History
Typical uremic neuropathy symptoms are insidious in onset and consist of a tingling and prickling sensation in the lower extremities. Paresthesia is the most common and usually the earliest symptom. Increased pain sensation is a prominent symptom. Weakness of lower extremities and atrophy follow the sensory symptoms. As disease progresses, symptoms move proximally and involve the upper extremities. Muscle cramps and restless legs syndrome were reported by 67% of uremic patients. These symptoms also can be seen in uremic patients without neuropathy. Patients report that crawling, prickling, and itching sensations in their lower extremities are relieved partially by movement of the affected limb. [22]
Autonomic dysfunction was revealed in 45–59% of uremic patients by autonomic nerve tests. Patients may complain of dizziness. It usually is associated with postural hypotension.
A Guillain-Barré type of presentation is rare, but a rapidly progressive course with respiratory failure has been reported. Generalized limb weakness develops over days or weeks with imbalance, numbness, and diminished reflexes. [23, 24]
Mononeuropathies in the form of compressive neuropathy can occur in the median nerve at the wrist, in the ulnar nerve at the elbow, or in the peroneal nerve at the fibular head. Already partially dysfunctional peripheral nerves may be more susceptible to local compression. Connective tissues and tendons are found to have amyloid deposits surrounding the carpal tunnel. [25] Multiple distal mononeuropathies present in an extremity following the construction of arteriovenous fistulas because of distal ischemia. [26]
Physical
See the list below:
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Impaired vibratory perception and absent deep tendon reflexes are the most common clinical signs, noted in 93% of patients. Sixteen percent had sensory loss to pinprick in a glove and stocking distribution.
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Paradoxical heat sensation was found in the feet of 42% of patients with chronic renal failure, as compared to less than 10% of healthy controls. [27]
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Muscular weakness and wasting were observed in 14%.
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Cranial nerve involvement is rare; transient nystagmus, miosis, impairment of extraocular movement, and facial asymmetry may be found rarely on physical examination. [18]
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Focal weakness, sensory loss, and positive Tinel sign at compression sites can be observed in the median, ulnar, or peroneal nerve distribution if compressive mononeuropathy is present.
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Abnormal Valsalva maneuver and orthostatic hypotension may be noted in patients with autonomic neuropathy.
Causes
The nature of the toxic substances in uremia is unknown. Myoinositol, a precursor of phosphoinositide, is metabolized rapidly in neural membranes. It is elevated abnormally in chronic renal failure, poorly eliminated by hemodialysis, but excreted by the renal cortex of successfully transplanted kidneys. Substances of moderate molecular weight (ie, 300–2000 Daltons) can be toxic agents in uremia. Advanced glycosylated end products and parathyroid hormone generally are recognized as major uremic toxins. Possible uremic toxins are listed here but remain unproven. [28]
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Small water-soluble compounds
Guanidines
Asymmetric dimethylarginine
Creatinine
Purines
Oxalate
Phosphorus
Urea
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Middle, large molecules
Advanced glycosylated end products
Parathyroid hormone
Oxidation products
Peptides (beta-endorphin, methionine-enkephalin, beta-lipotropin, granulocyte inhibiting proteins I and II, degranulation-inhibiting protein, adrenomedullin)
Beta 2-microglobulin
Complement factor D
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Protein-bound compounds
Indoles
3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid
Hippuric acid
Homocysteine
Indoxyl sulfate
P-cresol
Polyamines
Physical Examination
Neurological examination frequently finds sensory deficits to temperature, pin prick, vibration in distal extremities, and diminished deep tendon reflex, loss of ankle jerks. Autonomic dysfunction, such as orthostatic hypotension, and distal muscle weakness and atrophy may be seen in severe cases.
Complications
Individuals with uremic neuropathy can develop gait difficulty and are more likely to fall, which can result in severe fractures and subdural hematomas.
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Semithin transverse section of biopsied sural nerve in uremic neuropathy. The nerve shows severe axonal loss of large and small fibers. Toluidine blue stain, 200X. Image courtesy of Ling Xu, Consultants In Neurology, Kansas City, MO 64108. Used with permission 2001.
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Modified trichrome-stained sural nerve in uremic neuropathy. The same nerve exhibited marked loss of myelinated fibers. 200X. Image courtesy of Ling Xu, Consultants In Neurology, Kansas City, MO 64108. Used with permission 2001.
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Muscle biopsy in uremic neuropathy with ATPase stain (pH 9.4). The normal muscle mosaic pattern was replaced by fiber type grouping, which suggested chronic denervation and reinnervation. 100X. Image courtesy of Ling Xu, Consultants In Neurology, Kansas City, MO 64108. Used with permission 2001.
