See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/333646087

The relationship between the concentration of plasma homocysteine and

chronic kidney disease: a cross sectional study of a large cohort

Article  in  Journal of nephrology · June 2019

DOI: 10.1007/s40620-019-00618-x

CITATIONS READS

8 28

5 authors, including:

Ili Margalit Tzippy Shochat

Rabin Medical Center Rabin Medical Center
14 PUBLICATIONS   45 CITATIONS    99 PUBLICATIONS   519 CITATIONS   

SEE PROFILE SEE PROFILE

Elad Goldberg Ilan Krause

Rabin Medical Center Tel Aviv University
24 PUBLICATIONS   206 CITATIONS    146 PUBLICATIONS   3,837 CITATIONS   

SEE PROFILE SEE PROFILE

All content following this page was uploaded by Ili Margalit on 16 April 2020.

The user has requested enhancement of the downloaded file.

Journal of Nephrology (2019) 32:783–789
https://doi.org/10.1007/s40620-019-00618-x

ORIGINAL ARTICLE

The relationship between the concentration of plasma homocysteine

and chronic kidney disease: a cross sectional study of a large cohort
Eytan Cohen1,3,4 · Ili Margalit1 · Tzippy Shochat2 · Elad Goldberg1,3 · Ilan Krause1,3

Received: 19 March 2019 / Accepted: 26 May 2019 / Published online: 5 June 2019
© Italian Society of Nephrology 2019

Abstract
Background  High concentrations of homocysteine are considered a risk factor for developing atherosclerosis and coronary
artery disease. The aim of this study was to assess the concentrations of homocysteine in subjects with chronic kidney dis‑
ease (CKD).
Methods  Data were collected from medical records of individuals examined at a screening center in Israel between the years
2000–2014. Cross sectional analysis was carried out on 17,010 subjects; 67% were men.
Results  Significant differences were observed between four quartiles of homocysteine concentrations and estimated glo‑
merular filtration rate (eGFR)—the higher the homocysteine concentration, the lower the eGFR (p < 0.0001). In subjects
with CKD, homocysteine plasma levels were correlated with the stage of renal impairment. Mean (SD) homocysteine con‑
centrations in subjects with eGFR < 60 mL/min per 1.73 m2 compared to subjects with eGFR ≥ 60 mL/min per 1.73 m2 were:
16.3 (5.9) vs. 11.5 (5.5) μmol/L respectively. These findings remained significant after adjustment for age, smoking status,
body mass index, hypertension and diabetes mellitus (p < 0.0001). Compared to subjects with homocysteine concentrations
less than 15 μmol/L, those with homocysteine concentrations equal and above 15 μmol/L, had a significantly higher odds
ratio (95% CI) of having an eGFR < 60 mL/min per 1.73 m2; non adjusted model, 8.30 (6.17–11.16); adjusted model for age
smoking status, body mass index, hypertension and diabetes mellitus, 7.43 (5.41–10.21).
Conclusion  Plasma homocysteine concentrations are higher in subjects with CKD. This may contribute to an increased risk
for developing atherosclerosis and coronary artery disease in these patients.

Keywords  Homocysteine · Atherosclerosis · Gender · CKD

Introduction disease [3]. Many other studies identified a link between

Since the early 1960s, elevated homocysteine concentra‑
tions have been shown to be related to the risk of athero‑
sclerosis [1, 2]; although a large cohort study did not find
hyperhomocysteinemia to be a predictor for peripheral artery
* Eytan Cohen
dreytancohen@gmail.com
1
Department of Medicine F‑Recanati, Rabin Medical Center,
Beilinson Hospital, Petach Tikva, Israel
2
Statistical Counselling Unit, Rabin Medical Center, Beilinson
Hospital, Petach Tikva, Israel
3
Sackler Faculty of Medicine, Tel Aviv University,
Ramat Aviv, Israel
4
Department of Medicine F‑Recanati, and Clinical
Pharmacology Unit, Rabin Medical Center, Beilinson
Hospital, 4941492 Petach Tikva, Israel
high concentrations of homocysteine and coronary artery
disease [4–8]. Various possible mechanisms for the associa‑
tion between homocysteine and atherosclerosis have been
suggested. These include stimulation of smooth muscle
cell growth, reduction in endothelial cell growth, reduc‑
tion in endothelial cell relaxation and decreased synthesis
of high density lipoprotein [9]. However, it should be noted
that despite convincing evidence associating hyperhomoc‑
syteinemia with coronary artery disease, clinical trials
attempting to lower high homocysteine plasma concentra‑
tions in these patients have not shown a positive effect con‑
clusively [10–12].
Chronic kidney disease (CKD) is a growing public health
problem worldwide [13]. Some of the preventive measures
which can slow progression of CKD are strict blood pres‑
sure control, tight glycemic control and smoking cessation
[14]. Yet data shedding light on the relationship between

13
Vol.:(0123456789)

784
homocysteine and CKD remains scarce. Previous cross sec‑
tional studies have observed an association between elevated
homocysteine levels and decreased renal function however
these studies were limited; either they were restricted to a
relatively small cohort [15] or to a specific population from
the far East [16]. The theoretical question that may arise
concerning this issue is whether the high concentration of
homocysteine causes CKD, or are the high levels of homo‑
cysteine rather the result of CKD. Homocysteine is carried
in the circulation covalently bound to albumin [17]. This
probably excludes the filtration and absorption process in the
kidney as a factor affecting homocysteine plasma levels [18].
The possible theoretical explanations of high homocysteine
levels in CKD are renal or extra-renal impairment in the
metabolism of homocysteine [18, 19].
Nevertheless, patients with CKD may have high levels of
homocysteine which might be another risk factor for them to
develop atherosclerosis and coronary artery disease.
The aim of this study was to assess the association
between homocysteine plasma concentrations and CKD in
a cross sectional study involving a very large cohort of sub‑
jects, while adjusting for various confounder factors which
can affect the progression to CKD.
Materials and methods
Study population
The study population consisted of a cross-sectional sam‑
ple of men and (non-pregnant) women aged 20–80 years
referred by their employers for routine medical screening
at a tertiary medical center in Israel between the years 2000
and 2014. It should be noted that in Israel a national program
of folic acid fortification does not exist. None of the subjects
was hospitalized at the time. Screening consisted of a thor‑
ough medical history and a complete physical examination
along with a broad series of blood and urine tests, a chest
X-ray, an electrocardiogram, an exercise stress test, a res‑
piratory function test, and a full ophthalmology examination.
For the purpose of this study, we used the data from each
subject’s most recent visit.
Data on smoking habits were collected from direct ques‑
tioning on the day of examination at the screening center.
Blood tests were carried out after an overnight 12-h fast.
Analysis of plasma homocysteine concentrations was per‑
formed on an Abbott Axsym system. This assay is based on
the Fluorescence Polarization Immuno-Assay (FPIA) tech‑
nology. Bound homocysteine (oxidized form) is reduced to
free homocysteine that is enzymatically converted to S-aden‑
osyl-l-Homocysteine (SAH). SAH and labeled Fluorescein
Tracer compete for the sites on the monoclonal antibody
molecules. The intensity of the polarized fluorescence,
13
Journal of Nephrology (2019) 32:783–789
measured by FPIA optical assembly, is proportional to the
concentration of homocysteine in the sample. In the last
2 years of the survey the method of homocysteine analysis
was replaced by a chemiluminescent micro particle immu‑
noassay (CMIA) for the quantitative determination of total
l-homocysteine in human. This was using the Abbott Archi‑
tect system.
The normal range of homocysteine concentrations for
most laboratories is between 5 and 15 µmol/L [20]. Homo‑
cysteine concentrations above 15 µmol/L are considered
to be elevated. Creatinine serum levels were assessed on a
Beckman Coulter AU 2700 analyzer. The method involved
is based on the kinetic color test (Jaffe’s method), in which
the creatinine forms a yellow–orange colored compound
with picric acid in alkaline medium. The rate of change in
absorbance is proportional to the creatinine concentration in
the sample. The calibration of the method is traceable to the
Isotope Dilution Mass Spectroscopy (IDMS). For the pur‑
pose of this study, CKD patients were defined as those with
eGFR < 60 mL/min/1.73 m2. Estimated GFR was calculated
using the commonly used CKD-EPI equation [21].
A computer program was created to transfer all data, from
each visit, into a spreadsheet Excel file. Statistical analysis
was performed on this file.
The study was approved by the Helsinki Ethics Commit‑
tee of Rabin Medical Center.
Statistical methods
Baseline characteristics were compared between men and
women using Student’s t test and Chi-square test for con‑
tinuous and categorical variables respectively. Compari‑
son of eGFR in four quartiles of homocysteine concentra‑
tions was done using Analysis of Variance (ANOVA) with
the Tukey–Kramer adjustment for post hoc comparisons
between the quartiles.
Average homocysteine plasma concentrations were com‑
pared between subjects with eGFR < 60 mL/min/1.73 m2 and
those with eGFR ≥ 60 mL/min/1.73 m2. Univariate analy‑
ses were performed in Model 1. In Model 2 the data were
adjusted for age alone. For Model 3 adjustments were made
for age, smoking status, body mass index, hypertension and
diabetes mellitus. ANOVA was used for all these models.
Odds ratios (ORs) and 95% CI of having CKD were com‑
pared between those with homocysteine plasma levels, equal
and above 15 µmol/L, to those with homocysteine plasma
levels less than15 µmol/L. Again, univariate analyses were
performed in Model 1. Model 2 was adjusted for age alone
and Model 3 was adjusted for age smoking status, body mass
index, hypertension and diabetes mellitus. Logistic regres‑
sion was used for all these models.
Lastly, odds ratios (ORs) and 95% CI of having pro‑
teinuria (i.e. ≥ 50 mg/dl on the urine stick) was performed
Journal of Nephrology (2019) 32:783–789 785

comparing subjects with homocysteine plasma levels equal
and above 15 µmol/L to those with homocysteine plasma
levels less than 15 µmol/L. Again, univariate analyses were
performed in Model 1. Model 2 was adjusted for age alone;
Model 3 was adjusted for age smoking status, body mass
index, hypertension and diabetes mellitus. Logistic regres‑
sion was used again for these models.
For all analyses a p value of < 0.05 was considered signifi‑
cant. All analyses were performed using SAS v. 9.4.
Results
The cross sectional analysis included 17,010 subjects,
67% were men. The clinical and laboratory characteris‑
tics of the participants are presented in Table 1. Signifi‑
cant gender differences were observed in all parameters
apart from the prevalence of smoking and the use of folic
acid and vitamin B12 which was the same. It should be
noted that compared to women, men had higher average
plasma levels of homocysteine; 12.6 (6.1) vs. 9.6 (3.1)
μmol/L respectively. In contrast, men’s average eGFR was
found to be lower in comparison with women; 95.4 (14.2)
vs. 100.0 (14.1) ml/min/1.73 m2 respectively. The aver‑
age eGFR in 4 quartiles of homocysteine plasma levels
are shown in Fig. 1. A significant difference was found
between the average eGFR in the different quartiles; the
higher the homocysteine quartile levels, the lower the
average eGFR. This was true for all subjects and inde‑
pendently for both genders. Out of a cohort of 17,010
subjects, 180 had CKD (eGFR < 60  mL/min/1.73  m 2).
The distribution of homocysteine plasma levels in the dif‑
ferent stages of renal impairment are presented in Fig. 2.
It can be seen that the higher the stage or renal impair‑
ment, the higher the homocysteine plasma levels. This
was true for all subjects as well as for men and women
separately. Mean homocysteine plasma levels in subjects
with CKD were significantly higher than the mean homo‑
cysteine plasma levels of subjects with eGFR ≥ 60 mL/
min/1.73 m2 (Table 2). These differences were significant
for each model: the unadjusted data (Model 1), for age
adjustment (Model 2), and for adjustment for age, smok‑
ing status, body mass index, hypertension and diabetes
mellitus (Model 3). Compared to subjects with homo‑
cysteine concentrations less than 15 μmol/L, those with
homocysteine concentrations equal and above 15 μmol/L
had significantly higher odds ratio (95% CI) of having an
CKD i.e. eGFR < 60 mL/min/1.73 m2; non adjusted model,
8.30 (6.17–11.16); adjusted model for age smoking status,
body mass index, hypertension and diabetes mellitus, 7.43
(5.41–10.21) (p < 0.001). The relevant odds ratio for men
and women appear in Table 3 and it appears that the wom‑
en’s odds ratio for CKD was higher than in men. Urine
proteinuria was assessed in 12,900 subjects (76% of the
cohort) and 134 subjects had proteinuria of ≥ 50 mg/dl.
Compared to subjects with homocysteine concentrations

Table 1  Subjects characteristics Men N = 11396 Women N = 5614 p value

by gender
Age (years), mean (SD) 47.9 (10.0) 47.4 (10.0) 0.007
Smokers (%) 16.0 16.7 0.299
BMI (kg/m2), mean (SD) 27.4 (4.1) 25.6 (4.9) < 0.001
Waist circumference (cm),mean (SD) 93.1 (11.2) 79.7 (11.4) < 0.001
Systolic BP (mmHg), mean (SD) 122.1 (13.8) 113.3 (14.7) < 0.001
Diastolic BP (mmHg), mean (SD) 79.0 (7.7) 74.1 (8.4) < 0.001
Hypertension (%) 13.2 6.8 < 0.001
Serum glucose concentration (mg/dl), mean (SD) 100.3 (19.6) 94.2 (14.8) < 0.001
Diabetes Mellitus (%) 4.8 3.0 < 0.001
Total Cholesterol (mg/dl), mean (SD) 195.0 (36.6) 198.9 (37.7) < 0.001
Triglycerides (mg/dl), mean (SD) 137.1 (87.6) 107.1 (75.9) < 0.001
LDL cholesterol (mg/dl), mean (SD) 120.3 (31.2) 116.8 (31.5) < 0.001
HDL cholesterol (mg/dl), mean (SD) 47.5 (10.4) 60.3 (13.6) < 0.001
eGFR (CKD-EPI) ml/min/1.73 m2, mean (SD) 95.4 (14.2) 100.0 (14.1) < 0.001
Plasma Homocysteine concentrations (μmol/L) mean (SD) 12.6 (6.1) 9.6 (3.1) < 0.001
Medication usage (%):
 Folic acid and Vitamin B12 3.7 3.6 0.828
 ACE inhibitors 7.0 2.8 < 0.001
 ARB 2.1 1.3 < 0.001
 Hypoglycemic medications 3.7 1.8 < 0.001

ACE angiotensin converting enzyme, ARB angiotensin II receptor blocker

13

786 Journal of Nephrology (2019) 32:783–789

Fig. 1  Estimated glomerular All Men Women

filtration (eGFR) rate levels in 130
four quartiles of homocysteine
concentrations. *p < 0.001
comapring eGFR between 120
quartiles
* * * *
* * *
110 * *

eGFR mL/min per 1.73 m2

100

90

80

70

60
Q1 Q2 Q3 Q4

Quarles of homocysteine concentraons

Fig. 2  Homocysteine plasma 35
levels at different stages of renal All Men Women
impairment. Stage 3A = eGFR
between 45 and 59 mL/ 30
min/1.73 m2; Stage 3B = eGFR
between 30 and 44 mL/
Homocysteine plasma levels μmol/L

min/1.73 m2; Stage 4 = eGFR 25

between 15 and 29 mL/
min/1.73 m2
20

15

10

0
Stage 3A Stage 3B Stage 4
Stages of renal impairment

less than 15 μmol/L, those with homocysteine concen‑ Discussion

trations equal and above 15 μmol/L, had a significantly
higher odds ratio (95% CI) for having proteinuria, non- In this large cohort of 17,010 subjects, assessing the asso‑
adjusted model, 2.22 (1.47–3.35); adjusted model for age ciation between homocysteine plasma levels and renal
smoking status, body mass index, hypertension and dia‑ function we express four points. The first point was to
betes mellitus, 2.06 (1.34–3.16) (p < 0.001). show that the higher the homocysteine plasma levels the

13
Journal of Nephrology (2019) 32:783–789 787

Table 2  Mean homocysteine plasma levels in subjects with odds ratio (95% CI) of having proteinuria i.e. ≥ 50 mg/dl;
eGFR < 60 or ≥ 60 mL/min/1.73 m2 this remained significant after adjusting for age smoking
Mean Homocysteine plasma levels p value status, body mass index, hypertension and diabetes mel‑
μmol/L (SD) litus, 2.06 (1.34–3.16) (p < 0.001).
eGFR < 60 eGFR ≥ 60 Model 1 Model 2 Model 3 In our study, the 15 μmol/L was used as a cut off to define
hyperhomocysteinemia. However, different definitions of
All 16.3 (5.9) 11.5 (5.5) < 0.001 < 0.001 < 0.001 homocysteine normal range can be found in other studies
Men 16.7 (6.1) 12.5 (6.1) < 0.001 < 0.001 < 0.001 [4, 22]. In a review from the Lancet concerning hyperhomo‑
Women 14.9 (5.1) 9.5 (3.0) < 0.001 < 0.001 < 0.001 cysteinemia in uremic patients, an upper limit of 10 µmol/L
Model 1: crude for women and of 12 µmol/L for men was suggested [22].
Model 2: adjusted for age We therefore, reanalyzed our data accordingly (Table 4). The
Model 3: adjusted for age, smoking status, body mass index, hyper‑ Odds ratio (95% CI) of having CKD, comparing subjects
tension and diabetes mellitus with homocysteine above normal to those within normal
eGFR estimated glomerular filtration rate (mL/min/1.73 m2) range remained high for both men and women.
As mentioned in the introduction section, there is a ques‑
tion as to whether the high concentration of homocysteine, is
Table 3  Odds ratio (95% CI) of having CKD, comparing subjects a cause for CKD or rather the result of CKD. We have previ‑
with homocysteine plasma levels equal and above 15 μmol/L to those ously showed in a longitudinal historical prospective study
with homocysteine plasma levels less than 15 μmol/L
that elevated plasma homocysteine levels may be a predictor
All subjects Men Women of accelerated decline in renal function and future incidence
of CKD [23]. In that study, 3602 subjects with normal eGFR
Model 1 8.30 (6.17–11.16) 6.93 (4.97–9.67) 14.89 (7.44–29.81)
and no proteinuria, were divided into two groups according
Model 2 7.59 (5.53–10.41) 6.98 (4.96–9.82) 10.44 (5.05–21.55)
to plasma homocysteine levels (≤ 15, ≥ 15 μmol/L). Annual
Model 3 7.43 (5.41–10.21) 6.83 (4.84–9. 62) 10.26 (4.97–21.20)
eGFR decline was shown to be 25% higher in subjects with
Model 1: crude elevated plasma homocysteine (0.90 ± 0.16  mL/min per
Model 2: adjusted for age 1.73 m2 vs. 0.72 mL/min per 1.73 m2, p < 0.001). After a
Model 3: adjusted for age, smoking status, body mass index, hyper‑ median of 7.8 years subjects with elevated plasma homo‑
tension and diabetes mellitus cysteine levels had a significant higher odds ratio of develop‑
CKD chronic kidney disease defined as estimated GFR < 60  mL/ ing CKD (HR 4.85, 95% CI 2.48–9.49, p < 0.001). Similar
min/1.73 m2 results were demonstrated by Ninomiya et al., for a Japanese
population [24]. Nevertheless, renal impairment per se can
lower the creatinine clearance. Moreover, in different affect homocysteine levels by mechanisms which are not
stages of CKD the higher the stage of renal failure, the clearly understood. In a study by van Guldener et al. [18]
higher the homocysteine plasma levels. This was shown it was shown that there is no renal extraction of homocyst‑
for all subjects as well for men and women indepen‑ eine in fasting humans. This lack of filtration and absorp‑
dently. The second point was to show that subjects with tion process of homocysteine in the kidney may be due to
eGFR < 60  mL/min per 1.73  m 2, compared to subjects
with eGFR ≥ 60 mL/min per 1.73 m2 had a significantly
higher level of plasma homocysteine. This difference Table 4  Odds ratio (95% CI) of having CKD, comparing men with
homocysteine plasma levels equal and above 12 μmol/L to men with
remained significant after adjustment for other factors homocysteine plasma levels less than 12  μmol/L and comparing
which can affect kidney function such as age, smoking sta‑ women with homocysteine plasma levels equal and above 10 μmol/L
tus, body mass index, hypertension and diabetes mellitus to women with homocysteine plasma levels less than 10 μmol/L
(p < 0.001). The third point was to show that subjects with Men Women
homocysteine concentrations equal and above 15 μmol/L,
compared to subjects with homocysteine concentrations Model 1 5.76 (3.81–8.72) 11.08 (4.30–28.54)
less than 15 μmol/L, had significantly higher odds ratio Model 2 4.82 (3.16–7.35) 7.16 (2.75–18.60)
(95% CI) of having an eGFR < 60 mL/min per 1.73 m2; Model 3 4.93 (3.21–7.58) 7.03 (2.69–18.37)
this remained true after adjusting for age smoking status, Model 1: crude
body mass index, hypertension and diabetes mellitus, 7.43 Model 2: adjusted for age
(5.41–10.21). Lastly, the fourth point was to show that sub‑ Model 3: adjusted for age, smoking status, body mass index, hyper‑
jects with homocysteine concentrations equal and above tension and diabetes mellitus
15 μmol/L, compared to subjects with homocysteine con‑ CKD chronic kidney disease defined as estimated GFR < 60  mL/
centrations less than 15 μmol/L, had significantly higher min/1.73 m2

13

788
the fact that homocysteine is covalently bound to albumin
[17]. Therefore two theories explaining the effect of CKD on
homocysteine plasma levels have been suggested. The first
theory is that renal protein breakdown in CKD patients is
enhanced and the excess release of methionine is converted
to homocysteine in the liver. Alternatively it may be specu‑
lated that the extra-renal metabolism of homocysteine may
be impaired by factors related to uremia [18, 19]. Indeed,
in a recent study on dialysis patients, a unique uremic toxin
namely lanthionine was found. This toxin may contribute
to the genesis of hyperhmocysteienemia found in uremic
patients [25].
Possible mechanisms for the association between homo‑
cysteine and atherosclerosis were mentioned in the introduc‑
tion section [9]. The effect of renal impairment on athero‑
sclerosis is only partially mediated by homocysteine [26].
As to the direct effect of homocysteine on kidney function,
several pathophysiological factors are suggested. Homocyst‑
eine can act directly on glomerular cells inducing sclerosis,
and it can initiate renal injury by reducing plasma and tis‑
sue levels of adenosine. Decreased plasma adenosine leads
to enhanced proliferation of vascular smooth muscle cells
accelerating sclerotic process in arteries and glomeruli [27].
Homocysteine also oxidizes low-density lipoprotein and thus
promotes accelerated intra-renal atherosclerosis and/or arte‑
riolar hyalinosis; this results in reducing the renal perfusion
pressure [28, 29].
The inter-relationship between folic acid, vitamin B12,
homocysteine and CKD has been revised in detail in two
recent reviews [30, 31]. It is a widely known that homocyst‑
eine concentrations are affected by concentrations of vita‑
min B12 and folate, such that low concentrations of these
vitamins increase the level of homocysteine [32]. In CKD
patients comorbidities and multi drug therapies can lead to
malnutrition and subsequently to folic acid and vitamin B12
deficiency. Moreover, folic acid metabolism is impaired in
uremic patients and functional vitamin B12 deficiency can
be observed because of increased transcobalalmin losses in
the urine and reduced absorption in the proximal tubule [30].
Given that plasma homocysteine may contribute to renal
failure, it may be argued that lowering the levels of homo‑
cysteine may attenuate the risk of future CKD. This has
therefore been investigated in patients with coronary heart
disease, yet the results have proved contradictory [10–12].
As to CKD patients, three double blind randomized-con‑
trolled trials have assessed the effect of adding folic acid and
vitamin B12 on the progression of CKD. In the China Stroke
Primary Prevention Trial sub-study on 15,104 participants, it
was shown than adding folic acid delayed CKD progression
[33]. In the HOST study on 2056 CKD patients, adding high
dose of folic acid (40 mg/day) and vitamin B12 (2 mg/day)
did not affect CKD progression [34]. Lastly, in the DIVINe
study on 238 patients with diabetic nephropathy, adding
13
Journal of Nephrology (2019) 32:783–789
supplements of folic acid and vitamin B12 caused a greater
decrease in GFR [35].One of the possible explanations of
the beneficial effect of folic acid in the Chinese study is that,
in contrast with studies in the other regions, this study was
carried out in a country without folic acid grain fortification.
The main strength of our study is the inclusion of such
a large cohort (17010 men and women) with documented
homocysteine concentrations, together with complete data‑
sets of clinical and laboratory findings. Nevertheless, this
study has its limitations. The study group was not drawn
from a population sample, but rather from those attending an
examination center which limits the generalizability of the
findings. In addition, the cross-sectional design precludes
any conclusions regarding causality.
In conclusion, the findings of our current cross sectional
study, as with our previous longitudinal study, clearly show
an association between high levels of plasma homocysteine
and renal failure. More prospective studies, particularly in
countries that do not fortify foods with vitamins, should be
conducted to assess the effect of adding folic acid and vita‑
min B12 in CKD patients. Such studies may show a positive
effect on the progression of the kidney disease by attenuating
the homocysteine levels.
Compliance with ethical standards 
Conflict of interest  On behalf of all authors, the corresponding author
states that there is no conflict of interest.
Ethical approval  All procedures performed involving human partici‑
pants were in accordance with the ethical standards of the Helsinki
Ethics Committee of Rabin Medical Center, Israel and in accordance
with the 1964 Helsinki declaration and its later amendments or com‑
parable ethical standards.
Informed consent  Since all the ID numbers of all the participants
were changed into coded numbers before any analysis was performed,
the Helsinki Ethics Committee of the Rabin center did not request an
informed consent from the participants.
References
1. Gibson JB, Carson NA, Neill DW (1964) Pathological findings in
homocystinuria. J Clin Pathol 17:427–437
2. McCully KS (1969) Vascular pathology of homocysteinemia:
implications for the pathogenesis of arteriosclerosis. Am J Pathol
56:111–128
3. Ridker PM, Stampfer MJ, Rifai N (2001) Novel risk factors for
systemic atherosclerosis: a comparison of C-reactive protein,
fibrinogen, homocysteine, lipoprotein(a), and standard choles‑
terol screening as predictors of peripheral arterial disease. JAMA
285:2481–2485
4. Stampfer MJ, Malinow MR, Willett WC et al (1992) A prospective
study of plasma homocyst(e)ine and risk of myocardial infarction
in US physicians. JAMA 268:877–881
Journal of Nephrology (2019) 32:783–789 789
5. Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ (2000)
Association between total homocyst(e)ine and the likelihood for
a history of acute myocardial infarction by race and ethnicity:
results from the Third National Health and Nutrition Examination
Survey. Am Heart J 139:446–453
6. Al-Obaidi MK, Stubbs PJ, Collinson P et al (2000) Elevated
homocysteine levels are associated with increased ischemic myo‑
cardial injury in acute coronary syndromes. J Am Coll Cardiol
36:1217–1222
7. Soinio M, Marniemi J, Laakso M, Lehto S, Ronnemaa T (2004)
Elevated plasma homocysteine level is an independent predictor
of coronary heart disease events in patients with type 2 diabetes
mellitus. Ann Intern Med 140:94–100
8. Bates CJ, Mansoor MA, Pentieva KD, Hamer M, Mishra GD
(2010) Biochemical risk indices, including plasma homocysteine,
that prospectively predict mortality in older British people: the
National Diet and Nutrition Survey of People Aged 65 Years and
Over. Br J Nutr 104:893–899
9. Abraham JM, Cho L (2010) The homocysteine hypothesis: still
relevant to the prevention and treatment of cardiovascular disease?
Cleve Clin J Med 77:911–918
10. Lonn E, Yusuf S, Arnold MJ et al (2006) Homocysteine lowering
with folic acid and B vitamins in vascular disease. N Engl J Med
354:1567–1577
11. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM (2002) Effect
of homocysteine-lowering therapy with folic acid, vitamin B12,
and vitamin B6 on clinical outcome after percutaneous coronary
intervention: the Swiss Heart study: a randomized controlled trial.
JAMA 288:973–979
12. Lange H, Suryapranata H, De Luca G et al (2004) Folate therapy
and in-stent restenosis after coronary stenting. N Engl J Med
350:2673–2681
13. Gilbertson DT, Liu J, Xue JL et al (2005) Projecting the number
of patients with end-stage renal disease in the United States to the
year 2015. J Am Soc Nephrol 16:3736–3741
14. Frohlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ
(2013) Myocardial reperfusion injury: looking beyond primary
PCI. Eur Heart J 34:1714–1722
15. Francis ME, Eggers PW, Hostetter TH, Briggs JP (2004) Associa‑
tion between serum homocysteine and markers of impaired kidney
function in adults in the United States. Kidney Int 66:303–312
16. Chuang CH, Lee YY, Sheu BF et al (2013) Homocysteine and
C-reactive protein as useful surrogate markers for evaluating CKD
risk in adults. Kidney Blood Press Res 37:402–413
17. Togawa T, Sengupta S, Chen H et al (2000) Mechanisms for the
formation of protein-bound homocysteine in human plasma. Bio‑
chem Biophys Res Commun 277:668–674
18. van Guldener C, Donker AJ, Jakobs C et  al (1998) No net
renal extraction of homocysteine in fasting humans. Kidney Int
54:166–169
19. van Guldener C, Stehouwer CD (2003) Homocysteine metabolism
in renal disease. Clin Chem Lab Med 41:1412–1417
20. Ballal RS, Jacobsen DW, Robinson K (1997) Homocysteine:
update on a new risk factor. Cleve Clin J Med 64:543–549
21. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to
estimate glomerular filtration rate. Ann Intern Med 150:604–612
View publication stats
22. Ingrosso D, Cimmino A, Perna AF et al (2003) Folate treatment
and unbalanced methylation and changes of allelic expression
induced by hyperhomocysteinaemia in patients with uraemia.
Lancet 361:1693–1699
23. Levi A, Cohen E, Levi M et al (2014) Elevated serum homocyst‑
eine is a predictor of accelerated decline in renal function and
chronic kidney disease: a historical prospective study. Eur J Intern
Med 25:951–955
24. Ninomiya T, Kiyohara Y, Kubo M et  al (2004) Hyperhomo‑
cysteinemia and the development of chronic kidney disease in
a general population: the Hisayama study. Am J Kidney Dis
44:437–445
25. Perna AF, Di Nunzio A, Amoresano A et al (2016) Divergent
behavior of hydrogen sulfide pools and of the sulfur metabolite
lanthionine, a novel uremic toxin, in dialysis patients. Biochimie
126:97–107
26. Spence JD, Urquhart BL, Bang H (2016) Effect of renal impair‑
ment on atherosclerosis: only partially mediated by homocysteine.
Nephrol Dial Transpl 31:937–944
27. Perna AF, Ingrosso D, Violetti E et al (2009) Hyperhomocyst‑
einemia in uremia–a red flag in a disrupted circuit. Semin Dial
22:351–356
28. Haynes WG (2002) Hyperhomocysteinemia, vascular function
and atherosclerosis: effects of vitamins. Cardiovasc Drugs Ther
16:391–399
29. Meyrier A, Hill GS, Simon P (1998) Ischemic renal diseases: new
insights into old entities. Kidney Int 54:2–13
30. Capelli I, Cianciolo G, Gasperoni L et al (2019) Folic acid and
vitamin B12 administration in CKD, why not? Nutrients. https​://
doi.org/10.3390/nu110​20383​
31. Cianciolo G, De Pascalis A, Di Lullo L et al (2017) Folic acid and
homocysteine in chronic kidney disease and cardiovascular dis‑
ease progression: which comes first? Cardiorenal Med 7:255–266
32. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ (1993)
Vitamin B-12, vitamin B-6, and folate nutritional status in men
with hyperhomocysteinemia. Am J Clin Nutr 57:47–53
33. Xu X, Qin X, Li Y et al (2016) Efficacy of folic acid therapy
on the progression of chronic kidney disease: the renal substudy
of the china stroke primary prevention trial. JAMA Intern Med
176:1443–1450
34. Jamison RL, Hartigan P, Kaufman JS et al (2007) Effect of homo‑
cysteine lowering on mortality and vascular disease in advanced
chronic kidney disease and end-stage renal disease: a randomized
controlled trial. JAMA 298:1163–1170
35. House AA, Eliasziw M, Cattran DC et al (2010) Effect of B-vita‑
min therapy on progression of diabetic nephropathy: a randomized
controlled trial. JAMA 303:1603–1609
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
13