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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 17  |  Issue : 1  |  Page : 8-29

Correlations of serum magnesium with dyslipidemia in patients on maintenance hemodialysis


1 Department of Internal Medicine, Faculty of Medicine, Assuit University Hospitals, Assiut University, Assuit, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Assuit University Hospitals, Assiut University, Assuit, Egypt

Date of Submission18-Jul-2016
Date of Acceptance09-Nov-2016
Date of Web Publication13-Jun-2017

Correspondence Address:
Effat A.E. Tony
Department of Internal Medicine, Nephrology Unit, Faculty of Medicine, Assuit University, Assuit, 71515
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-9165.207900

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  Abstract 

Background
Chronic renal failure (CRF) is defined as a slowly progressive loss of kidney functions resulting in permanent kidney failure. Patients with chronic kidney disease (CKD) are at increased risk not only for end-stage kidney disease but also for cardiovascular (CV) disease. CKD is characterized by specific metabolic abnormalities of plasma lipoproteins (LPs). These abnormalities involve all LP classes and show variations depending on the degree of renal impairment, the etiology of the primary disease, the presence of nephrotic syndrome (NS), and the method of dialysis for patients undergoing renal replacement therapy. High LP-a indicates a coagulant risk for plaque thrombosis. Thus, it predicts risk for early atherosclerosis independently of other cardiac risk factors, including low-density lipoprotein (LDL), in patients with CKD. Dyslipidemia in CKD is associated with increased thickness and stiffness of the large arteries. Thus, strict control of dyslipidemia would be beneficial in preventing CVD, at least during the early stages of CKD. The kidney has a vital role in magnesium (Mg) homeostasis, and, although renal handling of Mg is highly adaptable, this ability deteriorates when renal function declines significantly. Mg homeostasis in humans primarily depends on the balance between intestinal uptake and renal excretion. Mg may be normal or decreased in dialysis patients, which is probably due to decreased dietary intake combined with impaired intestinal absorption. In patients on chronic hemodialysis (HD), the major determinant of Mg balance is concentration of Mg in the dialysate. Thus, in patients with CKD, there may be reduced intake, impaired absorption from the intestine, use of diuretics, and acidosis, which may result in decreased serum Mg, whereas reduced renal excretion may cause accumulation of Mg, resulting in increased serum Mg levels in CRF patients. This prospective study aimed to determine the correlation of serum Mg with dyslipidemia in patients on maintenance HD.
Patients and methods
This case–control observational prospective study was conducted on 37 end-stage renal failure patients on maintenance HD (age range: 20–70 years; mean age: 47.8±13.9 years; 16 men and 21 women) who were recruited from the Renal and Dialysis Unit, Department of Internal Medicine, Assuit University Hospitals, Egypt, from 2010 to 2012. In addition, 25 apparently healthy persons (age range: 17–70 years; mean age: 42.0±13.25 years; 13 male and 12 female) recruited mainly from among the medical staff and their families who underwent a health examination at Assuit University Hospitals were enrolled in the study as a control group. The study was approved by the ethical committee of the Faculty of Medicine, Assuit University, and written informed consent was obtained from each participant. The underlying causes of CRF were chronic glomerulonephritis, diabetes mellitus, chronic pyelonephritis, obstructive uropathy, analgesic and idiopathic nephropathy, polycystic kidney disease, and lupus nephritis. The duration of HD ranged from 5 to 15 years, with a mean duration of 7.0±2.9 years. The frequency of HD was three sessions per week. The type of dialyzer membrane was polysulfone with bicarbonate dialysate and the dialysate flow rate was 500 ml/min. Blood flow ranged from 250 to 300 ml/min. The Mg concentration in the dialysate fluid was 1 mEq/l. Dialysis adequacy was assessed by measuring urea kinetic modeling (mean urea kinetic modeling: 2.38±0.44). Glomerular filtration rate was estimated by the modified MDRD equation. Patients were excluded if they had been taking diuretics and/or lipid-lowering agents or had acute or chronic infections. All participants were subjected to thorough history taking, full clinical examination, and anthropometric measurements including weight, height, and BMI. Blood samples from both patients and controls were drawn in the morning after an overnight fast of 12–16 h. Peripheral hemogram, liver function, kidney function, lipid profile, LP-a, and serum electrolytes such as Ca, phosphorus (P), and Mg were assessed. An ECG was obtained with measurement of the corrected QT interval (QTc). Transthoracic echocardiography (ECHO) was performed in all studied groups on an interdialytic day in the evaluation phase. M-mode and two-dimensional images as well as spectral pulsed and color flow Doppler recordings were obtained.
Results
Significant renal dysfunction and lower levels of hemoglobin and platelets with higher mean corpuscular volume (MCV) and mean cell hemoglobin concentration (MCHC) with no statistical difference in the mean level of white blood cells (WBCs) were reported in our studied patients in comparison with controls. Notably, highly statistically significantly lower levels of high-density lipoprotein-cholestrol (HDL-C) with significantly lower levels of LDL-cholesterol (LDL-C) were seen in our HD patients. However, the mean levels of triglycerides (TG) and LP-a were statistically significantly higher, with no statistically significant differences in total cholesterol (TC) levels in the studied patients. The levels of P and Mg were highly statistically significantly higher, with lower Ca levels of no statistical difference, in HD patients. There were no statistically significant differences in the main levels of serum Mg among the studied patients. Lipid metabolism disturbances are frequently present in patients with CRF, representing an important factor in premature atherosclerosis development. The majority of patients with no ST-segment changes had more Mg retention and LP-a retention but with no statistical significance. Nonetheless, none of our patients had prolonged QTc interval in ECG, despite having more Mg retention and LP-a retention with no statistical significance. Left ventricular hypertrophy (LVH) was a striking finding in our patients who had more serum Mg retention and LP-a retention but with no statistical significance. A significant positive correlation between serum Mg level and ST-segment changes in ECG and a significant negative correlation between serum LP-a level and ST-segment changes in ECG were found in our studied patients. Moreover, there were positive correlations of serum Mg levels and LP-a levels with LVH in ECG and ECHO findings in our patients, with no statistical significance. The prolonged QTc interval in ECG had a significant positive correlation with the LP-a levels and a nonsignificant positive correlation with serum Mg level. A significant positive correlation of age with TC, TG, and HDL and a nonsignificant negative correlation with LDL were found in our studied patients. However, there were significant negative correlations of the duration of CKD with TC, TG, and LDL and a negative correlation with HDL in our studied patients, with no statistical significance. Nonsignificant negative correlations of BMI with LDL and HDL and significant negative correlations with TC and TG were found in our studied patients. Notably, there was a negative correlation of lipid profile with serum creatinine and blood urea. Nonsignificant negative correlations of serum calcium (Ca) and serum P with LDL were observed, whereas there were nonsignificant positive correlations of serum Ca with TC and TG and negative correlations of serum P with TC and TG, with no statistical significance. The HDL had a significant positive correlation with serum Ca and a significant negative correlation HDL was found in our studied patients, there was a significant negative correlation between HDL and serum phosphorus, however, serum Ca was positively correlated with HDL but with no statistical significance, but a significant positive correlation between LP-a level and MCHC. There were negative correlations between Mg level and hemoglobin, WBCs, and MCV, with no statistical significance, in our patients and significant negative correlations between Mg level and MCHC and platelets. In the current study, there were nonsignificant positive correlations between LP-a level and blood urea and a nonsignificant negative correlation with serum creatinine. Positive correlations of Mg level with blood urea and serum creatinine were found in the study. Notably, serum Mg was statistically significantly positively correlated with LP-a, TC, TG, and LDL-C; however, there was a highly significant negative correlation between HDL-C and serum Mg. No vascular calcification was found in any of the studied patients. Moreover, LP-a and serum Mg were statistically significantly positively correlated with TC, TG, and LDL-C, with nonsignificant negative correlation with HDL-C. A significant positive correlation of hypertension with LP-a and Mg level was found in our studied patients. Nonsignificant negative correlations of Mg level with the age of patients, height, and BMI were found in our studied patients, but significant positive correlations of LP-a with the age of patients and BMI and a nonsignificant positive correlation with weight were found. Meanwhile, there negative correlations of LP-a and serum Mg level with the duration of CKD and the height of patients. Serum P had a significant positive correlation with Mg level and a significant negative correlation with LP-a level in our study. However, a negative correlation of serum Ca with Mg and LP-a levels, with no statistical significance, was detected. In the multivariate logistic regression analysis of the association between serum Mg level, all laboratory parameters of end-stage renal disease (ESRD), and HD in the studied patients there were three factors associated with HD (Mg level, LDL-C, and LP-a). There was a 45-fold increase in the probability of HD per 1 mg/dl increase in the Mg level and this relation was statistically significant [odds ratio (OR)=45, 95% confidence interval (CI): 15.4–68.1, P<0.01]. Mg level revealed a 14% increase in the prediction level in the study sample compared with controls. There was also a 3% decrease in the probability of HD per 1 mg/dl decrease in the level of serum LDL, and this relation was statistically significant (OR=0.97, 95% CI: 0.95–0.99, P<0.05). LDL had a 5% increase in the predictive level. Moreover, there was 68% increase in the probability of HD per 1 mg/dl increase in the level of LP-a and this relation was statistically significant (OR=1.68, 95% CI: 1.01–2.3, P<0.05). LP-a revealed a 6% excess in the prediction of HD.
Conclusion
In essence, CKD is characterized by specific metabolic abnormalities of plasma LPs. High serum LP-a and low HDL-C are highly atherogenic and are two factors that accelerate atherosclerosis in patients with CKD and correlate with CV mortality. The kidney has a vital role in Mg homeostasis, and, although the renal handling of Mg is highly adaptable, this ability deteriorates when renal function declines significantly. Mg does not increase the LP synthesis. Patients with CKD on maintenance HD show positive correlations between serum Mg and serum HDL-C, LP-a, and TG levels. Therefore, Mg has a protective role in hypertension, arrhythmia, atherosclerosis, and vascular calcification in ESRD patients. Notably, the low serum Mg may be an independent risk factor for premature death in CKD patients. Although the exact role of Mg in bone metabolism is unclear, it may have both positive and negative effects, and it is uncertain what the optimal Mg levels are in uremic patients. Nonetheless, the dialysate Mg concentration is a major determinant of HD or peritoneal dialysis patients’ Mg balance, but the intradialytic CV and hemodynamic benefits of varying Mg concentration in patients’ dialysate are unclear. Acquired prolonged QT-interval syndrome is a highly prevalent condition in patients with CKD undergoing HD and is one of the known pathophysiological mechanisms of sudden death in this population. The high serum LP-a level and Mg depletion in CKD patients on maintenance HD displayed a high frequency of abnormal electrocardiographic findings, including a high prevalence of patients with prolonged QTc interval. Nephrologists must pay attention to identifying patients with prolongation of the QT interval and the associated clinical and laboratory conditions, such as structural changes of the heart, cardiac calcification, Mg depletion, high serum LP-a level, and the prescription of drugs that induce QT interval prolongation, particularly in patients already presenting an extended QT interval. LVH is a striking ECHO feature among our HD patients. Numerous studies now provide strong suggestive evidence for a protective role of Mg in vascular calcification, arrhythmias, and atherosclerosis in ESRD patients. Our results allow us to speculate on the possible salutary role of increasing plasma levels of Mg to facilitate the healing of vascular injuries and to prevent atherosclerosis, hypertension, arrhythmia, and chronic myocardial ischemia. Mg-based compounds have the additional advantage of being much cheaper to use than some newer alternatives. Nevertheless, in an era of numerous negative studies in nephrology, the long-term effects on either the inhibition of vascular calcifications, reduction of ischemic disease, prevention of arrhythmias, or changes in bone morphology have not been adequately investigated. Moreover, a link between BMI and the presence of Mg retention and high LP-a level was observed. New studies need to be outlined, using accurate nutritional status markers for HD patients, to better observe the possible link between malnourishment and prolonged QTc interval.

Keywords: chronic kidney disease, dyslipidemia, high-density lipoprotein, lipoprotein-a, low-density lipoprotein, magnesium, phosphorus hemodialysis, triglycerides


How to cite this article:
Tony EA, Tohamy MA, Amin NF, Abdel-Aal AM, Rahim SA. Correlations of serum magnesium with dyslipidemia in patients on maintenance hemodialysis. J Egypt Soc Nephrol Transplant 2017;17:8-29

How to cite this URL:
Tony EA, Tohamy MA, Amin NF, Abdel-Aal AM, Rahim SA. Correlations of serum magnesium with dyslipidemia in patients on maintenance hemodialysis. J Egypt Soc Nephrol Transplant [serial online] 2017 [cited 2017 Oct 18];17:8-29. Available from: http://www.jesnt.eg.net/text.asp?2017/17/1/8/207900


  Introduction Top


Chronic kidney disease (CKD) is a public health problem worldwide. CKD patients are at increased risk not only for end-stage kidney disease but also for cardiovascular disease [1]. CKD is characterized by specific metabolic abnormalities of plasma lipoproteins (LPs) [2],[3]. These abnormalities involve all LP classes and show variations depending on the degree of renal impairment, the etiology of primary disease, the presence of nephrotic syndrome (NS), and the method of dialysis [hemodialysis (HD) or peritoneal dialysis (PD)] in patients undergoing renal replacement therapy. Hypertriglyceridemia is one of the most common quantitative lipid abnormalities in patients with CKD [4]. The predominant mechanism responsible for increased concentration of triglyceride (TG)-rich LPs in predialysis patients is one of delayed catabolism [5]. The reduced catabolic rate is likely due to diminished LP lipase activity as a consequence of the downregulation of the enzyme gene [6] and the presence of lipase inhibitors [6]. Apolipoprotein C-III (Apo-C-III) is a potent inhibitor of LP lipase, whereas Apo-C-II is an activator of the same enzyme. A decrease in Apo-C-II/Apo-C-III ratio due to a disproportionate increase in plasma Apo-C-III is a possible cause of LP lipase inactivation in uremia [7]. The secondary hyperparathyroidism is involved in the impaired catabolism of TG-rich LPs, being an additional mechanism by which CKD may raise plasma TG concentrations [6]. Except for the low catabolic rate, the increased hepatic production of TG-rich LPs may also play a contributory role in the pathogenesis of dyslipidemia in renal disease [5]. It is well known that CKD causes insulin resistance, which can, in turn, promote hepatic very low-density lipoprotein (VLDL) production [8]. Thus, it could be hypothesized that the insulin resistance-driven overproduction of VLDL may significantly contribute to the development of hypertriglyceridemia in patients with CKD. Hypertriglyceridemia (due to accumulation of VLDL and remnant LPs such as intermediate-density lipoprotein) is also the predominant LP abnormality in a considerable number of cases with nephrotic range proteinuria [6]. This dyslipidemia results from a combination of increased production and reduced clearance of VLDL. It is well known that the progressive delipidation of TG-rich LPs is facilitated by the action of two different enzymes: endothelial-bound LP lipase and hepatic lipase. The expression of the genes of these enzymes has been found to be downregulated in patients with NS [9]. In addition, other factors such as hypoalbuminemia and proteinuria may further decrease the efficiency of LP lipase-induced lipolysis of TG-rich LPs by interfering with the endothelial binding of the enzyme and by changing the composition of VLDLs in a way that reduces their suitability as LP lipase substrates [10]. The initiation of renal replacement therapy, as well as the choice of dialysis modality, may also influence the levels of TG-rich LPs in end-stage renal disease (ESRD) patients [11]. The pathophysiological mechanisms responsible for these alterations seem to be generally similar to those described in predialysis patients with CKD. However, factors related to the procedure of renal replacement therapy seem to contribute to the increased levels of TG observed in this patient group. In HD patients the repeated use of low-molecular heparins for anticoagulation may lead to a defective catabolism of TG-rich LPs as heparin releases LP lipase from the endothelial surface and thus its chronic use may result in LP lipase depletion [9],[12]. Also, it has been shown that the use of high-flux polysulfone or cellulose triacetate membranes is accompanied by a significant reduction in serum TG. This improvement could, at least in part, be attributed to an increase in the Apo-C-II/Apo-C-III ratio, which increases the activity of LP lipase and facilitates the intravascular lipolysis of TG-rich LPs [13]. Kronenberg et al. [14] stated that hypertriglyceridemia is more prevalent in continuous ambulatory peritoneal dialysis (CAPD) patients. Although the pathophysiological mechanisms are not clear, it has been suggested that significant absorption of glucose from the dialysis fluid may play a large role as it can lead to an increase in insulin levels and may enhance the hepatic synthesis and secretion of VLDL [15]. Babazono et al. [16] indicated that the reduction of glucose load with the use of less-absorbed icodextrin-containing dialysis solution instead of glucose for the overnight dwell sufficiently improves the lipid profile of these patients. Total cholesterol (TC) is usually normal or reduced and occasionally elevated in ESRD patients. A significant factor that determines the levels of plasma cholesterol-rich LPs, except the deterioration in renal function, is the degree of proteinuria and low-density lipoprotein (LDL)-receptor-mediated hepatic cholesterol uptake [6]. CKD patients, with or without heavy proteinuria, display important qualitative alterations in LDL metabolism. The proportion of small dense LDL particles, which is considered to be highly atherogenic, is increased [6]. Small dense LDL is a subtype of LDL that has high propensity to penetrate the vessel wall, becomes oxidized, and triggers the atherosclerotic process. CAPD patients exhibit a more atherogenic lipid profile that is characterized by higher total and LDL-C values and increased concentrations of small dense LDL and Apo-B [6]. A number of possible factors associated with the PD treatment may explain those alterations in LP metabolism. It is known that CAPD patients lose substantial amounts of plasma proteins into the peritoneal dialysate. This protein loss may, in turn, stimulate the hepatic synthesis of albumin and other liver-derived proteins, including cholesterol-enriched LPs [6]. It should be also mentioned that, in CAPD patients, substantial amounts of Apos and intact LPs are lost through the peritoneal cavity. However, the pathophysiological significance of these losses remains unclear [9]. Patients with CKD have, generally, reduced plasma high-density lipoprotein-cholestrol (HDL-C) levels compared with individuals with normal renal function. This can be attributed to several mechanisms. Thus, patients with impaired renal function usually exhibit decreased levels of Apo-AI and Apo-AII (the main protein constituents of HDL), diminished activity of lecithin-cholesterol acyl transferase (LCAT) (the enzyme responsible for the esterification of free cholesterol in HDL particles) [17], as well as increased activity of cholesteryl ester transfer protein Kimura et al. [18] that facilitates the transfer of cholesterol esters from HDL to TG-rich LPs, thus reducing the serum concentrations of HDL-C. In addition to their reduced efficiency as cholesterol acceptors, HDL particles from individuals with impaired renal function have less effective antioxidative and anti-inflammatory function. This impairment can, at least in part, be attributed to the reduction in the activities of HDL-associated enzymes, such as paraoxonase (an enzyme that inhibits LDL oxidation) [19]. HD and PD procedures may also have a contributory role in the reduced HDL-C levels of dialysis patients [11]. Moreover, in dialysis patients the type of membrane and dialysate used in HD may influence the HDL-C levels. It has been shown that the use of high-flux instead of low-flux membranes is associated with an increase in Apo-AI and HDL-C values [9]. In addition, the type of dialysate may also significantly affect the serum levels of LPs in HD patients. Indeed, it has been shown that the use of bicarbonate dialysate may result in higher HDL-C concentrations than the use of acetate dialysate [9]. LP-a, consists of an LDL-like particle and the specific Apo-a, which is covalently bound to the Apo-B of the LDL-like particle. LP-a plasma concentrations are highly heritable and mainly controlled by the Apo-a gene and it is located on chromosome 6q26–27. The structure of Apo-a is highly homologous to the plasma protease zymogene plasminogen and tissue plasminogen activator and thus it has been suggested that LP-a may promote thrombogenesis by inhibiting fibrinolysis [9]. Apo-a is expressed by liver cells (hepatocytes) and the half-life of LP-a in the circulation is about 3–4 days [20]. The mechanism and sites of LP-a catabolism are largely unknown. The kidney has been identified as playing a role in LP-a clearance from plasma [21]. LP-a concentrations may be affected by disease states (e.g. kidney failure) but are only slightly affected by diet, exercise, and other environmental factors. In CAPD patients, increases in plasma LP-a levels occur in all Apo-a isoform groups, probably as a consequence of the pronounced protein loss and the subsequently increased production of this LP in the liver Kontush et al. [22]. LP-a carries cholesterol and thus contributes to atherosclerosis. In addition, it transports the more atherogenic proinflammatory oxidized phospholipids that attract inflammatory cells to vessel walls and leads to smooth muscle cell proliferation [23],[24] Tsimikas [25]. Therefore, high LP-a in blood is a risk factor for atherosclerosis, thrombosis, coronary heart disease, cerebrovascular disease (CVD), and stroke [26],[27]. Magnesium (Mg) is the second most abundant intracellular cation and the fourth one of the human body. Normal serum Mg values range from 1.8 to 2.4 mg/dl (1.4–2.1 mEq/l) [28]. The kidney has a vital role in Mg homeostasis. Mg homeostasis in humans primarily depends on the balance between intestinal uptake and renal excretion. Although renal handling of Mg is highly adaptable, this ability deteriorates when renal function declines significantly. In CKD, increases in the fractional excretion of Mg largely compensate for the loss of glomerular filtration rate to maintain normal serum Mg levels. However, in more advanced CKD (as creatinine clearance falls <30 ml/min), this compensatory mechanism becomes inadequate such that overt hypermagnesemia develops frequently in patients with creatinine clearances less than 10 ml/min [29]. Mg is regulated mainly through renal excretion and to a lesser extent by hormones that affect its gastrointestinal absorption and bone metabolism − for example, parathyroid hormone (PTH), calcitonin, vitamin D, and catecholamines [30],[31]. Mg has important roles: (a) it is a biologic competitor of calcium (Ca), antagonizing it in binding cellular membranes and proteins; (b) it functions as a cofactor in more than 300 essential enzymatic reactions; and (c) it has a role in the regulation of the passages of electrolytes through the cellular membranes [32]. Mg is required for protein and nucleic acid synthesis, for cell cycle progression, cytoskeletal and mitochondrial integrity, and for the binding of substances to the plasma membrane. Mg plays an important role in carbohydrate metabolism, and its deficiency may worsen insulin resistance, a condition that often precedes diabetes, or may be a consequence of insulin resistance [33]. Mg is required for the synthesis of glutathione, which is an important antioxidant, [34]. Mg is necessary for the activity of LCAT and LP lipase, which lowers TG [35]. Mg is essential for synthesis, release, and adequate tissue sensitivity to PTH. Hypermagnesemia, similar to hypercalcemia, inhibits PTH secretion [36]. Turgut et al. [37] showed that PTH, which has a major role in the development of vascular calcification, was significantly decreased with Mg therapy. Moreover, Turgut et al.[37] and Tzanakis et al. [38] have shown that low circulating Mg levels are associated with vascular calcification in HD patients. Mg can be considered a potent natural PTH hormone antagonist by decreasing the synthesis/secretion of PTH, and higher serum Mg concentrations may play an important protective role in the development of vascular calcification, independent of serum Ca and P in ESRD patients [30],[21]. Mg deficiency can result from reduced dietary intake, intestinal malabsorption, or renal loss. Symptoms of Mg deficiency include nausea, anorexia, vomiting, fatigue, and muscle weakness. As the deficiency worsens, additional symptoms might include nerve tingling, muscle cramps, seizures, abnormal heart rates, and spasms of the heart muscle or coronary arteries (Sheehan, 2011). Symptoms of Mg toxicity include abdominal cramps, nausea, diarrhea, anorexia, muscle weakness, breathing difficulties, low blood pressure, irregular heart beat, and alternations in mental status. It is important to note that Mg toxicity generally does not occur from high dietary intake of Mg. Instead, Mg toxicity generally results from nondietary sources of Mg, such as laxative, antacids, or Mg supplementation (Sheehan, 2011). Patients with ESRD who are receiving dialysis may develop various complications including hypertension, atherosclerosis, dyslipidemia, vascular calcification, and renal osteodystrophy. The disturbance of Mg balance in patients with ESRD may affect the development of these complications. Masaaki and Okuno [39] stated that serum Mg concentration is normal in patients with early renal failure. However, hypermagnesemia usually occurs in the advanced stage of renal failure because of the reduced urinary Mg excretion. With the introduction of chronic HD or CAPD treatment, the major factor to determine Mg balance is Mg levels in the dialysate [40]. Hypermagnesemia inhibits PTH secretion, which is considered an independent important risk factor for vascular calcification, left ventricular hypertrophy (LVH), and mortality in ESRD patients. Vascular calcifications play an important role in the pathogenesis of cardiovascular disease and is a strong risk factor for increased morbidity and mortality in patients with ESRD [37]. Finally an increasing body of evidence points toward a link between Mg and cardiovascular disease, even in patients without CKD. Renal failure is the most common cause of hypermagnesemia, which is usually mild and asymptomatic even in ESRD patients. In CKD until glomerular filtration rate (GFR) falls to below 30 ml/min, urinary Mg excretion may be normal or even increased. As CKD progresses (GFR<30 ml/min) urinary Mg excretion may be insufficient to balance intestinal Mg absorption, at which point dietary Mg intake becomes a major determinant of serum and total body Mg levels [41]. However, administration of Mg-containing drugs (e.g. antacids and laxatives) and high Mg concentrations of dialysate may provoke severe, symptomatic, or even fatal hypermagnesemia [42]. On the other hand, many factors are involved in controlling serum Mg in ESRD patients, and some conditions lead to a negative Mg balance in these patients, such as excessive intake of diuretics, reduced gastrointestinal uptake (due to acidosis and poor nutrition and absorption), and a low Mg concentration of dialysate. In patients with CKD on dialysis, bone Mg was increased by 66% in both cortical and trabecular bones, suggesting that dialysis patients have increased total body Mg stores. In dialysis patients, the dialytic procedure has the primary function of Mg removal; therefore, the serum Mg concentration parallels the dialysate Mg content. Baradaran and Nasri [43] stated that increased serum Mg level provided by dialysis fluids with a higher Mg content may suppress PTH synthesis and/or secretion, which is an independent risk factor for vascular calcification, LVH, and mortality in HD patients. In HD patients, low Mg levels were reported to be associated with increased atherosclerosis of the common carotid artery. Turgut and colleagues [65] also demonstrated an inverse association between serum Mg and carotid intima–media thickness of common carotid artery in HD patients. Mg can be considered a potent natural PTH hormone antagonist by decreasing the synthesis/secretion of PTH and that higher serum Mg concentrations may play an important protective role in the development of vascular calcification, independent of serum Ca and P, in ESRD patients [45]. Mg is regarded as a natural biological Ca antagonist inhibiting its entrance into endothelial and smooth muscle cells. By these means it regulates blood pressure and endothelial function, a role that is essential in the atherosclerotic process. Furthermore, low Mg promotes endothelial inflammation through oxidation of HDL-C [46],[47]. It has also been found that low Mg coexists with or even predisposes to diabetes, dyslipidemia, and metabolic syndrome, which are well-established atherosclerotic risk factors [48]. Evidence shows that Mg is an inhibitor of the calcification process, and consequently low Mg promotes vascular calcification. The underlying pathogenetic mechanism(s) of the latter action are not well understood, but there are three possible explanations: first, as has been shown in experimental models, ambient Mg2 can prevent early calcium phosphate hydroxyl apatite crystal growth by affecting crystal solubility in biological fluids [49]. Second, Mg is a cofactor of alkaline phosphatase, which is present in tissue of vascular calcification. Thus, Mg concentration may affect alkaline phosphatase activity leading to modulation of the calcification mechanism in ESRD patients [50]. Third, chronic hypermagnesemia may suppress PTH excretion in ESRD patients, which is implicated in the development of soft-tissue calcification, including vascular calcification [51].


  Patients and methods Top


This case–control observational retrospective study was conducted on 37 end-stage renal failure patients on maintenance HD (age range: 20–70 years; mean age: 47.8±13.9 years; 16 men and 21 women) who were recruited from the Renal and Dialysis Unit, Department of Internal Medicine, Assuit University Hospitals, Egypt, from 2010 to 2012. In addition, 25 apparently healthy persons (age range: 17–70 years; mean age: 42.0±13.25 years; 13 male and 12 female) who were recruited mainly from among the medical staff and their families who underwent health examination at Assuit University Hospitals were enrolled in the study as a control group. The study was approved by the Ethical Committee of the Faculty of Medicine, Assuit University, and written informed consent was obtained from each participant. The underlying causes of chronic renal failure (CRF) were as follows: chronic glomerulonephritis (n=10), diabetes mellitus (n=8), chronic pyelonephritis (n=7), obstructive uropathy (n=5), analgesic (n=1) and idiopathic (n=4) nephropathy, polycystic kidney disease (n=1), and lupus nephritis (n=1). The duration of HD ranged from 5 to 15 years (mean duration: 7.0±2.9 years). The frequency of HD was three sessions per week. The type of dialyzer membrane was polysulfone with bicarbonate dialysate, and the dialysate flow rate was 500 ml/min; blood flow ranged from 250 to 300 ml/min. The Mg concentration in the dialysate fluid was 1 mEq/l. Dialysis adequacy was assessed by measuring urea kinetic modeling (mean urea kinetic modeling: 2.38±0.44). GFR was estimated by the modified MDRD equation. Patients were excluded if they had been taking diuretics and/or lipid-lowering agents or had acute or chronic infections. All participants were subjected to thorough history taking, full clinical examination, and anthropometric measurements including weight, height, and BMI. Blood samples from both patients and controls were drawn in the morning after an overnight fast of 12–16 h. After centrifugation to yield platelet-poor plasma from samples on anticoagulant (3.8% sodium citrate) and serum from clotted blood samples, serum and plasma samples were stored in aliquots at −20°C until assay. Hemolysed samples were excluded. A peripheral hemogram was acquired on whole blood samples on EDTA using Beckman Coulter HmX (Brea, CA, USA). Liver function, kidney function, and serum electrolytes such as Ca and phosphorus (P) were measured by standard methods using a Hitachi 911 autoanalyser (Roche). Mg was measured by the calorimetric method. Levels of TC, TG, HDL-C, and LDL-C were measured using standard kits: LDL-C was calculated using Friedewalds formula: LDL=cholesterol−(TG+HDL-C). LP-a was measured with AssayMax human LP-a byenzyme linked immune assay with immune–biological laboratories kits was provided by Assaypro (St Charles, Missouri, USA) (catalog no.: EL3001-1). ECG was performed using a commercially available machine (Nihon Kohden model 9620l, power input: 45 VA, 220 V, 50–60 Hz; Nihon Kohden; Tokyo, Japan) in all participants for the detection of LVH as per the Sokolow criteria (LVH was defined as SV1+RV5>35 mm), ischemic changes, abnormalities of electrolyte disturbances, and prolongation of QT interval duration (ms). The QT-interval was measured from the beginning of the Q-wave to the end of the T-wave, which represents ventricular depolarization and repolarization. The corrected QT interval (QTc) was used, as it is considered more accurate because it takes heart rate into consideration. Consequently, QTc was calculated by applying Bazett’s equation: The QTc was considered prolonged when it was greater than 440. Transthoracic echocardiography (ECHO) was performed in all studied groups on an interdialytic day in the evaluation phase with a commercially available machine (Philips; envoiser coronary heart disease system no.: 20709686, prop S4-2 no. 02 vwoh, printer Sony up 897MD no. 94969; USA). M-mode and two-dimensional images as well as spectral pulsed and color flow Doppler recordings were obtained (ATL). M-mode measurements were taken according to the criteria of the American Society of Echocardiography. Left ventricular end-diastolic diameter, left ventricular end-systolic diameter, interventricular septal thickness, left atrial diameter, and left ventricular posterior wall thickness were measured. Pulsed-wave mitral flow velocities were measured from the apical four-chamber view by inserting a sample volume to the mitral leaflet tips. Mitral early diastolic velocity (E, cm/sn), late diastolic velocity (A, cm/sn), E/A ratio, E deceleration time (ms), and wall motion were determined. Left ventricular ejection fraction was calculated by Simpson’s rule.

Statistical analysis

Data were analyzed with the statistical package for the social sciences (SPSS, version 17; SPSS Inc., Chicago, Illinois, USA). Data for continuous variables were expressed as mean±SD and median. Categorical variables were expressed as absolute numbers and percentages. The χ2-test was used to compare the difference in distribution of frequencies among different groups. Student’s unpaired t-test was used to determine significance for numeric variables. Spearman’s rank univariate correlation study was conducted for determining the correlation between two continuous variables. P values less than 0.05 were considered statistically significant.


  Results Top


The current study included 16 (43.2%) male and 21 (56.8%) female CRF patients on HD and 13 (48.0%) healthy males and 12 (52.0%) healthy females as the control group. The age of the patients ranged from 20 to 70 years, with a mean age of 47.8±13.9 years; there were 27 (73%) individuals under 60 years and 10 (27%) above 60 years. The age of the control group ranged from 17 to 70 years, with a mean age of 42.0±13.9 years; there were 15 (60%) individuals under 60 years and 10 (40%) above 60 years. Thirty (81.1%) patients were from rural areas and seven (18.9%) were from urban areas. All controls were from urban areas (100%). As regards the BMI of the studied patients, seven (18.9%) cases were underweight (<18.5 kg/m2), 18 (48.7%) were normal (range: 18.5–24.9 kg/m2), 11 (29.7%) cases were overweight (range 25–30 kg/m2), and only one (2.7%) case weighed more than 30 kg/m2 (class 1, mild obesity). In the control groups four (16%) cases were underweight (<18.5 kg/m2), 15 (60%) cases were within normal (range: 18.5–24.9 kg/m2), and six (24%) cases were overweight (range: 25–30 kg/m2). The HD duration for the studied patients ranged from 5 to 15 years (mean±SD: 7.0±2.9 years). The HD frequency was three times per week for all patients. Healthy volunteers and the studied patients with CRF (on dialysis) did not differ significantly regarding age, sex, and BMI. The hemoglobin level and platelets were highly statistically significantly lower in the studied patients when compared with that in controls (mean±SD: 9.85±2.1 vs. 13.3±0.95, P<0.001 for hemoglobin; and 205.2±56.9 vs. 244.7±62.4, P<0.05 for platelets, respectively). However the mean corpuscular volume (MCV) and mean cell hemoglobin concentration (MCHC) levels were highly statistically significantly higher in patients compared with controls (mean±SD: 91.6±5.1 vs. 84. 2±5.5 for MCV and 32.4±2.5 vs. 28.4±1.7 for MCHC, respectively; P<0.05 for each). Notably, the mean level of white blood cells (WBCs) was not statistically different in patients when compared with controls. As regards renal function tests the mean levels of blood urea and serum creatinine were highly statistically significantly higher in studied patients in comparison with controls (mean±SD: 170.1±44.2 vs. 23.2±6.4 for blood urea, and 9.2±1.8 vs. 0.57±0.1 for creatinine, respectively; P<0.001 for each). As regards the lipid profile, no statistically significant differences were found in the mean levels of TC in patients when compared with controls (mean±SD: 158.3±42.3 vs. 178.8±39.8, respectively). Whereas the LDL-C levels were statistically significantly lower in the studied patients when compared with controls (mean±SD: 95.8±33.2 vs. 114.8±34.1; P<0.05), the mean levels of HDL-C were highly statistically significantly lower in the studied patients compared with controls (mean±SD: 23.9±14.5 vs. 38.4±7.8, respectively; P<0.001). The mean levels of TG and LP-a were statistically significantly higher in the studied patients compared with controls (mean±SD: 189.8±19.9 vs. 128.1±14.9, respectively, for TG and 36.1±18.2 vs. 25.5±17.3, respectively, for LP-a; P<0.05 for each). The low levels of Ca were observed with no statistical difference in patients when compared with controls (mean±SD: 8.3±2.1 vs. 8.6±1.5, respectively). However, the levels of P and Mg were highly statistically significantly higher in the studied patients compared with controls (mean±SD: 5.7±2.5 vs. 3.5±0.9 for P and 2.8±0.6 vs. 2.1±0.4 for Mg, respectively; P<0.001 for each), as shown in [Table 1]. The common underlying causes of CRF in the studied patients were chronic glomerulonephritis (n=10, 27.1%), diabetes mellitus (n=8, 21.6%), chronic pyelonephritis (n=7, 18.9%), obstructive uropathy (n=5, 13.5%), idiopathic nephropathy (n=4, 10.8%), analgesic nephropathy (n=1, 2.7%), polycystic kidney disease (n=1, 2.7%), and lupus nephritis (n=1, 2.7%) ([Figure 1]).
Table 1 Basic clinical and laboratory characteristics of the studied patients compared to controls

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Figure 1 Etiology of ESRD in the studied patients. ESRD, end-stage renal disease.

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Thirty patients with CKD on maintenance HD (81.1%) with normal ST-segment on ECG had more serum Mg retention (mean±SD: 3.1±0.9), whereas only seven (18.9%) patients with ST-segment changes either depressed or elevated in ECG had lower serum Mg levels (mean±SD: 2.8±0.5), but with no statistical significance. None of our patients had prolonged QTc interval in ECG, whereas all patients with normal QTc interval in ECG had more Mg retention (mean±SD: 2.9±0.7) but with no statistical significance. Twenty-seven (73.0%) patients with LVH findings in ECHO had higher Mg levels with a mean±SD of 2.82±0.6, whereas in eight (21.6%) patients with normal ECHO findings the mean±SD of serum Mg was 2.76±0.4. Nevertheless, only two (5.4%) patients with hypokinesia in ECHO findings in our study had more serum Mg retention, with mean±SD of 3.05±0.6, but with no statistical significance, as shown in [Table 2].
Table 2 The association between the serum Magnesium level and Findings in Electrocardiography (ECG) and Echocardiography (ECHO) in the studied patients

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[Table 3] shows the association between serum LP-a level and ECG and ECHO findings in the studied patients: 30 (81.1%) patients with normal ST-segment in ECG had more serum LP-a retention (mean±SD: 38.1±17.5), whereas seven (18.9%) patients with ST-segment changes either depressed or elevated in ECG had lower serum LP-a level (mean±SD: 27.9±20.1) but with no statistical significance. None of our patients had prolonged QTc interval in ECG and all patients with normal QTc interval in ECG had higher serum LP-a retention (mean±SD: 36.1±18.2) but with no statistical significance. Twenty-seven (73.0%) patients with LVH findings in ECHO had higher levels of serum LP-a (mean±SD: 36.9±19.9), whereas eight (21.6%) patients with normal ECHO findings had lower serum LP-a levels (mean±SD: 32.9±13.3). Nevertheless, only two (5.4%) patients with hypokinesia in ECHO findings in our study had higher serum LP-a retention (mean±SD: 37.5±16.2) but with no statistical significance.
Table 3 The association between the serum lipoprotein –a level and Findings in Electrocardiography (ECG) and Echocardiography (ECHO) in the studied patients

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[Table 4] shows significant positive correlations of the age of patients with TC, TG, and HDL (r=0.35, 0.24, and 0.33, respectively; P<0.05 for each) in our studied patients; however, a nonsignificant negative correlation was found between LDL and the age of patients (r=−0.08; P>0.05). Meanwhile, there were significant negative correlations of the duration of CKD with TC, TG, and LDL (r=−0.28, −0.31, and −0.21, respectively; P<0.05 for each) in our studied patients, and a negative correlation between the duration of CKD and HDL, with no statistical significance (r=−0.12; P>0.05). There was a significant negative correlation between height and TC (r=−0.22; P<0.05) in our studied patients. Meanwhile, a significant positive correlation between the height of patients and LDL (r=0.21; P<0.05) was found, and a nonsignificant positive correlation between the height of patients and TG (r=0.06; P>0.05). However, there was a negative correlation between height and HDL in our studied patients, with no statistical significance (r=−0.44; P>0.05). There were significant negative correlations of BMI with TC and TG in our studied patients (r=−0.25 and −0.31, respectively; P<0.05 for each). However, nonsignificant negative correlations of BMI with LDL and HDL (r=−0.09 and −0.19, respectively; P>0.05 for each) were found in our studied patients. There were nonsignificant negative correlations of the weight of patients with TC, LDL, and HDL (r=−0.06, −0.07, and −0.16, respectively; P>0.05 for each); however, there was a significant negative correlation between the weight of patients and TG (r=−0.34; P<0.05) in our studied patients. There was a significant positive correlation between hypertension and TC (r=0.24; P<0.05), but a significant negative correlation between hypertension and HDL in our studied patients (r=−0.22; P<0.05). There were nonsignificant positive correlations of hypertension with TG and LDL (r=0.18 and 0.08, respectively; P>0.05 for each). Regarding the laboratory characteristics of the studied patients there were nonsignificant positive correlations of hemoglobin level with TC and TG (r=0.07 and 0.14, respectively; P>0.05 for each); however, a negative correlation between hemoglobin level and HDL was found in our studied patients, with no statistical significance (r=−0.07; P>0.05). Nevertheless, a significant positive correlation between LDL and hemoglobin level was found in our studied patients (r=0.21; P<0.05). There were significant positive correlations of WBCs with TC and HDL in the current study (r=0.21 and 0.29, respectively; P<0.05 for each), but nonsignificant positive correlations of WBCs with TG and LDL (r=0.09 and 0.12, respectively; P>0.05). Moreover, in our study, nonsignificant positive correlations were found between MCV and TC, TG, LDL, and HDL (r=0.03, 0.12, 0.05, and 0.14, respectively; P>0.05 for each). A positive correlation of MCHC with LDL and HDL was found in our studied patients, with no statistical significance (r=0.11 and 0.05, respectively; P>0.05), and a significant positive correlation between MCHC and TC (r=0.24; P<0.05) with a highly significant positive correlation between TG and MCHC (r=0.49; P<0.01). In our patients, a nonsignificant positive correlation was found between platelets and TC (r=0.11; P>0.05); however, there was a significant positive correlation between platelets and HDL (r=0.24; P<0.05). Nevertheless, negative correlations of platelets with TG and LDL were found in our studied patients, with no statistical significance (r=−0.04 and −0.11, respectively; P>0.05 for each). Notably, there was a significant negative correlation between blood urea and TG (r=−0.27; P<0.05), but a nonsignificant negative correlation of blood urea with TC and LDL (r=−0.08 and −0.02, respectively; P>0.05 for each) and a nonsignificant positive correlation between blood urea and HDL (r=0.02; P>0.05). In the current study, there were significant negative correlations of serum creatinine with TC and HDL (r=−0.34 and −0.32, respectively; P<0.05 for each), but a negative correlation between serum creatinine and TG (r=−0.19; P>0.05) and a positive correlation between serum creatinine and LDL, with no statistical significance (r=0.02; P>0.05). There were no significant positive correlations of serum Ca with TC, TG, and HDL (r=0.11, 0.06, and 0.24, respectively; P>0.05 for each). However, a nonsignificant negative correlation between serum Ca and LDL (r=−0.19; P>0.05) was found in our studied patients. In our study, there were negative correlations of serum P with TC, TG, and LDL, with no statistical significance (r=−0.11, −0.01, and −0.02, respectively; P>0.05 for each), but a significant negative correlation between serum P and HDL (r=0.23; P>0.05).
Table 4 The Correlation between the lipid profile with Clinical and Laboratory characteristics of the studied patients

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[Table 5] showed significant positive correlations of serum TC level with ST-segment changes and QTc interval in ECG (r=0.34 and 0.23, respectively; P<0.05 for each) were found in our studied patients; however, there were negative correlations of serum TC level with LVH in ECG and ECHO findings, with no statistical significance (r=−0.8 and −0.19, respectively; P>0.05 for each). A nonsignificant positive correlation between the serum TG level and ST-segment changes in ECG (r=0.05; P>0.05) was found, and a significant positive correlation between TG and QTc interval in ECG (r=0.35; P<0.05 for each). However, there was a positive correlation between serum TG level and LVH in ECG and a negative correlation with ECHO findings in our patients, with no statistical significance (r=0.07 and r=−0.8, respectively; P>0.05 for each). Nonsignificant positive correlations of serum LDL level with ST-segment changes in ECG and with LVH in ECG and ECHO findings (r=0.08, 0.01, and 0.13, respectively; P<0.05 for each) were found in our studied patients; however, there was a negative correlation between serum LDL level and QTc interval in ECG, with no statistical significance (r=−0.17; P>0.05). Nonetheless, a significant positive correlation between serum HDL level and ST-segment changes in ECG (r=0.25; P<0.05) was found, and a nonsignificant positive correlation between HDL and QTc interval in ECG (r=0.26; P>0.05). However, there were significant negative correlations between serum HDL level and LVH in ECG and ECHO findings in our patients (r=−0.25 and −0.26, respectively; P<0.05 for each).
Table 5 The Correlation between lipid profile and Findings in Electrocardiography (ECG) and Echocardiography (ECHO) in the studied patients

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[Table 6] shows significant positive correlations of LP-a with age of patients and BMI were found in our study (r=0.27; P<0.05 for each); however, there was a nonsignificant positive correlation of LP-a with weight (r=0.19; P>0.05). Meanwhile, there were negative correlations between LP-a and the duration of CKD and height of patients, with no statistical significance (r=−0.13 and −0.07; P>0.05). A significant positive correlation between hypertension and LP-a level was found in our studied patients (r=0.23; P<0.05). Nevertheless, there were nonsignificant negative correlations of Mg level with the age of patients, height, and BMI in our studied patients (r=−0.19, −0.09, and −0.16, respectively; P>0.05 for each); however, there were significant negative correlations between Mg level and the duration of CKD and weight of patients (r=−0.20 and −0.24; P<0.05). A significant positive correlation was found between hypertension and Mg level in our studied patients (r=0.22; P<0.05). Notably, nonsignificant positive correlations of LP-a level with hemoglobin level and platelets were found (r=0.09 and 0.19, respectively; P>0.05); however, there were negative correlations between LP-a level and WBCs and MCV, with no statistical significance (r=−0.05 and −0.15, respectively; P>0.05). Nevertheless, a significant positive correlation between LP-a level and MCHC was found in our studied patients (r=0.26; P<0.05). There was a significant negative correlation between LP-a level and serum P (r=−0.20; P<0.05). However, there were nonsignificant positive correlations of LP-a level with blood urea and serum Ca (r=0.09 and 0.2, respectively; P>0.05) and a negative correlation between LP-a level and serum creatinine (r=−0.19; P>0.05), with no statistical significance. Nevertheless, there were negative correlations between Mg level and hemoglobin, WBCs, and MCV, with no statistical significance (r=−0.16, −0.02, and −0.15, respectively; P>0.05). However, there were significant negative correlations between Mg level and MCHC and platelets (r=−0.20 and −0.24, respectively; P<0.05). Meanwhile, there was a significant positive correlation of Mg level and serum creatinine (r=0.35; P<0.05) and a positive correlation between Mg level and blood urea, with no statistical significance (r=0.04; P>0.05). A significant positive correlation between Mg level and serum P was found in our studied patients (r=0.42; P>0.05), and a negative correlation between Mg level and serum Ca with no statistical significance (r=−0.06; P<0.05).
Table 6 The Correlation of the Lipoprotein –a level and Mg level with the clinical and Laboratory characterisitcs of the studied patients

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[Table 7] and [Figure 2] shows significant positive correlations between serum Mg level and ST-segment changes in ECG (r=0.23 with P<0.05) were found; however, there were positive correlations between serum Mg levels and QTc interval and with LVH in ECG and ECHO findings in our patients, with no statistical significance. A significant negative correlation was found between serum LP-a level and ST-segment changes in ECG (r=−0.27; P<0.05) and a significant positive correlation between LP-a levels and QTc interval in ECG (r=0.28; P<0.05). Nevertheless, there was a positive correlation between serum LP-a level and LVH in ECG and ECHO findings in our patients, with no statistical significance.
Table 7 The Correlation of the Lipoprotein –a level and Mg level with Findings in Electrocardiography (ECG) and Echocardiography (ECHO) in the studied patients

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Figure 2 Correlation between Serum Magnesium Level and ST-Segment changes in ECG of studied patients.

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The serum Mg level was statistically significantly positively correlated with LP-a, TC, TG, and LDL-C (r=0.233, 0.163, 0. 143, and 0.101, respectively; P<0.05 for each); however, there was a nonsignificant negative correlation between serum Mg level and HDL-C (r=−0.017; P>0.05) ([Figure 3]a–[Figure 3]e).
Figure 3 (a) Correlation between Serum Magnesium and serum Lipoprotein-a in studied patients. (b) Correlation between Serum Magnesium Level and Total Cholesterol level in studied patients. (c) Correlation between Serum Magnesium and serum Triglycerides in studied patients. (d) Correlation between Serum Magnesium and serum High Density Lipoprotein in studied patients. (e) Correlation between Serum Magnesium and serum Low Density Lipoprotein in studied patients.

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The LP-a level was statistically significantly positively correlated with TC and TG and nonsignificantly positively correlated with LDL-C (r=0.191 and 0.291, P<0.05 for each; and r=0.163, P<0.05 for LDL-C). However, there was a nonsignificant negative correlation between LP-a and HDL-C (r=−0.166; P>0.05) ([Table 8] and [Figure 4]a and [Figure 4]b).
Table 8 The Correlation between serum Lipoprotein-a level and Lipid profile in studied patients

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Figure 4 (a) Correlation between Serum Lipoprotein-a and serum Total Cholesterol Level in studied patients. (b) Correlation between Serum Lipoprotein-a and serum Triglyceride in studied patients.

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[Table 9] shows the multivariate logistic regression results of the association between serum Mg level, all laboratory parameters of ESRD, and HD in the studied patients. In the final model, there were three factors associated with HD (Mg level, LDL-C, and LP-a). There was a 45-fold increase in the probability of HD per 1 mg/dl increase in the Mg level and this relation was statistically significant [odds ratio (OR)=45, 95% confidence interval (CI): 15.4–68.1, P<0.01]. Mg level showed a 14% increase in the prediction level in the study sample compared with controls. There was also a 3% decrease in the probability of HD per 1 mg/dl decrease in the level of serum LDL, and this relation was statistically significant (OR=0.97, 95% CI: 0.95–0.99, P<0.05). LDL showed a 5% increase in the predictive level. Moreover, there was a 68% increase in the probability of HD per 1 mg/dl increase in the level of ‘LP-a’ and this relation was statistically significant (OR=1.68, 95% CI: 1.01–2.3, P<0.05). LP-a showed a 6% excess in the prediction of HD.
Table 9 Multivariate Logistic Regression of the association between disease, Mg. level and the other Risk Factors

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  Discussion Top


CRF is a common health problem worldwide. The prevalence of CRF is on the rise, as it is a consequence of the increased development of diseases causing renal function disturbances, principally diabetes mellitus and arterial hypertension [29]. In patients with CRF, and especially with ESRD, cardiovascular diseases are the leading cause of morbidity and mortality [1],[29]. There is a close clinical association between CKD and CVD. Many patients with CKD reaching end-stage failure have an established LVH, coronary ischemia, and disseminated atherosclerotic vascular disease with increased mortality [12],[51]. Numerous parameters contribute to accelerated atherogenesis and cardiovascular diseases in patients with CRF. The most important ones are lipid metabolism disturbances, oxidative stress, inflammation, physical inactivity, hypertension, vascular calcifications, endothelial dysfunction, and level of depressed nitric oxide [29]. Hyperlipidemia has been incriminated as a risk factor for atherosclerotic vascular disease in dialysed patients; therefore, CKD should be regarded as a high-risk condition and strict control of dyslipidemia would be beneficial in preventing CVD at least during early stages of CKD [12],[53]. Dyslipidemia is highly prevalent in patients on maintenance HD (MHD) with predominance of the atherogenic triad − that is, hypertriglyceridemia elevated VLDL and reduced HDL [54].

In the current study, we found significantly higher mean levels of TG and LP-a, whereas the mean levels of TC, LDL-C, and HDL-C were significantly lower in our CRF patients on MHD compared with controls. These findings were in agreement with Attman [4] and Pennell et al. [55], who stated that hypertriglyceridemia is one of the most common quantitative lipid abnormalities in patients with CKD and that decreased HDL concentrations with elevated VLDL are common in HD patients, particularly in the presence of hypertriglyceridemia. Moreover, Vasilis and Moses [6] reported that TC is usually normal or reduced and may be occasionally elevated in ESRD patients. Notably, Ansari et al. [54] and Deighan et al. [56] reported that, apart from quantitative plasma LP abnormalities (hypertriglyceridemia and hypo-HDL cholesterolemia and elevated LP-a (LP-a concentrations), CKD displays important qualitative alterations in LDL metabolism (small dense LDL, which is considered highly atherogenic) and HDL particles. Ansari et al. [54] stated that hyperlipidemia has been incriminated as a risk factor of atherosclerotic vascular disease both in nondialysed and in dialysed patients and is characterized by hypertriglyceridemia without cholesterol accumulation. Other dyslipidemias consist of decreased HDL-C, elevated serum LP-a, and LDL-C (which is usually not elevated). Tsimihodimos et al. [2] and Kaysen [3] stated that these variations depend on the degree of renal impairment, the etiology of primary disease, the presence of NS, and the method of dialysis (HD or PD) in patients undergoing renal replacement therapy. Abrass [57] claimed that the pathogenesis of hypertriglyceridemia in patients with CKD is related to an alteration in the composition of circulating TG (which become enriched with Apo-C-III) and their diminished clearance with reductions in the activity of LP lipase and hepatic TG lipase, which are involved in TG removal and has been thought to reflect increased inhibitor activity.

Al-Hwiesh [58] reported that lower serum concentration of HDL-C may be due to impaired maturation of these particles. Nevertheless, Ahmadi et al. [59] stated that a possible contributing mechanism is downregulation of LCAT leading to reduced etherification of cholesterol that is incorporated into HDL in TG removal. The elevated levels of intact PTH may be important in the pathogenesis of dyslipidemia in HD patients, but the underlying mechanisms are not clearly defined.

In the current study, we found that there was a significant positive correlation between the age of patients and their lipid profile, and this finding was in agreement with Mitwalli et al. [60], who stated that lipids increased with age and more markedly at age greater than 60 years and in dialysis patients. Therefore, younger patients had less disturbed lipid profile compared with elderly patients, and females had higher lipid values than did males. Factors such as hormones and individual capability to degrade excess lipids may play a role. However, a significant negative correlation of lipid profile with the duration of dialysis and BMI was found in our study. These findings could be explained by the fact that dialysis patients initially showed improvement in lipid profile. However, the increased length of dialysis was associated with gradual deterioration of dyslipidemia, which increases the risk for CVD by increasing atherogenesis, progresses over time in dialysis patients, and becomes worse in CAPD patients. This was in concordance with Mitwalli et al. [61], who reported that the length of dialysis was associated with increases in serum proatherogenic lipids. Moreover, the mode of dialysis may have a greater impact on lipid profile in these patients, with CAPD patients having a worse lipid profile compared with HD patients, even in the presence of hypertension, indicating that hypertension to some extent affected the lipid profiles of our patients. However, this argument needs to be further verified.

Kronenberg et al. [14] and Vaziri et al. [17] stated that many renal disease patients have dyslipidemia, often already in an early stage of renal failure. High serum LP-a and low HDL-C in CKD patients were highly atherogenic and could be considered one of the factors that accelerate atherosclerosis in patients on MHD. Among the parameters contributing to cardiovascular disease development is the elevated serum concentration of LP-a diagnosed in these patients, especially in the terminal stage of CRF. However, an elevated concentration of LP-a could influence the renal failure progression. According to these results, we concluded that for the risk assessment of premature atherosclerotic changes and renal failure progression in patients with CRF, determination of serum LP-a concentration is recommendable. Moreover, Baradaran and Nasri [53] and Ansari et al. [54] reported that LP-a is an independent risk factor for cardiovascular diseases.

In the current study, serum LP-a elevation in our HD patients could be explained by uremia itself. Uremia might cause elevation of LP-a by affecting its metabolism. The kidneys play a role in LP-a catabolism, and damage to kidneys causes elevation of its levels. This increase, however, depends markedly on the impairment of kidney function, the amount of proteinuria, and the treatment modality. In addition to these parameters, Cabarkapa et al. (2009) stated that there is strong evidence that the relative increase in LP-a also depends on the Apo-a K-IV repeat polymorphism. Notably, Baradaran and Nasri [53] and Rabin et al. [61] reported significant correlations between serum LP-a, interleukin 6, and tumor necrosis factor levels; it is hypothesized that an activated acute-phase reaction may be the underlying cause for the high levels of LP-a found in patients on chronic HD.

Mg is the second most abundant intracellular cation. The kidney has a vital role in Mg homeostasis, and, although the renal handling of Mg is highly adaptable, this ability deteriorates when renal function declines significantly. The renal handling of Mg depends to a great extent on the plasma Mg concentration: in hypermagnesemia, the fractional excretion of Mg is high, whereas during hypomagnesemia it is low. Therefore, Mg is regulated mainly through renal excretion and to a lesser extent by hormones that affect its gastrointestinal absorption and bone metabolism − for example, PTH, calcitonin, vitamin D, and catecholamines [30],[31],[62]. The regulation and elimination of Mg in patients with renal disease is somewhat understudied. Despite this incomplete understanding, we know that serum Mg levels increase when the GFR falls below 20–30 ml/min. Yet we do not know what happens to serum Mg concentration in patients with more modest falls in GFR.

In the current study we found a significant increase in the serum level of Mg in CKD patients on MHD compared with the control group. This finding was in agreement with those of Cunningham et al. [62], who stated that in moderate CKD increases in the fractional excretion of Mg largely compensate for the loss of glomerular filtration rate to maintain normal serum Mg levels. However, in more advanced CKD (as creatinine clearance falls <30 ml/min), this compensatory mechanism becomes inadequate such that overt hypermagnesemia develops frequently in patients with creatinine clearances less than 10 ml/min. Dietary Ca and Mg may affect the intestinal uptake of each other, although results are conflicting, and likewise the role of vitamin D on intestinal Mg absorption is somewhat uncertain. To date, to the best of our knowledge, no group has evaluated Mg as a cardiovascular (CV) risk factor in CKD patients, in whom closely inter-related factors and potential confounders such as endothelial dysfunction, insulin resistance, and inflammation were also considered.

Our results showed a significant negative correlation between serum Mg level and duration of dialysis. This finding was in agreement with Okuno and Inaba [39], who stated that serum Mg concentration is normal in patients with early renal failure. However, hypermagnesemia usually occurs in the advanced stage of renal failure because of reduced urinary Mg excretion. Moreover, Cunningham et al. [62] stated that because the renal excretion of Mg is so powerfully adaptable, impairment of renal function has long been recognized as a frequent prerequisite for the development of hypermagnesemia. However, in moderate CKD, the increase in the fractional excretion of Mg compensates for the loss of renal function, such that serum levels are maintained within the normal range. As renal function further deteriorates to CKD stages 4 and 5 and the patient comes under maintenance HD, the quantitative excretion of Mg tends to decrease and cannot be compensated any longer by an increased fractional excretion of Mg. This becomes apparent as creatinine clearance falls to below 30 ml/min and particularly lower than 10–15 ml/min. Thus, overt hypermagnesemia develops frequently in patients with creatinine clearances less than 10 ml/min on maintenance HD. Ganesh et al. [40] stated that with the introduction of chronic HD or CAPD treatment, the major factor to determine Mg balance is Mg levels in the dialysate.

Nonetheless, our study showed no significant correlations of age and BMI with serum Mg level; moreover, according to our study, patients with lower Mg concentrations were older than those with higher Mg concentrations. However, there was no significant difference in age between our patients with low and those with high Mg levels. These findings were in concordance with those of Khatami et al. [63], who stated that there were no correlations between serum Mg level and age, BMI, systolic blood pressure before dialysis, serum Ca, lipid profile, and Apo-a. Moreover, according to his study, the mortality was significantly higher in the low Mg group as compared with that in the high Mg group of maintenance HD patients. However, there was no significant difference in age between our patient groups with low and high Mg levels (cutoff level: 2.6 mg/dl). The greatest role in the development of hemostatic disturbances in HD patients is ascribed to platelets. Although factors that affect volume and count during HD are under investigation, it is believed that platelet aggregation and activation and coagulative activation are the most important and earliest phenomena that occur after contact between artificial membranes and blood. In our study a significant inverse correlation of serum Mg with platelets was found. This finding was in agreement with Rafieian-Kopaie ans Nasir [64]. Moreover, Cunha et al. [65] stated that lower concentrations of Mg are associated with oxidative stress, proinflammatory state, endothelial dysfunction, platelet aggregation, insulin resistance, and hyperglycemia.

Similarly to the study by Okuna and Inaba [39], in our study, there was a significant positive correlation between serum Mg levels and hypertension. Okuna and Inaba [39] found that the disturbance of Mg balance in patients with ESRD may affect the development of complications, including hypertension, atherosclerosis, dyslipidemia, vascular calcification, and renal osteodystrophy. Moreover, Cunha et al. [65] stated that many factors have been implicated in the pathogenesis of hypertension, including changes in intracellular concentrations of Ca, sodium, potassium, and Mg. There was a significant inverse correlation between serum Mg and incidence of cardiovascular diseases. Mg is a mineral with important functions in the body, such as antiarrhythmic effect, actions in vascular tone, contractility, glucose metabolism, and insulin homeostasis. Zheng et al. [66] stated that Mg regulates arterial blood pressure through reduction of total peripheral resistance despite a moderate increase in cardiac output, exerts an antithrombotic effect by inhibiting the upregulation of plasminogen activator inhibitor-1, stimulates nitric oxide synthesis, decreases inflammatory response, and facilitates the re-endothelialization of vascular injuries. Serum Mg levels greater than 10 mg/dl may also cause refractory hypotension, bradycardia, central nervous system depression, muscle weakness, and paralysis with secondary respiratory failure, bowel hypomotility, and hypocalcemia. Furthermore, Kanbay et al. [67] stated that higher serum Mg concentrations may play an important protective role in the development of vascular calcification, independent of serum Ca and phosphate in ESRD patients. Moreover, Khatami et al. [63] reported that low serum Mg causes endothelial dysfunction by generating a proinflammatory, prothrombotic, and proatherogenic environment that might lead to the development of cardiovascular disease. Nonetheless, Cunha et al. [65] stated that the conflicting results of studies evaluating the effects of Mg supplements on blood pressure and other CV outcomes indicate that the action of Mg in the vascular system is present but not yet established. Therefore, this mineral supplementation is not indicated as being a part of antihypertensive treatment, and further studies are needed to better clarify the role of Mg in the prevention and treatment of cardiovascular diseases. Notably, we found no significant negative correlation between high levels of serum Mg and Ca. This finding could be explained by the fact that increased levels of extracellular Mg inhibit Ca influx. Conversely, reduced extracellular Mg activates Ca influx through Ca channels. This finding was in agreement with that of Cunha et al. [65], who stated that low intracellular Mg concentrations stimulate inositoltrisphosphate 3-mediated mobilization of intracellular Ca and reduce Ca2+-ATPase activity. Thus, Ca efflux and sarcoplasmic reticular Ca reuptake are reduced, leading to cytosolic accumulation of Ca and increased intracellular Ca concentration, which is a crucial factor for vasoconstriction. Increased intracellular levels of Mg result in decreased intracellular free Ca concentration, promoting vasodilatation. The action of Mg as a Ca channel blocker may also help to reduce the release of Ca and thus reduce vascular resistance. In addition, Mg also activates the Na-K ATPase pump that controls the balance of these minerals, contributing to the homeostasis of electrolytes in cells.

Massy and Drüeke [68] reported that Mg is a natural Ca antagonist. Both human and animal studies have shown that low circulating Mg levels are associated with vascular calcification. Thus, low serum Mg may be an independent risk factor for premature death in CKD patients, and patients with mildly elevated serum Mg levels could have a survival advantage over those with lower Mg levels. However, Khatami et al. [63] stated that there were no correlations between serum Mg levels and atherogenic lipids, serum Ca, serum P, or PTH. In the current study, we found a significant positive correlation between serum Mg levels and P. This could be explained by the fact that, in CKD patients, Mg is important in regulating some aspects of mineral bone disorders associated with CRF. One important role of Mg is the effect on PTH lowering through the binding to the calcium-sensing receptor (Ca SR). Ca SR is expressed in both parathyroid gland and kidney, and it has distinct binding sites for both Ca and Mg. Furthermore, it seems that in the parathyroid gland, sensitivity to Mg is 2–3 times less than that for Ca. In situations of high serum Mg, Mg is thought to bind the Ca SR in the parathyroid gland and might cause reduced PTH release. Our finding was in agreement with those of Kanbay et al. [45] and Khatami et al. [63],[69], who stated that secondary hyperparathyroidism is present in most patients with ESRD. Excess levels of serum PTH, hyperphosphatemia, and high Ca×P product have been linked to uremic bone disease, vascular calcification, and death. Moreover, Kanbay et al. [30],[31] reported a protective role of Mg in vascular calcification in ESRD patients and also suggested that serum Mg concentrations in dialysis patients are independently associated with PTH levels. Thus, chronic mild hypermagnesemia may decrease PTH synthesis and/or secretion, and could be a very useful adjunctive therapy in alleviating complications of CKD mineral bone disease. In this way it can offer viable alternatives to the combination of Ca as a phosphate binder and vitamin D therapy, a strategy that may lead to frequent hypercalcemic episodes, Ca accumulation, and potentially harmful CV consequences. Nevertheless, in an era of numerous negative studies in nephrology, the long-term effects on either the inhibition of vascular calcifications, reduction of ischemic disease, prevention of arrhythmias, or changes in bone morphology have not been adequately investigated. Kanbay et al. [45] stated that the combination of calcium acetate/magnesium carbonate was found to be as effective as sevelamer in controlling serum phosphate levels, with a good tolerability profile. Moreover, Khatami et al. [63] stated that there were no correlations between serum Mg levels and atherogenic lipids, serum Ca, serum P, and PTH. Masaaki and Okuno [39] stated that with the introduction of chronic HD or CAPD treatment, the major factor for determining Mg balance was Mg levels in the dialysate; however, other factors such as nutrition and medications (e.g. laxatives or antacids) also play an important role. Kanbay et al. [63] reported that in dialysis patients, serum Mg concentrations are expected to be higher than that in the general population and are parallel to Mg levels in the dialysis solution. In a trial to review the correlation of serum Mg with dyslipidemia in our patients on maintenance HD, we found significant positive correlations of serum Mg with serum LP-a and serum TG, which were both highly elevated in the studied patients. These findings were in agreement with Ansari et al. [54], who found positive correlations of serum Mg with serum LP-a and serum TG. He attributed the elevation of serum LP-a in HD patients to the role of kidneys in LP-a catabolism and that uremia could influence LP-a metabolism; thus ESRD might result in elevated LP-a levels. Cabarkapa et al. (2009) stated that this LP has stimulatory effects at low concentrations, and cytotoxic effects at high concentrations on mesangial cell culture, referring to the well-known causes of lipid metabolism disturbance in CRF, such as factors retarding the LP catabolism, reduced enzyme activity of LP lipase, hepatic TG lipase, and LCAT, as well as factors retarding the LP cellular transfer − modification of Apo-content and modified lipid content, and hormonal factors (hyperinsulinemia and secondary hyperparathyroidism). Moreover, Baradaran and Nasri [53] and Rabin et al. [61] reported significant correlations between serum LP-a, interleukin 6, and tumor necrosis factor level, and that acute-phase reaction may be the underlying cause for the high levels of LP-a found in patients receiving chronic HD. Moreover, Cabarkapa et al. (2009) reported that elevated LP-a levels in patients with kidney diseases depend markedly on the impairment of kidney function, the amount of proteinuria, and the treatment modality. In addition to these parameters, there is strong evidence that the relative increase in LP-a also depends on the Apo-a K-IV repeat polymorphism. LP-a, a genetically determined LP in the blood, is one of the most powerful independent risk factors for cardiovascular disease. Apart from the fact that increased LP-a level is an independent risk factor for premature atherosclerosis development, there is an opinion that LP-a could also be important for renal disease progression. Nonetheless, Ansari et al. [54] reported that Mg does not increase the LP synthesis. It may be involved in the regulation of some enzymes responsible for LP synthesis. The elevated level of LP-a is considered a nontraditional factor of premature atherosclerosis. In addition, our results found significant positive correlations of serum Mg levels with serum TG levels and TC. Thus, elevated serum Mg level may be associated with dyslipidemia in maintenance HD. Correlation of serum Mg with serum TG can be due to changes in hepatic TG metabolism. These findings were in agreement with those of Robles et al. [70], who stated a significant positive correlation between serum Mg levels and TC and a nearly significant correlation between serum Mg and TG. Moreover, Baradaran and Nasri [53] stated that the trend toward an increase in TG levels with increasing Mg levels could be due to changes in hepatic TG metabolism. Notably, Vasilis and Moses [6] reported that TC is usually normal or reduced and occasionally elevated in ESRD patients with a nearly significant positive correlation between serum Mg and either TC and serum LDL. Furthermore, we found in our study a significant positive correlation between serum Mg and serum LDL. This finding was in agreement with those of Baradaran and Nasri [53] and Maheshwari et al. [71], who stated that serum Mg is significantly correlated with dyslipidemia in HD patients. However, Khatami et al. [63] stated that there were no significant differences in serum Mg between patients with LDL-C, low and high values of HDL-C, TG, and blood pressure. Notably, in agreement with Pennell et al. [55], the present study showed a negative correlation between serum Mg level and HDL in the studied patients. Pennell et al. [55] stated that decreased HDL concentrations with elevated VLDL were common in HD patients, particularly in the presence of hypertriglyceridemia, and that diminished clearance of TG results from reductions in the activity of LP lipase and hepatic TG lipase, which has been thought to reflect increased inhibitor activity. Moreover, Al-Hwiesh [58] stated that the lower serum concentration of HDL-C could be due to impaired maturation of these particles. A possible contributing mechanism is downregulation of LCAT leading to reduced esterification of cholesterol that is incorporated into HDL in TG removal. However, Ansari et al. [54] reported a significant positive correlation between serum Mg and serum HDL despite a nonsignificant correlation between serum Mg and serum LDL. Mg depletion, in general, is associated with changes in the ECG. The widening of the QRS complex and peaking of T-waves have been described with modest Mg loss, whereas more severe Mg depletion can lead to prolongation of the PR and QT intervals, progressive widening of the QRS complex, and diminution of the T-wave. Notably, Qu et al. [72] stated that the prevalence of Mg deficiency is much higher among patients with CVD than among other patients.

Cardiac arrhythmias are important complications in CRF patients. Bignotto et al. [73] stated that patients with CKD undergoing regular HD present a high prevalence of ECG abnormalities in the ECG, including a high prevalence of prolonged QTc interval while at rest. Patients with CKD on HD with Mg depletion had a high frequency of abnormal electrocardiographic findings, including a high prevalence of prolonged QTc interval. Moreover, acquired prolonged QT-interval syndrome is a highly prevalent condition in patients with CKD undergoing HD, and is one of the known pathophysiological mechanisms of sudden death in this population. However, in the current study, there was no prolongation in QTc interval in our patients, which could be explained by high serum Mg levels in our patients. Moreover, the cardiac arrhythmias like AF rhythm and junctional rhythm were seen only in a few patients. The suggested predisposing conditions to its development were older age, atrial dilation, presence of coronary disease, and low serum levels of albumin, which were well documented in the study. These results were in concordance with those of Taner et al. [74] and Spiegel (2011), who associated Mg depletion with prolonged QTc interval and cardiac arrhythmias. Notably, Bignotto et al. [73] and Taner et al. [74] stated that cardiac arrhythmias are an important complication of Mg depletion, and QT-interval elongation in Mg deficiency possibly arises from the incomplete membrane transportation of potassium. Moreover, the QT-interval elongation and QTc dispersion suggest that ventricular repolarization is delayed when intracellular Mg concentrations are low, leading to increased risk for developing ventricular arrhythmia. In addition, Mg levels alter the generation of potassium into the cell through the membrane ATP. Nephrologists must pay attention to identify patients with prolongation of the QT interval and the associated clinical and laboratory conditions, such as structural changes of the heart, cardiac calcification, and the prescription of drugs that induce QT interval prolongation, particularly in patients already presenting an extended QT interval.

In our study, the majority of patients had LVH and a few had hypokinesias with no evidence of vascular calcification on ECHO. These findings were in agreement with those of Jassal et al. [75], who stated that in the HD population the rate of left ventricular dysfunctions was 10–30-fold greater than that in the general population. Further, Foley et al. [76],[77] reported high rates of 75 and 31% of patients who had LVH and CHF at initiation of dialysis, respectively. However, a limiting factor in the study is conducting the ECG in the intradialytic period, in which changes in the concentrations of Ca, potassium, Mg, and bicarbonate due to HD may induce disturbances in the cardiac electrical conduction. Bignotto et al. [73] stated that the QTc interval was significantly more prolonged in patients with dialysate that contained the lowest concentrations of Ca and potassium and the highest concentrations of bicarbonate. Furthermore, in a study involving patients with CKD at HD stages IV and V, Bignotto et al. [73] showed that cardiac calcification, measured by the Ca score using computed tomography score, was an independent determining factor for the QT interval, presenting a linear and positive ratio, such that the higher the computed tomography score, the higher the dispersion of the QT interval. Moreover, the authors reported that the patients with a higher frequency of LVH, presence of bundle branch blocks, and nonsinus rhythm showed prolongation of the QT interval above 440 ms. On the basis of the results of the present study, we can state that strict monitoring of lipid profile and LPs can reduce the morbidity and mortality rate and will also improve the quality of life of CRF patients. Controlling hyperlipidemia, body weight normalization, dietary modification and regular exercise, and lipid-lowering treatment in CRF patients could prevent future episodes of CV events and will preserve the renal function. Large studies are required to establish Mg efficacy and safety, and probably to re-evaluate its appropriate concentration in HD and peritoneal dialysis fluids. The association of dyslipidemia with serum Mg levels is not clearly understood, and further large clinical studies are needed to understand this association better. One of the factors involved in accelerated atherosclerosis in HD patients is dyslipidemia. LP-a is considered a nontraditional factor of premature atherosclerosis. Its association with serum Mg needs more attention in HD patients. Mg’s role in the pathogenesis of vascular calcification has not been extensively studied. Long-term intervention with Mg in dialysis patients may retard arterial calcification. However, many questions remain unanswered. Nonetheless, several in-vitro and animal studies point toward a protective role of Mg through multiple molecular mechanisms. Much work remains to be done in this high-risk patient group with a significant burden of illness pertaining to left ventricular diameter. Large randomized controlled trials are necessary to establish evidence-based guidelines in the management of these patients. Further large-scale studies need to be outlined, using accurate nutritional status markers for HD patients, to better observe the possible link between malnourishment and prolonged QTc interval.

Financial support and sponsorship

Nil.

Conflicts of interest

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    Figures

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