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Journal of Nephrology

, Volume 32, Issue 5, pp 783–789 | Cite as

The relationship between the concentration of plasma homocysteine and chronic kidney disease: a cross sectional study of a large cohort

  • Eytan CohenEmail author
  • Ili Margalit
  • Tzippy Shochat
  • Elad Goldberg
  • Ilan Krause
Original Article

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 disease (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 glomerular 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 concentrations 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

Since the early 1960s, elevated homocysteine concentrations have been shown to be related to the risk of atherosclerosis [1, 2]; although a large cohort study did not find hyperhomocysteinemia to be a predictor for peripheral artery disease [3]. Many other studies identified a link between high concentrations of homocysteine and coronary artery disease [4, 5, 6, 7, 8]. Various possible mechanisms for the association between homocysteine and atherosclerosis have been suggested. These include stimulation of smooth muscle cell growth, reduction in endothelial cell growth, reduction in endothelial cell relaxation and decreased synthesis of high density lipoprotein [9]. However, it should be noted that despite convincing evidence associating hyperhomocsyteinemia with coronary artery disease, clinical trials attempting to lower high homocysteine plasma concentrations in these patients have not shown a positive effect conclusively [10, 11, 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 pressure control, tight glycemic control and smoking cessation [14]. Yet data shedding light on the relationship between homocysteine and CKD remains scarce. Previous cross sectional 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 homocysteine 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 subjects, 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 sample 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 thorough 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 respiratory 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 questioning 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 performed on an Abbott Axsym system. This assay is based on the Fluorescence Polarization Immuno-Assay (FPIA) technology. Bound homocysteine (oxidized form) is reduced to free homocysteine that is enzymatically converted to S-adenosyl-l-Homocysteine (SAH). SAH and labeled Fluorescein Tracer compete for the sites on the monoclonal antibody molecules. The intensity of the polarized fluorescence, 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 immunoassay (CMIA) for the quantitative determination of total l-homocysteine in human. This was using the Abbott Architect system.

The normal range of homocysteine concentrations for most laboratories is between 5 and 15 µmol/L [20]. Homocysteine 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 purpose 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 Committee of Rabin Medical Center.

Statistical methods

Baseline characteristics were compared between men and women using Student’s t test and Chi-square test for continuous and categorical variables respectively. Comparison of eGFR in four quartiles of homocysteine concentrations was done using Analysis of Variance (ANOVA) with the Tukey–Kramer adjustment for post hoc comparisons between the quartiles.

Average homocysteine plasma concentrations were compared between subjects with eGFR < 60 mL/min/1.73 m2 and those with eGFR ≥ 60 mL/min/1.73 m2. Univariate analyses 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 compared 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 regression was used for all these models.

Lastly, odds ratios (ORs) and 95% CI of having proteinuria (i.e. ≥ 50 mg/dl on the urine stick) was performed 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 regression was used again for these models.

For all analyses a p value of < 0.05 was considered significant. 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 characteristics of the participants are presented in Table 1. Significant 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 average 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 independently for both genders. Out of a cohort of 17,010 subjects, 180 had CKD (eGFR < 60 mL/min/1.73 m2). The distribution of homocysteine plasma levels in the different stages of renal impairment are presented in Fig. 2. It can be seen that the higher the stage or renal impairment, 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 homocysteine 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, smoking status, body mass index, hypertension and diabetes mellitus (Model 3). Compared to subjects with homocysteine 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 women’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 less than 15 μmol/L, those with homocysteine concentrations equal and above 15 μmol/L, had a significantly higher odds ratio (95% CI) for having proteinuria, non-adjusted model, 2.22 (1.47–3.35); adjusted model for age smoking status, body mass index, hypertension and diabetes mellitus, 2.06 (1.34–3.16) (p < 0.001).
Table 1

Subjects characteristics by gender

 

Men N = 11396

Women N = 5614

p value

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

Fig. 1

Estimated glomerular filtration (eGFR) rate levels in four quartiles of homocysteine concentrations. *p < 0.001 comapring eGFR between quartiles

Fig. 2

Homocysteine plasma levels at different stages of renal impairment. Stage 3A = eGFR between 45 and 59 mL/min/1.73 m2; Stage 3B = eGFR between 30 and 44 mL/min/1.73 m2; Stage 4 = eGFR between 15 and 29 mL/min/1.73 m2

Table 2

Mean homocysteine plasma levels in subjects with eGFR < 60 or ≥ 60 mL/min/1.73 m2

Mean Homocysteine plasma levels μmol/L (SD)

p value

 

eGFR < 60

eGFR ≥ 60

Model 1

Model 2

Model 3

All

16.3 (5.9)

11.5 (5.5)

< 0.001

< 0.001

< 0.001

Men

16.7 (6.1)

12.5 (6.1)

< 0.001

< 0.001

< 0.001

Women

14.9 (5.1)

9.5 (3.0)

< 0.001

< 0.001

< 0.001

Model 1: crude

Model 2: adjusted for age

Model 3: adjusted for age, smoking status, body mass index, hypertension and diabetes mellitus

eGFR estimated glomerular filtration rate (mL/min/1.73 m2)

Table 3

Odds ratio (95% CI) of having CKD, comparing subjects with homocysteine plasma levels equal and above 15 μmol/L to those with homocysteine plasma levels less than 15 μmol/L

 

All subjects

Men

Women

Model 1

8.30 (6.17–11.16)

6.93 (4.97–9.67)

14.89 (7.44–29.81)

Model 2

7.59 (5.53–10.41)

6.98 (4.96–9.82)

10.44 (5.05–21.55)

Model 3

7.43 (5.41–10.21)

6.83 (4.84–9. 62)

10.26 (4.97–21.20)

Model 1: crude

Model 2: adjusted for age

Model 3: adjusted for age, smoking status, body mass index, hypertension and diabetes mellitus

CKD chronic kidney disease defined as estimated GFR < 60 mL/min/1.73 m2

Discussion

In this large cohort of 17,010 subjects, assessing the association between homocysteine plasma levels and renal function we express four points. The first point was to show that the higher the homocysteine plasma levels the lower the creatinine clearance. Moreover, in different stages of CKD the higher the stage of renal failure, the higher the homocysteine plasma levels. This was shown for all subjects as well for men and women independently. The second point was to show that subjects with eGFR < 60 mL/min per 1.73 m2, compared to subjects with eGFR ≥ 60 mL/min per 1.73 m2 had a significantly higher level of plasma homocysteine. This difference remained significant after adjustment for other factors which can affect kidney function such as age, smoking status, body mass index, hypertension and diabetes mellitus (p < 0.001). The third point was to show that subjects with homocysteine concentrations equal and above 15 μmol/L, compared to subjects with homocysteine concentrations less than 15 μmol/L, had significantly higher odds ratio (95% CI) of having an eGFR < 60 mL/min per 1.73 m2; this remained true after adjusting for age smoking status, body mass index, hypertension and diabetes mellitus, 7.43 (5.41–10.21). Lastly, the fourth point was to show that subjects with homocysteine concentrations equal and above 15 μmol/L, compared to subjects with homocysteine concentrations less than 15 μmol/L, had significantly higher odds ratio (95% CI) of having proteinuria i.e. ≥ 50 mg/dl; this remained significant after adjusting for age smoking status, body mass index, hypertension and diabetes mellitus, 2.06 (1.34–3.16) (p < 0.001).

In our study, the 15 μmol/L was used as a cut off to define hyperhomocysteinemia. However, different definitions of homocysteine normal range can be found in other studies [4, 22]. In a review from the Lancet concerning hyperhomocysteinemia in uremic patients, an upper limit of 10 µmol/L for women and of 12 µmol/L for men was suggested [22]. We therefore, reanalyzed our data accordingly (Table 4). The Odds ratio (95% CI) of having CKD, comparing subjects with homocysteine above normal to those within normal range remained high for both men and women.
Table 4

Odds ratio (95% CI) of having CKD, comparing men with homocysteine plasma levels equal and above 12 μmol/L to men with homocysteine plasma levels less than 12 μmol/L and comparing women with homocysteine plasma levels equal and above 10 μmol/L to women with homocysteine plasma levels less than 10 μmol/L

 

Men

Women

Model 1

5.76 (3.81–8.72)

11.08 (4.30–28.54)

Model 2

4.82 (3.16–7.35)

7.16 (2.75–18.60)

Model 3

4.93 (3.21–7.58)

7.03 (2.69–18.37)

Model 1: crude

Model 2: adjusted for age

Model 3: adjusted for age, smoking status, body mass index, hypertension and diabetes mellitus

CKD chronic kidney disease defined as estimated GFR < 60 mL/min/1.73 m2

As mentioned in the introduction section, there is a question as to whether the high concentration of homocysteine, is a cause for CKD or rather the result of CKD. We have previously showed in a longitudinal historical prospective study that elevated plasma homocysteine levels may be a predictor of accelerated decline in renal function and future incidence of CKD [23]. In that study, 3602 subjects with normal eGFR and no proteinuria, were divided into two groups according to plasma homocysteine levels (≤ 15, ≥ 15 μmol/L). Annual eGFR decline was shown to be 25% higher in subjects with elevated plasma homocysteine (0.90 ± 0.16 mL/min per 1.73 m2 vs. 0.72 mL/min per 1.73 m2, p < 0.001). After a median of 7.8 years subjects with elevated plasma homocysteine levels had a significant higher odds ratio of developing CKD (HR 4.85, 95% CI 2.48–9.49, p < 0.001). Similar results were demonstrated by Ninomiya et al., for a Japanese population [24]. Nevertheless, renal impairment per se can affect homocysteine levels by mechanisms which are not clearly understood. In a study by van Guldener et al. [18] it was shown that there is no renal extraction of homocysteine in fasting humans. This lack of filtration and absorption process of homocysteine in the kidney may be due to 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 speculated 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 homocysteine and atherosclerosis were mentioned in the introduction section [9]. The effect of renal impairment on atherosclerosis is only partially mediated by homocysteine [26]. As to the direct effect of homocysteine on kidney function, several pathophysiological factors are suggested. Homocysteine can act directly on glomerular cells inducing sclerosis, and it can initiate renal injury by reducing plasma and tissue 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 arteriolar 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 homocysteine concentrations are affected by concentrations of vitamin 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 homocysteine 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, 11, 12]. As to CKD patients, three double blind randomized-controlled 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 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 datasets 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 vitamin B12 in CKD patients. Such studies may show a positive effect on the progression of the kidney disease by attenuating the homocysteine levels.

Notes

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 participants 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 comparable 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.

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Copyright information

© Italian Society of Nephrology 2019

Authors and Affiliations

  • Eytan Cohen
    • 1
    • 3
    • 4
    Email author
  • Ili Margalit
    • 1
  • Tzippy Shochat
    • 2
  • Elad Goldberg
    • 1
    • 3
  • Ilan Krause
    • 1
    • 3
  1. 1.Department of Medicine F-Recanati, Rabin Medical CenterBeilinson HospitalPetach TikvaIsrael
  2. 2.Statistical Counselling UnitRabin Medical Center, Beilinson HospitalPetach TikvaIsrael
  3. 3.Sackler Faculty of MedicineTel Aviv UniversityRamat AvivIsrael
  4. 4.Department of Medicine F-Recanati, and Clinical Pharmacology Unit, Rabin Medical CenterBeilinson HospitalPetach TikvaIsrael

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