eMedicine Specialties > Neurology > Neurotoxicology

Uremic Neuropathy

Author: Yi Pan, MD, PhD, Assistant Professor, Department of Neurology, Saint Louis University Hospital
Contributor Information and Disclosures

Updated: Oct 11, 2006

Introduction

Background

Uremic neuropathy is a distal sensorimotor polyneuropathy caused by uremic toxins. The severity of neuropathy is correlated strongly with the severity of the renal insufficiency. Uremic neuropathy is considered a dying-back neuropathy or central-peripheral axonopathy associated with secondary demyelination. However, uremia and its treatment can also be associated with mononeuropathy at compression sites.

Charcot suspected the existence of uremic neuropathy in 1880, and Osler suspected it in 1892. Since the introduction of hemodialysis and renal transplantation in the early 1960s, uremic neuropathy has been investigated thoroughly. Asbury, Victor, and Adams described the clinical and pathologic features in detail in 1962.

In 1971, Dyck and colleagues established the current concept of uremic neuropathy based on their extensive nerve conduction studies in vivo and in vitro and on light and electron microscopy studies. Using quantitative histology, they demonstrated axonal shrinkage. Myelin sheaths appeared to be affected out of proportion to axons. The dysfunction of the neuron, rather than the Schwann cell, resulted in a decrease in the diameter of the axon, rearrangement of myelin, and finally, complete degeneration of the axon.

Nielsen published numerous papers on clinical and electrophysiologic studies from 1970-1974. He is a major contributor in uremic neuropathy. Bolton and Young summarized uremic neuropathy thoroughly in their 1990 book.

Pathophysiology

The mechanism of uremic neuropathy remains unclear. Fraser and Arieff postulated that neurotoxic compounds deplete energy supplies in the axon by inhibiting nerve fiber enzymes required for maintenance of energy production. Although all neuronal perikarya would be affected similarly by the toxic assault, the long axons would be the first to degenerate since the longer the axon, the greater the metabolic load that the perikaryon would bear. In toxic neuropathy, dying back of axons is more severe in the distal aspect of the neuron and may result from a metabolic failure of the perikaryon. Energy deprivation within the axon may be especially critical at nodes of Ranvier, since these nodes demand more energy for impulse conduction and axonal transport.

Nielsen theorized that peripheral nerve dysfunction was related to an interference with the nerve axon membrane function and inhibition of Na+/K+ -activated ATPase by toxic factors in uremic serum. Bolton postulated that membrane dysfunction was occurring at the perineurium, which functioned as a diffusion barrier between interstitial fluid and nerve, or within the endoneurium, which acted as a barrier between blood and nerve. As a result, uremic toxins may enter the endoneural space at either site and cause direct nerve damage and water and electrolyte shifts with expansion or retraction of the space.

Frequency

United States

According to Bolton and Young, the incidence of clinical uremic neuropathy varies from 10-83% in patients with renal failure.

International

According to Nielsen, of 109 patients in Denmark with chronic renal failure, 77% reported clinical symptoms, and 51% had clinical signs of a neuropathy.

Mortality/Morbidity

Hemodialysis has reduced the incidence of severe uremic neuropathy and the rate of mortality of renal failure. Although deaths associated with complications related to quadriplegia and respiratory failure have been reported, the death rate from uremic neuropathy is not known.

Race

No reported study has examined the role of race in uremic neuropathy.

Sex

Uremic neuropathy is more common in males than in females. Nielsen reported the female-to-male ratio as 49:60 in his 109 patients.

Age

Uremic polyneuropathy may occur at any age once the degree of renal failure is sufficient.

Clinical

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.
  • 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.
  • 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.
    • Multiple distal mononeuropathies present in an extremity following the construction of arteriovenous fistulas because of distal ischemia.

Physical

  • 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.
  • 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.
  • Muscular weakness and wasting were observed in 14%.
  • Cranial nerve involvement is rare; transient nystagmus, miosis, impairment of extraocular movement, and facial asymmetry may be found rarely on physical examination.
  • 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.
  • 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.

  • Small water-soluble compounds
    • Guanidines
    • Asymmetric dimethylarginine
    • Creatinine
    • Purines
    • Oxalate
    • Phosphorus
    • Urea
  • 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
  • Protein-bound compounds
    • Indoles
    • 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid
    • Hippuric acid
    • Homocysteine
    • Indoxyl sulfate
    • P-cresol
    • Polyamines

More on Uremic Neuropathy

Overview: Uremic Neuropathy
Differential Diagnoses & Workup: Uremic Neuropathy
Treatment & Medication: Uremic Neuropathy
Follow-up: Uremic Neuropathy
Multimedia: Uremic Neuropathy
References
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References

  1. Angus-Leppan H, Burke D. The function of large and small nerve fibers in renal failure. Muscle Nerve. Mar 1992;15(3):288-94. [Medline].

  2. Asbury AK, Victor M, Adams RD. Uremic polyneuropathy. Arch Neurol. Apr 1963;8:413-28. [Medline].

  3. Asbury AK. Recovery from uremic neuropathy. N Engl J Med. May 27 1971;284(21):1211-2. [Medline].

  4. Bolton CF. Peripheral neuropathies associated with chronic renal failure. Can J Neurol Sci. May 1980;7(2):89-96. [Medline].

  5. Bolton CF. Chronic dialysis for uremia. N Engl J Med. Mar 27 1980;302(13):755. [Medline].

  6. Bolton CF, Young GB. Neurological Complications of Renal Disease. Stoneham, Mass:. Butterworth-Heinemann;1990:1-256.

  7. Bolton CF, McKeown MJ, Chen R, et al. Subacute uremic and diabetic polyneuropathy. Muscle Nerve. Jan 1997;20(1):59-64. [Medline].

  8. Bolton CF, Remtulla H, Toth B, et al. Distinctive electrophysiological features of denervated muscle in uremic patients. J Clin Neurophysiol. Nov 1997;14(6):539-42. [Medline].

  9. Braguer D, Gallice P, Yatzidis H, et al. Restoration by biotin of the in vitro microtubule formation inhibited by uremic toxins. Nephron. 1991;57(2):192-6. [Medline].

  10. Charcot JM. Lecons sur les maladies du systeme nerveux. XVI Des paraplegies urinares. 3rd ed. Paris:. 1880:295.

  11. Charra B, Calemard E, Uzan M, et al. Carpal tunnel syndrome, shoulder pain and amyloid deposits in long-term haemodialysis patients. Proc Eur Dial Transplant Assoc Eur Ren Assoc. 1985;21:291-5. [Medline].

  12. Chen QT. [Uremic neuropathy]. Zhonghua Shen Jing Jing Shen Ke Za Zhi. Feb 1989;22(1):35-6, 62-3. [Medline].

  13. Danziger CH. Uremic neuropathy and treatment with renal transplantation. ANNA J. Apr 1989;16(2):67-70. [Medline].

  14. Dhondt A, Vanholder R, Van Biesen W, et al. The removal of uremic toxins. Kidney Int. Aug 2000;58 Suppl 76:S47-59. [Medline].

  15. Djukanovic LJ, Mimic-Oka JI, Potic JB. The effects of hemodialysis with different membranes on middle molecules and uremic neuropathy. Int J Artif Organs. Jan 1989;12(1):11-9. [Medline].

  16. Dyck PJ, Johnson WJ, Lambert EH, et al. Segmental demyelination secondary to axonal degeneration in uremic neuropathy. Mayo Clin Proc. Jun 1971;46(6):400-31. [Medline].

  17. Dyck PJ, Johnson WJ, Lambert EH, et al. Comparison of symptoms, chemistry, and nerve function to assess adequacy of hemodialysis. Neurology. Oct 1979;29(10):1361-8. [Medline].

  18. Fraser CL, Arieff AI. Nervous system complications in uremia. Ann Intern Med. Jul 15 1988;109(2):143-53. [Medline].

  19. Hassan K, Simri W, Rubenchik I, et al. Effect of erythropoietin therapy on polyneuropathy in predialytic patients. J Nephrol. Jan-Feb 2003;16(1):121-5. [Medline].

  20. Hassan K, Amir S, Michael S, et al. Electrophysiological abnormalities in upper extremities after brachiocephalic A-V fistulas construction in predialysis patients. Ren Fail. Mar 2004;26(2):111-7. [Medline].

  21. Hupperts RM, Leunissen KM, van Hooff JP, et al. Recovery of uremic neuropathy after renal transplantation. Clin Neurol Neurosurg. 1990;92(1):87-9. [Medline].

  22. Jurcic D, Bago J, Eljuga D, et al. Features of uremic neuropathy in long-term dialysis. Coll Antropol. Jun 1998;22(1):119-25. [Medline].

  23. Lynch PG, Yuill GM, Nicholson JA. Acute polyneuropathy complicating chronic renal failure. Nephron. 1971;8(3):278-88. [Medline].

  24. Makita Z, Bucala R, Rayfield EJ, et al. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet. Jun 18 1994;343(8912):1519-22. [Medline].

  25. Manenti L, Vaglio A, Costantino E, et al. Gabapentin in the treatment of uremic itch: an index case and a pilot evaluation. J Nephrol. Jan-Feb 2005;18(1):86-91. [Medline].

  26. Marra TR. Proximal vs. distal nerve conduction measurements in uremic neuropathy. Electromyogr Clin Neurophysiol. Nov-Dec 1988;28(7-8):439-43. [Medline].

  27. Mitch WE. Dietary therapy in uremia: the impact on nutrition and progressive renal failure. Kidney Int. Apr 2000;57 Suppl 75:S38-43. [Medline].

  28. Nielsen VK. Recovery from peripheral neuropathy after renal transplantation. Acta Neurol Scand. 1970;46:Suppl 43:207+. [Medline].

  29. Nielsen VK, Winkel P. The peripheral nerve function in chronic renal failure. 3. A multivariate statistical analysis of factors presumed to affect the development of clinical neuropathy. Acta Med Scand. Jul-Aug 1971;190(1-2):119-25. [Medline].

  30. Nielsen VK. The peripheral nerve function in chronic renal failure. II. Intercorrelation of clinical symptoms and signs and clinical grading of neuropathy. Acta Med Scand. Jul-Aug 1971;190(1-2):113-7. [Medline].

  31. Nielsen VK. The peripheral nerve function in chronic renal failure. I. Clinical symptoms and signs. Acta Med Scand. Jul-Aug 1971;190(1-2):105-11. [Medline].

  32. Nielsen VK. The peripheral nerve function in chronic renal failure. IV. An analysis of the vibratory perception threshold. Acta Med Scand. Apr 1972;191(4):287-96. [Medline].

  33. Nielsen VK. The peripheral nerve function in chronic renal failure. VI. The relationship betweeen sensory and motor nerve conduction and kidney function, azotemia, age, sex, and clinical neuropathy. Acta Med Scand. Nov 1973;194(5):455-62. [Medline].

  34. Nielsen VK. The peripheral nerve function in chronic renal failure. V. Sensory and motor conduction velocity. Acta Med Scand. Nov 1973;194(5):445-54. [Medline].

  35. Nielsen VK. Sensory and motor nerve conduction in the median nerve in normal subjects. Acta Med Scand. Nov 1973;194(5):435-43. [Medline].

  36. Nielsen VK. The peripheral nerve function in chronic renal failure. X. Decremental nerve conduction in uremia?. Acta Med Scand. Jul-Aug 1974;196(1-2):83-6. [Medline].

  37. Nielsen VK. The peripheral nerve function in chronic renal failure. IX. Recovery after renal transplantation. Electrophysiological aspects (sensory and motor nerve conduction). Acta Med Scand. Mar 1974;195(3):171-80. [Medline].

  38. Nielsen VK. The peripheral nerve function in chronic renal failure. VII. Longitudinal course during terminal renal failure and regular hemodialysis. Acta Med Scand. Mar 1974;195(3):155-62. [Medline].

  39. Nielsen VK. The peripheral nerve function in chronic renal failure. 8. Recovery after renal transplantation. Clinical aspects. Acta Med Scand. Mar 1974;195(3):163-70. [Medline].

  40. Osler W. The Principles and Practice of Medicine. 7th ed. London:. Appleton & Lange;1892:684, 699.

  41. Panayiotopoulos CP, Lagos G. Tibial nerve H-reflex and F-wave studies in patients with uremic neuropathy. Muscle Nerve. Sep-Oct 1980;3(5):423-6. [Medline].

  42. Ropper AH. Accelerated neuropathy of renal failure. Arch Neurol. May 1993;50(5):536-9. [Medline].

  43. Siamopoulos KC, Tsianos EV, Dardamanis M, et al. Esophageal dysfunction in chronic hemodialysis patients. Nephron. 1990;55(4):389-93. [Medline].

  44. Spencer PS, Sabri MI, Schaumburg HH, et al. Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies?. Ann Neurol. Jun 1979;5(6):501-7. [Medline].

  45. Tegner R, Lindholm B. Uremic polyneuropathy: different effects of hemodialysis and continuous ambulatory peritoneal dialysis. Acta Med Scand. 1985;218(4):409-16. [Medline].

  46. Thomas PK. Screening for peripheral neuropathy in patients treated by chronic hemodialysis. Muscle Nerve. Sep-Oct 1978;1(5):396-9. [Medline].

  47. Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis. Sep 1996;28(3):372-8. [Medline].

  48. Yatzidis H, Koutsicos D, Agroyannis B, et al. Biotin in the management of uremic neurologic disorders. Nephron. 1984;36(3):183-6. [Medline].

  49. Yildiz A, Sever MS, Demirel S, et al. Improvement of uremic autonomic dysfunction after renal transplantation: a heart rate variability study. Nephron. Sep 1998;80(1):57-60. [Medline].

  50. Yosipovitch G, Yarnitsky D, Mermelstein V, et al. Paradoxical heat sensation in uremic polyneuropathy. Muscle Nerve. Jul 1995;18(7):768-71. [Medline].

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Further Reading

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Keywords

kidney failure, renal insufficiency, renal failure, uremia, distal sensorimotor polyneuropathy, uremic toxins, dying-back neuropathy, central-peripheral axonopathy associated with secondary demyelination

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Contributor Information and Disclosures

Author

Yi Pan, MD, PhD, Assistant Professor, Department of Neurology, Saint Louis University Hospital
Yi Pan, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Physiological Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

Medical Editor

J Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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