to the development of cardiovascular disease is the impact of increased activity of the sympathetic nervous system on the occurrence of tachycardia and hypertension.202122 In healthy individuals, this may not have any consequences, but in dialysis patients with multiple co-mor-bidities, it becomes a significant risk factor for mortality.23 La Manna et al1 detected some con-nection between RLS patients on HD and in-cident episodes of myocardial infarction, stroke and peripheral arterial occlusion. Although not statistically significant, this suggested that RLS may be primarily an indicator of poor health, especially pronounced for cardiovascular co-morbidity. In contrast, Filho et al14 suggest that in patients with chronic renal failure, there is no significant evidence of an association of RLS with co-morbid and etiologic categories of renal failure.
In the general population, Walters et al6 established a positive correlation between hyperten-sion, heart disease and stroke in patients with RLS, probably as a result of accelerated athero-sclerosis. However, we could not find any in-formation that correlated RLS and intima-media thickness as a marker of atherosclerosis in the HD population. The values obtained in our patients who died were significantly higher than in those who completed the study, without indi-cating the predictive significance of intima-media thickness in the occurrence of RLS. However, this result can be interpreted in rela-tion to the survival rate of our respondents on dialysis with hemodiafiltration, which was sig-nificantly higher than that for patients receiving bicarbonate hemodialysis.2425262728 This was most likely due to the increased clearance of small and medium-sized molecules, improved inter-dialytic hemodynamic stability and reduced complement activation during hemodiafiltration. The results also showed a certain influence of hemodiafiltration on intima-media thickness of carotid arteries due to improved biocompati-bility of the dialysis system thus reducing its inflammatory character. Such an effect could be reflected in a lower atherogenic profile.
Musci et al29 found no concrete evidence of a significant influence of HD dose on the preva-lence of RLS, but we observed that the quality of HD had a predictive value for increased sur-vival of patients who had clinical symptoms of RLS.
In patients with RLS who died, there was a high prevalence of individuals with diabetes mellitus as the cause of renal insufficiency, and also the mean concentration of serum glucose in this subgroup was significantly higher. How-ever, even though the correlation of RLS and diabetes mellitus was not confirmed in major trials,30 diabetes is a common cause of polyneuropathy, and, as expected, the prevalence of RLS in the subgroup of HD patients with dia-betes mellitus was higher. In our patients, the Cox regression survival analysis demonstrated the significance of diabetes mellitus (i.e., pa-tients with diabetic nephropathy) and RLS having a higher mortality rate.
Iron deficiency has a dual role; it causes anemia as well as lack of a co-factor in the metabolism of dopamine in the brain, which plays an important role in the pathophysiology of RLS. Therefore, correction of anemia with intra-venous iron and erythropoietin reduced the incidence of RLS and significantly improved the quality of life in HD patients.3132 Among our patients with RLS, nearly equal numbers of those who completed the study and those who died had received iron therapy, but the levels of hemoglobin and serum iron and transferrin saturation were significantly higher in patients who survived. However, there is a logical ques-tion and a dilemma about why there is this high rate of RLS among the large number of dialysis patients receiving intravenous iron. Obviously, there is a large group of mixed forms that may pose a differential diagnostic problem, because 80% of patients with RLS symptoms have noc-turnal myoclonus while about 30% of patients with nocturnal myoclonus have RLS.14
Limitations of the Study
Even though we used positive responses to all four questions as the criteria for diagnosis of RLS, we cannot exclude other forms that mimic RLS. Moreover, these criteria are not adapted to involve known vascular risk factors such as cardiovascular disease and diabetes mellitus. Also, a limitation of our study is that no neurologist was included in the selection of patients with RLS.
In conclusion, during the evaluation of pa-tients with RLS, we found that diabetes mellitus is an important feature of these patients. Pa-tients with RLS who completed the study were obese, had greater atherogenic profile, higher levels of hemoglobin and creatinine, greater satu-ration of transferrin and included a relatively larger relative number of patients who received erythropoietin and had residual diuresis. Among patients who died, there were more smokers, and they had a higher incidence of cardio-vascular disease and diabetes mellitus. Finally, our study established that presence of diabetes mellitus and inadequate HD are parameters predictive of mortality in patients with RLS.
Conflict of Interest
None
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