Uremic polyneuropathy

INTRODUCTION — 

Uremic polyneuropathy is common among patients on dialysis and patients with advanced nondialysis chronic kidney disease. However, for patients with end-stage kidney disease who receive adequate amounts of dialysis, 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' and "Indications for initiation of dialysis in chronic kidney disease".)

EPIDEMIOLOGY — 

Uremic polyneuropathy appears to be common among patients with a significantly reduced glomerular filtration rate [1-3]. However, different definitions of uremic polyneuropathy complicate reported prevalence rates. Estimates of prevalence are as follows:

●Patients on dialysis – Although most patients on dialysis (60 to 100 percent) have impaired nerve function on electrophysiologic testing [4-7], symptomatic neuropathy is much less common [8]. In a meta-analysis that included over 2400 patients on dialysis, the prevalence of neuropathic pain was approximately ten percent [9].

●Patients with nondialysis CKD – In an observational study of 100 adult patients with nondialysis CKD, sixty-four (64 percent) had symptomatic polyneuropathy [10]; of these, 13 patients had symptoms that were considered severe. An additional six patients (six 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.

PATHOLOGY AND PATHOGENESIS — 

Uremic polyneuropathy is a distal, symmetrical, mixed sensorimotor neuropathy that is characterized by axonal degeneration and demyelination [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 the following [11-15]:

●Deficiencies of thiamine, zinc, and biotin

●Decreased transketolase activity

●Retained phenols, myoinositol, beta2-microglobulin and other middle-molecular-weight substances

●Hyperparathyroidism

●Hyperkalemia

CLINICAL FEATURES — 

Uremic polyneuropathy is usually characterized by the following features:

●Sensory symptoms involve the distal aspect of both lower extremities. A tingling or prickling sensation is typically the initial symptom but burning pain may develop as the neuropathy gradually becomes more severe.

●Chronic sensory symptoms progress slowly, proximally, and symmetrically. Once the sensory defects have moved to or above the knees, patients may develop symptoms in their hands.

●As the sensory symptoms progress, patients with more advanced disease may also develop motor symptoms, including weakness of distal muscles and myoclonus.

●On physical examination, the findings typically include the following:

•Loss of position and vibration sense in the toes, bilaterally.

•Decreased deep tendon reflexes, beginning with the Achilles reflex.

•Paradoxical heat sensation, in which the application of low-temperature stimuli evokes the sensation of high temperature [16].

•Among patients with more advanced disease, muscle atrophy.

DIAGNOSIS

When to suspect uremic polyneuropathy — Uremic polyneuropathy should be suspected among patients with advanced chronic kidney disease (CKD) who have a distal, symmetrical, mixed sensorimotor neuropathy without an apparent alternative cause (see 'Clinical features' above and 'Differential diagnosis' below), especially in the setting of other uremic symptoms (for patients not on dialysis) or in the setting of inadequate dialysis (for patients already on dialysis). (See "Indications for initiation of dialysis in chronic kidney disease" and "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)

Establishing the diagnosis — Among patients with suspected uremic polyneuropathy (see 'When to suspect uremic polyneuropathy' above), our approach to diagnosis depends on the clinical response to kidney replacement therapy (see 'Treatment' below):

●If symptoms improve after initiation of dialysis, intensification of dialysis, or kidney transplant, and if other causes of polyneuropathy are excluded by history, we make the diagnosis of uremic polyneuropathy. (See 'Differential diagnosis' below.)

●If symptoms do not improve after initiation of dialysis, intensification of dialysis, or kidney transplant, we make the diagnosis of uremic polyneuropathy if the following two criteria are met:

•Electrophysiologic studies (ie, nerve conduction studies +/- electromyography) confirm predominantly axonal pathophysiology [17]. (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 [18] but is not as widely used. For patients with permanent hemodialysis access, 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 [6,19].

•Other causes of polyneuropathy are excluded by history and appropriate laboratory testing. (See 'Differential diagnosis' below and "Overview of polyneuropathy".)

Differential diagnosis — A complete differential diagnosis and the diagnostic evaluation of polyneuropathy are discussed elsewhere (see "Overview of polyneuropathy"). Other conditions besides uremic polyneuropathy may cause polyneuropathy in patients with advanced CKD:

●Systemic disease – Polyneuropathy can be caused by diseases that also cause CKD. These diseases include the following:

•Diabetes mellitus

•Systemic lupus erythematosus

•Systemic vasculitides

•Multiple myeloma

•Amyloidosis

•Graft-versus-host disease

Diabetes mellitus is a common cause of CKD and polyneuropathy; however, unlike uremic polyneuropathy, symptomatic diabetic ոеսroрathу is generally not reversible.

●Motor polyneuropathy – A rapidly evolving motor polyneuropathy has been described among patients with end-stage kidney disease (ESKD), with features of Guillain-Barré syndrome [20-22] (see "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis"). In almost all cases, the underlying kidney disease was membranous nephropathy [20-22]. However, the acute presentation and predominance of motor symptoms distinguishes this entity from uremic polyneuropathy.

TREATMENT

Initial therapy

General measures in all patients — For patients on diаlуѕis with suspected uremic polyneuropathy, optimizing the dialуѕis dose may decrease symptoms. In addition, all patients with polyneuropathy should receive supportive care. These measures are discussed below:

●For patients on diаlуsiѕ with Kt/V values that are less than generally accepted Kt/V targets for hеmοdiаlуsiѕ and peritoneal dialуѕiѕ, we increase the dose of diаlysiѕ to meet those targets. We do this because of overall benefit conferred as well as for the potential beneficial effect on uremic polyneuropathy. (See "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)

●We encourage physical exercise, which may prevent the loss of muscle power [5]. 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".)

●We encourage proper foot and nail care since patients with distal polyneuropathy are at increased risk for developing foot ulcers. Regular visits to a podiatrist can also help prevent problems.

Initiate or intensify dialysis — Dialysis is effective in stabilizing or improving the symptoms of uremic polyneuropathy [14]. For patients with suspected uremic polyneuropathy, our approach varies by dialysis status:

●For most patients with advanced chronic kidney disease (CKD) not yet on dialysis, suspected uremic polyneuropathy is an indication to initiate diаlуsis. However, polyneuropathy rarely is the sole precipitant of dialysis initiation; burdensome symptoms of uremic polyneuropathy generally occur in the setting of other uremic symptoms. (See "Indications for initiation of dialysis in chronic kidney disease".)

●For patients on hеmοdialуѕiѕ or peritoneal diаlуsis who have severe symptoms despite achieving optimal Kt/V targets, the diаlуsis dose may be increased further as a trial. For patients on thrice weekly hemodialysis who choose intensified diаlуѕiѕ, we generally target a single-pool Kt/V of 1.5 to 1.7 per hеmοdiаlуsis session. For patients on peritoneal ԁiаlyѕiѕ who choose intensified dialуsis, we generally target a total (ie, residual kidney plus peritoneal) Kt/V of 1.9 to 2.1 per week. If an inadequate response is observed after six to eight weeks, we resume the regular diаlysis regimen.

We do not select or switch dialysis modality to treat uremic polyneuropathy. No high-quality data suggest that a specific dialysis modality (ie, hemodialysis, peritoneal dialysis, or hemodiafiltration) is superior to another for controlling symptoms or progression. (See "Outcomes associated with chronic hemodiafiltration", section on 'Other outcomes'.)

Therapy for persistent symptoms — Some patients will have persistent symptoms of neuropathy despite initiation or intensification of dialysis. In addition, some patients elect not to undergo dialysis despite the onset of uremic symptoms. For such patients, pharmacologic treatment of neuropathy may be effective.

Gabapentin — For patients with persistent neuropathy symptoms despite the initiation or intensification of dialysis, we suggest gabapentin. The typical dose is 100 to 200 mg per day plus an additional 300 mg after each hemodialysis session for those on dialysis [23]. Our use of gabapentin in this setting is based upon studies of nonuremic polyneuropathy. (See "Overview of polyneuropathy", section on 'Treatment of symptoms and prevention of complications'.)

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

IMPACT OF TRANSPLANTATION — 

Kidney transplantation reverses the symptoms of neuropathy [24], except among the most severely affected patients. For patients who are undecided about whether to undergo a kidney transplant, persistent symptoms may provide incentive.

The clinical course after transplantation is often biphasic [8]. 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.

PROGNOSIS — 

Kidney transplantation is the definitive therapy for uremic polyneuropathy (see 'Impact of transplantation' above). The degree to which polyneuropathy improves with dialysis is directly related to the severity of clinical symptoms prior to initiation:

●Among patients who have only mild sensory symptoms, complete resolution may occur [1] despite subclinical abnormalities that may be detectable by electrophysiologic testing [25].

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

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Uremic polyneuropathy appears to be common among patients with a significantly reduced glomerular filtration rate. However, for patients with end-stage kidney disease who receive adequate amounts of dialysis, polyneuropathy is often subclinical and detectable only by electrophysiologic studies. (See 'Introduction' above and 'Epidemiology' above.)

●Pathogenesis – Uremic polyneuropathy is a distal, symmetrical, mixed sensorimotor neuropathy that is characterized by axonal degeneration and demyelination. Axonal degeneration appears to be the primary abnormality and results in secondary segmental demyelination. The cause is not known but multiple factors may contribute. (See 'Pathology and pathogenesis' above.)

●Clinical features – 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 may develop motor symptoms including weakness of distal muscles and myoclonus. Physical findings include loss of position and vibration sense in the toes and decreased deep tendon reflexes, beginning with the Achilles reflex. (See 'Clinical features' above.)

●Diagnosis – Among patients with suspected uremic polyneuropathy, our approach to diagnosis depends on the clinical response to kidney replacement therapy. Uremic polyneuropathy may be difficult to distinguish from other neuropathies caused by diseases that also cause chronic kidney disease (CKD). (See 'Diagnosis' above.)

●Treatment

•Initial therapy – Dialysis is effective in stabilizing or improving the symptoms of uremic polyneuropathy:

-For most patients with advanced CKD not yet on dialysis, suspected uremic polyneuropathy is an indication to initiate diаlуsis. However, polyneuropathy rarely is the sole precipitant of dialysis initiation; burdensome symptoms of uremic polyneuropathy generally occur in the setting of other uremic symptoms. (See "Indications for initiation of dialysis in chronic kidney disease".)

-For patients on dialysis who have severe symptoms despite achieving optimal Kt/V targets, we suggest a six to eight-week trial of intensified dialysis (Grade 2C). (See 'Initiate or intensify dialysis' above.)

•Therapy for persistent symptoms – For patients with persistent symptoms despite the initiation or intensification of dialysis, we suggest gabapentin (Grade 2C). If gabapentin is ineffective or not tolerated, a tricyclic antidepressant may be used. (See 'Therapy for persistent symptoms' above.)

●Prognosis – Kidney transplantation reverses the symptoms of uremic neuropathy, except among the most severely affected patients. The degree to which polyneuropathy improves with dialysis is directly related to the severity of clinical symptoms prior to initiation. (See 'Impact of transplantation' above and 'Prognosis' above.)

ACKNOWLEDGMENT — 

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