|Year : 2015 | Volume
| Issue : 1 | Page : 26-33
|Relationship between asymmetric dimethylarginine plasma level and left ventricular mass in hemodialysis patients
Yasser El Shahawy1, Yasser Soliman1, Ahmed Rifaie2, Howayda Shenawy1, Maha Behairy1, Gamal Mady1
1 Nephrology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Cardiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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|Date of Web Publication||8-Jan-2015|
| Abstract|| |
Left ventricular hypertrophy (LVH) and left ventricular dysfunction are highly prevalent in patients with end-stage renal disease (ESRD). Several studies suggest that left ventricular mass and function is strongly modulated by the nitric oxide (NO) system. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial-based NO synthase, is emerging as an important cardiovascular risk factor in ESRD patients. Our objective is to evaluate the relationship between plasma ADMA level and LVH among hemodialysis (HD) patients. Plasma ADMA measurements by enzyme-linked immunesorbent assay and echocardiographic evaluation were performed for 40 patients on regular HD, 20 patients with pre-dialysis chronic kidney disease, 20 hypertensive patients with left ventricular hypertrophy and normal kidney function and 20 healthy age and sex-matched subjects as a control group. Residual renal function (RRF) was measured in HD patients by urea clearance from a urine collection. Mean values of plasma ADMA level were significantly high in all patient groups when compared with the control group (P < 0.001). However, there was no significant difference between groups I, II and III as regards mean values of plasma ADMA (P >0.05) and between ADMA and RRF in HD patients (r = -0.20, P = 0.60). It was also seen that plasma ADMA was not correlated with left ventricular mass index; however, there could be an association between ADMA level and diastolic dysfunction. The plasma ADMA level was found to be high in the three studied patient groups in comparison with the control group. HD is not an effective procedure for adequate removal of ADMA.
|How to cite this article:|
El Shahawy Y, Soliman Y, Rifaie A, Shenawy H, Behairy M, Mady G. Relationship between asymmetric dimethylarginine plasma level and left ventricular mass in hemodialysis patients. Saudi J Kidney Dis Transpl 2015;26:26-33
|How to cite this URL:|
El Shahawy Y, Soliman Y, Rifaie A, Shenawy H, Behairy M, Mady G. Relationship between asymmetric dimethylarginine plasma level and left ventricular mass in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Feb 27];26:26-33. Available from: https://www.sjkdt.org/text.asp?2015/26/1/26/148718
| Introduction|| |
The mortality rates in hemodialysis (HD) patients from cardiovascular disease (CVD) are ten to 20-times higher than those in the general population.  Left ventricular hypertrophy (LVH) is present in 75% of the patients at the start of dialysis.  LVH proved to be an even more powerful predictor of mortality than coronary artery disease or left ventricular ejection fraction (EF%).  LVH in end-stage renal disease (ESRD) is a disorder of multifactorial origin: Hypertension, anemia, hyperparathyroidism and chronic volume expansion, inflammation and hyperhomocysteinemia.  Nitric oxide (NO) controls the growth of the myocardium and is influential in the development of cardiac remodeling, which in turn has an antiproliferative effect on the myocardium. As a peripheral vasodilator, it additionally reduces both after load and pre-load. This hemodynamic effect of NO helps the prevention of LVH. 
NO also prevents incidents that can trigger the development of atherosclerosis, such as leukocyte adhesion, platelet aggregation and vascular smooth muscle cell proliferation. It also controls vascular regeneration through angiogenesis thus protecting against the development of atherosclerosis. Asymmetric dimethylarginine (ADMA) eliminates these positive effects by suppressing NO synthesis, which may lead to cardiovascular events, including the development of atherosclerosis and LVH. As ADMA is partially eliminated through urine, kidney failure causes its level to increase. This increase is suggested to be related to an increase in cardiovascular risk commonly seen in dialysis patients. 
| Aim of the Work|| |
In the present study, we aimed to evaluate the relationship between plasma ADMA levels and left ventricular mass index (LVMI) in HD patients.
| Subjects and Methods|| |
This study was conducted at the Ain Shams University Hospital including 80 patients divided into three groups: Group 1, 40 ESRD patients on regular HD. All studies were performed during the mid-week on a non-dialysis day. Group 2 included 20 chronic kidney disease (CKD) patients not on dialysis (stages 3, 4 and 5). The glomerular filtration rate (GFR) was measured by the Modification of Diet in Renal Disease (MDRD) formula. Group 3 included 20 hypertensive patients with LVH and normal kidney function. In addition, 20 healthy subjects were included as a control group matched by age and sex.
Patients who were on regular HD for at least six months before the study and having HD three times weekly, 4 h for each session using bicarbonate dialysate, low-flux dialyzers and conventional heparin as an anticoagulant were included in the study. The urea reduction ratio (URR) was ≥65% for all patients. Dry weight was targeted in each case to achieve an edemafree state. Hypertensive patients were maintained on antihypertensive medications as deemed necessary. The age of the subjects was between 21 and 61 years.
Patients with hemoglobin < 10 g/dL, ejection fraction < 35% detected by echocardiography, those with clinical evidence of heart failure, history of stroke or transient ischemic attacks and coronary heart disease or myocardial infarcttion or valvular lesion were excluded from the study.
We also excluded diabetic patients, those with hyperparathyroidism (parathormone >300 pg/mL), hypoalbuminemia, uncontrolled blood pressure, malignancy and active inflammation. All subjects gave informed consent to participate in the study. All patients were subjected to full history and clinical examination, with stress on the cardiovascular system and duration of dialysis.
Blood pressure (BP) of patients on HD was estimated by averaging all pre-dialysis arterial pressure recordings during the month preceding the study (total of 12 measurements; i.e. three per week). Body mass index (BMI) was calculated according to the following equation: BMI = weight in kilograms/(height in meter)  . Calculation of residual renal function (RRF) was performed in patients on regular HD using the residual renal urea clearance (Kru) collecting the urine over the entire interdialytic interval (about 44 h)  and using the following formula:
With plasma urea 1 (mg/dL) being the urea at the beginning of the urine collection (end of the first HD session) and plasma urea 2 (mg/dL) being the urea at the end of the urine collection.
GFR was measured by the MDRD formula: 
GFR (mL/min/1.73 m 2 ) = 175 × (Scr) -1.154 × (Age) -0.203 × (0.742 in female) Serum creatinine (Scr) in mg/dL.
Blood samples were drawn after 12 h of fasting to determine the hemoglobin, C-reactive protein (CRP), blood urea nitrogen (BUN), serum creatinine, calcium, phosphate, total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, albumin and intact parathormone (iPTH) levels using standard methods in the routine biochemistry laboratory.
Plasma samples for ADMA measurement were stored at −70°C for a short period of time, and the tests were performed by the enzyme-linked immunosorbent assay (Immundiagnostik AG, Bensheim, Germany; lot number K 7828).
All subjects in the study were evaluated with 2D, M-Mode, pulse wave Doppler and tissue Doppler echocardiography using a Vivid 7 echocardiography machine, (General Electric Healthcare, Milwaukee, WI, USA). Echocardiographic evaluations were performed at the left lateral decubitus position with standard techniques. 2D long-axis views were used to obtain linear measurements of the left ventricular cavity. Left ventricular mass (LVM) was estimated by using the anatomically validated formula of Devereux et al; 
LVM = 0.8 (1.04 (IVST + LVID + LPWT) 3 − LVID 3 + 0.6
Where IVST = interventricular septal thickness, LVID = left ventricular internal dimension and LPWT = left posterior wall thickness.
LVMI was calculated afterwards as:
LVMI = LV mass/body surface area
Where body surface area
Where LVMI is normally < 95 gm/m 2 for females and < 115 gm/m 2 for males.
Mitral inflow velocities were obtained by pulse wave Doppler in the apical four-chamber view, with the sample volume placed at the tips of the mitral valve leaflets. The ratio of early diastolic to late diastolic mitral inflow velocities was measured. Color tissue Doppler imaging was performed from the apical fourchamber view and the images were digitized.
Myocardial velocity profiles of the lateral mitral annulus were obtained by placing a 6 mm sample volume at the junction of the mitral annulus and lateral myocardial wall. Early (Em), late diastolic (Am) velocities, systolic velocities and isovolumetric relaxation time (IVRT) were measured from two consecutive cardiac cycles and averaged. The ratios of early to late diastolic mitral annular velocities (Em/Am) were calculated.
| Statistical Analysis|| |
Data were tabulated and statistical analysis was performed using SPSS program V15. The following tests were used: Mean and standard deviation was calculated for continuous data and number and frequency was calculated for categorical data. T test was performed to compare two groups regarding continuous data. The Chi square test was performed to compare two or more groups regarding categorical data. The one-way analysis of variance test was performed to compare more than two groups regarding continuous data. The Pearson correlation coefficient was performed to test the correlation between two continuous variables. P-value was considered non-significant if >0.05, significant if < 0.05, highly significant if ≤ 0.01 and very highly significant if < 0.001.
Forward stepwise multiple regression analysis was performed to determine the independent association between relevant patient characteristics and clinical parameters as potential predictor variables (BMI, ADMA, systolic BP, diastolic BP, hypertension duration) and LVMI as the dependant variable.
| Results|| |
This study included 80 patients divided into three groups: Group 1, which included 40 ESRD patients on regular HD, 21 males (52.5%), 19 females (47.5%), 10 cigarette smokers (25%) and 30 non-smokers (75%). Nine patients (22.5%) had RRF with mean value 1.24 ± 0.78 mL/min. Causes of renal failure in this group were hypertensive glomerulosclerosis in 18 patients, chronic glomerulonephritis in seven patients, obstructive uropathy in four patients, chronic pyelonephritis in two patients, vesico-uretric reflux in one patient, polycystic kidney disease in one patient, analgesic nephropathy in one patient, lupus glomerulonephritis in one patient, Alport syndrome in one patient and unknown etiology in four patients. Group 2 included 20 patients with CKD stage 3, 4 and 5 but not yet initiated on dialysis, 14 females (70%), six males (30%). There were one cigarette smoker (5%) and 19 non-smokers (95%). The mean GFR estimated by MDRD formula was 12.05 ± 8.1 mL/min/1.73 m². Causes of CKD were hypertensive glomerulosclerosis in six patients, lupus nephritis in four patients, chronic glomerulonephritis in three patients, chronic pyelonephritis in two patients, obstructive uropathy in one patient, amyloidosis in one patient and unknown etiology in three patients. Group 3 included 20 patients hypertensive with LVH and normal kidney function. There were 12 males (60%) and eight females (40%), seven cigarette smokers (35%) and 11 non-smokers (55%). In addition, 20 healthy subjects were recruited as a control group, 12 females (60%), eight males (40%). All mean values of the anthropometric, demographic and biochemical parameter data of all groups are shown in [Table 1]. All tissue Doppler echocardiographic parameters of all groups are shown in [Table 2]. In our study, the mean values of plasma ADMA levels were significantly high in all patient groups when compared with the control group (P < 0.001). No significant difference was observed between HD patients with RRF (n = 9) and HD patients without RRF (n = 31) as regards mean values of plasma ADMA. There was no significant correlation between ADMA and RRF in HD patients. There was no significant difference for the duration of dialysis, hypertension duration, mean systolic/ diastolic BPs, hemoglobin, iPTH, Ca, PO 4 , albumin and CRP levels between HD patients with and without RRF.
|Table 1: The mean values of anthropometric, demographic and biochemical data of all groups.|
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|Table 2: The mean values of tissue Doppler echocardiographic parameters in all groups.|
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We found no significant difference between Group 1 and Group 2 as regards mean values of ADMA levels (P = 0.966) and also between Group 1 and Group 3 (P = 0.564) [Figure 1]. There was no significant difference of ADMA levels between Group 2 and Group 3 (P = 0.55). There was no significant correlation between ADMA level and GFR in Group 2 patients (r = -0.377, P = 0.1). LVMI was significantly higher in the HD patients compared with the control subjects (P < 0.001). Regarding the diastolic function parameters obtained through tissue Doppler echocardiography, the Em and Em/Am levels were significantly lower in the HD patients when compared with the control group (P < 0.001). CKD patients in pre-dialysis stages had LVMI significantly higher than control, and Em and Em/Am significantly lower than controls (P < 0.001).
|Figure 1: Comparison between all patient groups and control as regards plasma ADMA levels.|
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There was no significant correlation between plasma ADMA and LVMI or EF% in HD patients (P > 0.05). But, there were highly significant correlations between plasma ADMA and Em (r = -0.74, P = 0.000) and Em/Am (r = -0.68, P = 0.000) in Group 1 as shown in [Figure 2]. A significant correlation between ADMA and Em (r = -0.64, P = 0.002) and Em/Am (r = -0.52, P = 0.017) was also observed in Group 2.
|Figure 2: Significant correlation between plasma ADMA and Em and Em/Am in hemodialysis patients of Group 1.|
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| Discussion|| |
This study showed that the mean value of ADMA levels was significantly higher in HD patients than the control group. These results were in agreement when compared with the results of several previous studies. ,, In all these studies, plasma ADMA levels were elevated in HD patients compared with the control groups by 1.4-10.3-fold. Hence, the well-documented endothelial dysfunction in patients with ESRD could possibly be the consequence of an increased plasma ADMA concentration.
Our results showed that the mean values of ADMA were significantly higher in CKD patients in the pre-dialysis stages (3, 4, 5) in comparison with the control group. Several studies showed markedly elevated plasma ADMA levels not only in patients with ESRD but also in patients with progressive chronic kidney disease. ,, These findings were attributed to decreased renal elimination of ADMA. In our study, there was no significant difference between Group 1 and Group 2 as regards mean values of ADMA. Our results are supported by a study by Fleck et al who mentioned that HD is not a suitable procedure for adequate removal of dimethylarginines.  Moreover, our results are also in agreement with Kielstein et al, who assessed plasma concentrations of ADMA in 30 patients with ESRD. During regular HD, they found a lack of effectiveness of dialysis to lower the level of plasma ADMA and attributed that to protein binding and possible redistribution of this molecule during HD. 
Although Fliser et al assessed plasma ADMA concentrations in 227 patients with non-diabetic kidney diseases and mild to moderate renal failure, they found that plasma ADMA concentrations in renal patients were correlated significantly with serum creatinine and GFR. 
However, in our study, we did not find any significant correlation between ADMA and GFR in Group 2 and also no significant correlation between RRF and plasma ADMA in HD patients of Group 1.
Our results are also in agreement with the results of Fleck et al's study that was conducted on 221 patients, 96 patients with CKD, 85 patients on maintenance HD and 40 patients after renal transplantation. He found that ADMA plasma levels did not correlate with GFR in all the groups. 
We analyzed the ADMA level in hypertensive patients with LVH and normal kidney function. We found enhanced ADMA levels with significant difference between this group and the control group. Increased ADMA level in this group is also suggested to be related to the development of endothelial dysfunction. These results are in agreement with Bai and Hui, who found that endothelial dysfunction is pronounced in hypertensive patients with LVH. 
Surprisingly, there was no significant difference between Group 1, Group 2 and Group 3 as regards plasma ADMA levels in our study. It could be assumed that ADMA is more dependent on metabolism, production and enzymatic degradation rather than on GFR. 
In our study, there were highly significant differences between Group 1 and the control as regards mean values of LVMI being higher in patients of Group 1 and also higher among patients of Group 2 in comparison with the control group. Moreover, we also observed highly significant differences between Group 1 and control with regard to mean values of Em, Em/Am and systolic velocity by tissue Doppler echocardiography, which indicate diastolic dysfunction and impaired myocardial contractility in HD patients despite having no clinical manifestation of cardiac disease. These findings were also seen in Group 2. These results are supported by the findings of Cerasola et al, who demonstrated an independent relationship between renal function and diastolic function. 
There was no significant correlation between ADMA levels and LVMI of HD patients. But, there was a highly negative significant correlation between ADMA levels and Em and Em/Am. This result suggests that elevated ADMA levels may worsen left ventricular diastolic functions in HD patients. These results could be explained by the fact that endogenous NO production is believed to be integral to the maintenance of normal LV relaxation and diastolic distensibility not only due to its acute hemodynamic benefits but also because of its long-term inhibition of adverse ventricular remodeling.  Therefore, inhibition of nitric oxide synthase (NOS) by ADMA may negatively affect diastolic function.
Haksun et al found that elevated plasma ADMA levels may negatively affect left ventricular diastolic functions in ESRD patients on peritoneal dialysis and, although he found a significant correlation between ADMA and LVMI, regression analysis could not find ADMA as an independent risk factor for LVMI in ESRD. 
Our result is also supported by Lieb et al's study on a large community-based sample (1919 Framingham Offspring Study participants), and found that ADMA is not correlated with LV mass, LA size and FS in multi-variable models, considering that ADMA is a non-specific inhibitor of all NOS isoforms, which may each differentially affect cardiovascular remodeling. Furthermore, vascular resistance and compliance are also modulated by multiple mechanisms other than the NO pathway. 
On the other hand, Zoccali et al in a study conducted on 198 patients on HD, showed that 147 patients displayed LVH. He confirmed that plasma ADMA was independently correlated with LVMI on multivariate analysis.  In our study, serum ADMA did not correlate with LVMI in all patient groups by the regression analysis.
| Conclusion|| |
We conclude that in patients with renal failure, high plasma ADMA level could possibly be an indicator of endothelial dysfunction and, apparently, is not related to GFR. Hemodialysis is not a suitable procedure for longlasting removal of ADMA. Elevated ADMA levels may be related to left ventricular diastolic dysfunction in ESRD patients but cannot be used as a marker of LVMI in HD patients. We recommend more interventional studies to determine whether the link between ADMA and left ventricular dysfunction is a causal one, and also further cohort studies on a large number of patients to further elucidate these findings.
Conflict of interest: None
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Dr. Yasser El Shahawy
Nephrology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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