Uremic polyneuropathy

INTRODUCTION — Uremic polyneuropathy is common among patients with end-stage kidney disease (ESKD) [1-3]. Polyneuropathy generally develops only in patients with significantly reduced glomerular filtration rate (GFR) and is an indication to initiate dialysis. However, patients already being adequately dialyzed may also develop polyneuropathy, although, among such patients, the polyneuropathy is often subclinical and detectable only by electrophysiologic studies.

This topic reviews uremic polyneuropathy. Restless leg syndrome, and other neurologic manifestations associated with uremia or dialysis are discussed elsewhere. (See "Sleep disorders in end-stage kidney disease", section on 'Restless legs syndrome and periodic limb movement disorder'.)

PATHOLOGY AND PATHOGENESIS — Uremic polyneuropathy is a distal, symmetrical, mixed sensorimotor neuropathy that is characterized by demyelination and axonal degeneration [1]. Axonal degeneration appears to be the primary abnormality and results in secondary segmental demyelination. These changes are most severe distally, and longer axons are affected first. In addition to peripheral nerve involvement, demyelination of the posterior columns and other portions of the central nervous system has also been described [2].

The cause of uremic polyneuropathy is not known [2]. Factors that have been suggested to contribute include deficiencies of thiamine, zinc, and biotin and decreased transketolase activity [4]. Increases in phenols, myoinositol, beta2-microglobulin and other middle-molecular-weight substances, hyperparathyroidism, and hyperkalemia have also been suggested to contribute [5-8].  

EPIDEMIOLOGY — Uremic polyneuropathy is common among patients on dialysis and patients with nondialysis chronic kidney disease (CKD). Among patients on dialysis, 60 to 100 percent of patients have electrophysiologic signs of impaired nerve function, although a lower percentage of patients are symptomatic [9-12].

The best data regarding prevalence among patients with nondialysis CKD are from an observational study that included 100 patients not on dialysis between ages 18 to 65 years who had serum creatinine >2 mg/dL [13]. Sixty-four percent of patients had symptomatic polyneuropathy, and an additional 6 percent were asymptomatic but had abnormalities observed on nerve conduction studies or elicited with careful clinical exam. The prevalence of neuropathy increased with severity of kidney dysfunction; among patients with creatinine 2 to 3.4, 3.5 to 4.9, and >5 mg/dL, the prevalence of neuropathy was 35, 89, and 100 percent, respectively.

Uremic polyneuropathy is more common in males than females.

CLINICAL MANIFESTATIONS — Patients with uremic polyneuropathy initially present with sensory symptoms involving the distal aspect of the lower extremities. Early sensory symptoms include paresthesias such as tingling or prickling. Burning pain develops as neuropathy becomes more severe.

Symptoms progress proximally; once the sensory defects have moved to or above the knees, patients may develop symptoms in their hands.

Patients with more advanced disease develop motor symptoms including weakness of distal muscles, myoclonus, and even paralysis. These symptoms rarely if ever occur before the onset of sensory symptoms.

On physical examination, the initial findings in uremic polyneuropathy include loss of position and vibration sense in the toes and decreased deep tendon reflexes, beginning with the Achilles reflex. Paradoxical heat sensation is another sensory manifestation, in which application of low-temperature stimuli evokes the sensation of high temperature [14].

Among patients with more advanced disease, physical examination may reveal muscle atrophy.

DIAGNOSIS — The diagnosis of polyneuropathy is suggested by the clinical presentation and confirmed by electrophysiologic studies [15]. (See "Evaluation of peripheral nerve and muscle disease", section on 'Diagnostic testing'.)

Motor nerve conduction velocity, often measured in the peroneal nerve, is the most common parameter used to assess motor function. Sensory nerve conduction velocity of the sural nerve is even more sensitive in detecting early dysfunction but is not as widely used.

The nerves from the extremity that has the fistula or graft should not be used for electrophysiologic studies, since results are affected by local lesions related to the dialysis access [11,16].

In addition to early diagnosis, electrophysiologic testing can also be used to monitor the course of disease once kidney replacement therapy is initiated; however, this is rarely done if clinical symptoms of neuropathy respond to dialysis.

DIFFERENTIAL DIAGNOSIS — Uremic polyneuropathy is difficult to distinguish from multiple other types of polyneuropathies caused by diseases that also cause chronic kidney disease (CKD). These diseases include diabetes mellitus, systemic lupus erythematosus, systemic vasculitides, multiple myeloma, amyloidosis, and graft-versus-host disease. These diseases are generally excluded by history.

A rapidly evolving motor polyneuropathy has been described among patients with end-stage kidney disease (ESKD), with features of Guillain-Barré syndrome [17-19] (see "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis"). In almost all cases, the underlying kidney disease was membranous nephropathy [17-19]. However, the acute presentation and predominance of motor symptoms distinguishes this entity from uremic polyneuropathy.

A complete differential diagnosis and the diagnostic evaluation of polyneuropathy are discussed elsewhere. (See "Overview of polyneuropathy" and "Overview of polyneuropathy", section on 'Etiology and pathogenesis'.)

TREATMENT — Among patients with chronic kidney disease (CKD) who are not yet on dialysis, uremic polyneuropathy is an indication for kidney replacement therapy, including either dialysis or transplantation. Both dialysis and transplantation are effective in stabilizing or improving the symptoms of polyneuropathy, although transplantation is generally more effective [7,20]. It is likely that hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) are equally effective in reducing symptoms of polyneuropathy.

Among patients who are on dialysis, symptoms of uremic neuropathy are an indication to determine if the dialysis prescription is adequate and usually to increase the amount of delivered dialysis, even if the minimum target Kt/V is being achieved with the current prescription. (See "Prescribing and assessing adequate hemodialysis".)

Some patients will have persistent symptoms of neuropathy despite increasing the amount of dialysis. For suitable transplantation candidates, transplantation may reverse the symptoms of neuropathy, even when dialysis has failed to do so [20]. However, some patients are not suitable transplant candidates, and even suitable candidates may be waiting for a deceased-donor kidney for a number of years. In addition, some patients elect not to undergo dialysis despite the onset of uremia.

For such patients, pharmacologic treatment of neuropathy may be effective.

Based upon studies of nonuremic polyneuropathy, gabapentin may be used. A suggested dose is 100 to 200 mg per day plus an additional 300 mg after each hemodialysis session for those on dialysis [21]. (See "Overview of polyneuropathy", section on 'Treatment of symptoms and prevention of complications'.)

If gabapentin is ineffective or not tolerated, a tricyclic antidepressant may be used (eg, desipramine 10 to 50 mg at night).

Physical exercise may prevent the loss of muscle power [10]. As with other types of neuropathy, the appropriate use of ankle-foot orthoses, splints, and walking assistance devices can significantly improve lifestyle in the face of significant disability. (See "Overview of polyneuropathy".)

Patients with distal polyneuropathy are at increased risk for developing foot ulcers; proper foot and nail care is especially important in this population. Regular visits to a podiatrist can also help prevent problems.

PROGNOSIS — The degree to which polyneuropathy improves with dialysis is directly related to the severity of clinical symptoms prior to initiation. Complete resolution may occur among patients who have only mild sensory symptoms [1], although subclinical abnormalities may still be detectable by electrophysiologic testing [22].

Among patients with more severe neurologic symptoms, neurologic symptoms may persist even after many years of dialysis.

Kidney transplantation completely reverses the symptoms of neuropathy, except among the most severely affected patients. The clinical course after transplantation is often biphasic [23]. There is initial rapid improvement, which occurs over days or weeks; this phase is then followed by continued, gradual improvement over a period of several months.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Uremic polyneuropathy is common among patients on dialysis and patients with nondialysis chronic kidney disease (CKD). In patients with nondialysis CKD, the prevalence increases as kidney function declines. Uremic polyneuropathy is more common in males than females. (See 'Introduction' above and 'Epidemiology' above.)

●Pathogenesis – Uremic polyneuropathy is characterized by demyelination and axonal degeneration. The cause is not known but may involve deficiencies of thiamine, zinc, and biotin and decreased transketolase activity. Increases in phenols, myoinositol, beta2-microglobulin and other middle-molecular-weight substances, and hyperparathyroidism may also contribute. (See 'Pathology and pathogenesis' above.)

●Clinical manifestations – Patients initially present with sensory symptoms involving the distal aspect of the lower extremities. Early sensory symptoms include paresthesias such as tingling or prickling, and, as neuropathy becomes more severe, burning pain develops. Patients with more advanced disease develop motor symptoms including weakness of distal muscles, myoclonus, and even paralysis. (See 'Clinical manifestations' above.)

●Findings on physical examination – Physical findings include loss of position and vibration sense in the toes and decreased deep tendon reflexes, beginning with the Achilles reflex. Among patients with more advanced disease, the physical examination may reveal muscle atrophy. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis is suggested by a characteristic clinical presentation and confirmed by electrophysiologic studies. Uremic polyneuropathy is difficult to distinguish from other neuropathies caused by diseases that also cause CKD. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Treatment by initiation or intensification of kidney replacement therapy – Symptoms of uremic polyneuropathy are an indication for kidney replacement therapy, including either dialysis or transplantation. Among patients who are on dialysis, symptoms are an indication to increase the amount of dialysis, even if the minimum target Kt/V is being achieved with the current prescription. (See 'Treatment' above.)

●Pharmacologic treatment – For patients with persistent symptoms despite dialysis, pharmacologic treatment of neuropathy may be effective. Pharmacologic therapies that have been used are the same as for other types of polyneuropathy and include gabapentin and tricyclic antidepressants. (See 'Treatment' above.)

●Prognosis – Symptoms may persist even after many years of dialysis but are usually completely reversed with kidney transplantation. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.