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The Egyptian Journal of Uremia

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					                                 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 end-
stage 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 (P<0.001) after 6 months of daily dialysis. We have found no
significant changes in dmlat, nor CV in the median, ulnar and CP nerves on both sides after 6 months of 3/wk
dialysis (P>0.05). (Egypt J. Neurol. Psychiat. Neurosurg., 2004, 41(1): 303-312).

          INTRODUCTION                                      failure (ESRF). It should be regarded as an
                                                            indicator of the degree of renal failure and its
                                                            control by hemodialysis.
     The uremic syndrome is characterized by
                                                                  Bolton pointed out that 60% of patients
overall deterioration of biochemical and
                                                            receiving hemodialysis for uremia have
physiological functions in parallel with the
                                                            neuropathy by electrodiagnostic criteria 1.
progression of renal failure. Uremia results in
                                                                  The most common neuropathy is the carpal
variable symptoms pointing to damage of
                                                            tunnel syndrome, which was initially attributed
multiple     organs.     Major       neurotoxins
                                                            to the vascular shunt on the upper arm between
accumulating in uremia are urea, creatinine, uric
                                                            the brachial artery and antecubital vein, also
acid, middle molecules and others 1.
                                                            causing     associated    radial    and     ulnar
     Despite the beneficial effects of
                                                            neuropathies1.
hemodialysis, uremic polyneuropathy represents
a well-known complication of end-stage renal

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     Charra et al.2, demonstrated amyloid              is usually a late symptom in well established
deposits in the connective tissues and tendons,        neuropathies. Darting pain along the peroneal
surrounding the carpal tunnel of uremic patients.      nerve from foot to knee, irradiating pain in the
Shirahama et al.3, showed that the amyloid of          thigh, pain along the course of the ulnar nerve
chronically dialysed uremic patients derived           and diffuse pain in the feet brought on by
from beta 2-microglobulin was not cleared by           pressure are reported. The burning feet
the kidney. Due to reduced renal function beta         syndrome: It is defined as server insomnia, due
2-microglobulin accumulate. The common                 to the burning sensation in the feet.
peroneal nerve can also be compressed at the                Those symptoms however, as stated by
fibular head in a similar pattern.                     Bolton and Young1 are not necessarily related to
     The middle molecule (MM) hypothesis               the neuropathy, but due possibly to transient
states that molecules in the molecular weight          disturbances of peripheral sensory receptors,
range of 500 to 2000 daltons/ molecule                 induced by fluctuation in water and electrolytes.
accumulate in uremia and are one cause of              They may occur either prior to or during a
peripheral neuropathy 4.                               regular hemodialysis program, the latter could
     The spectrum of uremic toxins cleared by          indicate that the achieved control is not optimal.
different dialytic techniques varies widely            Clinical signs of uremic polyneruopathy include
depending on duration, membrane 5 and blood            symmetric muscle weakness, areflexia and
and dialysate flow rates 6. The observation that       sensory loss for all modalities, especially pin-
prolongation of dialysis can prevent or reverse        prick and vibration. An early finding is elevation
uremic neuropathy independent of the                   of the vibratory threshold 1.
predialysis urea level led to the concept of the            Currently, most hemodialysis patients
middle-molecule hypothesis 7.                          undergo dialysis treatment two or three times a
     The removal rate of middle-molecular-             week. This dialysis schedule results            in
weight toxins is so slow that the diffusion            important fluctuations of body fluid volume and
gradient remains high throughout dialysis and          solutes which are in contrast to the normal
the net removal is proportional to the number of       physiological situation in which healthy kidneys
hours per week undergoing dialysis, unaffected         maintain a state of homeostasis.
by blood and dialysate flow within a specified              A higher dialysis frequency may mimic the
range 8.                                               healthy situation better, resulting in lower peaks
     The      main     symptoms      of     uremic     and smaller amplitudes of fluctuations of solute
polyneuropathy as stated by Nielsen9, are:             concentrations and body fluid volume,
Cramps: They are often painful and develop             diminishing the so called "unphysiology of
mostly during the night. They tend to be               dialysis" 10.
localized to single muscles or muscle groups,
usually in the lower extremity, while the upper
extremity is rarely affected. Restless legs: that is
                                                        PATIENTS AND METHODS
defined as an irresistible restlessness in the
calves. This often develops in the afternoon or              The cases of this study were patients under
in the evening, whenever the patient relaxes in a      regular hemodialysis in the Nephrology Unit,
chair. Paresthesia: A pricking, tingling,              Medical Department, Ain Shams University.
effervescent sensation, sometimes painful,                   Twenty patients on chronic hemodialysis
especially when located to the soles, sometimes        program were chosen. All patients showed the
causing a warm sensation in the skin. Dysthesia:       criteria of end-stage renal failure (ESRF). The
Dysthetic sensations were defined as abnormal          patients were dialysed for 4 hours three times
sensations which may be felt in the fingertips or      per week. We excluded only patients with
feet. Dysthesia occurred relatively late in the        abnormal blood sugar test, collagen profile and
course of renal failure as well as in the              those suffering from paraproteinemias as those
development of peripheral neuropathy. Pain: It         disorders were known to cause peripheral

304
                                Mohamed M. Mostafa and Mohamed El Tayeb


neuropathy, abnormal electromyography (EMG)                motor nerve conduction studies, distal
and nerve conduction velocity (NVCV) studies               latencies, conduction velocities were
regardless of renal dysfunction.                           measured in the forearm for the median and
                                                           ulnar nerves and in the legs for the peroneal
We then classified our patients into:
                                                           nerves.
1. Group I: Ten patients with ESRF under
                                                           All patients were studied for a period of six
    thrice weekly hemodialysis for less than 3
                                                       months from September 1999 to February 2000.
    years.
2. Group II: Ten patients originally under
    thrice weekly hemodialysis for less than 3                         RESULTS
    years who experience a shift of the regimen
    of hemodialysis to daily hemodialysis                    The present study was conducted on a
    except Fridays for 6 months.                       group of 20 patient suffering from ESRD, they
3. Ten healthy normal volunteers of matching           were subdivided into two groups (group I
    age and sex were the control group.                "thrice-weekly dialysis group" and group II "
The methods applied in this study were as              daily dialysis group" and control group of ten
follows:                                               healthy normal volunteers of matching age and
1. Clinical evaluation with special stress on          gender.
     neurologic examination. Special stress was              From table (1) it can be noticed that both
     laid upon manifestations of uremic                groups I and II were sex- and age-matched.
     polyneuropathy: Restless legs, burning feet,            From table (2) it can be noticed that, apart
     parasthesiae, muscle wasting, hypotonia,          from parasthesia that showed significant
     muscle weakness, depressed ankle jerks,           difference, both groups I and II showed no
     glove and stocking hypoasthesia and               significant difference as regards the mentioned
     depressed vibration sense at the medial           neurological symptoms.
     malleolus.                                              Neurological examination of all 20 patients
2. Laboratory        investigations   including:       before initiation of our study revealed that all
     predialysis blood urea, serum creatinine,         patients were fully conscious with normal
     serum Na, K, Ca and phosphate, serum              speech, gait and intact cranial nerves, trophic
     albumin, total protein, cholesterol, uric         changes nor palpable nerves. Fatigability on
     acid, AST, LT and CPK for possible                exercise was positive in all patients. Motor
     variation in such levels in cases of              system: Muscle state: Wasting was detected in 3
     muscular dysfunction, CBC: to assess the          cases (30%) in group I and in 2 cases (20%) in
     severity of anemia, FBS and 2hr                   group II. In those cases it was localized in both
     postprandial blood sugar: to exclude              feet (extensor digitorum brevis muscle) in the
     diabetes, ANA and antiDNA (using the              lower limbs and or the thenar eminence of both
     immunoflurorescence technique) to exclude         hands. Muscle tone: was normal in all cases.
     collagen diseases, and ESR, protein               Muscle power: mild motor weakness was
     electrophoresis:          to        exclude       present in 4 cases in the upper limbs (40%) in
     paraproteinemias and Kt/v: to assess the          the thenar and hypothenar eminences and in 2
     adequacy of hemodialysis. Kt/v was                cases (40%) in group II with a scattered
     estimated at the beginning of the study,          distribution in the hands. Reflexes: Superficial
     using the nomogram approach described by          reflexes: planter reflex was normal in all studied
     Daugirdas and Depner 11.                          patients. Deep tendon jerks: the ankle jerk was
3. Nerve conduction velocity and latency: To           diminished in 2 patients bilaterally; one (10%)
     study the changes of nerve conduction             in group I and one (10%) in group II. Knee jerk
     velocity in hemodialysis patients including       was normal in all cases except 4 cases where it
     both median nerves, both ulnar and both           was diminished, 2 in group I (20%) and 2 in
     peroneal nerves, for both sensory and             group II (20%). In the upper limbs the biceps,

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Egypt J. Neurol. Psychiat. Neurosurg.                                                Vol. 41 (1) - Jany 2004


triceps and supinator jerks were normal in all           dialysis group (at the beginning of the study,
patients.    Sensory      system      examination:       after 6 months of dialysis and percentage of
Superficial sensations: On examination of the            change on dialysis values) and daily dialysis
superficial sensation in the lower limbs; 2 cases        group (at the beginning of the study, after 6
were found to have superficial sensory                   months of dialysis and percentage of change on
impairment, one (10%) in group I and one                 dialysis values).
(10%) in group II (pain and touch sensation).                 A highly significant improvement in NCV
The sensory affection was bilateral and                  was noticed in the median, ulnar and common
symmetrical resembling L4-L5 distribution                peroneal nerves after 6 months of daily dialysis,
affection. In the upper limb; superficial sensory        while no significant improvement was noticed in
affection in the form of glove sensory                   the CV of those nerves after 6 months of thrice
impairment was noticed in two cases, one in              weekly dialysis (table 4).
group I (10%) and one (10%) in group II where
affection was symmetrical and bilateral in the           Motor nerve conduction studies
index and mid finger. Deep sensations: The                    Distal motor latency expressed in msec was
sense of position and sense of movement and              determined in the three studied groups
vibration sense were intact in all cases.                including; control group, thrice-weekly dialysis
     From table (3), it can be noticed that non of       group (at the beginning of the study, after 6
the above mentioned neurological signs showed            months of dialysis and percentage of change on
significant improvement on thrice weekly or              dialysis values) and daily dialysis group (at the
daily dialysis.                                          beginning of the study, after 6 months of dialysis
                                                         and percentage of change on dialysis values)
Nerve Conduction Studies:                                (table 5).
Sensory nerve conduction studies:                             No significant improvement was noticed in
    Sensory nerve conduction expressed in                the distal motor latency of median, ulnar and
m/sec were determined in the three studied               common peroneal nerves after 6 months of
groups including; control group, thrice-weekly           dialysis (whether thrice or daily).

Table 1. Age, sex and duration of hemodialysis in studied groups.
                                         Thrice-weekly group                     Daily group
 Age
 MeanSD range                              37.49.6 (28-51)                   33.64.3 (29-49)
 T value                                                            1.424
 P value                                                            0.268
 Significance                                                        NS
 Sex
 Male                                                8                                 7
 Female                                              2                                 3
 X2 (Fisher exact test)                                             0.267
 P value                                                            1.000
 Significance                                                        NS
 Duration of hemodialysis
 MeanSD range                             30.75.17 (24-36)                   15.33.4 (12-24)
 T value                                                            7.388
 P value                                                            0.000
 Significance                                                        HS

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                                Mohamed M. Mostafa and Mohamed El Tayeb


Table 2. Neurological symptoms in the studied groups.




                                                                   Burning feet



                                                                                                Numberness
                                Restless legs




                                                                                                                                 Parasthesia




                                                                                                                                                                                                                      Dysthesia
                                                                                                                                                                Cramps



                                                                                                                                                                                         Pain
 At beginning of the study
 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%)
 After 6 months on dialysis
 Thrice-weekly                4 (40%)                            4 (40%)                      5 (50%)                          5 (50%)                        6 (60%)                  3 (30%)                       1 (10%)
 Daily                        2 (20%)                            1 (10%)                      4 (40%)                          1 (10%)                        4 (40%)                  1 (10%)                       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                                 *
 Significance                   NS                                 NS                           NS                               NS                             NS                       NS




Table 3. Neurological signs in the studied groups.




                                                                                                                                                                                                Glvoe and stocking
                                                                                                             Muscle waekness
                                                Muscle wasting




                                                                                                                                                ankle jerk



                                                                                                                                                                          knee jerk




                                                                                                                                                                                                                                   vibration
                                                                                  Hypotonia




 At beginning of the study
 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%)
 After 6 months on dialysis
 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%)
   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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Egypt J. Neurol. Psychiat. Neurosurg.                                               Vol. 41 (1) - Jany 2004


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.
                                        Thrice-weekly group                      Daily group
 Median
 At the beginning                         40.34.69 (33-49)                   40.46.63 (35-46)
 After 6 months                           41.34.32 (33-48)                   43.54.22 (39-51)
 T value                                       1.627                               4.122
 P value                                       0.138                               0.003
 Significance                                    NS                                  HS
 Ulnar
 At the beginning                             46.75.81                       44.63.53 (38-50)
 After 6 months                           47.66.20 (38-60)                   47.73.77 (41-53)
 T value                                        1.711                              3.382
 P value                                        0.121                              0.004
 Significance                                    NS                                  HS
 Common peroneal
 At the beginning                         30.33.30 (22-34)                   30.22.78 (26-35)
 After 6 months                           31.52.95 (27-35)                    33.706 (29-41)
 T value                                       1.765                                5.496
 P value                                       0.111                                0.000
 Significance                                    NS                                  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.
                                        Thrice-weekly group                      Daily group
 Median
 At the beginning                        40.320.31(3.8-5.0)                  4.294.20 (3.4-4.7
 After 6 months                           4.20.44 (3.4-4.9                    4.10.46 (3.5-4.7
 T value                                       1.964                                2.029
 P value                                       1.964                                0.073
 Significance                                    NS                                   NS
 Ulnar
 At the beginning                         3.490.73 (2.5-4.9)                 3.860.59 (3-4.7)
 After 6 months                           3.093.60 (2.4-3.5)                3.410.69 (2.4-4.7)
 T value                                        1.395                              1.517
 P value                                        0.196                              0.164
 Significance                                    NS                                 NS
 Common peroneal
 At the beginning                         6.220.75 (5.3-7.7)                6.160.55 (5.3-7.2)
 After 6 months                           6.140.76 (5.3-7.7)                6.030.53 (5.4-7.1)
 T value                                        1.714                              1.857
 P value                                        0.121                              0.096
 Significance                                    NS                                 NS

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                                Mohamed M. Mostafa and Mohamed El Tayeb


             DISCUSSION                                and highly significant improvement in CV in CP
                                                       nerve (P<0.001) after 6 months of daily dialysis.
                                                       There was no significant improvement in dmlat.
     Our daily hemodialysis protocol has been
                                                       In median, ulnar or CP nerves after 6 months of
held to compare the neuromuscular function
                                                       daily dialysis, however, on individual bases the
among hemodialysis patients, thrice weekly
                                                       number of patients with prolonged latency
versus daily and to monitor the effect of
                                                       dropped from 90 to 6 and from 7 to 4 in median
reduction of the interdialytic interval on the
                                                       and ulnar nerves respectively, while no change
various systems of the body of the dialysis
                                                       in the number of patents with prolonged CP
patient.
                                                       nerve latency after 6 months of daily dialysis,
     It was possible to obtain the compliance of
                                                       was noticed. There were no significant changes
both the hospital staff and the patients, who
                                                       in dmlat.nor motor CV in the median, ulnar or
were convinced by the level of well being
                                                       CP nerves on both sides after 6 months of 3/wk
achieved and the good clinical results
                                                       dialysis (P>0.05). However, on individual bases,
     A comparison was made with a healthy
                                                       the number of patients who had prolonged
control population matched for age and sex.
                                                       median nerve latency in the beginning of the
     In general the symptoms and signs did not
                                                       study dropped from 9 to 8 patients after 6
differ in character from those into the
                                                       months of thrice weekly dialysis.
neuropathies. There was a remarkable tendency
                                                            The number of patients with prolonged
among the uremic patients to neglect relevant
                                                       ulnar nerve latency was 2 and increased to 3
symptoms, either because they had gradually
                                                       after 6 months of thrice weekly dialysis, while
become accustomed to them, or more often
                                                       the number of patients with prolonged CP nerve
because neurological complaints had become
                                                       latency dropped from 10 to 9 after 6 months of
overshadowed by other uremic symptoms.
                                                       thrice weekly dialysis. As regard the CV, the
     The early subjective complaints of
                                                       number of patients with decreased CV of
neuropathy in uremic patients were commonly
                                                       median and CP nerves was 9 and remained the
characterized as burning sensations in the feet,
                                                       same after 6 months of thrice weekly dialysis.
and painful tender soles in contradiction to
                                                       The number of patients with decreased ulnar
Jennekens who recorded the burning feet
                                                       nerve CV was 4 then increased to 6 after 6
syndrome in only five of his 82 patients, and all
                                                       months of thrice weekly dialysis.
five had severe neuropathy 12.
                                                            Previous studies on daily dialysis have
     Cramps and restless leg were by far the
                                                       shown improvement of uremic peripheral
most frequent of all complaints. Also they were
                                                       neuropathy by increasing the frequency of
the earliest symptoms from the peripheral
                                                       dialysis through assessment of NCV in peroneal
neuromuscular system during the course of
                                                       and median nerves. Peroneal NCV increased in
progressive renal failure. Some authors consider
                                                       5 out of 6 cases. An average increase from 32 to
them to be important and early indications of
                                                       40 m/s was found after 3-8 months of daily
neuropathy 13.
                                                       dialysis14. Other studies on patients receiving
     Paresthesia was found to occur early in
                                                       long term daily dialysis have shown that the
those patients. In the present study, no
                                                       conduction velocity of the peripheral nerves
significant changes in the above mentioned
                                                       remained stable in the first 6 months of the
neurological symptoms were noticed after 6
                                                       study. Another former study has also proved
months of dialysis.
                                                       improvement in both central and peripheral
     In the present study, as regard sensory
                                                       neuropathy and in muscular strength and
NCS, we have found significant improvement in
                                                       physical ability in patients shifted from different
CV (increased) in median and ulnar (P<0.05)
                                                       methods of dialysis to DHD 15.

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Egypt J. Neurol. Psychiat. Neurosurg.                                            Vol. 41 (1) - Jany 2004


     In a previous study on 54 patients under        clinical results are better than those obtained
regular HD who were compared to a group of           with standard dialysis due to better correction of
normal controls of matching age and sex, a           some uremia induced pathologies (Anemia,
delay was found the motor CV of the deep             metabolic      profiles      and    hemodynamic
peroneal nerve, a delay in the sensory CV of the     instabilities)
sural nerve with, a delay in median and ulnar              To sum up our results Peripheral
sensory nerve conduction velocities and a delay      neuropathy is one of the complications of
in the motor CV of the median nerve. The deep        chronic renal failure. The cause of uremic
peroneal nerve motor conduction velocity and         peripheral neuropathy is mainly the major
the sural nerve sensory conduction velocity          neurotoxins accumulating in uremia such as
showed the most significant differences 16.          urea, creatinine, uric acid, middle molecules and
In a former study, NCS were performed on a           others. Daily dialysis improved neuromuscular
group of patients before and after 3 months of       function in uremics better than standard
achieving a Kt/v of 1.3/ session for patients        hemodialysis. This improvement is due to the
dialysed 3 times and 1.6/session for patients        fact that more frequent removal of the smaller
dialysed twice/week. In that study the median        sized molecules (BUN and creatinine) may
nerve conduction velocity showed no significant      promote the conversion of more toxic middle
increase at the end of the study 17.                 molecules to the less toxic smaller molecules.
     In a former study which has been                The absence of wide biochemical fluctuations
performed on two groups of patients where            and disequilibrium in frequent short dialysis also
group I received frequent short hemodialysis         may allow tolerance of higher ultrafiltration
(FSHD) while group II received standard thrice       settings and could be responsible for better
weekly hemodialysis, NCS were performed for          middle molecule clearances.
both groups on median, ulnar an CP nerves. The
average change of combined motor and sensory         Conclusion and Recommendations
nerve conduction velocities in group I patients           In this work we started daily dialysis for a
was -1.69 msec versus -2.51 msec in group II         short period of 6 months on 10 patients only.
patients, the negative sign indicating decrease in   Further studies on the effects of long term daily
conduction velocities.                               dialysis on wider scales are recommended. The
     In our study the average change in distal       protocol of daily hemodialysis opens the way for
latencies in group I patients was --0.33 msec        further studying of protocols entailing a greater
versus +0.15 msec in group II patients, the          frequency of dialysis. Further works are required
negative sign indicating shortening and positive     to study the effect of daily home hemodialysis
sign indicating lengthening of latency periods.      on the different clinical and biochemical and
Despite the mild reduction in motor nerve            psychological aspects of dialysis patients as well
conduction velocities (MNCVs) in group I             as the economic aspects of the daily regimen of
patients, their clinical neurological status         HD.
remained stable. The distal latencies actually
improved in group I while they deteriorated in
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    Shideman JR, Von Hartitzsch B and Buselmeier         18. Manohar NL, Louis BM, Gorfien P and Lipner
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                                               ‫انمهخص انعربي‬
                         ‫تأثير االستصفاء اندموى انيومي عهي اعتالل األعصاب انطرفية‬
                                         ‫انناتج عن انفشم انكهوى‬


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