Clinical manifestations

Presentation and course

There is a strong correlation between the severity of neuropathy and of the chronic renal insufficiency. Although most patients with chronic renal failure have subclinical evidence of a polyneuropathy, significant neuropathy generally occurs when the creatinine clearance falls below 5 mL/min, or the glomerular filtration rate falls below 20 mL/min (45).

Uremic neuropathy symptoms are insidious in onset and consist of a tingling and prickling sensation in the legs. Paresthesias are usually the earliest symptom. Numbness and burning sensation were observed in the distal lower limbs in 48.2% of patients and in the distal upper limbs in 3.6% of patients with uremic neuropathy (81). Hyperalgesia is common. Pruritus affects many patients with end-stage renal disease and may be related to both somatic and autonomic neuropathy (82). Weakness and atrophy will follow the sensory symptoms. As disease progresses, symptoms move proximally and also involve the arms. Muscle cramps and restless legs syndrome occur in 67% of uremic patients but may be independent of neuropathy (53). Patients report that crawling, prickling, and itching sensations in their legs are partially relieved by movement of the affected limb. Autonomic dysfunction is associated with postural hypotension, impaired sweating, sexual dysfunction, and alteration in gastric motility (08; 24; 65). Uremic optic neuropathy is rarely reported (27; 06; 63). Other cranial neuropathies were of cranial nerves III and VII and have presented as facial diplegia and ophthalmoplegia (35). A Guillain-Barre type of presentation with rapid progression to respiratory failure has been reported. Generalized limb weakness develops over days or weeks with imbalance, numbness, and diminished reflexes (47; 64; 61). Mononeuropathies in the form of compressive neuropathy can occur in the median nerve at wrist, in the ulnar nerve at the elbow, or in the peroneal nerve at the fibular head. Already dysfunctional peripheral nerves may be susceptible to local compression. The connective tissues and tendons surrounding the carpal tunnel may contain amyloid deposits (15). Carpal tunnel syndrome may also present distal to forearm arteriovenous fistulas because of distal ischemia (25).

Physical examination reveals impaired vibratory perception and absent deep tendon reflexes in 93% of patients. Pinprick sensation in a glove and stocking distribution was impaired in 16%, and muscular weakness and wasting were observed in 14% (53). Paradoxical heat sensation was found in the foot in 42%, compared to less than 10% in normal controls. Paradoxical heat sensation probably results from lowering of heat pain threshold (80). Autonomic dysfunction is demonstrated as postural hypotension and abnormal Valsalva maneuver. Cranial nerve involvement is rare; transient nystagmus, miosis, heterophoria, and facial asymmetry can occur (23). Focal weakness, sensory loss, and Phalen or Tinel signs at compression sites may be found in the median, ulnar, or peroneal nerve distribution.

Prognosis and complications

The prognosis in untreated uremic polyneuropathy is poor, as it often progresses to a disabling sensorimotor neuropathy. Untreated, its course resembles the cases in the original reports from the 1960s. Later patient series describe patients after renal transplantation or undergoing various forms of hemodialysis. With intermittent hemo- or peritoneal dialysis the clinical manifestations of neuropathy generally stabilize or improve slowly over time. Those with mild disease may recover peripheral nerve function completely, whereas more severely affected individuals recover incompletely, and some may continue to progress despite treatment. The prognosis after renal transplantation is more favorable, with excellent recovery of peripheral nerve function, especially in those without coexistent systemic illnesses such as diabetes (10; 54). Complications of uremic neuropathy are progressive disability including falls, which can result in severe fractures and subdural hematomas.

Clinical vignette

A 35-year-old woman noted leg numbness and weakness over the previous 2 years. Her medical history was notable for chronic glomerulonephritis, complicated by progressive renal failure over the previous 6 years. A neurologic examination revealed moderate wasting and weakness of all muscles below the knees. Vibratory and pinprick sensation were diminished below the knees. Deep tendon reflexes were intact in the arms, reduced at the knees, and absent at the ankles. Her gait was slightly unstable. She had undergone weekly hemodialysis for the past 3 years. Nerve conduction studies and EMG revealed a generalized sensorimotor polyneuropathy with moderate slowing of conduction velocities and denervation in muscles of the distal legs. Laboratory studies were notable for a creatinine clearance of 4 mL/min. There was no evidence of diabetes. She underwent a successful cadaveric renal transplantation. Over the next 6 months, leg sensation and strength slowly improved.

Biological basis

Etiology and pathogenesis

The etiology of uremic neuropathy remains unclear. Today, most authorities believe the neuropathy is secondary to toxin or metabolite accumulation that cannot be excreted by the nonfunctioning kidneys. In addition, malnutrition and arterial stiffness are significantly associated with small fiber neuropathy in patients undergoing hemodialysis (43). The nature of the toxic substances in uremia is also unknown. Several candidates have been proposed over the years, including small water-soluble compounds (guanidine, asymmetric dimethylarginine, creatinine, purines, oxalate, phosphorus, urea, kynurenine), middle molecules, advanced glycosylated end products (glycation), parathyroid hormone, oxidation products, beta-endorphin, methionine-enkephalin, beta-lipotropin, granulocyte inhibiting proteins I and II, degranulation–inhibiting protein, adrenomedullin, beta-2-microglobulin, complement factor D, and protein-bound compounds (homocysteine, Indoles, 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid, hippuric acid, indoxyl sulfate, p-cresol, polyamines) (18; 62; 59). An etiologic role for chronic hyperkalemia in uremic neuropathy has been suggested (38; 40; 42; 41). In patients with diabetic kidney disease, neuropathy was significantly more common versus other chronic kidney diseases or type II diabetes (p <  0.05); nerve excitability was more severely affected with increasing serum K+ (p <  0.01) (30).

Among these uremic toxins, the middle molecule hypothesis (75; 48) has gained the greatest attention. Because middle molecules with molecular weights in the range of 300 daltons to 2000 daltons are more difficult to remove with dialysis than small molecules, such as blood urea nitrogen and creatinine, which pass easily through dialysis membranes, these middle molecules may in some way be responsible for the neuropathy (19). Advanced glycosylated end products and parathyroid hormone are generally recognized as major uremic toxins (62). Bolton and colleagues postulated advanced glycosylated end products, which result from enzymatic reactions between glucose and proteins, as playing a role in uremic neuropathy (11). They noted that three of four patients who had been switched from conventional to high-flux hemodialysis, which removes advanced glycosylated end products, had clinical improvement in strength. Myoinositol, a precursor of phosphoinositide, is rapidly metabolized in neural membranes. It is abnormally elevated in chronic renal failure, poorly eliminated by hemodialysis, but excreted by renal cortex of successfully transplanted kidney (09).

The mechanism of uremic neuropathy, however, is poorly understood. Fraser and Arieff postulated that neurotoxic compounds deplete energy supplies in the axon by inhibiting nerve fiber enzymes required for energy production (23). Although all neuronal perikarya would be similarly affected by a toxic assault, the long axons would be the first to degenerate, as the longer the axon, the greater the metabolic load that the perikaryon bears (69). Axonal energy deprivation might be especially critical at nodes of Ranvier, which have higher energy demands for impulse conduction and axonal transport. Nielsen hypothesized that peripheral nerve dysfunction is related to an interference with axon membrane function and inhibition of sodium potassium activated ATPase by toxic factors in uremic serum (53). Bolton postulated that membrane dysfunction occurs at the perineurium, which functions as a diffusion barrier between interstitial fluid and nerve or within the endoneurium, which acts as barrier between blood and nerve. As a result, uremic toxins might enter the endoneural space at either site and cause not only direct nerve damage but also water and electrolyte shifts with expansion or retraction of this space (09). In two separate studies, axonal membrane properties were investigated by measuring nerve excitability in chronic renal failure patients before, during, and after hemodialysis (38; 42; 41). The authors suggested that motor and sensory axons in uremic patients were depolarized before dialysis and that hyperkalemia was primarily responsible for uremic depolarization; this process could contribute to the development of neuropathy.

In uremic neuropathy, the pathologic features are severe axonal degeneration in the most distal nerve trunks with secondary segmental demyelination. Dyck and colleagues found that the number of myelinated fibers at the mid-calf level was about half of normal, and only one third of normal at the ankle. In transverse electron microscope sections, most of the myelinated fibers of the uremic nerve had a normal appearance except for irregularities of the myelin sheath, such as splitting of the myelin lamellae and separation of axolemma from compact myelin (20). Muscle biopsy revealed fiber-type grouping from chronic denervation and reinnervation. Muscle was severely denervated in Guillain-Barré-type neuropathy. In advanced cases, electron microscopy revealed necrosis of myofibers, Z-band streaming, and aggregation of glycogen (16).

Epidemiology

Incidence and prevalence of uremic polyneuropathy are controversial, in part due to differing definitions of neuropathy based on clinical, electrophysiologic, and neuropathologic criteria. Approximately 70% to 80% of patients with chronic hemodialysis have evidence of neuropathy (52; 37). In 109 patients with chronic renal failure, 77% of patients reported clinical symptoms, and 51% of patients had clinical signs of neuropathy according to Nielsen (53). Most large studies since the 1960s include patients receiving dialysis and estimate that 50% to 65% of individuals in chronic renal failure have some evidence of peripheral neuropathy by clinical or electrophysiologic criteria just before or after beginning dialysis. In a study of 100 patients with chronic kidney disease and serum creatinine above 2 mg/dL, neurologic symptoms progressed, and NCVs decreased with higher serum creatinine. In 6%, the neuropathy was asymptomatic, in 51% symptomatic, and in 13% disabling (02). Uremic polyneuropathy may occur at any age. A prevalence of 22% was found in children on dialysis (average age 12.08 years) (01). The prevalence of subclinical, neurophysiologically diagnosed neuropathy in children aged 2 to 14 was 29% (68). A female-to-male ratio of 40:60 has been reported (53). There are no reports on the role of ethnicity.

Prevention

The occurrence of neuropathy is highly correlated with the severity and duration of renal failure. Chronic dialysis may prevent neuropathy in some patients, especially if begun early. Renal transplantation is generally the most successful method to prevent neuropathy (10; 53; 54).

Differential diagnosis

The differential diagnosis of a distal symmetric sensorimotor polyneuropathy is large. It is linked to numerous systemic disorders and toxins. In the setting of chronic renal failure, one should look for those disorders that can be associated with both renal failure and peripheral neuropathy. Such disorders include diabetes mellitus, nutritional deficiency, multiple myeloma, primary amyloidosis, and some of the vasculitis and connective tissue disorders including polyarteritis nodosa and systemic lupus erythematosus. Certain clues such as an asymmetric, painful, or acute presentation may suggest the presence of an underlying systemic disorder. In addition, one must always consider exposure to a neurotoxin that might be especially potent in patients with chronic renal failure. For example, both nitrofurantoin and colchicine can cause a peripheral neuropathy, especially in patients with renal dysfunction. Alcohol abuse must be considered in patients with renal failure and polyneuropathy. Finally, chronic inflammatory demyelinating polyneuropathy, which may respond to immunomodulating therapy, has been described in the setting of chronic renal failure and may be noted by the prominent demyelination on nerve conduction studies (26).

Diagnostic workup

The presence of a uremic peripheral neuropathy is established by medical history, neurologic examination, and electrophysiologic studies.

Laboratory findings. There are no specific features of neuropathy in chronic renal failure. Other metabolic disorders, neurotoxins, or inflammatory disorders may occur in association with chronic renal failure. Other causes of neuropathies should be ruled out by lab tests, including diabetes, vitamin deficiencies, thyroid dysfunction, inflammatory disorders, and toxins. The cerebrospinal fluid may show a moderately elevated protein, usually less than 100 mg/dL in about half the patients, whereas cell count and glucose are normal. Although the cerebrospinal fluid protein can be elevated in uremic patients without neuropathy, it is more likely to be elevated in patients with neuropathy.

Electrophysiologic evaluation. Nerve conduction study is a sensitive test for diagnosis of neuropathy in uremic patients. The most commonly involved nerves are the sural, ulnar sensory, median sensory, peroneal, and tibial (33). Sensory and motor nerve conduction velocities are reduced. Prolonged distal latencies are due to involvement of distal nerve segments; reduced compound action potential amplitudes are due mainly to reduced density of large, myelinated motor and sensory fibers. Prolongation of tibial and peroneal F-wave latencies and of H-reflexes is typical of patients with chronic renal failure (58; 36; 55). Distal denervation is often seen on needle exam, although at times it may be minimal or absent (12). Electrical amplitudes improve after dialysis, which is consistent with a pathogenic role of toxic substances and suggests that some features of uremic neuropathy are functional, not structural (50). Stosovic and colleagues reported that motor nerve conduction velocity predicted mortality in patients with uremic neuropathy (70). In compressive mononeuropathies, the conduction velocity will be slowed across the compression site. Carpal tunnel syndrome is common in the presence of uremic neuropathy. In patients with end-stage kidney disease, the frequency of carpal tunnel syndrome was 15% with routine nerve conduction studies and 25% with median-versus-ulnar comparison studies (66). Among the median-ulnar comparison, lumbrical-interossei comparison was most sensitive. Guillain-Barré–type neuropathy in chronic renal failure has moderate to severe conduction slowing, and conduction block may occur. Small fiber dysfunction was found in 32% of hemodialysis patients by cutaneous silent period measurement (17). Testing of autonomic function, including R-R interval and sympathetic skin responses, may be abnormal, even in patients without clinically evident autonomic dysfunction (24; 65). Esophageal manometry has been used to study subclinical manifestation of autonomic neuropathy in uremia. Eleven out of 16 patients were reported to show abnormal motility in the lower two thirds of the esophageal body (67).

Ultrasound. Sonographic alterations of peripheral nerve cross-sectional areas were demonstrated in diabetic kidney disease (31).

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

Treatment of uremic neuropathy with dialysis and vitamin supplements is unsatisfactory, whereas renal transplantation in early-stage uremic neuropathy produces a favorable outcome.

Bolton concluded that modern methods of managing renal failure have decreased the incidence of uremic neuropathy (09). Chronic intermittent peritoneal dialysis or hemodialysis are both effective in stabilizing or improving some peripheral nerve function in patients with chronic renal failure, especially those with mild symptoms. By electrophysiologic evaluation, the frequency of peripheral neuropathy and carpal tunnel syndrome remained stable for more than 5 years of peritoneal dialysis (07). The incidence of uremic neuropathy may be lower with peritoneal dialysis than with hemodialysis because of peritoneal dialysis’ higher capacity for middle molecule removal (22). In a study, patients on peritoneal dialysis had more normal nerve excitability than those in the hemodialysis group despite similar duration of dialysis (03). In the process of hemodialysis, some previously inactive axons recover due to removal of toxic substances. Paresthesias may improve rapidly when dialysis begins, but other symptoms persist (74). The dialysis regimen can be optimized in a variety of ways, including changing the type of dialyzer or dialysis membrane (73; 75). Low weight gain between sessions, a low ultrafiltration rate, and peritoneal dialysis may improve autonomic symptoms (44; 24). Chronic hemodialysis may stabilize the neuropathy in most patients. However, the course of the neuropathy cannot be improved with certainty by simply manipulating the dialysis schedule (21; 09). The achievement of normokalemia has been suggested as a priority in the treatment of uremic patients (42; 41). The emergency of optic neuropathy must be addressed aggressively, with a regimen that includes dialysis, correction of anemia and hypotension, and corticosteroids (76; 63). Diabetes management in patients with diabetic kidney disease is important to reduce the severity of peripheral neuropathy (49).

Biotin is a low molecular weight coenzyme loosely bound to serum proteins, which may be removed during dialysis. A dose of 10 mg biotin three times a day was recommended in a series of nine patients whose mental function, sensory symptoms, and gait improved after 3 months of treatment (77). In addition, it was found that biotin counteracts the inhibitory effect of uremic plasma on microtubule formation in vitro (13). The use of vitamin B6 is controversial because although neuropathy symptoms may improve, it may be more toxic in uremia (56; 46).

Subcutaneous injection of erythropoietin has been used to treat anemia in patients with renal failure. In a study of 22 subjects with chronic renal failure and subclinical polyneuropathy, 15 completed a 5-month course of erythropoietin 80 units/kg per week (28). Compared with pretreatment nerve conduction studies, the motor nerve conduction velocities of the median, peroneal, and tibial nerves improved significantly (p< 0.05). Compound muscle action potentials of the median nerve were also increased significantly (p=0.01). However, there was no improvement in sensory nerve amplitude or velocity. No significant correlation was found between the increase in hemoglobin and the improvement in polyneuropathy.

Paresthesias can be treated as usual with anticonvulsants or tricyclic or other antidepressants. Please refer to the MedLink Neurology article “Neuropathic pain: treatment.” Gabapentin is frequently used, with the dose adjusted to the renal function or timing of dialysis. In the author’s experience, however, gabapentin can be titrated up cautiously, with the final dose dictated by efficacy and side effects. Because gabapentin is excreted only via the kidneys, it can be administered as a single dose after dialysis in the anuric patient. Venlafaxine is an antidepressant that is metabolized in liver; it has been reported to resolve burning and painful sensations in the feet and is well tolerated (79).

High-tone external muscle stimulation (HTEMS) therapy was investigated in 28 patients with chronic hemodialysis with neuropathy who received HTEMS for 1 hour during hemodialysis three times weekly for 12 weeks (71). In 64% general well-being improved, in 61% physical capacity increased, and in 57% the feeling of cold feet decreased. Ulnar NCVs improved in 19 patients. HTEMS also benefited physical and social functions and pain (39).

If the neuropathy continues to worsen, renal transplantation can be considered (60). Improvement was reported for all patients following the procedure (54). Paresthesias disappeared over 1 to 3 months in mild cases. Nerve conduction velocity rapidly improved after successful transplantation. The sympathetic and parasympathetic autonomic dysfunction is reversed as early as 3 to 6 months after transplantation. Improvement of erectile dysfunction was also reported (32). Its benefit for neuropathy is less with coexisting conditions such as diabetes. Optimization of comorbidities and avoidance of neurotoxic agents is of utmost importance.

Other neuropathy supportive measures are discussed in MedLink neurology article “Rehabilitation of peripheral nerve diseases.”