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Klinische Abteilung für Nephrologie und
Dialyse, Universitätsklinik
für Innere Medizin III, Vienna,
Austria
Klinisches Institut für Medizinische und
Chemische Labordiagnostik, University of Vienna, Vienna, Austria
3. Medizinische Abteilung, Krankenhaus Lainz, Vienna, Austria
§
1. Medizinische Abteilung, Donauspital, Vienna, Austria
||
1. Medizinische Abteilung, Kaiser Franz Josef Spital, Vienna,
Austria.
Correspondence to Dr. Gere Sunder-Plassmann, Klinische Abteilung für Nephrologie und Dialyse, Universitätsklinik für Innere Medizin III, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: +43 1 40400 4391; Fax: +43 1 40400 4392; E-mail: Gere.Sunder-Plassmann{at}akh-wien.ac.at
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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T and 1298A C) had
no influence. Nevertheless, patients with the MTHFR 677TT genotype
more frequently attained normal total homocysteine plasma levels than patients
with the CC or CT genotype (P = 0.025). In response to 60 mg of folic
acid per day, TT genotype patients had lower folate plasma levels compared to
CC or CT genotype patients (P = 0.016). After completion of the 4-wk
treatment period with 30 or 60 mg of folic acid per day, there was a marked
rebound of total homocysteine plasma levels at the end of the follow-up in
patients with the MTHFR 677TT genotype, which even exceeded baseline
values in several patients (P = 0.0001). This study clearly
demonstrates that doses of 30 or 60 mg of folic acid per day are not more
effective than 15 mg/d in reducing hyperhomocysteinemia in regular
hemodialysis patients. Patients with the MTHFR 677TT genotype are
more likely to realize normal total homocysteine plasma levels. Folic acid at
30 or 60 mg/d but not 15 mg/d results in a rebound of total homocysteine
plasma concentrations when treatment is stopped. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T and 1298A C
of MTHFR modulate the response to high dose folic acid therapy. We
followed the patients for an additional 6 mo after treatment was stopped to
assess the long-term results of folic acid therapy. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on the assumption that the reference dose of folic acid (15 mg) can
reduce a mean total homocysteine plasma level of 24 µmol/L by 30% (8
µmol/L), our study had a power of 80% (
level of 0.05) to detect an
11 µmol/L reduction (45%) of total homocysteine plasma levels by the test
dose (30 or 60 mg of folic acid) with 50 patients in each treatment group.
The study protocol was approved by the review boards of each of the four
hospitals according to the Declaration of Helsinki and the Austrian Law on
Gene Technology. Two hundred and two regular hemodialysis patients were
eligible for the study, and all 150 patients who enrolled in the study gave
written informed consent. Randomization to treatment was performed according
to a blocked code generated by a computer at the Institute of Medical
Statistics at the University of Vienna. Capsules containing 15, 30, or 60 mg
of folic acid were manufactured at the pharmacy of the University Hospital of
Vienna under supervision of a pharmacist. Patients were consecutively assigned
to treatment at the four dialysis units. Both study physicians and patients
were blinded to the treatment code. The patients were instructed to bring back
the capsule container for compliance control at the end of the study. Patient
inclusion criteria were: a minimum age of 19 yr, maintenance on regular
hemodialysis treatment for at least 4 wk, and normal or elevated total
homocysteine plasma concentration. Exclusion criteria were: hemoglobin of
8 g/dl, the presence of megaloblastic anemia due to vitamin B12
deficiency without concomitant vitamin B12 therapy, and current
treatment with anticonvulsive agents. The majority of the patients were on
regular therapy with recombinant human erythropoietin and iron.
Study Protocol
Patients were randomly assigned to take 15, 30, or 60 mg of folic acid per
day for 4 wk (treatment period), and were followed for 6 mo after stopping
folic acid therapy (follow-up period) in an attempt to document the decline of
folate plasma levels and any increase in total homocysteine plasma
concentrations over time. Based on the study of Bostom et al.
(12), which showed that 8 wk
of folic acid therapy was not more effective than 4 wk, a 4-wk treatment
period was chosen. Predialysis blood samples for analysis of total
homocysteine, folate, and vitamin B12 plasma levels, as well as for
analysis of MTHFR 677C T and 1298A C genotypes, were
collected at baseline. Total homocysteine, folate, and vitamin B12
plasma levels were measured weekly during the 4-wk treatment period, and every
4 wk thereafter until completion of the 24-wk follow-up period. Potential side
effects of treatment were assessed by interview during each hemodialysis
session.
Biochemical Assays
Before the dialysis session, blood anticoagulated with citrate was drawn,
immediately placed on ice, and centrifuged within 30 min at 2000 x
g at 4°C (20 min). Plasma aliquots and 500 µl of citrated
blood for DNA isolation were snap-frozen and stored at -70°C.
Using the method originally described by Araki and Sako (16) as a basis for this study, total homocysteine (= free and protein-bound homocysteine-derived moieties in either sulfhydryl or disulfide form) plasma concentrations were determined by automated HPLC with reversed-phase separation and fluorescence detection. Hyperhomocysteinemia was defined as total homocysteine levels >15 µmol/L. Intraassay variability was 1.4 to 1.7% and interassay variability was 1.5 to 1.9%.
Folate (5-methyltetrahydrofolate) and vitamin B12 plasma levels were measured with a radioassay to allow for simultaneous determination of both vitamin concentrations in a single reaction tube (SimulTRAC — SNB; Becton Dickinson, Toronto, Ontario, Canada). Folate deficiency was defined as a plasma concentration of <3.4 nmol/L. Vitamin B12 deficiency was defined as a plasma concentration of <118 pmol/L.
Identification of the 677C T transition and the 1298A C
transversion in the MTHFR gene was performed according to Frosst
et al. (13) and
Weisberg et al. (15),
using restriction fragment length polymorphism analysis. According to the
coding sequence of MTHFR (GenBank accession no. U09806), the correct
positions of the two polymorphisms 677C T and 1298A C are 668C
T and 1289A C, respectively. However, we refer to the primarily
published nucleotide positions. The identification of the 677T allele is
possible by restriction enzyme cleavage of a 198-bp PCR product using
HinfI (13). The
presence of the mutation creates a HinfI recognition sequence that
leads to cleavage of the 198-bp product into fragments of 175 and 23 bp.
Therefore, heterozygous subjects show three fragments (198, 175, and 23 bp,
respectively), whereas individuals homozygous for the mutant T allele display
only the two fragments of 175 and 23 bp. The identification of the 1298A
C polymorphism was performed according to the protocol of Weisberg
et al. (15), because
it allows for the discrimination of the 1298A C polymorphism from a
silent 1317T C transition in the same exon, which is not the case using
the restriction enzyme MboII
(14). The PCR primers
published by Weisberg et al.
(15) generate a 138-bp PCR
fragment that is cleaved by the restriction enzyme Fnu4HI into 119-
and 19-bp fragments in the presence of the mutation.
Statistical Analyses
Descriptive statistics included mean values ± SD for continuous data
and percentages for categorical data. Mean values with 95% confidence
intervals (CI) are also expressed for the key end points of total homocysteine
and folate plasma levels.
For age, time on treatment, and the baseline values of total homocysteine
and folate plasma levels, a one-way ANOVA of the grouping variable doses was
performed to exclude potential differences between the three different dose
groups at baseline. Differences in gender and mode of dialysis treatment were
analyzed by 
2 test. Differences between the four study centers
were also assessed by ANOVA.
The effect of the 30- or 60-mg folic acid dose per day on total
homocysteine plasma concentrations compared to the standard dose of 15 mg/d
was analyzed using data from all 144 patients who completed the 4-wk treatment
period. Comparisons over time were performed by an ANOVA with repeated
measurements for 4 wk (time point 0, and weeks 1, 2, 3, and 4). This analysis
included the grouping variable MTHFR 677C T genotype (CC, CT,
TT), the regression variable doses (15, 30, or 60 mg of folic acid per day),
the interaction "doses x MTHFR 677C T," and
the values of the baseline total homocysteine plasma concentrations as
covariables (using the individual deviations from the median of the total
sample). A similar analysis was performed for the folate plasma concentrations
and for the grouping variable MTHFR 1298A C (AA, AC, CC).
For the follow-up period, an ANOVA with repeated measurements was performed
for the time points of weeks 4, 8, 12, 16, 20, 24, and 28 with the grouping
variable MTHFR 677C T (CC, CT, TT), the covariable doses (15,
30, or 60 mg/d), and the interaction term "doses x MTHFR
677C T." This analysis was performed for total homocysteine and
folate plasma levels for all 121 patients who completed the follow-up
period.
Comparison of the number of patients who had hyperhomocysteinemia at
baseline and who completed the 4-wk study period (n = 120) with
normal total homocysteine plasma concentrations (<15 µmol/L)
versus patients presenting with persistent hyperhomocysteinemia at
time point week 4, according to the MTHFR 677C T genotype (TT
genotype versus pooled CC and CT genotypes), was performed by
Mantel-Haenszel 2 test.
Comparison of the proportion of patients who had folate plasma levels of
<100 nmol/L at 4 wk after stopping folic acid therapy who were either
treated by low-flux dialysis or high-flux dialysis and hemodiafiltration was
performed by 2 test for each treatment group. All calculations
were performed using the statistical software package SAS (SAS Institute,
Inc., Cary, NC).
|
Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Demographic and Clinical Characteristics
Selected demographic and clinical parameters of the 148 patients who
underwent baseline testing are shown in
Table 1. Patient
characteristics and hemodialysis modalities according to the four
participating centers are given in Table
2. ANOVA revealed that there was no difference in baseline values
of total homocysteine and folate plasma levels between the three treatment
groups (Tables 3 and
4). There was also no
difference in age, gender, and time on treatment and number of patients
treated either by low-flux dialysis, high-flux dialysis, or hemodiafiltration
between the three treatment groups.
|
|
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|
Effect of High Dose Folic Acid Therapy on Total Homocysteine Plasma
Concentrations
Total homocysteine plasma concentrations declined rapidly within 1 wk of
high dose folic acid therapy and then remained stable in the majority of
patients throughout the rest of the treatment period
(Table 3). Total homocysteine
plasma concentrations of the 144 patients according to the three folic acid
dose groups are displayed in Figure
2.
|
One hundred and twenty of the 144 patients who completed folic acid therapy presented with hyperhomocysteinemia at baseline and had their total homocysteine plasma concentration reduced by an average of 32.8% (range, -82.9 to +26.4%) at the end of the treatment period. At week 4, 38 of these 120 patients (31.7%) had their total homocysteine plasma levels normalized. Nine patients (7.5%) had higher total homocysteine plasma concentrations compared to baseline. Four of these patients had folate plasma levels <1000 nmol/ml and were presumably noncompliant.
In contrast, 12 of 24 patients (50%) with normal total homocysteine plasma levels at baseline had even higher plasma levels at week 4. Two of these 12 presented with moderate hyperhomocysteinemia at this time point (mean reduction of total homocysteine plasma levels in all 24 patients by 2.2%; range, -36.0 to +43.2%). One of these patients had low folate plasma levels, indicating noncompliance with folic acid therapy.
Standard dose of 15 mg of folic acid per day resulted in a reduction of
mean total homocysteine plasma concentration by 32.8% (range, -82.8 to
+26.4%). However, there was no significant improvement in treatment efficacy
in patients treated with 30 mg (-29.9%; range, -69.6 to +43.2%) or 60 mg of
folic acid (-37.8%; range, -76.4 to +39.6%) per day (P = 0.1433 and
P = 0.2880 for both MTHFR polymorphism models). The
MTHFR 677C T and 1298A C polymorphisms had no influence
on treatment efficacy in this analysis (P = 0.980 and P =
0.2240, respectively). There also was no significant effect based on the
interaction "folic acid doses x MTHFR 677C T
genotype" or "folic acid doses x MTHFR 1298A
C genotype" (P = 0.123 and P = 0.922, respectively). A
highly significant independent predictor of the effect of folic acid therapy
on total homocysteine plasma concentrations was the total homocysteine plasma
level before treatment in both MTHFR genotype models (P =
0.0001 and P = 0.0001, respectively).
Effect of High Dose Folic Acid Therapy on Folate Plasma
Concentrations
Folate plasma concentrations increased rapidly with folic acid therapy and
remained high throughout the treatment period. The folate plasma levels of all
three patient groups are displayed in Table
4. The time course of folate plasma levels in the 144 patients who
completed the intervention period are shown in
Figure 2. There was a
significant difference in folate plasma levels in the three different dose
groups (P = 0.0001). Neither MTHFR 677C T nor
MTHFR 1298A C demonstrated an independent influence on folate
plasma levels. Baseline folate plasma levels did not influence the response to
folic acid therapy as measured by folate plasma levels in both MTHFR
models (P = 0.1378 and P = 0.1929, respectively).
Conversely, there was a significant interaction between "doses x
MTHFR 677C T" (P = 0.0163): We observed a
significant smaller increase of folate plasma levels in response to 60 mg of
folic acid per day in patients who were homozygous for the MTHFR 677C
T transition (TT genotype) compared with MTHFR 677CT or
MTHFR 677CC (Figure
3). This interaction was not significant for the other
MTHFR polymorphism ("doses x MTHFR 1298A
C", P = 0.1002).
|
Total Homocysteine Plasma Levels during the Follow-Up Period
The follow-up values of total homocysteine plasma levels of all patients
are given in Table 3.
Figure 4 shows the time course
of the total homocysteine plasma levels of the 121 patients who completed the
follow-up period. There was a significant increase in total homocysteine
plasma levels between week 12 and week 16 compared with total homocysteine
plasma levels after the 4-wk treatment period in all groups (P =
0.0002). The difference in increase of total homocysteine plasma levels
between the three folic acid dose groups was not significant (P =
0.0767). However, there was a significant interaction of "time x
doses" (P = 0.0001) and "time x doses x
MTHFR 677C T" (P = 0.0001), indicating a
dose-dependent rebound of total homocysteine plasma levels over time in the
various MTHFR 677C T genotypes. This effect is illustrated by
the more pronounced increase of total homocysteine plasma levels in patients
who had received 30 or 60 mg of folic acid per day during the treatment period
and who were homozygous for the MTHFR 677T allele (TT genotype). This
result of stopping high dose folic acid therapy is outlined in
Figure 5.
|
|
Folate Plasma Levels during the Follow-Up Period
Table 4 shows folate plasma
levels at baseline, during 4 wk of treatment, and during the follow-up period
for all patients. The time course of folate plasma levels of the 121 patients
who completed the 6-mo follow-up period is illustrated in
Figure 4. There was a rapid
decline in folate plasma levels at week 8 (4 wk after stopping high dose folic
acid therapy), and by the end of the study folate plasma levels nearly reached
baseline values (P = 0.0001). The folate plasma level at week 4
significantly influenced folate plasma levels in the follow-up period (the
higher the folate plasma level at week 4, the less the folate plasma levels
declined during follow-up; P = 0.0018) and a significant interaction
"time x folate plasma level at week 4" (P =
0.0373), but no effect of the daily folic acid dose on the posttreatment
behavior of folate plasma levels was found (P = 0.3119).
At week 8 the proportion of patients who reached plasma levels of <100 nmol/L was equal in the low-flux dialysis or high-flux dialysis/hemodiafiltration group in all three folic acid dose groups (Table 5).
|
MTHFR 677C T and Normalization of Total Homocysteine Plasma
Levels
Of 144 patients who completed the 4-wk treatment period, 120 patients had
total homocysteine plasma concentrations >15 µmol/L at baseline. These
patients were subdivided according to their MTHFR 677C T
alleles. Only 27 of 99 (27.3%) pooled MTHFR 677CC and CT genotype
patients had their total homocysteine plasma concentrations normalized at the
end of 4 wk of treatment. In contrast, 11 of 21 MTHFR 677TT genotype
patients (52.4%) with hyperhomocysteinemia at baseline had normal total
homocysteine plasma concentrations at the end of the treatment period
(P = 0.025).
Vitamin B12 Plasma Levels
Five of 148 patients had subnormal vitamin B12 plasma levels at
baseline (97 to 105 pmol/L), four of 144 patients had subnormal vitamin
B12 plasma levels at the end of the treatment period (91 to 115
pmol/L), and four of 121 patients had low vitamin B12 plasma levels
at the end of the follow-up (104 to 117 pmol/L). Because 42 patients at one
center received routine intravenous vitamin therapy including thiamin,
pyridoxine, and cobalamin, which resulted in supranormal vitamin
B12 plasma levels, we have not included these data in the analysis.
However, there was no significant change in mean vitamin B12 plasma
levels during folic acid therapy or follow-up in patients without intravenous
vitamin supplementation (data not shown).
Compliance
Capsule containers were returned at the end of the intervention period for
counting by 136 of the 144 hemodialysis patients (94.4%) who completed the
intervention period. Eight patients had lost the containers after the
intervention period. As estimated from counting capsules, average compliance
was 96%. Twenty of the returned containers held one to three, 12 contained
four to seven, and five contained more then seven capsules (eight to 15
capsules). Folate plasma levels were measured in all patients during the
intervention and during the follow-up. Mean folate plasma levels (from week 1
to week 4) remained <100 nmol/L in three patients, <500 nmol/L in four
patients, and <1000 nmol/L in four patients.
|
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Wilcken et al. (11) investigated the effect of 5 mg of folic acid per day on total free homocysteine (total non-protein-bound homocysteine) plasma concentrations in 21 predialysis patients. Only 10% of these patients presented with normal homocysteine plasma levels at the end of the study. A higher pretreatment homocysteine plasma level resulted in a better response to folic acid therapy. These findings are in line with the results of the present study, clearly demonstrating that the pretreatment total homocysteine plasma level is the most powerful predictor of the response to folic acid therapy.
Two separate studies of hemodialysis patients showed that 5 mg of folic acid per day lowered mean total homocysteine plasma concentrations by 32.9% from 32.6 ± 10.0 to 21.9 ± 6.9 (17) or 52.5% from 50.5 ± 14.3 to 24.0 ± 1.8 µmol/L (18), respectively. Dierkes et al. (19) treated 70 hemodialysis patients with 2.5 or 5 mg of folic acid three times weekly. The percentage of patients with normal predialysis total homocysteine plasma concentrations increased from 0 to 16%. Total homocysteine plasma levels after dialysis were normal in 50% of the patients before folate treatment. After folic acid therapy, 74% of the patients had normal postdialysis total homocysteine levels (19).
In the first placebo-controlled study of hyperhomocysteinemic end-stage renal failure patients, Bostom et al. (12) showed that multivitamin therapy resulted in a 25.8% reduction of total homocysteine plasma levels from 29.5 to 21.9 µmol/L within 8 wk. Only five of 15 patients treated with 15 mg of folic acid, 100 mg of vitamin B6, and 1 mg of vitamin B12 per day in addition to chronic low dose vitamin supplementation exhibited normalized total homocysteine plasma levels after 8 wk of treatment. There was no difference in total homocysteine plasma levels at week 4 compared to week 8 of folic acid and vitamin therapy (12).
Two other studies focused on the effect of up to 15 mg of folic acid per day on endothelial function in renal failure patients (20,21). In both studies, only a minority of patients had normal total homocysteine plasma levels after treatment. No beneficial effect of folic acid therapy on functional and blood-derived markers of blood vessel function was observed.
Therefore, the question arose as to whether higher doses of folic acid would be more effective. Our study clearly demonstrates that 30 or 60 mg of folic acid per day provides no additional benefit in lowering total homocysteine plasma levels compared to daily doses of 15 mg of folic acid in regular hemodialysis patients.
The effect of genetic variants of MTHFR on the response to folic
acid therapy was also analyzed. The enzyme 5,10-methylenetetrahydrofolate
reductase provides 5-methyltetrahydrofolate, which serves as methyl-donor in
the methylation reactions building methionine from homocysteine. Previous
studies have shown that a polymorphism in the MTHFR gene
(MTHFR 677C T) aggravates hyperhomocysteinemia in patients on
renal replacement therapy
(22,23,24).
Another polymorphism in this gene (MTHFR 1298A C) also has
recently been shown to influence total homocysteine plasma concentrations and
to be a risk factor for neural tube defects
(14,15).
In the present study, no independent influence of these MTHFR
polymorphisms on the response to folic acid treatment could be discerned.
Nevertheless, patients homozygous for the C to T transition at nucleotide
position 677 were more likely to normalize their total homocysteine plasma
concentrations than the pooled CC and CT genotype patients. This is in line
with the observation of Malinow et al.
(25), who reported that the
MTHFR 677C T transition has some influence on the response to
folic acid therapy in subjects without renal failure. Not unexpectedly, TT
genotype patients treated with 60 mg of folic acid per day had significantly
lower folate plasma levels during the treatment period than patients with the
CC or CT genotype. This effect in TT genotype patients is due to a decreased
intracellular formation of 5-methyltetrahydrofolate, the principal form of
folate in the plasma (26).
Another finding in our study that is of considerable importance is the rebound of total homocysteine plasma concentrations above baseline plasma levels when treatment was stopped in several patients with the TT genotype who received 30 or 60 mg of folic acid per day. One possible explanation for this phenomenon might be the presence of excess formylated tetrahydrofolates, which were recently shown to accumulate in red blood cells of healthy individuals with the MTHFR 677TT genotype (27). Based on these results, Bagley and Selhub (27) speculated that the formation of folate species other than 5-methyltetrahydrofolate may be partly responsible for the elevation of total homocysteine plasma concentrations in subjects with the MTHFR 677TT genotype due to effects on methylation reactions.
There may be also some influence of the dialysis method on folate levels, thus also influencing total homocysteine plasma concentrations. However, the proportion of patients whose plasma folate levels returned to <100 nmol/L at week 8 of this study (that is 4 wk after stopping high dose folic acid therapy) was not different in patients on low-flux dialysis compared with patients maintained on high-flux dialysis or hemodiafiltration within each folic acid dose group.
Folic acid in doses up to 60 mg/d was previously well tolerated from subjects without renal failure (28). Nevertheless, high dose folic acid therapy may lead to adverse events like allergic reactions or gastrointestinal symptoms. However, in our study we observed no major side effects during the treatment period, suggesting that high dose folic acid therapy can be well tolerated by renal failure patients.
A potential limitation in our study is that serum albumin and serum
creatinine, which are also predictors of total homocysteine plasma levels in
renal failure patients, have not been included in this analysis. Serum albumin
levels may have some influence on the response to folic acid therapy since
albumin may serve as a carrier protein for plasma folate. The importance of
serum creatinine is difficult to evaluate, particularly in patients undergoing
regular hemodialysis therapy. It can be argued that red blood cell folate is a
better indicator for folate status in hemodialysis patients compared with
plasma folate levels (29). Red
blood cell folates were not determined in our patients, but a recent study
failed to detect a change in red blood cell folates following treatment with
10 mg of folic acid per day in hemodialysis patients
(29). Another point of concern
is the potential influence of compound heterozygosity for the MTHFR
677T allele and the MTHFR 1298C allele, which was not analyzed in
this study. Because neither homozygosity for the MTHFR 677C T
transition nor the MTHFR 1298A C transversion showed an
independent influence on the overall response to folic acid therapy in the
present study, it is not likely that compound heterozygosity would have had an
important role in this particular setting.
Therapy with folic acid also may have some effect on the response to treatment with recombinant human erythropoietin (30). However, a subgroup analysis of 21 patients from one center who had stable hemoglobin levels and a constant erythropoietin and iron dose for at least 3 mo before folic acid therapy showed no change of hemoglobin level or need for erythropoietin dose adjustment during the 3 mo after high dose folic acid therapy (data not shown).
A potential beneficial effect of folic acid supplementation in renal failure patients is the normalization of the S-adenosylmethionine/S-adenosylhomocysteine ratio. Perna et al. (31) demonstrated convincingly that treatment with 5-methyltetrahydrofolate (the active form of folate) resulted in a more pronounced increase of S-adenosylmethionine than S-adenosylhomocysteine. The result was an increase of the S-adenosylmethionine/S-adenosylhomocysteine ratio, which likely indicated some improvement of methylation reactions in uremic subjects. 5-Methyltetrahydrofolate therapy (10 mg/d) also lowered the total homocysteine plasma levels substantially by 72.2% from 67.99 ± 14.89 to 18.87 ± 2.37 µmol/L in this study (31). Nine of the 14 patients had initial total homocysteine plasma levels >40 µmol/L. Five of 13 (38%) patients with hyperhomocysteinemia (>20 µmol/L) had their total homocysteine plasma levels normalized after treatment (31). We have not measured S-adenosylmethionine/S-adenosylhomocysteine ratios in our patients. Although Perna et al. (31) used 5-methyltetrahydrofolate in their study, this ratio also may have been improved in some of our patients on high dose folic acid therapy.
A possible cause for the limited response of elevated total homocysteine plasma concentrations to folic acid therapy in uremic subjects may be the accumulation of cysteinesulfinic acid (29). The hypothesis that a block in decarboxylation of cysteinesulfinic acid is linked to hyperhomocysteinemia in end-stage renal failure was raised after treatment with 15 mg of folic acid and 200 mg of pyridoxine per day for 4 wk, where cysteinesulfinic acid plasma levels remained unchanged in hemodialysis patients (29).
In summary, our study shows that high doses of 30 or 60 mg of folic acid per day have no more beneficial effect on total homocysteine plasma levels in hemodialysis patients than a dose of 15 mg/d. Patients with the MTHFR 677TT genotype are more likely to respond to folic acid therapy by normalizing their total homocysteine plasma levels than MTHFR 677CC and CT genotypes. TT genotype patients treated with 60 mg of folic acid per day had lower folate plasma levels during the treatment period compared with CC and CT patients. For those patients who were homozygous for the MTHFR 677T allele, high dose folic acid therapy resulted in a total homocysteine rebound when treatment was stopped. The consequences of such a rebound may be detrimental to the health of the patients. This study clearly demonstrates that hyperhomocysteinemia in end-stage renal disease patients cannot be cured solely by folic acid therapy regardless of the dose. Therefore, other therapeutic strategies need to be developed to combat the risk associated with atherosclerosis and cardiovascular disease.
|
Acknowledgments |
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Footnotes |
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Journal of the American Society of Nephrology
|
References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
T on plasma total homocysteine levels in renal
graft recipients. Kidney Int55
: 1072-1080,1999[Medline]
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 A. Scholze, C. Rinder, J. Beige, R. Riezler, W. Zidek, and M. Tepel Acetylcysteine Reduces Plasma Homocysteine Concentration and Improves Pulse Pressure and Endothelial Function in Patients With End-Stage Renal Failure Circulation, January 27, 2004; 109(3): 369 - 374. [Abstract] [Full Text] [PDF]
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H. Refsum, A. D. Smith, P. M. Ueland, E. Nexo, R. Clarke, J. McPartlin, C. Johnston, F. Engbaek, J. Schneede, C. McPartlin, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion Clin. Chem., January 1, 2004; 50(1): 3 - 32. [Abstract] [Full Text] [PDF]
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 A. Y.-M. Wang, M. M.-M. Sea, R. Ip, M. C. Law, K. M. Chow, S. F. Lui, P. K.-T. Li, and J. Woo Independent effects of residual renal function and dialysis adequacy on dietary micronutrient intakes in patients receiving continuous ambulatory peritoneal dialysis Am. J. Clinical Nutrition, September 1, 2002; 76(3): 569 - 576. [Abstract] [Full Text] [PDF]
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G. Buccianti, S. Raselli, I. Baragetti, F. Bamonti, E. Corghi, C. Novembrino, C. Patrosso, F. M. Maggi, and A. L. Catapano 5-methyltetrahydrofolate restores endothelial function in uraemic patients on convective haemodialysis Nephrol. Dial. Transplant., May 1, 2002; 17(5): 857 - 864. [Abstract] [Full Text] [PDF]
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D. Ducloux, A. Aboubakr, G. Motte, G. Toubin, V. Fournier, J.-M. Chalopin, T. Drueke, and Z. A. Massy Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12 Nephrol. Dial. Transplant., May 1, 2002; 17(5): 865 - 870. [Abstract] [Full Text] [PDF]
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K. Koyama, T. Usami, O. Takeuchi, K. Morozumi, and G. Kimura Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation Nephrol. Dial. Transplant., May 1, 2002; 17(5): 916 - 922. [Abstract] [Full Text] [PDF]
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F. Locatelli, D. Fouque, O. Heimburger, T. B. Drueke, J. B. Cannata-Andia, W. H. Horl, and E. Ritz Nutritional status in dialysis patients: a European consensus Nephrol. Dial. Transplant., April 1, 2002; 17(4): 563 - 572. [Abstract] [Full Text] [PDF]
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S. Billion, B. Tribout, E. Cadet, C. Queinnec, J. Rochette, P. Wheatley, and P. Bataille Hyperhomocysteinaemia, folate and vitamin B12 in unsupplemented haemodialysis patients: effect of oral therapy with folic acid and vitamin B12 Nephrol. Dial. Transplant., March 1, 2002; 17(3): 455 - 461. [Abstract] [Full Text] [PDF]
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 A. N. FRIEDMAN, A. G. BOSTOM, J. SELHUB, A. S. LEVEY, and I. H. ROSENBERG The Kidney and Homocysteine Metabolism J. Am. Soc. Nephrol., October 1, 2001; 12(10): 2181 - 2189. [Abstract] [Full Text] [PDF]
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K. Bennett-Richards, M. Kattenhorn, A. Donald, G. Oakley, Z. Varghese, L. Rees, and J.E. Deanfield Does Oral Folic Acid Lower Total Homocysteine Levels and Improve Endothelial Function in Children With Chronic Renal Failure? Circulation, April 16, 2002; 105(15): 1810 - 1815. [Abstract] [Full Text] [PDF]
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