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Int J Pharm Biomed Res 2013, 4(1), 65-68
Research article
International Journal of
PHARMACEUTICAL
AND BIOMEDICAL
RESEARCH
ISSN No: 0976-0350
Efficacy of IV methylcobalamin and oral folic acid in the treatment of uremic
neuropathy in chronic haemodialysis patients
L.Venu Madhavi 1 *, D.Santha Rao 2 , T.Ushasree 1 , S.Ramesh 1
1 Department of Pharmacology, Gandhi Medical College, Secunderabad-500 003, Andhra Pradesh, India
2 Department of Biochemistry, Guntur Medical College, Kannavari Thota, Guntur-522 004, Andhra Pradesh, India
Received: 26 Feb 2013 / Revised: 04 Mar 2013 / Accepted: 06 Mar 2013 / Online publication: 23 Mar 2013
ABSTRACT
The aim of the present study was to assess the efficacy of methylcobalamin and folic acid for the treatment of uremic
neuropathy. The study was conducted on 35 chronic renal failure patients on maintenance haemodialysis. All the patients
were given 500µg of intravenous methylcobalamin thrice weekly after each dialysis session and 5mg of folic acid orally daily
for 6 months. The following points were noted at the start and at the end of the study–(i) Serum vitamin B 12 levels (ii) Serum
folic acid levels (iii) Neuropathic pain/paresthesia grading (Modified published criteria by Dyck et al) (iv) Neurological
disability score (v) Neurological symptom score (vi) Nerve conduction studies. High dose supplementation of
methylcobalamin and folic acid led to ultrahigh serum levels along with significant clinical and electrophysiological
improvement in neuropathy.
Key words: Folic acid, High dose, Improvement, Methylcobalamin, Nerve conduction studies, Uremic neuropathy
1. INTRODUCTION
Peripheral neuropathy became clearly established as a
complication of chronic renal failure in early 1960s, and it
was only then that any particular significance attached to the
association of neuropathy and renal disease. Neuropathy is
found in 65% of patients on or nearing dialysis when GFR
falls to 10% of normal. Uremic neuropathy is a distal
sensorimotor polyneuropathy caused by uremic toxins. The
severity of neuropathy is correlated strongly with the severity
of the renal insufficiency. Initially, sensory nerves are
involved more than motor nerves, the lower extremities more
than the upper and the distal portions of the extremities more
than the proximal. If dialysis is not initiated soon after the
onset of sensory abnormalities, motor involvement follows,
including loss of deep tendon reflexes, weakness, peroneal
nerve palsy (foot drop) and eventually, flaccid quadriplegia.
Available therapies for uremic neuropathy are not
satisfactory. Erythropoietin has showed improvement in
*Corresponding Author. Tel: +91 9666643383
Email: madhu2034@yahoo.co.in
Fax:
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motor nerve conduction velocity in predialysis patients.
Renal transplantation has had striking beneficial effects, but
the response to haemodialysis has been varied. Clinical signs
of neuropathy tend to persist or improve very slowly, and the
condition of some patients worsens in spite of an increase in
the frequency of dialysis or switching to a more efficient
dialyzer [1].
The aim of the present study is to find out the efficacy of
IV methylcobalamin and oral folic acid therapy in the
treatment of uremic neuropathy, which might prove to be a
new, safe, non-invasive, efficacious and economical
therapeutic option to uremic neuropathy patients.
2. MATERIALS AND METHODS
The present study was a prospective, open, interventional
study done on 35 chronic haemodialysis patients. Written
voluntary informed consent was taken from the participants
and the study was approved by the Institutional Ethics
Committee (XVIII IEC meeting held on 30/10/2010).
The inclusion criteria were patients aged 25-65 years of
either sex on maintenance haemodialysis for at least 2 years,
suffering from uremic neuropathy with normal serum

L.Venu Madhavi et al, Int J Pharm Biomed Res 2013, 4(1), 65-68 66
Vitamin B 12 and folic acid levels. Patients with diabetes,
sepsis, leprosy, HIV, dialysis related amyloidosis, peripheral
vascular disease, CVA, meningitis, encephalitis, chronic liver
disease, malabsorption syndromes were excluded.
Patients receiving maintenance haemodialysis with
polyneuropathy and serum B 12 and folic acid levels in the
normal range were selected based on a) Serum B 12 and folic
acid levels b) Clinical assessment of sensory and motor
neuropathy c) Neuropathic pain/paresthesia grading [2] d)
Neurological disability score [2] e) Neurological symptom
score [3] f) Nerve conduction studies [4].
Patients are given IV Methylcobalamin (500µg) 3 times a
week, after each haemodialysis along the dialysis line and
oral folic acid (5mg) daily for 6 months. At the end of 6
months, improvement in neuropathy is assessed by the above
mentioned criteria and serum vitamin B 12 and folic acid
levels were estimated. The blood samples are collected in
fasting state before initiation of dialysis. They are protected
from light and stored at 4-8°C, serum separated and analyzed
within 4 hrs of collection. (Reference ranges: Serum vitamin
B 12 : 200-835pg/mL, Serum folic acid: 3-20ng/mL) [5,6].
Data is analyzed by using Microsoft Excel Sheet and
Graph Pad Prism software, employing paired student t test.
Results are expressed as mean±SEM and p value < 0.05 is
considered significant.
28.57
20
%
71.43
Fig.2. Sex distribution
%
2.86
77.14
Fig.3. Duration of dialysis
males
females
2‐4 years
5‐7 years
8‐10 years
3. RESULTS
The mean age of the study sample is 45.6 (Fig.1) with
majority males (71.43%) (Fig.2). 54.3% of patients were
symptomatic. The mean duration of dialysis of study sample
is 3.24years (Fig.3).The causes for renal failure in the
patients is presented in Fig.4.
80
70
60
50
68.57
%
28.17
%
20
25‐35
36‐45
46‐55
40
30
20
10
0
20
8.57
2.86
Congenital Hypertension Renal TB Idiopathic
%
17.14
34.28
56‐65
Fig.4. Cause of renal failure
Fig.1. Age distribution
At the start of study, serum vitamin B 12 concentration
ranged from 365-932pg/mL (mean± SEM, 647.14±29.8) and
serum folic acid 14-28ng/mL (mean±SEM, 20.11±0.65) all
values being within normal range. Intravenous
methylcobalamin administration resulted in extremely high
serum vitamin B 12 concentrations (mean±SEM,
77194.4±2375.1, range: 51685-94460pg/mL). 6 months of
oral folic acid therapy resulted in extremely high serum folic
acid levels (mean±SEM, 4545.86±159.38), range: 3274-
6752ng/mL.
At entry, majority of patients had motor predominant
polyneuropathy. Lower limbs are affected more than upper
limbs and distal part of the extremities affected more than the
proximal part. The neuropathic symptom score (NSS)
showed significant decrease with 2.37±0.48 (mean±SEM) at
the start of the study to 0.83±0.29 at the end of the study
period of 6 months. The neuropathic pain grading (NPG)
scores also showed significant decrease from 1.08±1.17 to
0.28±0.45. Neurological disability scores (NDS) are only

L.Venu Madhavi et al, Int J Pharm Biomed Res 2013, 4(1), 65-68 67
Fig.5.Role of B12 and folic acid in DNA synthesis
Table 1
Scores before and after treatment
Before treatment
(Mean±SEM)
After treatment
(Mean±SEM)
P Value
NPG 1.08±0.2 0.28±0.08

L.Venu Madhavi et al, Int J Pharm Biomed Res 2013, 4(1), 65-68 68
administration of methylcobalamin suppressed the
spontaneous firing in the dorsal root that developed after
loading hypoxia.
Kuwabara et al [9] reported that ultrahigh dose of
intravenous methylcobalamin is a safe and potentially
beneficial therapy for neuropathy in chronic haemodialysis
patients. They elucidated that the lack of urinary excretion
likely accounts for the ultrahigh concentrations in uremic
patients and possibly for the positive effects on neuropathy.
They speculated that the accumulation of exogenous
methylcobalamin promotes nerve regeneration and
remyelination. Our study employing both methylcobalamin
and folic acid has shown similar results but with a greater
magnitude.
Koyama et al [10] concluded that in uremic patients, the
ability to detoxify cyanide is impaired and that this
impairment would be related to the development of uremic
neuropathy. Methylcobalamin is considered to be utilized in
cyanide detoxication process via cyanocobalamin synthesis
and its clinical use can result in favourable neurological
effects. Since large amount of methylcobalamin is required to
detoxify intracellular cyanide, intravenous methylcobalamin
is preferred to oral therapy.
Folic acid is vital for several metabolic reactions
involving one carbon units. Methylcobalamin, one of the
active coenzyme forms of Vitamin B 12 acts as a methyl donor
for the synthesis of lecithin, a major component of the myelin
sheath. It is also closely involved in folate metabolism which
is pivotal for the synthesis of purines and pyramidines and
therefore of DNA (Fig.5). Methylcobalamin acts as a cofactor
of the enzyme methionine synthase which functions to
transfer methyl groups for the generation of methionine from
homocysteine. Koyama et al [11] deduced that
methylcobalamin deficiency in uremic patients leads to
deterioration of the above said remethylation pathway and
high dose folic acid and methylcobalamin supplementation is
required for remethylation pathway to regain its normal
activity. The ultra-high concentrations of these vitamins upregulate
gene transcription [12,13] which may increase
protein synthesis for nerve regeneration. Since the metabolic
pathways of methylcobalamin and folic acid are
interdependent the combination therapy might prove to be
synergistic in the treatment of uremic neuropathy.
5. CONCLUSIONS
Uremic neuropathy is an important cause of morbidity
among patients undergoing chronic haemodialysis. The
current treatment protocol of administering vitamins,
analgesics and antiepileptics is of only modest value.
Although dialysis itself can provide symptomatic relief and
improvement in neuropathy, many patients improve very
slowly and a few worsen. The only definitive treatment
option is renal transplantation, which has its own limitations
like availability, cost, morbidity and mortality associated
with surgery. The results of the present study indicate that
high dose supplementation of methylcobalamin and folic acid
might prove to be an efficacious, economical and safe
therapeutic option and can improve the quality of life of
chronic haemodialysis patients.
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