Article

Folic Acid Therapy and Cardiovascular Disease in

ESRD or Advanced Chronic Kidney Disease: A Meta-
Analysis *Institute of Biomedicine,
Anhui Medical
University, Hefei, China;

Department of
Xianhui Qin,* Yong Huo, Craig B. Langman, Fanfan Hou, Yundai Chen, Debora Matossian, Xiping Xu, and Cardiology and Heart
Xiaobin Wang** Center, Peking University
First Hospital, Beijing,
China; Division of
Summary Kidney Diseases,
Background and objectives The efficacy of folic acid therapy to lower homocysteine (Hcy) levels in an effort Childrens Memorial
Hospital, Northwestern
to reduce cardiovascular disease (CVD) risk in patients with ESRD or advanced chronic kidney disease University Feinberg
(ACKD; creatinine clearance, 30 ml/min) remains inconclusive. We conducted a meta-analysis of relevant School of Medicine,
randomized trials to further examine this issue. Chicago, Illinois;

Division of Nephrology,
Nanfang Hospital,
Design, setting, participants, & measurements This meta-analysis included 3886 patients with ESRD/ACKD Southern Medical
University, Guangzhou,
from seven qualified randomized trials using folic acid therapy and with CVD reported as one of the end China; Department of
points. Cardiology, Peoples
Liberation Army General
Hospital, Beijing, China;
Results When pooling the seven trials, folic acid therapy reduced the risk of CVD by 15% (RR, 0.85; 95% CI,
Division of
0.76 to 0.96; P 0.009). A greater beneficial effect was observed among those trials with a treatment dura- Epidemiology and
Biostatistics, University of
tion 24 months (RR, 0.84; 95% CI, 0.72 to 0.98; P 0.02), a decrease in Hcy level 20% (RR, 0.83; 95% CI, Illinois at Chicago School
0.73 to 0.95; P 0.007), and no or partial folic acid fortification (RR, 0.80; 95% CI, 0.65 to 0.99; P 0.04). of Public Health,
The beneficial effect also was seen when Hcy levels decreased 20%, even in the presence of folic acid for- Chicago, Illinois; and
**Mary Ann and J.
tification (RR, 0.85; 95% CI, 0.73 to 0.99; P 0.04). In the corresponding comparison groups, the estimated Milburn Smith Child
RRs were attenuated and insignificant. Health Research
Program, Department of
Pediatrics, Northwestern
Conclusions Folic acid therapy can reduce CVD risk in patients with ESRD/ACKD by 15%. A greater bene- University Feinberg
ficial effect was observed among those trials with no or partial folic acid fortification or a decrease in Hcy School of Medicine and
Childrens Memorial
level 20% regardless of folic acid fortification. Hospital and Childrens
Clin J Am Soc Nephrol 6: 482 488, 2011. doi: 10.2215/CJN.05310610 Memorial Research
Center, Chicago, Illinois

Correspondence: Dr.
Introduction vascular morbidity and mortality in patients with Xiaobin Wang, Mary
People with chronic kidney disease (CKD) have a ESRD (1,5). Ann and J. Milburn
markedly elevated risk for cardiovascular disease However, the question as to whether Hcy-lowering Smith Child Health
Research Program,
(CVD) (1,2) when compared with the general popu- therapy can reduce CVD risk in patients with ESRD or Childrens Memorial
lation. For example, approximately 50% of patients advanced chronic kidney disease (ACKD) remains to Hospital and Childrens
with ESRD die from a CVD cause, and CVD mortality be answered. Their characteristically high Hcy levels, Memorial Research
Center, Northwestern
for patients with ESRD is 15 to 30 times higher than extensive vascular disease, and high mortality rates
University Feinberg
the age-adjusted CVD mortality in the general popu- make the ESRD/ACKD population particularly suit- School of Medicine,
lation (3). Thus, prevention and treatment of CVD are able for testing the benefit of Hcy-lowering therapy. 2300 Childrens Plaza,
major considerations in the management of individ- In light of the growing number of published trials, Box 157, Chicago, IL
60614-3394. Phone:
uals with CKD (1). each of which by itself is lacking sufficient sample size 312-573-7738; Fax:
Many potential causes may contribute to the ele- and power, a comprehensive meta-analysis of all of 312-573-7825; E-mail:
vated risk of CVD in patients with CKD. Traditional the available data is warranted to further examine xbwang@
cardiovascular risk factors only partially account whether folic acid therapy has a beneficial effect on childrensmemorial.org

for this increased CVD morbidity and mortality (3).
As such, identification of other significant and
treatable risk factors is critical to reduce the excess
burden of CVD morbidity and mortality in patients
with CKD (4). Homocysteine (Hcy) is of consider-
able interest because hyperhomocysteinaemia is
highly prevalent and significantly related to cardio-
CVD risk in ESRD/ACKD patients.
A meta-analysis by Heinz et al. (5) included three
folic acid trials (one not randomized) in patients un-
dergoing maintenance dialysis. This meta-analysis in-
cluded all of the pertinent published trials up to Au-
gust 2010 and aimed to assess the relationship
between folic acid therapy (with or without vitamin

482 Copyright 2011 by the American Society of Nephrology www.cjasn.org Vol 6 March, 2011
Clin J Am Soc Nephrol 6: 482 488, March, 2011
B6 and B12) and the risk of CVD in ESRD/ACKD. We are
particularly interested in whether the effect of folic acid
therapy on CVD is affected by the factors that could influ-
ence the treatment effects and whether there are subgroups
that might particularly benefit from folic acid therapy.
Materials and Methods
Search Strategy and Selection Criteria
We attempted to conform to QUOROM (Quality of Re-
porting of Meta-analyses) guidelines in the report of this
meta-analysis (6). To select pertinent studies, we per-
formed a comprehensive and independent literature
search of the Medline database from January 1966 to Au-
gust 2010, with the MESH terms cardiovascular disease,
cerebrovascular accident, coronary disease, coronary
thrombosis, myocardial ischemia, coronary stenosis, Role of the Funding Source
coronary restenosis, cerebrovascular accident, cere- There was no funding source for this study. The research
brovascular disease, stroke and folic acid, folate, team had full access to all of the data used for this meta-
multivitamin, chronic kidney disease, end-stage re- analysis and had final responsibility for publication. All of
nal disease, advanced chronic kidney disease, and di- the authors have seen and approved the final version of the
alysis. Manual searches of the bibliographies of all of the
relevant trials and review articles were also conducted. The
search was restricted to human studies and clinical trials.
There were no language restrictions. A team of experts in
the relevant disciplines was assembled.
A standard protocol for study selection and data ab-
straction was developed by our multidisciplinary team
with expertise in clinical medicine, epidemiology, clini-
cal trials, and biostatistics. Studies were eligible for in-
clusion if: (1) the study was a randomized controlled
trial; (2) the number of cardiovascular events that oc-
curred during the study were reported by intervention
and control groups; and (3) the intervention consisted of
folic acid therapy (with or without additional B vita-
mins). To minimize clinical heterogeneity, this meta-
analysis was limited to patients with ESRD/ACKD (cre-
atinine clearance, 30 ml/min). Further elaboration on
this point can be found in the Discussion.
Data Collection
Of the 49 studies potentially eligible, each of the ab-
stracts was reviewed independently by two investigators
to determine whether it met the eligibility criteria for in-
clusion. All of the data from the eligible trials were inde-
pendently abstracted in duplicate by two independent in-
vestigators using the standard protocol. Discrepancies
were resolved by discussion with the third investigator
and the multi-disciplinary team who developed the proto-
col.
Primary and Secondary Outcome
The primary outcome was the occurrence of all of the
fatal or nonfatal cardiovascular events (CVD events in each
trial are presented in Table 2). The secondary outcome was
a composite of nonfatal myocardial infarction, nonfatal
stroke, or death from cardiovascular cause (such data were
available from five of the seven trials).
Statistical Analyses
Relative risk (RR) with a 95% confidence interval (CI)
was used as a measure of the effect of folic acid therapy
Folic Acid Therapy and CVD, Qin et al. 483
on CVD risk. Although both fixed-effect and random-
effect models yielded similar findings, results from the
random-effect models are presented herein because of
the different intervention regimens, intervention dura-
tions, and dietary intakes of folic acid that were involved
in the original trials. Furthermore, many investigators
consider the random-effect approach to be a more nat-
ural choice than the fixed-effect in contexts of medical
decision making (7,8). Heterogeneity between studies
was assessed by Cochrans Q with a significance level set
at 0.10. We also conducted a sensitivity analysis by
removing each individual trial from the meta-analysis.
All of the analyses were performed using STATA ver-
sion 10.0 (StataCorp, College Station, TX).
manuscript.
Results
Figure 1 depicts the flow of the study selection process.
Of the 49 potentially relevant reports identified and
screened, 40 were excluded by review of abstracts because
they were not randomized controlled trials (RCTs) or had
no cardiovascular disease outcomes. For example, the re-
port by Mann et al. (9) was a post hoc analysis of a sub-
sample of a parent RCT (HOPE-2) and thus was excluded.
Of the nine trials retrieved for detailed evaluations, two
(10,11) were further excluded because the subjects were not
ESRD or ACKD. Our final analysis included seven RCTs
(1218) comprising a total of 3886 subjects with ESRD or
ACKD.
The characteristics of the study participants and design fea-
tures of each trial are presented in Tables 1 and 2, respectively.
Of the seven trials, two (16,18) were conducted in the
United States and Canada, three (12,13,17) were in Euro-
pean countries, one (14) was in Australia and New Zea-
land, and one (15) was in Brazil.
As shown in Figure 2, pooling the seven trials, folic acid
therapy (with or without other B vitamins) significantly
reduced the risk of primary CVD outcome by 15% (RR,
0.85; 95% CI, 0.76 to 0.96; P 0.009). Table 3 presents the
Figure 1. | Study selection.
484 Clinical Journal of the American Society of Nephrology

RRs stratified by duration of folic acid supplementation

Change in Hcy

Treatment (%)
(24 versus 24 months); degree of Hcy lowering (20%
versus 20%), prior folic acid fortification (yes, no/partly),

during

52.0
10.9
40.6
17.4
55.3
25.1
30.0
treatment regimen (folic acid alone versus folic acid plus
vitamin B6 and B12), mean daily folic acid dose (5 mg
versus 5 mg), and pre-existing renal conditions (ESRD
versus ESRD/ACKD). A greater beneficial effect was ob-
served among those trials with a treatment duration of 24
(SD) (mol/L)

months (RR, 0.84; 95% CI, 0.72 to 0.98; P 0.02); a decrease

Median 25.0

Median 29.0
Hcy, Mean

32.9 (20.0)

27 (13.0)
in Hcy level 20% (RR, 0.83; 95% CI, 0.73 to 0.95; P
50.3 (6.0)

35.0 (1.4)

24.1 (8.8)
0.007); and no/partial folic acid fortification (RR, 0.80; 95%
CI, 0.65 to 0.99; P 0.04). The beneficial effect also was
seen when Hcy lowering was 20% even in the presence of
folic acid fortification/supplement (RR, 0.85; 95% CI, 0.73
to 0.99; P 0.04). In the corresponding comparison groups,
the estimated RRs were attenuated and insignificant. The
Median 189.2
Cholesterol,

198.7 (90.0)
183.8 (44.0)
196.0 (78.8)
200.8 (46.3)
182.5 (35.9)
166.6 (43.9)
Mean (SD)

stratified analysis by treatment regimen, mean daily folic

(mg/ml)
Total

acid dose, and pre-existing renal conditions showed a sim-

ilar beneficial effect across the strata.
We conducted heterogeneity testing for all of the anal-
yses in Table 3. All of the resultant P values were larger
than 0.10, meaning that heterogeneity is NS in either the
overall analysis or in the stratified analyses. Sensitivity
Diabetes

analyses showed that the RRs and 95% CI were not

13.6
45.5
19.3
23.2
22.6

40.0
55

altered substantially by removing any one of the seven

trials (data not shown).
As presented in Table 4, we performed an additional
Table 1. Baseline characteristics and change in Hcy during treatment of individual trials (total n 3886)

of CVD
History

analysis of pooling five trials with available data on sec-

34.6
34.1
58.0
35.0
23.7

48.0
NR

ondary CVD outcome (a composite of nonfatal myocardial

infarction, nonfatal stroke, or death from cardiovascular
cause). Consistently, we found that folic acid therapy (with
or without other B vitamins) reduced the risk of secondary
ESRDorACKDb
ESRDorACKDa

ACKD serum creatinine of 0.40 mmol/L or greater (creatinine clearance, 25 ml/min).

CVD end points by 13 to 14%.

Pre-existing
Diseases

ACKD with an estimated creatinine clearance of less than or equal to 30 ml/min.

Discussion
ESRD
ESRD
ESRD

ESRD

ESRD

A recent meta-analysis concluded that the total Hcy level may

be a risk factor for CVD events and total mortality in patients
with ESRD not receiving vitamin supplementation or folic acid
fortification (5). However, randomized clinical trials have not
Male

55.7
50.0
56.0
68.0
59.1
98.0
58.0

been able to demonstrate a convincing beneficial effect of folic

acid therapy on CVD (1218) in ESRD/ACKD. Our power
analysis demonstrated that each of the individual trials did not
Age, Mean (SD)

have sufficient power to discern a 15% reduction in CVD risk

64.0 (14.0)
60.2 (15.1)
64.3 (11.7)
56.0 (13.5)
48.5 (12.9)
65.8 (11.8)
61.0 (13.0)

(data not shown). This meta-analysis, by pooling seven random-

(years)

ized controlled trials (1218) comprising a total of 3886 subjects

with ESRD or ACKD, achieved greater statistical power to reach
a valid conclusion. More importantly, our meta-analysis exam-
ined factors that could have contributed to the inconsistent or
null findings from previously published trials and provided
Subjects

new insight on the efficacy and causality of folic acid therapy on

Total

81
510
88
315
186
2056
650

CVD risk in patients with ESRD/ACKD.

Of note, in discussing our findings, one must keep in mind
that meta-analysis has inherent limitations, including its retro-
spective and aggregate nature and its inability to adjust for
Zoungas et al. (14)

Jamison et al. (16)

Righetti et al. (12)

Righetti et al. (13)

Vianna et al. (15)

individual variables. The sample size of the trials included in this

Wrone et al. (18)

NR, not reported.

Heinz et al. (17)
Data Source

analysis varied, and the results were more likely influenced by

the trials with larger sample sizes. However, we performed
sensitivity testing and found that removing any single trial did
not significantly alter our results. Furthermore, our testing of
heterogeneity between studies did not demonstrate a significant
b
a

difference. Publication bias is an important issue for meta-anal-

Table 2. Study design characteristics of individual trials

Duration of Funding
Data Source Blinding Active Treatment Control CVD Events Fortification Intervention Sources
(months)

Righetti Open Folic acid 5 or 15 mg/d Usual care Angina, MI, carotid No 12 Not listed
et al. (12) artery stenoses,
Clin J Am Soc Nephrol 6: 482 488, March, 2011

thrombotic stroke
Wrone Double Folic acid 5 or 15 mg/d Folic acid 1 mg/d MI, revascularization, Yesa 24 Public,
et al. (18) and vitamins B6 and and vitamins B6 stroke corporate
B12 and B12
Righetti Open Folic acid 5 mg/d or 5 Vitamins B6 and MI, stroke, angina, No 29 Not listed
et al. (13) mg every other day B12 sudden cardiac arrest,
and vitamins B6 and cerebrovascular TIA
B12
Zoungas Double Folic acid 15 mg/d Placebo MI, stroke, angina, Partly 43 Public,
et al. (14) revascularization, foundation
peripheral vascular
disease
Vianna Double Folic acid 10 mg, 3 Placebo Nonfatal/fatal No 24 Foundation
et al. (15) times/wk cardiovascular event
Jamison Double Folic acid 40 mg/d and Placebo MI, stroke Yes 38 Public,
et al. (16) vitamins B6 and B12 corporate
Heinz Double Folic acid 5 mg, 3 Folic acid 0.2 mg/d MI, stroke, angina, Yesa 24 Public,
et al. (17) times/wk and and vitamins B6 revascularization, corporate
vitamins B6 and B12 and B12 sudden cardiac arrest,
peripheral vascular
disease, pulmonary
embolism, thromboses

MI, myocardial infarction; TIA, transient ischemic attack.

a
Folic acid supplement in control group.
Folic Acid Therapy and CVD, Qin et al. 485
 486 Clinical Journal of the American Society of Nephrology

Figure 2. | Forest plot of RR and 95% CI of primary cardiovascular outcome for folic acid treatment versus control in individual trial and
pooled data.

Table 3. Risk estimates of primary cardiovascular outcome for folic acid intervention versus control in pooled and stratified analysis by
pertinent factors

Primary CVD Events/

Total Subjects
Stratification Variables RR 95% CI P
Active Control

Overall (1218) 391/2038 431/1848 0.85 0.76, 0.96 0.009

Intervention duration
24 months (12,15,17,18) 164/813 155/614 0.88 0.72, 1.06 0.17
24 months (13,14,16) 227/1225 276/1234 0.84 0.72, 0.98 0.02
Hcy lowering
20% (14,18) 86/498 69/327 0.99 0.66, 1.48 0.95
20% (12,13,1517) 305/1540 362/1521 0.83 0.73, 0.95 0.007
Folic acid fortification
yes (1618) 291/1701 305/1515 0.88 0.76, 1.02 0.10
yes and Hcy lowering 20% (16,17) 249/1359 289/1347 0.85 0.73, 0.99 0.04
no or partly (1215) 100/337 126/333 0.80 0.65, 0.99 0.04
Treatment regimen
folic acid only (12,14,15) 83/300 94/282 0.83 0.65, 1.06 0.14
folic acid and vitamins B6 and B12 308/1738 337/1566 0.86 0.75, 0.99 0.03
(13,1618)
Daily folic acid dose
5 mg (13,15,17) 126/457 160/467 0.82 0.68, 0.99 0.04
5 mg (12,14,16,18) 265/1581 271/1381 0.88 0.75, 1.02 0.09
Pre-existing conditions
ESRD (12,13,15,17,18) 181/850 187/665 0.85 0.71, 1.01 0.06
ESRD/ACKD (14,16) 210/1188 244/1183 0.86 0.73, 1.01 0.07

ysis, in which positive results are more likely to be published,
and as such, meta-analysis may overestimate the true effect or
association. However, because of the highly controversial nature
of this topic, the published trials so far have ranged from posi-
tive findings to no effect and/or negative findings. These trials
varied in quality according to treatment assignment procedure,
adherence and follow-up, and statistical analysis (data not
shown), but sensitivity analyses showed that the RRs and 95%
CI were not altered substantially by removing any of the trials.
Finally, our meta-analysis included trials in patients with ESRD
and ESRD/ACDK. These two groups of patients appear to have
comparable effects of folic acid treatment on CVD outcome. Our
finding is consistent with other published reports (HOST study
[16] and Jungers et al. [19]). The generalizability of our findings
to other chronic renal conditions remains to be determined.
Who Can Particularly Benefit from Folic Acid Therapy?
The question remains whether there is a subgroup of
patients with ESRD/ACKD who can particularly benefit
from folic acid therapy. Our meta-analysis showed that, on
Clin J Am Soc Nephrol 6: 482 488, March, 2011
Table 4. Risk estimates of secondary cardiovascular outcome for folic acid intervention versus control in individual trial and pooled
data
Secondary CVD Events/Total
Subjects
Data Source
Active
Wrone et al. (18) 28/342
Righetti et al. (13) 6/37
Zoungas et al. (14) 46/156
Heinz et al. (17) 53/327
Jamison et al. (16) 166/1032
Overall (13,14,1618) 299/1894
Overall (13,14,16,17)a 271/1552
a
Wrone et al. was excluded because the control group was given folic acid 1 mg/d.
average, folic acid therapy reduced the risk of CVD by 15%
(RR, 0.85; 95% CI, 0.76 to 0.96; P 0.009) in patients with
ESRD/ACKD. In the stratified analyses, a greater benefi-
cial effect was observed among those trials with a treat-
ment duration 24 months (RR, 0.84; 95% CI, 0.72 to 0.98;
P 0.02); a decrease in Hcy level 20% (RR, 0.83; 95% CI,
0.73 to 0.95; P 0.007); and no/partial grain fortification
(RR, 0.80; 95% CI, 0.65 to 0.99; P 0.04). The beneficial
effect also was seen when the decrease in Hcy levels was
20% in the presence of folic acid fortification (RR, 0.85;
95% CI, 0.73 to 0.99; P 0.04).
A 1998 meta-analysis of 12 RCTs evaluating the effects of
folic acid and B vitamins on Hcy showed that reductions in
Hcy are significantly greater when the pretreatment Hcy
level is high (20). Of note, folic acid fortification of North
Americans (140 g/100 g of flour) lowered the population
mean of Hcy to about 8 to 10 mol/L (21). As a conse-
quence, the ability of folic acid to reduce Hcy among North
Americans was reduced from 25 to 15% (22). This attenu-
ated Hcy lowering effect was not considered in the design
of some RCTs, and it is likely that folic acid fortification
might have contributed to the no-effect findings among
these trials. As expected, our analysis showed that folic
acid fortification was an important determinant for the
treatment effect of the trials.
Is There a Ceiling Effect of Folic Acid Therapy in CVD
Prevention?
Among the published trials of folic acid therapy on CVD
outcomes, there were considerable variations in the dosage
of folic acid. Uncertainty remains regarding an optimum
dose of folic acid supplementation in CVD prevention.
Like any essential nutrient, one would expect that in pop-
ulations with adequate folic acid intake, further reductions
in Hcy level and CVD risk by folic acid supplementation
would be limited. Likewise, excessive doses of folic acid
therapy will not lead to an additional beneficial effect. A
meta-analysis of 25 randomized controlled trials (22)
showed that daily doses of 0.8 mg of folic acid had
achieved the maximum reduction in plasma Hcy concen-
trations produced by folic acid supplementation.
Of the seven trials included in this meta-analysis,
three trials used 5 mg of folic acid daily and four used
5 mg of folic acid daily. As shown in Table 3, there was
Folic Acid Therapy and CVD, Qin et al. 487
RR 95% CI P
Control
12/168 1.15 0.60, 2.20 0.68
13/51 0.64 0.27, 1.52 0.31
55/159 0.85 0.62, 1.18 0.33
58/323 0.90 0.64, 1.27 0.55
191/1024 0.86 0.71, 1.04 0.12
329/1725 0.87 0.75, 1.00 0.06
317/1557 0.86 0.74, 0.99 0.04
no evidence of an added benefit from larger doses of
folic acid in comparison with lower doses on CVD out-
come in patients with ESRD/ACKD. Of note, the pla-
cebo group in some trials also received folic acid treat-
ment, which might have contributed to the no-effect
findings. For example, the placebo group in the trial by
Wrone et al. (18) received 1 mg/d of folic acid, which
exceeded the ceiling of 0.8 mg daily. It is not surprising
then that this trial yielded no-effect findings with regard
to folic acid therapy.
Is There an Adverse Effect of Folic Acid Therapy in ESRD/
ACKD?
A trial recently reported by House et al. (11) suggested
that among patients with diabetic nephropathy, high doses
of B vitamins compared with a placebo resulted in a
greater decrease in GFR and an increase in vascular events.
However, there were a number of factors that could have
affected the results and interpretation of the trial, such as
small sample size, the between-group imbalance in impor-
tant baseline characteristics, low adherence with the inter-
vention, and the difference in cumulative proportion of
composite outcome between the placebo and intervention
groups within the first 8 months. When the events that
occurred in the first eight months were removed, there was
no group difference from 8 to 36 months of the trial.
The finding by House et al. was not seen in any pre-
vious B-vitamin trials, including trials in patients with
ESRD/ACKD. Even in trials with high-dose folic acid
(40 mg/d) (16), there was no significant difference in the
number and types of adverse events (including serious
adverse events) between the treatment and control
groups. Our meta-analysis provided no evidence that
folic acid therapy (with or without B vitamins) increased
the risk of primary and secondary CVD outcomes.
Clinical and Research Implications
Our findings remain to be confirmed by data from large,
ongoing and future trials. As with any meta-analysis, our
findings should be interpreted in the context of available
evidence in the fields. Given the ongoing controversy over
homocysteine-lowering therapy to reduce CVD risk in the
general population and in patients with ESRD/ACKD,
clarifying whether there are targeted groups of individuals
488 Clinical Journal of the American Society of Nephrology
who may benefit from this simple intervention is very
important from a research and population health perspec-
tive. To efficiently assess the efficacy and causality of folic
acid therapy on CVD in the general population or in pa-
tients with ESRD/ACKD, future clinical trials should be
conducted in regions without folic acid fortification and in
populations with low intake of folic acid, high Hcy con-
centrations, and high prevalence of CVD. For example, in
many developing countries such as China, Hcy plasma
concentrations (median, 13 to 15 mol/L) and prevalence
of CVD are high (23). We speculate that in populations
with these characteristics, folic acid supplementation could
be a safe and inexpensive strategy to reduce CVD risk. The
issue of folic acid therapy alone or in combination with
other B vitamins, as well as optimal dosage, should also be
carefully considered in future trials.
Conclusions
Our meta-analysis provided coherent evidence that, on
average, folic acid therapy can reduce CVD risk in patients
with ESRD/ACKD by approximately 15%, and greater
beneficial effect may be expected in patients with adequate
duration of treatment, in patients with greater reduction in
Hcy during treatment, and in populations without folic
acid fortification/supplementation.
Acknowledgments
We thank Ms. Tami Bartell for intensive English editing.
Disclosures
None.
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Received: June 20, 2010 Accepted: October 12, 2010
Published online ahead of print. Publication date available at
www.cjasn.org.