Abstract: We included nine studies enrolling 220 dialysis participants. Seven studies were deemed to have moderate to high risk of bias. All studies were small in size and had a short follow-up period (two to six months). Studies evaluated the effects of six different interventions against placebo or standard treatment. The interventions studied included aerobic resistance exercise, gabapentin, ropinirole, levodopa, iron dextran, and vitamins C and E (individually and in combination). Aerobic resistance exercise showed a significant reduction in severity of RLS compared to no exercise (2 studies, 48 participants: MD -7.56, 95% CI -14.20 to -0.93; I2 = 65%), and when compared to exercise with no resistance (1 study, 24 participants: MD -11.10, 95% CI -17.11 to -5.09), however there was no significant reduction when compared to ropinirole (1 study, 22 participants): MD -0.55, 95% CI -6.41 to 5.31). There were no significant differences between aerobic resistance exercise and either no exercise or ropinirole in the physical or mental component summary scores (using the SF-36 form). Improvement in sleep quality varied. There was no significant difference in subjective sleep quality between exercise and no exercise; however one study reported a significant improvement with ropinirole compared to resistance exercise (MD 3.71, 95% CI 0.89 to 6.53). Using the Epworth Sleepiness Scale there were no significant differences between resistance exercise and no exercise, ropinirole, or exercise with no resistance. Two studies reported there were no adverse events and one study did not mention if there were any adverse events. In one study, one patient in each group dropped out but the reason for dropout was not reported. Two studies reported no adverse events and one study did not report adverse events. Gabapentin was associated with reduced RLS severity when compared to placebo or levodopa, and there was a significant improvement in sleep quality, latency and disturbance reported in one study when compared to levodopa. Three patients dropped out due to lethargy (2 patients), and drowsiness, syncope and fatigue (1 patient). Because of a short duration of action, rebound and augmentation were noted with levodopa treatment even though it conferred some benefit in reducing the symptoms of RLS. Reported adverse events were severe vomiting, agitation after caffeine intake, headaches, dry mouth, and gastrointestinal symptoms. One study (25 participants) reported iron dextran reduced the severity of RLS at weeks one and two, but not at week four. Vitamins C, E and C plus E (1 study, 60 participants) helped the symptoms of RLS with minimal side effects (nausea and dyspepsia) but more evidence is needed before any conclusions can be drawn. Given the small size of the studies and short follow-up, it can only be concluded that pharmacological interventions and intra-dialytic exercise programs have uncertain effects on RLS in haemodialysis patients. There have been no studies performed in non-dialysis CKD, peritoneal dialysis patients, or kidney transplant recipients. Further studies are warranted before any conclusions can be drawn. Aerobic resistance exercise and ropinirole may be suitable interventions for further evaluation.

Plain-language summary: The quality of the studies was deemed to be moderate. Of the nine studies, one was sponsored by a pharmaceutical company and funding sources were reported for only two other studies. The included studies were heterogeneous, small in size and had short follow-up periods. The interventions studied included exercise, gabapentin, ropinirole, levodopa, iron dextran, and vitamins C and E (individually and in combination). All interventions reduced the severity of RLS compared to a control. Intradialytic aerobic exercise reduced the severity of RLS however the safety of this intervention is unclear. Resistance exercise did not improve sleep quality but improved the mental health component on a quality of life questionnaire. This improvement in mental health component was not significant when compared to no exercise or ropinirole. Ropinirole reduced the symptoms of RLS and improved quality of sleep without any reported side effects. Gabapentin and levodopa improved the symptoms of RLS; however there were several adverse events reported included lethargy, drowsiness and fatigue for gabapentin, and vomiting, agitation, headaches, dry mouth, and gastrointestinal symptoms for levodopa. Iron dextran infusion reduced the symptoms of RLS but was only significant up to two weeks after treatment. Vitamin C, E and their combination also reduced RLS symptoms with minimal side effects. Small size and short duration of follow-up were the major drawbacks of these studies. The small number of studies, small sample sizes and short duration of follow up make it difficult to draw any firm conclusions. The effects of aerobic exercise and other pharmacological agents on RLS are uncertain in haemodialysis patients. There is a need to perform high quality randomised studies to establish the best treatment for RLS in patients with CKD. Aerobic exercise and ropinirole may be suitable interventions for further evaluation.