|Year : 2017 | Volume
| Issue : 3 | Page : 663-671
Study of association between carboxymethyllysine and circulating soluble receptor for advanced glycation end products and cardiovascular dysfunction in nondiabetic chronic kidney disease
Hassan Abdel-Hady, Said S. A. Khamis, Hany Elbarbary, Seham A Khodeer, Heba E Kasem MBBCh
Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||04-Mar-2016|
|Date of Acceptance||22-May-2016|
|Date of Web Publication||15-Nov-2017|
Heba E Kasem
Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, 32511
Source of Support: None, Conflict of Interest: None
The objective of this study was to evaluate the association between serum advanced glycation end products (AGEs) and their soluble receptors assessed on the basis of carboxymethyllysine (CML) and soluble receptor for advanced glycation end products (sRAGE) and the presence of cardiovascular dysfunction in nondiabetic chronic kidney disease (CKD) patients.
AGE is involved in left ventricular hypertrophy (LVH) and myocardial damage, whereas sRAGE attenuates the progression of heart disease and prevents death in diabetic and nondiabetic CKD patients.
Patients and methods
Eighty nondiabetic CKD patients were subclassified according to estimated glomerular filtration rate (GFR) into two subgroups, CKD-3 patients with GFR between 30 and 59 ml/min/1.73 m2 and CKD-4 patients with GFR between 16 and 29 ml/min/1.73 m2 (CKD-4), using the modification of diet in renal disease formula. Our controls comprised 40 individuals with preserved kidney function of more than 90 ml/min/1.73 m2 matched by age and sex. Routine and specific investigations [serum CML and sRAGE measurement using enzyme-linked immunosorbent assay, carotid intima − media thickness (IMT) measurement using ultrasonographic scanning of the carotid artery, and conventional echocardiography] were performed.
CML and sRAGE correlated negatively with estimated GFR (ml/min/1.73 m2) (r = −0.755 and − 0.668, respectively; P < 0.001). CML had a high significant correlation with LVH (r = 0.755; P < 0.001) and IMT (r = 0.617; P < 0.001) in CKD patients. In a logistic regression, plasma sRAGE was an inverse and independent predictor of LVH [odds ratio (OR): 15.6; confidence interval (CI): 2.5–98.9; P < 0.05], and CML was the independent risk factor for LVH (OR: 23.1; CI: 3.4–158.8; P < 0.001) and IMT (OR: 8.2; CI: 1.05–64.1; P < 0.05) in nondiabetic CKD patients.
AGEs assessed on the basis of CML can be a good predictor and a nontraditional risk factor for the occurrence of cardiovascular morbidity in nondiabetic CKD patients, whereas circulating sRAGE levels are associated in an inverse manner with carotid atherosclerosis and LVH.
Keywords: advanced glycation end products, chronic kidney disease, intima - media thickness, left ventricular hypertrophy, soluble receptor for advanced glycation end products
|How to cite this article:|
Abdel-Hady H, Khamis SS, Elbarbary H, Khodeer SA, Kasem HE. Study of association between carboxymethyllysine and circulating soluble receptor for advanced glycation end products and cardiovascular dysfunction in nondiabetic chronic kidney disease. Menoufia Med J 2017;30:663-71
|How to cite this URL:|
Abdel-Hady H, Khamis SS, Elbarbary H, Khodeer SA, Kasem HE. Study of association between carboxymethyllysine and circulating soluble receptor for advanced glycation end products and cardiovascular dysfunction in nondiabetic chronic kidney disease. Menoufia Med J [serial online] 2017 [cited 2019 Nov 17];30:663-71. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/663/218252
| Introduction|| |
Chronic kidney disease (CKD) is a growing public health epidemic that is associated with markedly increased risk for cardiovascular disease (CVD) and mortality . Although CKD populations manifest a high prevalence of traditional risk factors for atherosclerosis, such as hypertension and diabetes mellitus, these classic risk factors do not fully account for the burden of CVD in patients with CKD . Further studies led to the identification of multiple nontraditional risk factors that might play a direct causal role, and of markers for pre-existing CVD or other factors that increase the risk for CVD .
Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars . AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE)  in pathways that are considered to play a pivotal role in the pathogenesis of atherosclerosis, heart failure, and other diabetes complications .
Besides AGEs, RAGE has the ability to bind several other proinflammatory molecules  given the high number of proinflammatory ligands. RAGE exists in several variants – that is, as a transmembrane receptor on the cell surface or as an isoform lacking the N-terminal domain (N-truncated variant) or the C-terminal (transmembrane) domain (C-truncated variant). The C-truncated RAGE variant, a 50-kDa protein, is mainly produced in endothelial cells by means of regulated alternative splicing or carboxyterminal truncation through metalloproteinases .
This receptor is known as soluble receptor for advanced glycation end products (sRAGE) or endogenous secretory RAGE, a naturally occurring inhibitor of the AGE–RAGE interaction. Clinical studies in nondiabetic individuals have shown that higher levels of endogenous sRAGE may be associated with a lower incidence of coronary artery disease  and hypertension .
Renal insufficiency may contribute to a pathogenic role of oxidative stress in AGE formation, especially in end-stage renal disease (ESRD). In addition, there is evidence that nonoxidative chemistry also contributes to the formation of reactive carbonyl compounds and AGEs in uremia .
AGE peptides are degraded after being filtered by the glomerulus and absorbed by tubular cells. Furthermore, the kidney is known to play an important role in the metabolism of AGEs. The proximal tubule has been identified as the site of catabolism of AGE proteins and peptides bothin vivo andin vitro. Patients having ESRD revealed highest AGE levels. Thus, AGEs are considered a class of uremic toxins . We analyzed the association between serum glycated end products and their soluble receptors [assessed on the basis of carboxymethyllysine (CML) and sRAGE] and the presence of cardiovascular dysfunction in nondiabetic CKD patients.
| Patients and Methods|| |
This study was carried out at Menoufia University Hospital (Egypt). All participants provided informed consent and this study was approved by the local ethics committee of Menoufia University Hospital.
The population studied included 80 CKD patients subclassified according to estimated glomerular filtration rate (GFR) into two subgroups. Subgroup 1 included CKD-3 patients with GFR between 30 and 59 ml/min/1.73 m2, and subgroup 2 included CKD-4 patients with GFR between 16 and 29 ml/min/1.73 m2, on the basis of the modification of diet in renal diseases formula  and according to the Kidney Disease Outcomes Quality Initiative . A total of 40 healthy individuals with preserved kidney function defined by normal blood urea and serum creatinine and GFR higher than 90 ml/min/1.73 m2 matched by age and sex were included in this study.
Patients were eligible for the study if they were not less than 18 years of age and were of CKD stage 3 or CKD stage 4. All participants recruited in this study underwent a standard procedure consisting of assessment of detailed history and complete physical examination. Blood pressure measurements were performed, and were the mean of measurements on three different occasions in the sitting position. The mean arterial pressure (MAP) was calculated from the following formula: MAP = diastolic pressure + 1/3(systolic pressure − diastolic pressure). BMI was calculated using the equation BMI = weight (kg) divided by the square of the height (m).
Patients known to be diabetic, those with autoimmune disease, malignancy, fever, and acute liver disease, and those on hemodialysis, peritoneal dialysis, or renal transplantation were excluded from the study.
Blood samples were obtained from all patients and immediately centrifuged, separated into aliquots for further assays, and stored at −201°C until measurement. Blood urea and serum creatinine were measured using an autoanalyzer synchron CX5 Beckman (Diamond Diagnostics, Holliston, MA, USA). Serum phosphate, calcium, albumin, liver function tests, serum sodium, and potassium were measured using standard commercial assays. Standard ECG and abdominopelvic ultrasound (Fukuda FX 2100; Hongo, Bunkyo-ku, Tokyo, Japan) were performed. Estimated GFR was calculated according to the modification of diet in renal diseases equation :
Carboxymethyllysine and soluble receptor for advanced glycation end product
CML and sRAGE were assessed using an enzyme-linked immunosorbent assay kit (human immunoassay; R and D System Inc., Minneapolis, Minnesota**, USA). Principle of the assay: the assay uses the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for RAGE (extracellular domain) and CML has been precoated onto a microplate.
Carotid intima − media thickness (echo–color Doppler study)
Both in patients and controls, ultrasonographic studies on common carotid arteries were performed bilaterally by a single observer blinded to the clinical and biochemical data. All studies were performed with Logi 3 (R and D System Inc., Minneapolis, Minnesota, USA) Pro using a 10-MHz high-resolution probe. The intima–media thickness (IMT) was defined as a low level echo gray band that does not project into the arterial lumen. IMT was measured at end diastole as the distance from the leading edge of the second echogenic line of the far walls of the distal segment of the common carotid artery, the carotid bifurcation, and the initial tract of the internal carotid artery on both sides. Measurements were performed at 0.5, 1, and 2 cm below and above the bifurcation (six measurements on each side), and the average measurement was taken as IMT. The internal diameter of the common carotid artery was measured bilaterally 2 cm below the bifurcation at end diastole, and the average measurement was taken as diameter of common carotid artery. IMT and diameter of the common carotid artery measurements were always performed in plaque-free arterial segments. The number of atherosclerotic plaques [either as faint gray echoes (soft plaques) or bright white echoes (calcified plaque) protruding into the lumen] that were detected in the bulbar area (from 2 cm below to 2 cm above the bifurcation) of the carotid arteries were recorded on both sides and summed up .
All echocardiographic examinations were made by one investigator who was blinded to the study; the examinations were made with a Hewlett Packard 77020 A ultrasound systems (Hewlett Packard Inc., Chicago, USA) equipped with a 2.5 MHz transducer, together with the lead II ECG. Left ventricular mass and left ventricular mass indexed (LVMI) to body surface area were estimated using left ventricular cavity dimension and wall thickness at end diastole . Left ventricular hypertrophy (LVH) was defined as LVMI greater than 95 g/m2 for female LVMI greater than 115 g/m2 for male patients. Mean wall thickness was. The relative wall thickness (2×posterior wall thickness/left ventricular end diastolic diameter) was also calculated, as an index of the left ventricular geometric pattern.
The collected data were coded, tabulated, and statistically analyzed using SPSS program (statistical package for the social sciences; SPSS Inc., IBM, Chicago, USA) software, version 17.0. Descriptive statistics was performed and numerical parametric data were presented as mean, SD, and minimum and maximum of the range and numerical nonparametric data were presented as median and first and third interquartile range, whereas categorical data were presented as number and percentage.
Inferential analyses were performed for quantitative variables using the independent t-test in cases of two independent groups with parametric data and using the Mann–Whitney U-test in cases of two independent groups with nonparametric data. Inferential analyses were performed for qualitative data using the χ2-test for independent groups. However, correlations were made using Pearson's correlation for numerical parametric data, and logistic regression models were used to examine the relation between serum CML, sRAGE, and other factors with LVH and IMT.
| Results|| |
The current study included 80 CKD patients: 33 (41%) patients with GFR between 30 and 59 ml/min/1.73 m2 (CKD-3) and 47 (59%) patients with GFR between 16 and 29 ml/min/1.73 m2 (CKD-4). As shown in [Table 1], CKD patients and healthy individuals were accurately matched for age and sex. However, CKD patients had higher mean arterial blood pressure, triglycerides, cholesterol, and calcium phosphate product, and lower hemoglobin when compared with controls. The plasma concentration of sRAGE and CML were significantly higher in CKD patients (P < 0.001) than in controls. The carotid intima thickness, internal diameter of carotid arteries, and total number of plaques were significantly higher in CKD patients than in controls [Table 1] and [Table 2]**.
|Table 1: Demographic, laboratory, and radiological characteristics of all patients|
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|Table 2: Correlation coefficient (r) between carboxymethyllysine (soluble receptor for advanced glycation end products) and clinical and laboratory characteristic of the studied group (I) (chronic kidney disease patients) (N=80)|
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Plasma carboxymethyllysine, soluble receptor for advanced glycation end products, and renal function
CML (pg/dl) was significantly higher in CKD-4 patients (1706.9 ± 750.3) than in CKD-3 patients (1095.8 ± 557.9) (P < 0.001) [Table 3]. There was a high significant negative correlation between estimated GFR (ml/min/1.73 m2) and each of CML (pg/dl) and sRAGE (pg/dl) in group I (r=−0.755 and − 0.668, respectively; P < 0.001).
|Table 3: Carboxymethyllsine and soluble receptor for advanced glycation end product in group I (chronic kidney disease) patients according to stage of chronic kidney disease|
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Echocardiographic data in chronic kidney disease patients
LVMI was markedly higher (62.5%) in CKD patients than in healthy individuals. Fifty of 80 (62.5%) patients displayed LVH at echocardiography, and LVH was of the concentric type in 54% of cases and eccentric in other cases [Table 4].
|Table 4: Left ventricular ejection fraction (%) and pattern of left ventricular hypertrophy in group I (chronic kidney disease patient) according to the presence or absence of left ventricular hypertrophy|
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Carboxymethyllysine's effect on cardiovascular dysfunction
CML (pg/dl) had a high significant correlation with left ventricular hypertrophy measured with the LVMI (g/m2) in group I (r = 0.755; P < 0.001) and associated with concentric LVH pattern (2278.7 ± 650.9) than with eccentric pattern (1253.9 ± 589.7) (P < 0.001). There was a high significant correlation between CML (pg/dl) and carotid intima thickness (IMT) in group I (r = 0.617; P < 0.001) [Table 5] and [Table 6]**].
|Table 5: Laboratory characteristic of the studied group I (chronic kidney disease patient) according to the presence or absence of left ventricular hypertrophy measured using left ventricular mass index (g/m2)|
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|Table 6: Correlation coefficient between carotid intima-media thickness and carboxymethyllysine (soluble receptor for advanced glycation end products) of the studied group (I) (chronic kidney disease patients) (N=80)|
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Soluble receptor of advanced glycated end product effect on cardiovascular dysfunction
sRAGE had a negative significant correlation with carotid intima thickness (IMT) in group I (r = −0.27; P < 0.05) [Table 6]. However, there was no significant correlation between sRAGE and left ventricular hypertrophy measured using the LVMI (g/m2) in group I (r = −0.02; P > 0.05).
The validity of CML and sRAGE in the prediction of LVH in group I (CKD) patients was determined. It was found that CML had a cutoff point of 990 pg/dl, a sensitivity of 80%, and specificity of 66.7% with 75% accuracy, whereas sRAGE had a cutoff point of 1300 pg/dl, a sensitivity of 76%, and a specificity of 63.3% with 71.3% accuracy.
In a logistic regression for prediction of LVH in CKD patient model testing the interactions between LVH and other risk factors (CML, sRAGE, triglyceride, cholesterol, phosphorus, and hypertension), plasma sRAGE was confirmed as an inverse and independent predictor of LVH in CKD patients [odds ratio (OR): 15.6; confidence interval (CI): 2.5–98.9; P < 0.05). CML was the independent risk factor for LVH in group I (CKD) patients (OR: 23.1; CI: 3.4–158.8; P < 0.001), followed by MAP (OR: 10.04; CI: 1.3–77.5; P < 0.05) [Table 7] and [Table 8]. Moreover, in a multiple logistic regression for prediction of carotid intima thickness in CKD patients, CML (OR: 8.2; CI: 1.05–64.1; P < 0.05), triglyceride (OR: 9.7; CI: 1.2–80.2; P < 0.05), and cholesterol (OR: 6.4; CI: 1.2–35.6; P < 0.05) were independent risk factors for the prediction of the presence of IMT in the studied CKD patients [Table 6] and [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6].
|Table 7: Logistic regression for prediction of left ventricular hypertrophy in group I (chronic kidney disease) patients|
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|Table 8: Logistic regression for prediction of carotid intima thickness in group I (chronic kidney disease) patients|
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|Figure 1: Distribution of left ventricular hypertrophy (LVH) in group I (chronic kidney disease) patients.|
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|Figure 2: Correlation coefficient between estimated glomerular filtration rate (GFR) (ml/min/1.73 m2) and carboxymethyllysine (CML) (pg/dl).|
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|Figure 3: Correlation coefficient between estimated glomerular filtration rate (GFR) (ml/min/1.73 m2xs) and soluble receptor of advanced glycated end product (sRAGE) (pg/dl).|
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|Figure 4: Correlation coefficient (r) between left ventricular mass index (g/m2) and carboxymethyllysine in group I (chronic kidney disease patients).|
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|Figure 5: Receiver operating curve (ROC) for validity of carboxymethyllysine in the prediction of left ventricular hypertrophy in group I chronic kidney disease patients.|
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|Figure 6: Receiver operating curve (ROC) for validity of soluble receptor for advanced glycation end products in the prediction of left ventricular hypertrophy in group I chronic kidney disease patients.|
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| Discussion|| |
This work aimed at studying the association between serum CML and sRAGE and the presence of cardiovascular dysfunction in nondiabetic CKD patients and shows that in patients with CKD there was a high prevalenceof LVH measured using the LVMI (62.5%), mainly concentric pattern rather than eccentric pattern. CML was the independent risk factor for LVH and carotid intima thickness in group I (CKD), whereas circulating sRAGE is the most protective factor of LVH in group I (CKD).
LVH is recognized as a fundamental component of risk for death and cardiovascular complications in CKD, and accumulation of connective tissue in the myocardium is considered as a distinguishing feature of LVH in these patients . The prevalence of this alteration increases as the GFR declines, and as much as 78% of stage 5D CKD patients are eventually affected by LVH . The mechanisms underlying LVH involve afterload (arterial pressure and compliance), preload (intravascular volume and anemia), and a variety of other factors, including sympathetic overactivity, accumulation of the endogenous inhibitor of nitric oxide synthase, hyperparathyroidism, insulin resistance, and other factors. However, collectively these risk factors only in part explain the variability in left ventricular mass in patients with CKD. Atherosclerosis also is a major cause of death and cardiovascular complications in patients with CKD, and several studies have documented that the risk for such complications starts to rise when the GFR falls below 60 ml/min .
AGEs are a heterogeneous group of bioactive molecules resulting from nonenzymatic glycation and oxidation of proteins and lipids. RAGE, a 35 kDa transmembrane receptor of the immunoglobulin superfamily, is the main receptor mediating the effects of AGEs at cell level. Besides AGEs, RAGE is also able to bind other ligands and it is therefore classified as a classical pattern recognition receptor. RAGE stimulation potently activates several proinflammatory genes and represents a fundamental element of a pathway implicated in a variety of inflammatory disorders spanning from diabetes to cancer .
High AGE levels in patients with ESRD have been associated with concentric LVH, a geometric pattern that accompanies arterial stiffness in this population, but other studies in patients with moderate-to-severe CKD failed to show an independent relationship between AGEs and LVH . The interpretation of the link between AGEs and LVH in CKD is complex because these compounds are affected by inflammation and wrong diet – the two factors that are also associated with LVH. Furthermore, the RAGE signaling pathway may indicate activation of not only AGEs but also other inflammatory ligands that are increased or amplified in CKD .
RAGE is expressed in a variety of tissues, including cardiac myocytes, and this pathway through activation by AGE is involved in LVH and cardiomyopathy in diabetic rats. Candido et al.  found that skin autofluorescence was 30% higher in patients with CVD history than in those without CVD. Skin autofluorescence had a significant effect on CVD in both the diabetic group and the nondiabetic group. In our study, CML had a significant correlation with the LVMI in CKD patients with concentric pattern than in those with eccentric pattern.
An accumulation of AGEs in serum and tissues due to declining renal function may potentially exacerbate endothelial dysfunction and atherosclerosis. AGEs play a role in atherosclerosis by accumulating in arterial walls, increasing arterial stiffness by cross-linking collagen, contributing to the oxidation of low-density lipoprotein (LDL), cross-linking collagen, contributing to the oxidation of LDL, cross-linking with LDL and immunoglobulins in the subendothelium, initiating monocyte migration across endothelial cells, and upregulating inflammation through receptor for AGE (RAGE) and activation of transcription factor nuclear factor-κB . In our study, CML had a significant correlation with carotid intima thickness and in logistic regression for prediction of IMT. CML was an independent risk factor for IMT.
Linden et al.  found that serum CML correlated with RAGE and inversely with postocclusive reactive hyperemia, and an inverse correlation with thyroid hormone was also noted.
The soluble form of RAGE is a decoy receptor shedded from cell surface, which effectively binds circulating AGEs. By binding circulating AGEs, sRAGE attenuate RAGE signaling at cell level, thereby exerting a protective action on various organ systems .
A protective role of high sRAGE has coherently emerged in various experimental studies in which sRAGE administration either prevented or attenuated tissue damage triggered by RAGE stimulation, including microvascular and macrovascular disease and ischemia–reperfusion injury in murine models. Of note, in animal models of chronic diseases, sRAGE suppresses chronic cellular activation and dysfunction more markedly than full abrogation of RAGE receptors .
A protective role of circulating sRAGE in humans is suggested by the observation that the plasma concentration of these receptors is lower in patients with coronary artery disease than in age-matched healthy controls and that carotid atherosclerosis is inversely associated with sRAGE in diabetic and nondiabetic patients . In our study, sRAGE was the most protective factor of LVH and had a negative correlation with carotid intima thickness. Thus, CML and sRAGE were significantly increased in the studied nondiabetic CKD patients compared with healthy controls; this increase is significantly higher in stage 4 than in stage 3 CKD.
| Conclusion|| |
The significant increase and significant correlation between CML and each of LVH and IMT could indicate that AGEs can be a good predictor and a nontraditional risk factor for the occurrence of cardiovascular morbidity in nondiabetic CKD patients, whereas circulating sRAGE levels are associated in an inverse manner to carotid atherosclerosis and LVH.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]