RLS from different studies seems to be associated with an increased risk of cardiovascular events, hypertension, diabetes, and related disorders. Concerning the relationship between RLS and cardiovascular disease (CVD), there are different hypothesis. First, RLS may increase the risk for CVD and related disorders due to a chronic activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. Several recent studies suggested that RLS is characterized by autonomic dysregulation. Compared with general population, adults with RLS have shown significant elevations in nocturnal blood pressure and pulse rate [26, 27], as well as cortical (electroencephalography) arousals, in association with periodic limb movements during sleep (PLMS). PLMS are stereotyped, repetitive jerking movements of the lower limbs that frequently accompany RLS. Cortical arousals often precede PLMS onset [28], suggesting that increased sympathetic drive may play a key etiological role in RLS-associated PLMS. The repetitive occurrence of such arousals may lead to a cumulative increase in sympatho-excitation and consequently of the cardiovascular risk. In addition, certain anti-hypertensive medications, including beta-blockers (e.g., propranolol) and alpha-adrenergic agonists (e.g., clonidine), which reduce sympathetic activation, are known to attenuate symptoms of RLS [29, 30]. This is another finding in support to a possible role of autonomic dysfunction in RLS etiology, with the emerging evidence that RLS is associated with HPA axis activation. In a recent study on 73 RLS patients and 34 controls, Schilling et al. found a significantly increased nocturnal cortisol release in the group of RLS patients. Cortisol levels were unrelated to the frequency of PLMS, suggesting that the presence of PLMS may not completely explain the HPA activity in RLS [31]. Sympathetic hyperactivity, chronic HPA axis activation, and reduced parasympathetic tone have been strongly implicated in the pathogenesis of metabolic syndrome and in the development and progression of Diabete type 2 (DM2), hypertension (HTN), and CVD [32, 33].

Second, RLS could also increase the risk for CVD and diabetes due to its well-documented negative effect on sleep and mood. Sleep disturbance can promote glucose intolerance, proinflammatory changes, dyslipidemia, obesity, and HTN [34, 35]. In different studies, an impaired sleep has been linked with an increased risk for DM2 disease [36] and for CVD morbidity and mortality. [37, 38].

In patients affected by chronic kidney disease, cardio- and cerebrovascular events represent the first cause of morbidity and mortality, a risk that can be aggravated by the presence of RLS. Patients with CKD not only have a higher prevalence of traditional CVD risk factors than general population, but they are also exposed to other nontraditional uremia-related CVD risk factors [39, 40].

In a recent article, La Manna et al. enrolled 100 patients in ESRD and they observed that RLS affected 31% of the study population. After a follow up of 18 month, they showed a higher number of cardiovascular events and a higher short-term mortality in patients with RLS than in those without RLS. New cardiovascular events occurred in 64.5% of patients with and 39.1% without RLS (p = 0.019). Furthermore, the authors showed that new cardiovascular events increased with the severity of RLS, being higher in patients with continuous RLS than in patients with intermittent RLS [41].

The increased cardiovascular events are not completely attributable to well-known cardiovascular risk factors such as arterial hypertension, diabetes, smoking, obesity, and physical inactivity. Additional specific risk factors related to ESRD condition such as uraemia, mineral metabolism disorders, inflammation, oxidative stress, and malnutrition may be involved in cardiovascular events [42]. In particular, chronic inflammation affects 30–50% of haemodialysis patients and high C-reactive protein (CRP) levels are strongly associated with a three to fivefold increased rate of coronary events and of cardiovascular or all-causes mortality in the general population as well as in ESRD patients undergoing haemodialysis [43]. Some data have shown a correlation between sleep restriction and increased inflammation, both in general population [44] and in dialysis patients [45]. In a recent study, Merlino et al. (2012) observed that CRP levels were significantly higher in HD patients with RLS than in those without the sleep disorder. In addition, the multivariate analysis, including several variables known to be able to cause inflammation in HD patients, confirmed that RLS was independently associated with CRP in this specific population [46].

More recently, authors had access to echocardiographic data of some dialyzed patients, including 32 cases on hemodialysis and 16 on peritoneal dialysis. In these patients, echocardiography was not based on specific medical indication. The comparison between those with and without RLS showed no difference in any echocardiographic data, including left ventricular ejection fraction (LVEF), cardiac dimensions, systolic and diastolic cardiac dysfunction, and pulmonary artery pressure (PAP).

To our knowledge, only few data regarding RLS with CKD not under dialysis are available. In particular, in a study of 301 CKD patients (RLS prevalence of 18.3%), Quinn et al. showed no significant differences regarding hypertension, congestive heart failure, diabetes and COPD between patients having or not the sleep disorder [47].

In general population only few studies analyzed the relationship between RLS and mortality.

In a cohort of 5102 subjects, Mallon et al. applied a questionnaire including questions about RLS, daytime sleepiness, demographic and lifestyle variables, sleep habits, medical conditions, and depression. In a multivariate model, they showed that the women complaining of restless legs symptoms and daytime sleepiness were associated with increased mortality risk, compared to women without RLS and daytime sleepiness (HR: 1.85 95% CI: 1.20–2.85; p = 0.005) [48]. On the contrary, in a recent work, Szentkiràlyi et al. compared four independently conducted prospective cohort studies. The prevalence of RLS ranged between 7.4% and 11.9% and during a follow up ranging between 6 and 11 years, the presence of RLS did not increase the risk of all-cause mortality in any of the four studies [49].

If we considered RLS in patients with chronic kidney disease, Unruh et al. in a population of 894 dialyzed patients observed, after adjustment for others risk factors, that the presence of RLS was associated to an increased risk of death (HR: 1.39 95% CI: 1.08–1.79). In particular, a higher risk of death was associated with patients complaining of the most severe RLS symptoms. There was no difference in the distribution of atherosclerotic CVD as the primary cause of death between those with and those without severe RLS (58.0% vs. 56.4%; p = 0.84) [15]. La Manna et al. in a population of dialyzed patients showed an increased risk of death in RLS patients. Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (p = 0.04) [41]. This study confirmed the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality.

In a previous study, Winkelmann et al. found an increased mortality risk in dialyzed patients with RLS than in those without the sleep disorder. They also observed that RLS was independently associated with an increased rate of premature discontinuation of dialysis. The poor adherence to dialysis prescription may play a role in increasing the mortality risk in the RLS population [45].

Patients undergoing dialysis therapy due to ESRD present a high prevalence of sleep disorders such as insomnia, excessive daytime sleepiness (EDS), sleep disordered breathing, and movement disorders during sleep than in general population. These disturbances appear to have a negative impact on the life quality of these patients [50, 51]. One of the most important effects on sleep is represented by insomnia. There is a bidirectional, very strong link between insomnia and depression; insomnia is considered to be a symptom of depression, but it is also a risk factor for developing major depressive disorder [52]. Several potential mechanisms, such as fatigue, social isolation, chronic pain, lack of diagnosis and treatment, could contribute to the sleep-independent association between RLS and depression [44]. Szentkiralyi et al. in a large cohort of patients with chronic renal failure (already transplanted or in transplantation waiting list) found that depressive symptoms were more than twice as frequent among patients with RLS compared with those without RLS symptoms (56 and 22%). In a multivariate analysis, they demonstrated that RLS symptoms were associated with depression, independently of the presence of insomnia. However, the strength of the association was attenuated when insomnia was entered into the multivariate model. These results suggest that both sleep-related and sleep-independent factors may play a role in depressive symptoms in RLS patients [44]. RLS symptoms that are not exclusively related to sleep, specifically paraesthesias, discomfort and restlessness, may also have a significant negative impact on the QoL of patients suffering from the syndrome [53].

As well as the severity of RLS symptoms tend to increase with the impairment of the renal function, also the prevalence of depression appeared to be higher in patients with renal failure, rather than in those with preserved renal function. Aritake-Okada et al. found that the presence of depressive symptoms was associated with the existence of RLS and the level of chronic kidney disease, being more severe in those with renal failure [54]. In different case series it has been analyzed the important impact of depression in RLS patients, the prevalence of depression ranging from 15 to 61% [55, 56].

Patients undergoing dialysis due to ESRD present a higher prevalence of sleep disorders than the general population. Gigli et al. demonstrated than in a sample of 407 dialysis patients (31.2% with RLS symptoms), RLS patients were significantly more affected by symptoms of insomnia, difficultly in falling asleep, higher number of nocturnal awakenings, early morning awakenings, use of hypnotics, mood disorders due to sleep deprivation and excessive daytime somnolence compared with those not complaining RLS symptoms [8]. Similarly, Winkelman et al. found that the presence of RLS was associated with poor sleep measures including lengthening of sleep onset, increased number of nocturnal awakenings, and total sleep reduction, as well as a significantly increased mortality risk (a lengthening of sleep onset, an increased number of nocturnal awakenings and a reduction in total sleep time were all directly correlated with the RLS symptom score) [56].

Mucsi et al., in a sample of 333 patients on dialysis, reported that RLS patients (13.5%) were twice as likely to have significant insomnia as patients without RLS (35 vs. 16%; p < 0.05). In multivariate regression models, the presence of RLS was the strongest significant independent predictor of the AIS (Athens Insomnia Scale) score or the presence of insomnia [53]. The same findings regarding sleep problems were found by Molnar et al. in a sample of 1067 kidney transplanted patients. Even if the prevalence of RLS in kidney transplanted patients seems to be similar to that of the general population, patients complaining RLS symptoms were more than three times more likely to have insomnia and had significantly higher AIS scores than patients without RLS. Patients with RLS reported more frequently problems with sleep initiation, sleep fragmentation, early awakening, and daytime consequences of poor sleep [57].

Szentkiralyi et al. found a stronger association between RLS symptoms and depression in waitlisted patients than in transplanted patients. They did not exclude the possibility that the more pronounced renal failure in the waitlisted group could somehow account for this observation. However, the dialysis sessions impose a 4-h immobilization test three times a week on waitlisted patients, which may provoke and exacerbate RLS symptoms. These can also explain the higher prevalence compared with kidney transplanted patients [58].

Regarding the type of dialysis, different studies have reported a similar prevalence of RLS symptoms between peritoneal and hemodialysis patients [8, 15, 46].

Jaber et al. demonstrated that home short daily hemodialysis (SDHD) is associated with long-term improvement in the prevalence and severity of RLS, sleep disturbances, and depressive symptoms. They affirmed that these favorable changes might be due in part to the location of the therapy in the home setting and self-care dialysis [59].

Different studies have showed the negative impact of RLS on the quality of life. RLS interferes with sleep, resulting in impaired daytime well-being, increased daytime sleepiness and reduced mental and physical functioning capacity. Unruh et al. (2004), in a large dialysis cohort, described that patients with severe RLS had lower QoL indicators, including lower physical and mental component summary scores, lower vitality, higher bodily pain, and lower sleep quality, and had a 39% risk increase in all-cause mortality [15]. Similarly, Molnar et al. in a sample of kidney transplanted patients, described a worse QoL in patients with RLS for both the general domains assessing physical health status and also for the mental aspects of QoL [57].

Giannaki et al., in a sample on 70 patients on hemodialysis, found that 30 of them (42%) had RLS symptoms. In RLS patients, they found an higher level of muscle atrophy [60]. One explanation was that RLS is associated with sleep deprivation, which in turn could evoke alterations in anabolic hormones secretion and circulation such as in growth hormone (GH) and insulin-like growth factor I (IGF-I) [61] eventually affecting the patient’s anabolism and muscle mass. However in this study, the lower level of QoL reported by the RLS patients on hemodialysis seems to be due mainly to mental health- and sleep-related aspects rather than the physical aspects. (In this study RLS patients had an impaired QoL; however, the differences with patients not complaining RLS symptoms was better explained by their diminished mental rather than their physical aspects).

Rijsman et al. (2004) found that almost 90% of all dialysis patients with RLS also have PLM. RLS appears to be the most important factor for PLM and is associated with low quality sleep and emotional distress. Patients without RLS may still have severe PLM; therefore, this disorder can have clinical relevance on sleep quality [13]. Beecroft et al. found that kidney transplantation was associated with a significant reduction in periodic limb movement index in all patients [62].

RLS in uremic patients appears to develop markedly more severe symptoms within a short period of time after starting dialysis. In this population, RLS is associated with a higher frequency of the indicators of insomnia and a higher prevalence of symptoms suggesting other sleep disorders. It is also associated with significantly impaired QoL and increased risk of cardio- and cerebrovascular disease and mortality. Therefore, clinicians should make every effort to diagnose and treat symptoms of restless legs in this at-risk population.