Uraemic Neuropathy

Uraemic neuropathy is a length dependent, predominantly axonal sensorimotor polyneuropathy caused by retained uraemic toxins in advanced kidney failure. It develops when eGFR falls under about 12 mL/min/1.73 m² and affects 60 to 100% of patients on long term dialysis when tested by nerve conduction studies, although fewer have symptoms.

Contributors are guanidino compounds and middle molecules, hyperkalaemia induced axonal membrane depolarisation, secondary hyperparathyroidism, vitamin B12, folate and thiamine deficiency, diabetes, and drugs. Autonomic neuropathy, restless legs syndrome and focal compressive neuropathies (carpal tunnel syndrome from beta-2 microglobulin amyloid, ischaemic monomelic neuropathy after fistula formation) coexist.

Natural history. Progression stops or improves with adequate dialysis and often improves within 6 to 12 months of successful transplantation; severe established axonal loss recovers slowly or incompletely.

• Sensory symptoms first: burning, tingling, aching in the feet (worse at night), progressing to the lower legs and then the hands; glove and stocking loss of vibration and pinprick, absent ankle jerks.
• Motor: cramps, distal weakness, foot drop in advanced disease, muscle wasting.
• Restless legs syndrome: urge to move the legs in the evening, relieved by movement; periodic limb movements of sleep.
• Autonomic: intradialytic and postural hypotension, gastroparesis, diarrhoea or constipation, impotence, impaired sweating, abnormal heart rate variability.
• Focal syndromes: carpal tunnel syndrome (median nerve), ulnar neuropathy, and ischaemic monomelic neuropathy (sudden severe pain, weakness and sensory loss in the forearm and hand within hours of arteriovenous fistula creation).
• Cranial: hearing loss and optic neuropathy in rare cases.

Red flags

• Rapid progression over weeks, asymmetry, or proximal weakness: consider Guillain-Barre syndrome, inflammatory demyelinating neuropathy, vasculitis, POEMS syndrome, or amyloid.
• Acute pain with weakness after fistula surgery: ischaemic monomelic neuropathy.
• Respiratory muscle weakness, bulbar involvement, or sphincter loss.
• Foot ulceration or Charcot changes in diabetes.

• Clinical examination of vibration, pinprick, proprioception, reflexes and strength; monofilament test; Romberg sign.
• Nerve conduction studies: reduced sensory and motor amplitudes with mildly slowed velocities (axonal pattern); sural nerve involved early. Needle electromyography if mixed with myopathy.
• Blood tests: glucose and HbA1c, vitamin B12 and folate, thiamine (erythrocyte transketolase), thyroid function, serum protein electrophoresis and free light chains, ferritin and transferrin saturation (restless legs), calcium, phosphate, parathyroid hormone, potassium, ANCA and cryoglobulins if asymmetric, hepatitis B and C, HIV, lead and aluminium where exposure is possible.
• Dialysis adequacy: Kt/V and urea reduction ratio.
• Autonomic testing: lying and standing blood pressure, heart rate response to deep breathing.
• Nerve biopsy only when vasculitis or amyloid is suspected.

Differential diagnosis

• Diabetic neuropathy, vitamin deficiency, alcohol, hypothyroidism, paraproteinaemic neuropathy, amyloid, vasculitic neuropathy, drug toxicity (isoniazid, metronidazole, nitrofurantoin, linezolid, vincristine, amiodarone, colchicine), lumbosacral radiculopathy, peripheral arterial disease, POEMS syndrome.

First line: optimise dialysis and remove contributors

• Start dialysis when neuropathy appears with other uraemic symptoms; aim for Kt/V of at least 1.2 on thrice weekly haemodialysis, with longer or more frequent sessions if symptoms persist. Transplantation gives the best recovery.
• Replace deficiencies: hydroxocobalamin 1 mg intramuscularly alternate days for 2 weeks then every 3 months; folic acid 5 mg daily for 4 months; thiamine 100 mg orally daily.
• Control potassium (dialysate potassium 2 mmol/L, binders), calcium, phosphate and parathyroid hormone; optimise glucose control.
• Stop or substitute neurotoxic drugs; dose adjust renally cleared drugs.

Neuropathic pain

• Gabapentin 100 mg orally after each haemodialysis session (or 100 mg at night), increased to a maximum of 300 mg after dialysis; pregabalin 25 mg at night, increased to a maximum of 75 mg daily. Watch for sedation, dizziness, myoclonus and falls.
• Amitriptyline 10 mg at night, increased to a maximum of 25 mg (anticholinergic effects, arrhythmia risk); avoid duloxetine when eGFR is under 30.
• Topical capsaicin 0.025% cream up to four times daily for localised pain; lidocaine 5% plaster to the painful area for up to 12 hours daily.

Restless legs syndrome

• Correct iron deficiency (replace iron when ferritin is below 200 microg/L or transferrin saturation is below 20%: iron sucrose 100 mg intravenously at each of 10 consecutive dialysis sessions), exercise during dialysis, avoid caffeine and sedating antihistamines.
• Gabapentin 100 mg at night, or pregabalin 25 mg at night. Dopamine agonists as second line: ropinirole 0.25 mg 1 to 2 hours before bed, increased every 3 days to a maximum of 2 mg; risk of augmentation, nausea and hypotension.

Autonomic and focal neuropathy

• Intradialytic hypotension: cool dialysate (35.5 to 36.5°C), sodium profiling, avoid eating during dialysis, midodrine 2.5 to 5 mg orally 30 minutes before dialysis (maximum 10 mg), lower ultrafiltration rate.
• Carpal tunnel syndrome: wrist splint at night, local corticosteroid injection (methylprednisolone 40 mg), surgical release for persistent disease.
• Ischaemic monomelic neuropathy: emergency; urgent vascular surgical review for ligation or banding of the fistula within hours to prevent permanent deficit.

Foot and falls care. Daily foot inspection, podiatry, protective footwear, falls assessment, physiotherapy.

Referral and escalation. Neurology for atypical, rapid or asymmetric neuropathy; vascular surgery urgently for suspected steal or monomelic neuropathy; nephrology for dialysis intensification or transplant assessment.

Special groups

• Diabetes: dual contribution; stricter foot surveillance and glycaemic control.
• Children: growth and developmental delay; early transplantation.
• Elderly: lower doses of gabapentinoids, assess for cognitive effects and falls.