Some patients with kidney disease will feel very uncomfortable in their legs when sleeping, and they need to move their legs vigorously or get out of bed and walk to relieve it, and then when they lie down to rest, that strange discomfort will come back and make people miserable. If this condition occurs repeatedly, it is likely to be caused by restless legs syndrome.
What is restless legs syndrome?
Restless legs syndrome (RLS) is a common neurological disorder characterized by indescribable paresthesias in both limbs below the knee, such as ant walking, pins and needles, burning, or itching, which worsen at night or at rest, and may be reduced by moving the affected limb.
Restless legs syndrome can be divided into two categories: primary and secondary. There are many causes of secondary restless legs syndrome, and chronic kidney disease is one of them.
Pathogenesis of restless legs syndrome in patients with CKD
Several key metabolic and neural mechanisms of RLS are thought to be involved in CKD. Low iron storage in iron deficiency anemia or in the absence of anemia is thought to be a key factor in the pathogenesis of RLS. Iron deficiency is common in patients with chronic kidney disease, and low iron leads to decreased dopamine metabolism, impairing the function of dopaminergic neurons in the central nervous system, leading to RLS symptoms.
Uremic toxins can also interfere with dopaminergic pathways in the brain, and peripheral neuropathy of the legs secondary to uremia and/or diabetes can lead to altered sensory processing and exacerbated sensation in RLS.
Other metabolic imbalances associated with renal dysfunction, including hyperphosphatemia, hypocalcemia, and alterations in serum magnesium, can also lead to changes in neurotransmitter release that exacerbate RLS symptoms.
Diagnosis of restless legs syndrome
According to the diagnostic criteria formulated by the American Academy of Sleep Medicine (AASM) International Classification of Sleep Disorders, 3rd Edition (ICSD-3) and the International Restless Legs Syndrome Study Group (IRLSSG) in 2012, the diagnosis needs to meet both A~C:
A. There is an urgent need to move the legs, usually accompanied by or thought to be due to leg discomfort, and the following symptoms are met: (1) symptoms appear or worsen at rest or inactivity, such as lying or sitting, (2) symptoms can be partially or completely relieved by exercise, such as walking or stretching the legs, at least with activity, (3) symptoms occur wholly or mainly in the evening or at night.
B. The above symptoms cannot be explained by other disorders or behavioral problems (such as leg cramps, postural discomfort, myalgia, varicose veins, lower extremity edema, arthritis, or habitual tiptoeing).
C. The above symptoms cause anxiety, distress, sleep disturbance, or psychological, physical, social, occupational, educational, behavioral, and other important functional impairments.
Treatment of restless legs syndrome
General treatment
1. It is recommended to avoid drugs that may induce RLS
- dopamine receptor antagonists, such as phentolamine, nitroglycerin, nitroprusside, metoclopramide, and antipsychotics;
- Antidepressants: tricyclic antidepressants, serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors, etc.;
- Antihistamines: diphenhydramine, etc.;
- Calcium-channel blockers: nifedipine, amlodipine.
2. Improve dialysis adequacy
High-throughput dialysis not only ensures the full clearance of small molecule toxins from uremia, but also strengthens the clearance of medium and large molecule toxins, so for dialysis patients, improving the adequacy of dialysis can improve restless legs syndrome.
3. It is recommended to maintain good sleep hygiene
Develop healthy sleep habits, such as trying to fall asleep at the same time every day after a period of relief from leg discomfort, bathing or doing simple activities before bedtime may be effective, avoiding sleep deprivation as much as possible, and avoiding or reducing caffeine, tea, energy drinks, nicotine, alcohol, etc.
drug therapy
1. Iron supplements
Peripheral iron deficiency can further worsen iron deficiency in certain areas of the brain in some individuals. Compared with other drugs used to treat RLS, iron is more likely to improve the pathophysiology of iron deficiency in the brain in RLS. Commonly used oral iron supplements are: ferrous succinate, ferrous sulfate, ferrous fumarate and polysaccharide iron complex. Intravenous iron includes iron sodium gluconate, iron sucrose, ferric carboxymaltose, low molecular weight iron dextran, iron isomaltic anhydride 1000 and superparamagnetic nano iron oxide. The most common adverse effects were nausea and constipation.
Iron supplementation is recommended when the patient's serum ferritin level < 75 micrograms/L and/or transferrin saturation <45%. Oral iron therapy is recommended for 3 months and ferritin levels are assessed; If oral iron is ineffective, intravenous iron may be considered as an alternative. The choice of intravenous iron is based on the clinical experience of the physician and the feasibility of intravenous iron in the local hospital; Because of the risk of anaphylactic shock, intravenous iron supplementation is recommended in the hospital.
2. Dopamine receptor agonists
Such as pramipexole, ropinirole, rotigotine, etc.
Pramipexole is a D1, D2, and D3 receptor agonist with high affinity for D3 receptors. Pramipexole can reduce periodic limb movement index, improve subjective sleep quality, quality of life, and mood disorders. Ropinirole is a D2 and D3 receptor agonist with a high affinity for D3 receptors. Ropinirole reduces clinical symptoms and sleep quality in patients with moderate to severe RLS. Rotigotine is a D1-D5 dopamine receptor agonist that also activates 5-HT1a and α-adrenergic receptors. It can improve the severity of RLS symptoms, periodic limb movements during sleep, subjective sleep quality, and quality of life.
3. Dopaminergic preparations
Compound levodopa preparations (levodopa-carbidopa, dopaserazide): levodopa was the first dopaminergic drug used in the treatment of RLS. 100~200 mg was effective in reducing the symptoms of RLS and PLMI, but the improvement in health-related quality of life was not significant. Symptom deterioration is the main adverse reaction of long-term treatment of levodopa, and the incidence of symptom deterioration is as high as 40%~60% after 6 months of continuous treatment
4. α2δ calcium channel ligand
α2δ calcium channel ligands such as gabapentin-ennacarbi, gabapentin, and pregabalin are alternative to dopaminergic therapy. Compared with dopaminergic drugs, these drugs have the advantage of not having adverse effects similar to dopamine agonists and the risk of symptom exacerbation is relatively low, but these drugs are not currently approved for the treatment of RLS in China.
5. Opioid receptor agonists
Opioid agonists have long been used by clinicians as an alternative treatment to RLS based on clinical experience. At present, there are relevant studies on the effectiveness of long-acting oxycodone-naloxone extended-release agents and oxycodone in improving RLS symptoms, but there is insufficient evidence to support the use of methadone, tramadol, and intrathecal morphine for the treatment of RLS. Overall, opioids are well tolerated and less likely to worsen. The main adverse effects are the potential risk of abuse, inducing or aggravating sleep apnea and suppressing the cardiovascular system.
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Source: Today's Kidney Disease is compiled from the Guidelines for the Diagnosis and Treatment of Restless Legs Syndrome in China (2021 Edition), Nephrology Nutrition, Department of Nephrology, Jiangsu Provincial People's Hospital
