S^vV
Effect of chronic renal failure, dialysis and transplantation on motor nerve conduction velocity in children G.S. Arbus, md, frcp[c]; N.-A. Barnor, md; A.C. Hsu, mb, bs; E.G. Murphy, md, frcp[c]; I.C. Radde, md, ph d, frcp[c]
Summary: Ulnar and peroneal motor nerve conduction velocities (MNCVs) were measured in 47 children in a dialysis-transplantation program. Mean peroneal MNCV was significantly decreased from normal in children with mild renal failure (serum creatinine concentration, 1.5 to 2.9 mg/dl), whereas ulnar MNCV was significantly decreased only when the serum creatinine value was at least 9 mg/dl. Both ulnar and peroneal MNCVs remained unchanged during
long-term hemodialysis
or
peritoneal dialysis; however,
after individual dialyses ulnar MNCV increased. After renal transplantation ulnar MNCV returned to normal within a year and peroneal MNCV within 3 years. Before dialysis was required and during long-term dialysis most plasma magnesium values were elevated; ionized calcium activity was decreased in about 50% of determinations. After transplantation the concentration of divalent cations rapidly returned to normal. These children differed from adults studied in that (a) there was no correlation between severity of renal failure and MNCV, (b) long-term dialysis did not improve MNCV and (c) peroneal velocities did not recover for 3 years after transplantation. Resume: L'effet de I'insuffisance renale chronique, de la dialyse et de la transplantation sur la vitesse de conduction des nerfs moteurs chez I'enfant Chez 47 enfants soumis a un programme de dialyse-transplantation, la vitesse de conduction des nerfs moteurs (VCNM), soit le cubital et le peronier, a ete mesuree. La VCNM moyenne du peronier etait nettement diminuee, par rapport a sa valeur normale chez I'enfant, dans I'insuffisance renale benigne (concentration de la creatinine serique, de 1.5 a 2.9 mg/dl), tandis que la VCNM du cubital n'etait nettement diminuee que dans le cas ou la concentration serique du creatinine etait d'au moins 9 mg/dl. Par contre, la VCNM du cubital et du peronier est demeuree inchangee au cours d'hemodialyse ou de From the divisions of nephrology, neurology and endocrinology of the department of medicine, The Hospital for Sick Children, Toronto, and the department of pediatrics, University of Toronto A summary of this study was presented before the Canadian Paediatric Society, Qu6bec, June 1973. Reprint requests to: Dr. G.S. Arbus, The Hospital for Sick Children, 555 University Ave., Toronto, Ont. M5G 1X8
dialyse peritoneale a long terme, bien qu'on ait note une augmentation de la VCNM cubital apres des dialyses sporadiques. Apres transplantation renale la VCNM
cubital a ete normalisee dans un delai d'un an et la VCNM peronier en 3 ans. Avant que se soit imposee la dialyse et durant la periode de dialyse chronique, la majorite des valeurs de la magnesinemie etait anormalement elevee. L'activite du calcium ionise etait diminuee dans 50% des analyses. Apres transplantation la concentration des cations bivalents s'est normalisee rapidement. Par rapport aux adultes, ces enfants presentaient les differences suivantes: (a) il n'y avait aucune correlation entre la severite de I'insuffisance renale et le VCNM, (b) une dialyse a long terme n'a pas amelioree la VCNM et (c) la vitesse de la conduction du peronier ne s'est pas amelioree avant un delai de 3 ans apres la transplantation.
Peripheral neuropathy is common in patients with chronic renal failure.1,2 During early stages of failure nerve conduc¬ tion velocities can be reduced in the absence of any chemical or symptomatic abnormality.3,4 The contribution of various electrolyte abnormalities to the severity of the neuropathy remains controversial.5 All previous reports except one6 dealt with data from adults. With the establishment of a regular dialysis-trans¬ plantation program at The Hospital for Sick Children, Toronto, we studied motor nerve conduction velocity (MNCV) in children during three stages of chronic renal failure: stage 1, failure not requiring dialysis; stage II, failure requiring long-term dialysis; and stage III, after successful renal transplantation. Our aims were to determine the changes in MNCV through the stages of renal failure in children and to correlate MNCV with divalent cation status.
Patients and
procedures
Patients
Forty-seven patients, of mean age 12 years, were included in the study. Distribution by sex and diagnosis, and the number of patients tested during each stage are shown in CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113 517
patients measurements were done during the three stages of their disease and in 20, during two of the three stages. Clinical management The goal of the dialysis-transplantation program is trans¬ plantation in all patients, maintaining them on dialysis until they have a successfully functioning kidney transplant. Dialysis is usually begun when the patient's serum crea¬ tinine concentration is consistently greater than 10 mg/dl or the blood urea nitrogen (BUN) concentration is greater than 125 mg/dl. Occasionally our patients had complica¬ tions that necessitated their entering the dialysis program before these values were reached. When the dialysis-transplantation program began in 1967 hemodialysis was done once a week for approximately 8 hours. From 1971 all patients underwent hemodialysis at least twice a week for 6 to 8 hours each time (calcium concentration in the hemodialysis fluid, approximately 4.4 meq//; that of magnesium, approximately 1.0 meq//). Peri¬ toneal dialysis was performed for 24 to 48 hours per week with Dianeal (Baxter Laboratories of Canada Ltd.) (calcium concentration, 3.5 meq//; magnesium concentration, 1.5 meq//). Blood for cation determinations was usually drawn before dialysis, and MNCV measurements were performed always before dialysis and in five patients also at the end of dialysis. Before and during dialysis patients received various medi¬ cations depending on their clinical state, including antihy¬ pertensive drugs, aluminum hydroxide and calcium prepara¬ tions, and vitamin D and other vitamin supplements. Except in one patient, cadaver kidneys were transplanted. After transplantation patients were given prednisone (3 mg/kg»d); this dose was gradually reduced, so that at 3 to 6 months after successful renal transplantation the main¬ tenance dose was 10 to 25 mg q48h. All patients also re¬ ceived azathioprine (3 mg/kg«d) after transplantation unless the leukocyte count was less than 4 x 107/. For acute episodes of rejection additional corticosteroid therapy was given, either alone or in combination with cyclophospha¬ mide, actinomycin D or irradiation to the graft area. Antilymphocyte globulin was not used. Most patients needed antihypertensive medication for 3 to 6 months after trans¬ plantation; thereafter about 20% of the patients required continued antihypertensive therapy despite good renal func¬ tion. Usually dietary restriction was not needed after a successful kidney transplant but sodium intake was occa¬ sionally restricted if the patient was hypertensive. Table I. In 5
stimuli (150 V, 200 /xs) were given, and occasionally, to obtain a response, duration of the stimulus was increased to 500 or 1000 fis. The apparatus was modified to deliver not more than 150 V. Ulnar and peroneal MNCVs were usually determined in the right arm and leg unless previous trauma or infection made this impossible. The procedure was that described by Marcus and colleagues.7 Control values7 for ulnar and peroneal MNCVs were obtained from a group of 24 children who had recovered from minor head injuries, were of the same mean age as the study patients and had no peripheral or chronic central nervous system disorder and no history of renal abnormal¬ ity. Testing was done just before discharge from hospital. Blood was obtained usually after the MNCV measure¬ ment. Plasma ionic calcium activity was determined by the method of Radde and colleagues;8 total calcium and magne¬ sium concentrations were determined by emission and atomic absorption flame spectrophotometry,9'10 respectively; and inorganic phosphorus concentration was measured by the Gomori procedure,11 adapted to automatic analysis. Results
Stage I In 31 patients with chronic renal failure (serum creati¬ nine concentration, consistently > 1.5 mg/dl) 48 MNCV measurements were made while the patients were not yet on the dialysis program. Nine were examined repeatedly in this stage. The serum creatinine concentration varied from 1.5 to 22.8 mg/dl. Values for ulnar and peroneal MNCVs, arranged accord¬ ing to increasing serum creatinine concentration, and fre¬ quency of decreased MNCV are shown in Fig. 1. Even with relatively mild renal failure (i.e., serum creatinine concentration, 1.5 to 2.9 mg/dl) the mean peroneal MNCV was significantly lower than normal (P < 0.05). The mean ulnar MNCV was significantly lower than the normal mean only in patients with serum creatinine values of at least 9 mg/dl. Approximately one out of four ulnar MNCVs was reduced below the normal range. In contrast, about half the peroneal MNCVs were reduced. With increasing serum creatinine concentration or increasing duration of renal disease no further decrease in mean MNCV occurred. When repeated measurements in individual patients were examined by paired f-testing during stage I there was no
ULNAR MNCV
PERONEAL MNCV
Methods MNCVs were determined with the portable HewlettPackard electromyograph, model 1510 A. Supramaximal Table I.Distribution of 47 patients with chronic renal failure by sex and diagnosis, and number tested* during each stage No. of patients Female
Variable
Diagnosis
Chronic glomerulonephritis Chronic pyelonephritis Bilateral "small" kidneys Other
Stagef
(n 32) =
TrJnf
Male
(n 15) =
4/8 9/19 4/11 5/10
10 12 4 6
6.08.9
^9.0 CREATININE
31 (48) 20 (28) 27 (68)
II lll ?Number of observations for each stage in parentheses. fl, chronic renal failure not requiring dialysis; II, failure requiring long-term hemodialysisor peritoneal dialysis; lll, after successful renal transplantation.
518 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
JL£J_Liiiil_L£J_t££l-
1.52.9
3.05.9
6.08.9
^9.0
mg/dl
FIG. 1.Ulnar and peroneal motor nerve conduction velocities (MNCVs) during stage I. Numbers in bars indicate number of reduced MNCVs per total observations. Solid and interrupted horizontal lines indicate mean ± range of values for normal population (children). Asterisks indicate significant difference from normal mean.
evidence of significant deterioration of MNCV (P > 0.20). Most of the plasma magnesium values were elevated during this stage of the disease and a decrease in plasma calcium ion activity was detected in less than half the determinations (Table II). Only 1 of 30 plasma magnesium values exceeded 3 meq// and plasma calcium ion activity was significantly decreased « 1.80 meq//) only twice. The decrease in MNCV was not correlated with the severity of cation abnormality.
Stage II In 20 patients 28 MNCV measurements were made while the patients were in the dialysis stage. In five patients meas¬ urements of MNCV and plasma divalent cations were carried out before and after dialysis on eight occasions. In two other patients plasma for divalent cation estimations was obtained before and after dialysis but MNCV was measured only before dialysis. Mean MNCVs for these patients at the time of dialysis, according to time after start of the dialysis program, are shown in Fig. 2. No significant difference from normal in mean ulnar MNCV occurred with increasing time on dial¬ ysis, but the frequency of reduced ulnar MNCV decreased. Mean peroneal MNCVs were always significantly less than normal, but the decrease observed with increasing time on PERONEAL MNCV
ULNAR MNCV m/s 7060-
6/11 f;;;;;l
7>12 012 6 TIME ON DIALYSIS PROGRAM
III
In 27 children 68 MNCV measurements
were
made after
transplantation. For the first 6 months after transplantation decreased ulnar and peroneal MNCVs were observed in about half the patients and the mean values were signi¬ ficantly reduced from the normal means (ulnar, P < 0.05; peroneal, P < 0.001) (Fig. 4). Between 7 and 36 months only 3 of 34 ulnar MNCVs were still reduced and after 3 years all ulnar values were within the normal range. Mean peroneal MNCVs remained decreased much longer ulnar velocities. Until the end of the 3rd year than half the measurements were still below the normal range and mean values also differed significantly from normal means. Even more than 3 years after success-
30 H o6
Stage
mean
more
ii"""ii
40 H
3/8
dialysis program was not significant (P < 0.20); the frequency of reduced peroneal MNCV also did not change with the time the patient was in the program. Paired /-testing in individual patients likewise did not disclose any trend in MNCV with increasing duration of the dialysis program. Of the 28 ulnar MNCVs only 1 was outside the normal range, whereas 16 of 28 peroneal values were significantly below the normal range. When MNCV was compared before and after eight individual dialyses the increase in ulnar MNCV was highly significant (P < 0.01), whereas that of peroneal MNCV was not (P < 0.20). All ulnar MNCVs were in the normal range at the end of dialysis, but five of eight peroneal MNCVs remained less than normal (Fig. 3). Plasma magnesium values were usually elevated during the dialysis phase, whereas calcium ion activity was usually within the normal range (Table II). The changes in bio¬ chemical values during individual dialyses can be seen in Table III. After dialysis plasma ionic calcium activity in¬ creased and inorganic phosphorus concentration decreased (both on comparing group means and on paired /-testing) but total calcium and magnesium concentrations did not change significantly.
than
pfo 50
3./11 I...3
the
6/8
4/9
712
>12
Table II.Plasma total magnesium concentration and ionic calcium activity after measurement of motor nerve conduction
velocity
(MONTHS)
FIG. 2.Ulnar and peroneal MNCVs during stage II. Interpretation of numbers in bars and horizontal lines as in Fig. 1.
ULNAR
PERONEAL
n/s 70-
60-
50H
fb~U~X-
40 H
*Normal values:
Mg, 1.40 to 2.00 meq//; Ca2+, 2.00 to 2.50 meq//.
Table lll.Biochemical values* in
t;-*r*y
hemodialysis
plasma before and after
Variable
plT
30-1
Ca2+ activity
(meq//) (meq//) Mg (meq//)P Inorganic (mg/dl) Total protein
Total Ca -i.i.i.i.r.i.r-
-i.n.i.i
i
i
i
12 3 4 5 6 7 8 2 3 4 5 6 7 8 CASE NUMBER
FIG. 3.Change in MNCVs during eight individual dialyses. Base of arrow = predialysis value; tip of arrow = final postdialysis value. Interpretation of horizontal lines as in
Fig. 1.
(g/dl)_standard error of mean.
*Mean
fNS
=
±
not significant.
CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113 519
ful transplantation 2 of 11 patients had decreased values and in both, the serum creatinine concentration was less than 1.5 mg/dl. On the other hand, two MNCVs in two different patients were within the normal range while the patients' serum creatinine concentration was elevated (> 3 mg/dl). In the 15 patients who had repeated MNCV measurements after transplantation, both ulnar and peroneal values were higher in the last determination than in the first after transplantation (P K 0.01; paired t-test). In three of the patients the serum creatinine concentration was consistently greater than 1.5 mg/dl and in two of these, peroneal values remained decreased, whereas ulnar velocities were within the normal range. MNCVs in one patient during the three stages of chronic renal failure are shown in Fig. 5, which illustrates that peroneal velocity recovers slowly after successful transplantation. Plasma total magnesium values after renal transplantation were normal in 36 of 43 instances (Table II), in contrast to the elevation noted during earlier stages of renal failure. Plasma ionic calcium values were also predominantly in the normal range, as they had been in earlier stages.
Stewart.5 We believe, therefore, that in contrast to the situation with adults, serial measurements of MNCV in children have little predictive value in determining the need either to start dialysis or to increase the frequency and duration of individual dialyses. After transplantation we found that the MNCV improved but we could not substantiate a correlation between MNCV and serum creatinine concentration. Unlike adults, in whom there is a relatively rapid return to normal ulnar and peroneal MNCV,58'19 the children did not show significant improvement in mean peroneal MNCV until at least 3 years had elapsed after transplantation. Mean ulnar velocities became normal much sooner than peroneal after successful transplantation. We thank the nursing and technical staff of the dialysis unit of The Hospital for Sick Children for their interest and help, Mrs. J. Sheepers, RT for her skilful assistance in performing the chemical analyses, and the Muscular Dystrophy Association of Canada for providing funds for a summer studentship (for N.-A. Barnor) in 1971 and 1972. The study was supported in part by the Medical Research Council of Canada (grant MT 1797). References
Discussion This study showed that MNCV was decreased early and frequently in children with chronic renal failure. Peroneal velocities were depressed more often and more severely than ulnar velocities, in contrast to findings in adults, in whom the MNCV of each nerve studied decreased at a similar rate.'2 Furthermore, in children the peroneal MNCV was frequently reduced when the serum creatinine value was only mildly elevated. There was no correlation between serum creatinine concentration and the degree of depression of the MNCV. Thus, in children, in contrast to the findings in adults,'3 a lowering of the MNCV does not appear to correlate with the severity of the renal failure. Many studies in adults have shown that with long-term dialysis an improvement in the MNCV is evident after 1 year,14-'6 although other investigators have found deterioration of* peroneal MNCV during prolonged dialysis.17 Our results in children showed no significant changes in MNCV after long-term dialysis. However, after individual dialyses ulnar and occasionally peroneal MNCVs improved. This improvement was not related to changes in plasma magnesium concentration, as suggested by Fleming, Lenman and
PERONEAL MNCV
ULNAR MNCV
chronic renal insufficiency. JAMA 192: 1124, 1965
13. BLAGG CR, KEMBLE F, TAVERNER D: Nerve conduction velocity in relationship to the severity of renal disease. Nephron 5: 290, 1968 14. JEBSEN RH, TENCKHOFF HA, HONET JC: Natural history of uremic polyneuropathy and effects of dialysis. N Engi I Med 277: 327, 1967 15. CURTIS JR, EASTWOOD JB, SMITH EKM, et al: Maintenance haemodialysis. Q / Med 38: 49, 1969 16. CAMBI V, SvAzzI G, ARISI L, et al: Dialysis schedule and peripheral neuropathy in Proceedings of the European Dialysis an dTransplant Association 10th Congress, Vienna, Austria, 1973, edited by MOORHEAD, Pitman, 1973, pp 271-81 17. CODFISH SD, CRESS RH: Motor and sensory conduction in uremic patients undergoing repeated dialysis. Arch Phys Med Rehabil 52: 260, 1971
18. BOLTON CF, BALTZAN MA, BALTZAN RB: Effects of renal transplantation on uremic neuropathy. A clinical and electrophysiologic study.
*
*
rn/s
1. TYLER HR: Neurologic disorders in renal failure. Am J Med 44: 734, 1968 aspects of uraemic polyneuropathy. Nephron 8: 414, 1971 3. HONET JC, JEBSEN RH, TENCKHOFF HA, et al: Motor nerve conduction velocity in chronic renal insufficiency. Arch Phys Med Rehabal 47: 647, 1966 4. WATSON H: Subclinical polyneuropathy in renal insufficiency. Lancet 2: 731, 1964 5. FLEMING LW, LENMAN JAR, STEWART WK: Effect of magnesium on nerve conduction velocity during regular dialysis treatment. I Neurol Neurosurg Psychiatry 35: 342, 1972 6. McVIcAR M, GAUTHIER B, GOODMAN CT: Uremic neuropathy: monitoring of transketolase activity inhibition in a child. Am I Dis Child 125: 263, 1973 7. MARCUS J, EHELICH R, KELLY M, Ct al: Nerve conduction in childhood diabetes. Can Med Assoc 1 108: 1116, 1973 8. RADDE IC, HOFFKEN B, PARKINSON DK, et al: Practical aspects of a measurement technique for calcium ion activity in plasma. Clin Chem 17: 1002, 1971 9. MACINTYRE I: Flame photometry. Adv Clin Chem 4: 1, 1961 10. ALCOCK N, MACINTYRE I, RADDE I: The determination of magnesium in biological fluids and tissues by flame spectrophotometry. / Clin Pathol 13: 506, 1960 11. GOMORI G: A modification of the colorimetric phosphorus determination for use with the photoelectric colorimeter. I Lab Clin Med 27: 955, 1942 12. TENcKHOFF HA, BOEN FST, JERsEN RH, et al: Polyneuropathy in 2. JENNEKENS FGI, MEES EJD, VAN DEE MOST VAN SPIJK D: Clinical
N Engl I Med 284: 1170, 1971 transplantation on uraemic neuropathy. Lancet 2: 739, 1974
19. IsRAHIM MM, CROSLAND JM, HONIGSBERGER L, et al: Effect of renal
70
RENAL FAILURE
rn/s
60
so
70
1Ai.
[1
-
-
H MONTHS >5T 7/17 0 6
/8 2/15 0/11 0/11 7 13 24 36 12
40.1fl 1i.IL*i i 10/17 5/ /15 9/11 2/11 0 7 13- 25- >36 36 6 12 24 TRANSPLANTATION
FIG 4-Ulnar and peroneal MNCVs during stage III. Interpretation of numbers in bars and horizontal lines as in Fig 1 Asterisks indicate significant difference from means 0 to 6 months after transplantation 520 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
DIALYSIS BEFORE AFTER
1
.oI
0
AFTER TRANSPLANTATION 6 18 24 Months
.-----
-.
0
_________________ULNAR
50.1-. . 460
PERONEAL So-..-0.----..40 0
30 0
20 01'
FIG. 5-MNCVs in one patient during three stages of disease. Interpretation of horizontal lines as in Fig. 1.
Effect of chronic renal failure, dialysis and transplantation on motor nerve conduction velocity in children G.S. Arbus, md, frcp[c]; N.-A. Barnor, md; A.C. Hsu, mb, bs; E.G. Murphy, md, frcp[c]; I.C. Radde, md, ph d, frcp[c]
Summary: Ulnar and peroneal motor nerve conduction velocities (MNCVs) were measured in 47 children in a dialysis-transplantation program. Mean peroneal MNCV was significantly decreased from normal in children with mild renal failure (serum creatinine concentration, 1.5 to 2.9 mg/dl), whereas ulnar MNCV was significantly decreased only when the serum creatinine value was at least 9 mg/dl. Both ulnar and peroneal MNCVs remained unchanged during
long-term hemodialysis
or
peritoneal dialysis; however,
after individual dialyses ulnar MNCV increased. After renal transplantation ulnar MNCV returned to normal within a year and peroneal MNCV within 3 years. Before dialysis was required and during long-term dialysis most plasma magnesium values were elevated; ionized calcium activity was decreased in about 50% of determinations. After transplantation the concentration of divalent cations rapidly returned to normal. These children differed from adults studied in that (a) there was no correlation between severity of renal failure and MNCV, (b) long-term dialysis did not improve MNCV and (c) peroneal velocities did not recover for 3 years after transplantation. Resume: L'effet de I'insuffisance renale chronique, de la dialyse et de la transplantation sur la vitesse de conduction des nerfs moteurs chez I'enfant Chez 47 enfants soumis a un programme de dialyse-transplantation, la vitesse de conduction des nerfs moteurs (VCNM), soit le cubital et le peronier, a ete mesuree. La VCNM moyenne du peronier etait nettement diminuee, par rapport a sa valeur normale chez I'enfant, dans I'insuffisance renale benigne (concentration de la creatinine serique, de 1.5 a 2.9 mg/dl), tandis que la VCNM du cubital n'etait nettement diminuee que dans le cas ou la concentration serique du creatinine etait d'au moins 9 mg/dl. Par contre, la VCNM du cubital et du peronier est demeuree inchangee au cours d'hemodialyse ou de From the divisions of nephrology, neurology and endocrinology of the department of medicine, The Hospital for Sick Children, Toronto, and the department of pediatrics, University of Toronto A summary of this study was presented before the Canadian Paediatric Society, Qu6bec, June 1973. Reprint requests to: Dr. G.S. Arbus, The Hospital for Sick Children, 555 University Ave., Toronto, Ont. M5G 1X8
dialyse peritoneale a long terme, bien qu'on ait note une augmentation de la VCNM cubital apres des dialyses sporadiques. Apres transplantation renale la VCNM
cubital a ete normalisee dans un delai d'un an et la VCNM peronier en 3 ans. Avant que se soit imposee la dialyse et durant la periode de dialyse chronique, la majorite des valeurs de la magnesinemie etait anormalement elevee. L'activite du calcium ionise etait diminuee dans 50% des analyses. Apres transplantation la concentration des cations bivalents s'est normalisee rapidement. Par rapport aux adultes, ces enfants presentaient les differences suivantes: (a) il n'y avait aucune correlation entre la severite de I'insuffisance renale et le VCNM, (b) une dialyse a long terme n'a pas amelioree la VCNM et (c) la vitesse de la conduction du peronier ne s'est pas amelioree avant un delai de 3 ans apres la transplantation.
Peripheral neuropathy is common in patients with chronic renal failure.1,2 During early stages of failure nerve conduc¬ tion velocities can be reduced in the absence of any chemical or symptomatic abnormality.3,4 The contribution of various electrolyte abnormalities to the severity of the neuropathy remains controversial.5 All previous reports except one6 dealt with data from adults. With the establishment of a regular dialysis-trans¬ plantation program at The Hospital for Sick Children, Toronto, we studied motor nerve conduction velocity (MNCV) in children during three stages of chronic renal failure: stage 1, failure not requiring dialysis; stage II, failure requiring long-term dialysis; and stage III, after successful renal transplantation. Our aims were to determine the changes in MNCV through the stages of renal failure in children and to correlate MNCV with divalent cation status.
Patients and
procedures
Patients
Forty-seven patients, of mean age 12 years, were included in the study. Distribution by sex and diagnosis, and the number of patients tested during each stage are shown in CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113 517
patients measurements were done during the three stages of their disease and in 20, during two of the three stages. Clinical management The goal of the dialysis-transplantation program is trans¬ plantation in all patients, maintaining them on dialysis until they have a successfully functioning kidney transplant. Dialysis is usually begun when the patient's serum crea¬ tinine concentration is consistently greater than 10 mg/dl or the blood urea nitrogen (BUN) concentration is greater than 125 mg/dl. Occasionally our patients had complica¬ tions that necessitated their entering the dialysis program before these values were reached. When the dialysis-transplantation program began in 1967 hemodialysis was done once a week for approximately 8 hours. From 1971 all patients underwent hemodialysis at least twice a week for 6 to 8 hours each time (calcium concentration in the hemodialysis fluid, approximately 4.4 meq//; that of magnesium, approximately 1.0 meq//). Peri¬ toneal dialysis was performed for 24 to 48 hours per week with Dianeal (Baxter Laboratories of Canada Ltd.) (calcium concentration, 3.5 meq//; magnesium concentration, 1.5 meq//). Blood for cation determinations was usually drawn before dialysis, and MNCV measurements were performed always before dialysis and in five patients also at the end of dialysis. Before and during dialysis patients received various medi¬ cations depending on their clinical state, including antihy¬ pertensive drugs, aluminum hydroxide and calcium prepara¬ tions, and vitamin D and other vitamin supplements. Except in one patient, cadaver kidneys were transplanted. After transplantation patients were given prednisone (3 mg/kg»d); this dose was gradually reduced, so that at 3 to 6 months after successful renal transplantation the main¬ tenance dose was 10 to 25 mg q48h. All patients also re¬ ceived azathioprine (3 mg/kg«d) after transplantation unless the leukocyte count was less than 4 x 107/. For acute episodes of rejection additional corticosteroid therapy was given, either alone or in combination with cyclophospha¬ mide, actinomycin D or irradiation to the graft area. Antilymphocyte globulin was not used. Most patients needed antihypertensive medication for 3 to 6 months after trans¬ plantation; thereafter about 20% of the patients required continued antihypertensive therapy despite good renal func¬ tion. Usually dietary restriction was not needed after a successful kidney transplant but sodium intake was occa¬ sionally restricted if the patient was hypertensive. Table I. In 5
stimuli (150 V, 200 /xs) were given, and occasionally, to obtain a response, duration of the stimulus was increased to 500 or 1000 fis. The apparatus was modified to deliver not more than 150 V. Ulnar and peroneal MNCVs were usually determined in the right arm and leg unless previous trauma or infection made this impossible. The procedure was that described by Marcus and colleagues.7 Control values7 for ulnar and peroneal MNCVs were obtained from a group of 24 children who had recovered from minor head injuries, were of the same mean age as the study patients and had no peripheral or chronic central nervous system disorder and no history of renal abnormal¬ ity. Testing was done just before discharge from hospital. Blood was obtained usually after the MNCV measure¬ ment. Plasma ionic calcium activity was determined by the method of Radde and colleagues;8 total calcium and magne¬ sium concentrations were determined by emission and atomic absorption flame spectrophotometry,9'10 respectively; and inorganic phosphorus concentration was measured by the Gomori procedure,11 adapted to automatic analysis. Results
Stage I In 31 patients with chronic renal failure (serum creati¬ nine concentration, consistently > 1.5 mg/dl) 48 MNCV measurements were made while the patients were not yet on the dialysis program. Nine were examined repeatedly in this stage. The serum creatinine concentration varied from 1.5 to 22.8 mg/dl. Values for ulnar and peroneal MNCVs, arranged accord¬ ing to increasing serum creatinine concentration, and fre¬ quency of decreased MNCV are shown in Fig. 1. Even with relatively mild renal failure (i.e., serum creatinine concentration, 1.5 to 2.9 mg/dl) the mean peroneal MNCV was significantly lower than normal (P < 0.05). The mean ulnar MNCV was significantly lower than the normal mean only in patients with serum creatinine values of at least 9 mg/dl. Approximately one out of four ulnar MNCVs was reduced below the normal range. In contrast, about half the peroneal MNCVs were reduced. With increasing serum creatinine concentration or increasing duration of renal disease no further decrease in mean MNCV occurred. When repeated measurements in individual patients were examined by paired f-testing during stage I there was no
ULNAR MNCV
PERONEAL MNCV
Methods MNCVs were determined with the portable HewlettPackard electromyograph, model 1510 A. Supramaximal Table I.Distribution of 47 patients with chronic renal failure by sex and diagnosis, and number tested* during each stage No. of patients Female
Variable
Diagnosis
Chronic glomerulonephritis Chronic pyelonephritis Bilateral "small" kidneys Other
Stagef
(n 32) =
TrJnf
Male
(n 15) =
4/8 9/19 4/11 5/10
10 12 4 6
6.08.9
^9.0 CREATININE
31 (48) 20 (28) 27 (68)
II lll ?Number of observations for each stage in parentheses. fl, chronic renal failure not requiring dialysis; II, failure requiring long-term hemodialysisor peritoneal dialysis; lll, after successful renal transplantation.
518 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
JL£J_Liiiil_L£J_t££l-
1.52.9
3.05.9
6.08.9
^9.0
mg/dl
FIG. 1.Ulnar and peroneal motor nerve conduction velocities (MNCVs) during stage I. Numbers in bars indicate number of reduced MNCVs per total observations. Solid and interrupted horizontal lines indicate mean ± range of values for normal population (children). Asterisks indicate significant difference from normal mean.
evidence of significant deterioration of MNCV (P > 0.20). Most of the plasma magnesium values were elevated during this stage of the disease and a decrease in plasma calcium ion activity was detected in less than half the determinations (Table II). Only 1 of 30 plasma magnesium values exceeded 3 meq// and plasma calcium ion activity was significantly decreased « 1.80 meq//) only twice. The decrease in MNCV was not correlated with the severity of cation abnormality.
Stage II In 20 patients 28 MNCV measurements were made while the patients were in the dialysis stage. In five patients meas¬ urements of MNCV and plasma divalent cations were carried out before and after dialysis on eight occasions. In two other patients plasma for divalent cation estimations was obtained before and after dialysis but MNCV was measured only before dialysis. Mean MNCVs for these patients at the time of dialysis, according to time after start of the dialysis program, are shown in Fig. 2. No significant difference from normal in mean ulnar MNCV occurred with increasing time on dial¬ ysis, but the frequency of reduced ulnar MNCV decreased. Mean peroneal MNCVs were always significantly less than normal, but the decrease observed with increasing time on PERONEAL MNCV
ULNAR MNCV m/s 7060-
6/11 f;;;;;l
7>12 012 6 TIME ON DIALYSIS PROGRAM
III
In 27 children 68 MNCV measurements
were
made after
transplantation. For the first 6 months after transplantation decreased ulnar and peroneal MNCVs were observed in about half the patients and the mean values were signi¬ ficantly reduced from the normal means (ulnar, P < 0.05; peroneal, P < 0.001) (Fig. 4). Between 7 and 36 months only 3 of 34 ulnar MNCVs were still reduced and after 3 years all ulnar values were within the normal range. Mean peroneal MNCVs remained decreased much longer ulnar velocities. Until the end of the 3rd year than half the measurements were still below the normal range and mean values also differed significantly from normal means. Even more than 3 years after success-
30 H o6
Stage
mean
more
ii"""ii
40 H
3/8
dialysis program was not significant (P < 0.20); the frequency of reduced peroneal MNCV also did not change with the time the patient was in the program. Paired /-testing in individual patients likewise did not disclose any trend in MNCV with increasing duration of the dialysis program. Of the 28 ulnar MNCVs only 1 was outside the normal range, whereas 16 of 28 peroneal values were significantly below the normal range. When MNCV was compared before and after eight individual dialyses the increase in ulnar MNCV was highly significant (P < 0.01), whereas that of peroneal MNCV was not (P < 0.20). All ulnar MNCVs were in the normal range at the end of dialysis, but five of eight peroneal MNCVs remained less than normal (Fig. 3). Plasma magnesium values were usually elevated during the dialysis phase, whereas calcium ion activity was usually within the normal range (Table II). The changes in bio¬ chemical values during individual dialyses can be seen in Table III. After dialysis plasma ionic calcium activity in¬ creased and inorganic phosphorus concentration decreased (both on comparing group means and on paired /-testing) but total calcium and magnesium concentrations did not change significantly.
than
pfo 50
3./11 I...3
the
6/8
4/9
712
>12
Table II.Plasma total magnesium concentration and ionic calcium activity after measurement of motor nerve conduction
velocity
(MONTHS)
FIG. 2.Ulnar and peroneal MNCVs during stage II. Interpretation of numbers in bars and horizontal lines as in Fig. 1.
ULNAR
PERONEAL
n/s 70-
60-
50H
fb~U~X-
40 H
*Normal values:
Mg, 1.40 to 2.00 meq//; Ca2+, 2.00 to 2.50 meq//.
Table lll.Biochemical values* in
t;-*r*y
hemodialysis
plasma before and after
Variable
plT
30-1
Ca2+ activity
(meq//) (meq//) Mg (meq//)P Inorganic (mg/dl) Total protein
Total Ca -i.i.i.i.r.i.r-
-i.n.i.i
i
i
i
12 3 4 5 6 7 8 2 3 4 5 6 7 8 CASE NUMBER
FIG. 3.Change in MNCVs during eight individual dialyses. Base of arrow = predialysis value; tip of arrow = final postdialysis value. Interpretation of horizontal lines as in
Fig. 1.
(g/dl)_standard error of mean.
*Mean
fNS
=
±
not significant.
CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113 519
ful transplantation 2 of 11 patients had decreased values and in both, the serum creatinine concentration was less than 1.5 mg/dl. On the other hand, two MNCVs in two different patients were within the normal range while the patients' serum creatinine concentration was elevated (> 3 mg/dl). In the 15 patients who had repeated MNCV measurements after transplantation, both ulnar and peroneal values were higher in the last determination than in the first after transplantation (P K 0.01; paired t-test). In three of the patients the serum creatinine concentration was consistently greater than 1.5 mg/dl and in two of these, peroneal values remained decreased, whereas ulnar velocities were within the normal range. MNCVs in one patient during the three stages of chronic renal failure are shown in Fig. 5, which illustrates that peroneal velocity recovers slowly after successful transplantation. Plasma total magnesium values after renal transplantation were normal in 36 of 43 instances (Table II), in contrast to the elevation noted during earlier stages of renal failure. Plasma ionic calcium values were also predominantly in the normal range, as they had been in earlier stages.
Stewart.5 We believe, therefore, that in contrast to the situation with adults, serial measurements of MNCV in children have little predictive value in determining the need either to start dialysis or to increase the frequency and duration of individual dialyses. After transplantation we found that the MNCV improved but we could not substantiate a correlation between MNCV and serum creatinine concentration. Unlike adults, in whom there is a relatively rapid return to normal ulnar and peroneal MNCV,58'19 the children did not show significant improvement in mean peroneal MNCV until at least 3 years had elapsed after transplantation. Mean ulnar velocities became normal much sooner than peroneal after successful transplantation. We thank the nursing and technical staff of the dialysis unit of The Hospital for Sick Children for their interest and help, Mrs. J. Sheepers, RT for her skilful assistance in performing the chemical analyses, and the Muscular Dystrophy Association of Canada for providing funds for a summer studentship (for N.-A. Barnor) in 1971 and 1972. The study was supported in part by the Medical Research Council of Canada (grant MT 1797). References
Discussion This study showed that MNCV was decreased early and frequently in children with chronic renal failure. Peroneal velocities were depressed more often and more severely than ulnar velocities, in contrast to findings in adults, in whom the MNCV of each nerve studied decreased at a similar rate.'2 Furthermore, in children the peroneal MNCV was frequently reduced when the serum creatinine value was only mildly elevated. There was no correlation between serum creatinine concentration and the degree of depression of the MNCV. Thus, in children, in contrast to the findings in adults,'3 a lowering of the MNCV does not appear to correlate with the severity of the renal failure. Many studies in adults have shown that with long-term dialysis an improvement in the MNCV is evident after 1 year,14-'6 although other investigators have found deterioration of* peroneal MNCV during prolonged dialysis.17 Our results in children showed no significant changes in MNCV after long-term dialysis. However, after individual dialyses ulnar and occasionally peroneal MNCVs improved. This improvement was not related to changes in plasma magnesium concentration, as suggested by Fleming, Lenman and
PERONEAL MNCV
ULNAR MNCV
chronic renal insufficiency. JAMA 192: 1124, 1965
13. BLAGG CR, KEMBLE F, TAVERNER D: Nerve conduction velocity in relationship to the severity of renal disease. Nephron 5: 290, 1968 14. JEBSEN RH, TENCKHOFF HA, HONET JC: Natural history of uremic polyneuropathy and effects of dialysis. N Engi I Med 277: 327, 1967 15. CURTIS JR, EASTWOOD JB, SMITH EKM, et al: Maintenance haemodialysis. Q / Med 38: 49, 1969 16. CAMBI V, SvAzzI G, ARISI L, et al: Dialysis schedule and peripheral neuropathy in Proceedings of the European Dialysis an dTransplant Association 10th Congress, Vienna, Austria, 1973, edited by MOORHEAD, Pitman, 1973, pp 271-81 17. CODFISH SD, CRESS RH: Motor and sensory conduction in uremic patients undergoing repeated dialysis. Arch Phys Med Rehabil 52: 260, 1971
18. BOLTON CF, BALTZAN MA, BALTZAN RB: Effects of renal transplantation on uremic neuropathy. A clinical and electrophysiologic study.
*
*
rn/s
1. TYLER HR: Neurologic disorders in renal failure. Am J Med 44: 734, 1968 aspects of uraemic polyneuropathy. Nephron 8: 414, 1971 3. HONET JC, JEBSEN RH, TENCKHOFF HA, et al: Motor nerve conduction velocity in chronic renal insufficiency. Arch Phys Med Rehabal 47: 647, 1966 4. WATSON H: Subclinical polyneuropathy in renal insufficiency. Lancet 2: 731, 1964 5. FLEMING LW, LENMAN JAR, STEWART WK: Effect of magnesium on nerve conduction velocity during regular dialysis treatment. I Neurol Neurosurg Psychiatry 35: 342, 1972 6. McVIcAR M, GAUTHIER B, GOODMAN CT: Uremic neuropathy: monitoring of transketolase activity inhibition in a child. Am I Dis Child 125: 263, 1973 7. MARCUS J, EHELICH R, KELLY M, Ct al: Nerve conduction in childhood diabetes. Can Med Assoc 1 108: 1116, 1973 8. RADDE IC, HOFFKEN B, PARKINSON DK, et al: Practical aspects of a measurement technique for calcium ion activity in plasma. Clin Chem 17: 1002, 1971 9. MACINTYRE I: Flame photometry. Adv Clin Chem 4: 1, 1961 10. ALCOCK N, MACINTYRE I, RADDE I: The determination of magnesium in biological fluids and tissues by flame spectrophotometry. / Clin Pathol 13: 506, 1960 11. GOMORI G: A modification of the colorimetric phosphorus determination for use with the photoelectric colorimeter. I Lab Clin Med 27: 955, 1942 12. TENcKHOFF HA, BOEN FST, JERsEN RH, et al: Polyneuropathy in 2. JENNEKENS FGI, MEES EJD, VAN DEE MOST VAN SPIJK D: Clinical
N Engl I Med 284: 1170, 1971 transplantation on uraemic neuropathy. Lancet 2: 739, 1974
19. IsRAHIM MM, CROSLAND JM, HONIGSBERGER L, et al: Effect of renal
70
RENAL FAILURE
rn/s
60
so
70
1Ai.
[1
-
-
H MONTHS >5T 7/17 0 6
/8 2/15 0/11 0/11 7 13 24 36 12
40.1fl 1i.IL*i i 10/17 5/ /15 9/11 2/11 0 7 13- 25- >36 36 6 12 24 TRANSPLANTATION
FIG 4-Ulnar and peroneal MNCVs during stage III. Interpretation of numbers in bars and horizontal lines as in Fig 1 Asterisks indicate significant difference from means 0 to 6 months after transplantation 520 CMA JOURNAL/SEPTEMBER 20, 1975/VOL. 113
DIALYSIS BEFORE AFTER
1
.oI
0
AFTER TRANSPLANTATION 6 18 24 Months
.-----
-.
0
_________________ULNAR
50.1-. . 460
PERONEAL So-..-0.----..40 0
30 0
20 01'
FIG. 5-MNCVs in one patient during three stages of disease. Interpretation of horizontal lines as in Fig. 1.
