Mohamed M. Mostafa and Mohamed El Tayeb

The effect of daily hemodialysis on uremic peripheral neuropathy Mohamed M. Mostafa1, Mohamed El Tayeb2 Departments of Neurology1, Internal Medicine2, Ain Shams University

ABSTRACT The uremic syndrome is characterized by overall deterioration of biochemical and physiological functions in parallel with the progression of renal failure. Despite the beneficial effects of hemodialysis, uremic polyneuropathy represents a well-known complication of end-stage renal failure (ESRF). It should be regarded as an indicator of the degree of renal failure and its control by hemodialysis. The pathogenesis of uremic neuropathy has been proved to be caused by major neurotoxins accumulating in uremia such as urea, creatinine, uric acid, middle molecules and others. Those uremic toxins can be cleared by different dialytic techniques which vary widely depending on duration, membrane, and blood band dialysate flow rates. Recent attention is paid to the precious role of daily dialysis in improving the patients clinically and biochemically. In this work, we studied 20 patients on chronic hemodialysis program. All patients showed the criteria of endstage renal failure (ESRF).We classified our patients into: 1. Group 1: Ten patients with ESRF under thrice weekly hemodialysis for less than 3 years. 2. Group II: Ten patients originally under thrice weekly hemodialysis for less than 3 years who were shifted to the regimen of daily hemodialysis except Fridays for 6 months. 3. Group III: Ten healthy normal volunteers of matching age and sex were the control group. In the present study, all patients stated improvement with the daily hemodialysis schedule considering a better physical performance. Several subjective symptoms disappeared or improved. The cumulative weekly Kt/v remained constant exceeding three with no change between daily and standard hemodialysis. In the present study; no significant changes were noticed as regard neurological symptoms after 6 months of both regimens of dialysis. As regard NCS, there was no significant improvement in dmlat, in the median, ulnar and CP nerves after 6 months of daily dialysis. There was a highly significant improvement in CV (increased) in median, ulnar and common peroneal nerves (P0.05). (Egypt J. Neurol. Psychiat. Neurosurg., 2004, 41(1): 303-312).

INTRODUCTION The uremic syndrome is characterized by overall deterioration of biochemical and physiological functions in parallel with the progression of renal failure. Uremia results in variable symptoms pointing to damage of multiple organs. Major neurotoxins accumulating in uremia are urea, creatinine, uric acid, middle molecules and others 1. Despite the beneficial effects of hemodialysis, uremic polyneuropathy represents a well-known complication of end-stage renal

failure (ESRF). It should be regarded as an indicator of the degree of renal failure and its control by hemodialysis. Bolton pointed out that 60% of patients receiving hemodialysis for uremia have neuropathy by electrodiagnostic criteria 1. The most common neuropathy is the carpal tunnel syndrome, which was initially attributed to the vascular shunt on the upper arm between the brachial artery and antecubital vein, also causing associated radial and ulnar neuropathies1.

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Charra et al.2, demonstrated amyloid deposits in the connective tissues and tendons, surrounding the carpal tunnel of uremic patients. Shirahama et al.3, showed that the amyloid of chronically dialysed uremic patients derived from beta 2-microglobulin was not cleared by the kidney. Due to reduced renal function beta 2-microglobulin accumulate. The common peroneal nerve can also be compressed at the fibular head in a similar pattern. The middle molecule (MM) hypothesis states that molecules in the molecular weight range of 500 to 2000 daltons/ molecule accumulate in uremia and are one cause of peripheral neuropathy 4. The spectrum of uremic toxins cleared by different dialytic techniques varies widely depending on duration, membrane 5 and blood and dialysate flow rates 6. The observation that prolongation of dialysis can prevent or reverse uremic neuropathy independent of the predialysis urea level led to the concept of the middle-molecule hypothesis 7. The removal rate of middle-molecularweight toxins is so slow that the diffusion gradient remains high throughout dialysis and the net removal is proportional to the number of hours per week undergoing dialysis, unaffected by blood and dialysate flow within a specified range 8. The main symptoms of uremic polyneuropathy as stated by Nielsen9, are: Cramps: They are often painful and develop mostly during the night. They tend to be localized to single muscles or muscle groups, usually in the lower extremity, while the upper extremity is rarely affected. Restless legs: that is defined as an irresistible restlessness in the calves. This often develops in the afternoon or in the evening, whenever the patient relaxes in a chair. Paresthesia: A pricking, tingling, effervescent sensation, sometimes painful, especially when located to the soles, sometimes causing a warm sensation in the skin. Dysthesia: Dysthetic sensations were defined as abnormal sensations which may be felt in the fingertips or feet. Dysthesia occurred relatively late in the course of renal failure as well as in the development of peripheral neuropathy. Pain: It

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is usually a late symptom in well established neuropathies. Darting pain along the peroneal nerve from foot to knee, irradiating pain in the thigh, pain along the course of the ulnar nerve and diffuse pain in the feet brought on by pressure are reported. The burning feet syndrome: It is defined as server insomnia, due to the burning sensation in the feet. Those symptoms however, as stated by Bolton and Young1 are not necessarily related to the neuropathy, but due possibly to transient disturbances of peripheral sensory receptors, induced by fluctuation in water and electrolytes. They may occur either prior to or during a regular hemodialysis program, the latter could indicate that the achieved control is not optimal. Clinical signs of uremic polyneruopathy include symmetric muscle weakness, areflexia and sensory loss for all modalities, especially pinprick and vibration. An early finding is elevation of the vibratory threshold 1. Currently, most hemodialysis patients undergo dialysis treatment two or three times a week. This dialysis schedule results in important fluctuations of body fluid volume and solutes which are in contrast to the normal physiological situation in which healthy kidneys maintain a state of homeostasis. A higher dialysis frequency may mimic the healthy situation better, resulting in lower peaks and smaller amplitudes of fluctuations of solute concentrations and body fluid volume, diminishing the so called "unphysiology of dialysis" 10.

PATIENTS AND METHODS The cases of this study were patients under regular hemodialysis in the Nephrology Unit, Medical Department, Ain Shams University. Twenty patients on chronic hemodialysis program were chosen. All patients showed the criteria of end-stage renal failure (ESRF). The patients were dialysed for 4 hours three times per week. We excluded only patients with abnormal blood sugar test, collagen profile and those suffering from paraproteinemias as those disorders were known to cause peripheral

Mohamed M. Mostafa and Mohamed El Tayeb

neuropathy, abnormal electromyography (EMG) and nerve conduction velocity (NVCV) studies regardless of renal dysfunction. We then classified our patients into: 1. Group I: Ten patients with ESRF under thrice weekly hemodialysis for less than 3 years. 2. Group II: Ten patients originally under thrice weekly hemodialysis for less than 3 years who experience a shift of the regimen of hemodialysis to daily hemodialysis except Fridays for 6 months. 3. Ten healthy normal volunteers of matching age and sex were the control group. The methods applied in this study were as follows: 1. Clinical evaluation with special stress on neurologic examination. Special stress was laid upon manifestations of uremic polyneuropathy: Restless legs, burning feet, parasthesiae, muscle wasting, hypotonia, muscle weakness, depressed ankle jerks, glove and stocking hypoasthesia and depressed vibration sense at the medial malleolus. 2. Laboratory investigations including: predialysis blood urea, serum creatinine, serum Na, K, Ca and phosphate, serum albumin, total protein, cholesterol, uric acid, AST, LT and CPK for possible variation in such levels in cases of muscular dysfunction, CBC: to assess the severity of anemia, FBS and 2hr postprandial blood sugar: to exclude diabetes, ANA and antiDNA (using the immunoflurorescence technique) to exclude collagen diseases, and ESR, protein electrophoresis: to exclude paraproteinemias and Kt/v: to assess the adequacy of hemodialysis. Kt/v was estimated at the beginning of the study, using the nomogram approach described by Daugirdas and Depner 11. 3. Nerve conduction velocity and latency: To study the changes of nerve conduction velocity in hemodialysis patients including both median nerves, both ulnar and both peroneal nerves, for both sensory and

motor nerve conduction studies, distal latencies, conduction velocities were measured in the forearm for the median and ulnar nerves and in the legs for the peroneal nerves. All patients were studied for a period of six months from September 1999 to February 2000.

RESULTS The present study was conducted on a group of 20 patient suffering from ESRD, they were subdivided into two groups (group I "thrice-weekly dialysis group" and group II " daily dialysis group" and control group of ten healthy normal volunteers of matching age and gender. From table (1) it can be noticed that both groups I and II were sex- and age-matched. From table (2) it can be noticed that, apart from parasthesia that showed significant difference, both groups I and II showed no significant difference as regards the mentioned neurological symptoms. Neurological examination of all 20 patients before initiation of our study revealed that all patients were fully conscious with normal speech, gait and intact cranial nerves, trophic changes nor palpable nerves. Fatigability on exercise was positive in all patients. Motor system: Muscle state: Wasting was detected in 3 cases (30%) in group I and in 2 cases (20%) in group II. In those cases it was localized in both feet (extensor digitorum brevis muscle) in the lower limbs and or the thenar eminence of both hands. Muscle tone: was normal in all cases. Muscle power: mild motor weakness was present in 4 cases in the upper limbs (40%) in the thenar and hypothenar eminences and in 2 cases (40%) in group II with a scattered distribution in the hands. Reflexes: Superficial reflexes: planter reflex was normal in all studied patients. Deep tendon jerks: the ankle jerk was diminished in 2 patients bilaterally; one (10%) in group I and one (10%) in group II. Knee jerk was normal in all cases except 4 cases where it was diminished, 2 in group I (20%) and 2 in group II (20%). In the upper limbs the biceps,

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triceps and supinator jerks were normal in all patients. Sensory system examination: Superficial sensations: On examination of the superficial sensation in the lower limbs; 2 cases were found to have superficial sensory impairment, one (10%) in group I and one (10%) in group II (pain and touch sensation). The sensory affection was bilateral and symmetrical resembling L4-L5 distribution affection. In the upper limb; superficial sensory affection in the form of glove sensory impairment was noticed in two cases, one in group I (10%) and one (10%) in group II where affection was symmetrical and bilateral in the index and mid finger. Deep sensations: The sense of position and sense of movement and vibration sense were intact in all cases. From table (3), it can be noticed that non of the above mentioned neurological signs showed significant improvement on thrice weekly or daily dialysis.

dialysis group (at the beginning of the study, after 6 months of dialysis and percentage of change on dialysis values) and daily dialysis group (at the beginning of the study, after 6 months of dialysis and percentage of change on dialysis values). A highly significant improvement in NCV was noticed in the median, ulnar and common peroneal nerves after 6 months of daily dialysis, while no significant improvement was noticed in the CV of those nerves after 6 months of thrice weekly dialysis (table 4). Motor nerve conduction studies Distal motor latency expressed in msec was determined in the three studied groups including; control group, thrice-weekly dialysis group (at the beginning of the study, after 6 months of dialysis and percentage of change on dialysis values) and daily dialysis group (at the beginning of the study, after 6 months of dialysis and percentage of change on dialysis values) (table 5). No significant improvement was noticed in the distal motor latency of median, ulnar and common peroneal nerves after 6 months of dialysis (whether thrice or daily).

Nerve Conduction Studies: Sensory nerve conduction studies: Sensory nerve conduction expressed in m/sec were determined in the three studied groups including; control group, thrice-weekly

Table 1. Age, sex and duration of hemodialysis in studied groups. Thrice-weekly group Age MeanSD range T value P value Significance Sex Male Female X2 (Fisher exact test) P value Significance Duration of hemodialysis MeanSD range T value P value Significance

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Daily group

37.49.6 (28-51)

33.64.3 (29-49) 1.424 0.268 NS

8 2

7 3 0.267 1.000 NS

30.75.17 (24-36)

15.33.4 (12-24) 7.388 0.000 HS

Mohamed M. Mostafa and Mohamed El Tayeb

Burning feet

Numberness

Parasthesia

Cramps

Pain

Thrice -weekly

5 (50%)

4 (40%)

6 (60%)

5 (50%)

8 (80%)

3 (30%)

1 (10%)

Daily

4 (40%)

3 (30%)

6 (60%)

7 (70%)

7 (70%)

3 (30%)

1 (10%)

Thrice-weekly

4 (40%)

4 (40%)

5 (50%)

5 (50%)

6 (60%)

3 (30%)

1 (10%)

Daily

1 (10%)

Dysthesia

Restless legs

Table 2. Neurological symptoms in the studied groups.

At beginning of the study

After 6 months on dialysis 2 (20%)

1 (10%)

4 (40%)

1 (10%)

4 (40%)

1 (10%)

X2 (Yates chi square)

0.056

1.181

0.000

5.486

0.034

0.750

P value

0.813

0.277

1.000

0.019

0.855

0.386

NS

NS

NS

NS

NS

NS

Significance

*

Muscle wasting

Hypotonia

Muscle waekness

 ankle jerk

 knee jerk

Glvoe and stocking

 vibration

Table 3. Neurological signs in the studied groups.

Thrice -weekly

3 (30%)

0 (0%)

6 (60%)

1 (10%)

2 (20%)

1 (10%)

0 (0%)

Daily

2 (20%)

0 (0%)

4 (40%)

1 (10%)

2 (20%)

1 (10%)

0 (0%)

Thrice-weekly

3 (30%)

0 (0%)

6 (60%)

1 (10%)

2 (20%)

1 (10%)

0 (0%)

Daily

2 (20%)

0 (0%)

4 (40%)

1 (10%)

2 (20%)

1 (10%)

0 (0%)

At beginning of the study

After 6 months on dialysis

2

X (Yates chi square) P value

*

Significance

* Yates chi square could not be calculated due to equality between the two proportions (NS)

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Table 4. Descriptive statistics and comparison between values at the beginning of the study versus values after 6 months regarding conduction velocity in both dialysis groups. Median At the beginning After 6 months T value P value Significance Ulnar At the beginning After 6 months T value P value Significance Common peroneal At the beginning After 6 months T value P value Significance

Thrice-weekly group

Daily group

40.34.69 (33-49) 41.34.32 (33-48) 1.627 0.138 NS

40.46.63 (35-46) 43.54.22 (39-51) 4.122 0.003 HS

46.75.81 47.66.20 (38-60) 1.711 0.121 NS

44.63.53 (38-50) 47.73.77 (41-53) 3.382 0.004 HS

30.33.30 (22-34) 31.52.95 (27-35) 1.765 0.111 NS

30.22.78 (26-35) 33.706 (29-41) 5.496 0.000 HS

Table 5. Descriptive statistics and comparison between values at the beginning of the study versus values after 6 months regarding distal motor latency in both dialysis groups. Median At the beginning After 6 months T value P value Significance Ulnar At the beginning After 6 months T value P value Significance Common peroneal At the beginning After 6 months T value P value Significance

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Thrice-weekly group

Daily group

40.320.31(3.8-5.0) 4.20.44 (3.4-4.9 1.964 1.964 NS

4.294.20 (3.4-4.7 4.10.46 (3.5-4.7 2.029 0.073 NS

3.490.73 (2.5-4.9) 3.093.60 (2.4-3.5) 1.395 0.196 NS

3.860.59 (3-4.7) 3.410.69 (2.4-4.7) 1.517 0.164 NS

6.220.75 (5.3-7.7) 6.140.76 (5.3-7.7) 1.714 0.121 NS

6.160.55 (5.3-7.2) 6.030.53 (5.4-7.1) 1.857 0.096 NS

Mohamed M. Mostafa and Mohamed El Tayeb

DISCUSSION Our daily hemodialysis protocol has been held to compare the neuromuscular function among hemodialysis patients, thrice weekly versus daily and to monitor the effect of reduction of the interdialytic interval on the various systems of the body of the dialysis patient. It was possible to obtain the compliance of both the hospital staff and the patients, who were convinced by the level of well being achieved and the good clinical results A comparison was made with a healthy control population matched for age and sex. In general the symptoms and signs did not differ in character from those into the neuropathies. There was a remarkable tendency among the uremic patients to neglect relevant symptoms, either because they had gradually become accustomed to them, or more often because neurological complaints had become overshadowed by other uremic symptoms. The early subjective complaints of neuropathy in uremic patients were commonly characterized as burning sensations in the feet, and painful tender soles in contradiction to Jennekens who recorded the burning feet syndrome in only five of his 82 patients, and all five had severe neuropathy 12. Cramps and restless leg were by far the most frequent of all complaints. Also they were the earliest symptoms from the peripheral neuromuscular system during the course of progressive renal failure. Some authors consider them to be important and early indications of neuropathy 13. Paresthesia was found to occur early in those patients. In the present study, no significant changes in the above mentioned neurological symptoms were noticed after 6 months of dialysis. In the present study, as regard sensory NCS, we have found significant improvement in CV (increased) in median and ulnar (P