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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2016  |  Volume : 27  |  Issue : 3  |  Page : 546-552
The relationship between concentrations of magnesium and oxidized low-density lipoprotein and Beta2-microglobulin in the serum of patients on the end-stage of renal disease


1 1st Department of Medicine - Propaedaetic, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
2 Department of Nuclear Medicine, General Hospital "LAIKO", Athens, Greece

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Date of Web Publication13-May-2016
 

   Abstract 

The end-stage of renal disease is associated with increased oxidative stress and oxidative modification of low-density lipoproteins (LDLs). Beta2 microglobulin (beta2M) is accumulated in the serum of dialysis patients. Magnesium (Mg) plays a protective role in the development of oxidative stress in healthy subjects. We studied the relationship between concentrations of magnesium and oxidized LDL (ox-LDL) and beta2M in the serum of patients on the end stage of renal disease. In 96 patients on on-line- predilution hemodiafiltration, beta2M and intact parathormone were measured by radioimmunoassays. High-sensitivity C-reactive protein (hsCRP) and ox-LDL were measured using ΕLISA. Serum bicarbonate levels were measured in the blood gas analyser gas machine. We performed logistic regression analysis models to investigate Mg as an important independent predictor of elevated ox-LDL and high beta2M serum concentrations, after adjustment to traditional and specific for dialysis patients' factors. We observed a positive correlation of Mg with ox-LDL (r = 0.383, P = 0.001), but the association of Mg with beta2M, hsCRP, and serum bicarbonate levels was significantly inverse (r = −0.252, P = 0.01, r = −0.292, P = 0.004, and r = −0.282, P = 0.04 respectively). The built logistic-regression analysis showed that Mg act as a significant independent factor for the elevated ox-LDL and beta2M serum concentrations adjusting to traditional and specific factors for these patients. We observed a positive relationship between magnesium and acidosis status- related ox-LDL concentrations, but the inverse association between magnesium and beta2M serum concentrations in hemodialysis patients.

How to cite this article:
Raikou VD, Kyriaki D. The relationship between concentrations of magnesium and oxidized low-density lipoprotein and Beta2-microglobulin in the serum of patients on the end-stage of renal disease. Saudi J Kidney Dis Transpl 2016;27:546-52

How to cite this URL:
Raikou VD, Kyriaki D. The relationship between concentrations of magnesium and oxidized low-density lipoprotein and Beta2-microglobulin in the serum of patients on the end-stage of renal disease. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Jul 17];27:546-52. Available from: http://www.sjkdt.org/text.asp?2016/27/3/546/182396

   Introduction Top


Despite increasing knowledge and technical advances in the field of dialysis therapy, the risk of death, related to atherosclerosis, is still high among patients undergoing hemodialysis, due to either uremia-related risk factors (such as anemia, hyperparathyroidism, inflammation, oxidative stress, and malnutrition) or to tradi- tional ones (age, diabetes, obesity, hyperten- sion, smoking, and dyslipidemia).[1]The uremic environment is associated with a chronic, low- grade inflammation, as well as oxidative stress; it increases the risk of endothelial dysfunction and oxidative modification of low-density lipoproteins (LDLs).[2]

Magnesium (Mg), the fourth most abundant cation in the human body, plays an essential role in a wide range of cellular reactions; it activates many pathways in the synthesis of proteins and nucleic acids. The importance of this mineral has been now well recognized due to its antiatherosclerotic effect.[3]Previously, it has been shown that Mg deficiency is asso- ciated with oxidative stress and the inflamma- tory process.[4]Recently, it has been reported that intake of Mg contributes to the reduction of oxidized-LDL (ox-LDL) in healthy subjects and in patients with Type 1 diabetes.[5],[6]How- ever, according to the best of our knowledge, studies among patients with the end-stage renal disease (ESRD) have not been reported until now.

On the other hand, beta2 microglobulin (beta2M), which is recognized as a surrogate marker of middle-molecule uremic toxins, is a key component in the pathogenesis of dialysis- associated amyloidosis, causing bone cysts, vascular inflammation, and atherosclerosis in patients on ESRD.[7],[8]

In this study, we studied the relationship between concentrations of magnesium and ox- LDL and beta2M in the serum of patients with ESRD.


   Materials and Methods Top


Subjects

We studied 96 dialyzed patients at Nephro- logy Department of "Laiko, University Gen- eral Hospital of Athens" and Renal Unit of "Diagnostic and Therapeutic Center of Athens Hygeia SA." 62 males and 34 females partici- pated in this study, with mean age 62.1 ± 14.27 years. Patients with acute illness, signi- ficant infection, or malignancy were excluded from our study.

On-line-predilution hemodiafiltration was ap- plied in total enrolled patients, and the median duration on dialysis was 5.0, interquartile range 2.1-9 years.

The hemodialysis treatment was performed three times weekly with a dialysis time of 3.5-4 h per session, using a filter of 1.5-2 m[2]surface area and a blood flow of 350-400 mL/ min. A bicarbonate-based ultrapure dialysis solution was used with a dialysate flow rate of 500-600 mL/min, a calcium concentration of 1.50-1.75 mmol/L, a sodium concentration of 138-145 mmol/L, a magnesium concentration of 1 mEq/L (0.5 mmol/L), and low molecular weight heparin as anticoagulant therapy.

The enrolled patients did not have inter- dialytic peripheral edema, high blood pressure, interdialytic orthostatic hypotension, or other characteristics of an inaccurate dry body weight. However, patients with predialysis blood pressure ≥160/90 (n = 40, a ratio of 41.7%) were considered hypertensive, or if they were receiving antihypertensive drugs.

We used filters with the high-flux synthetic membrane, with an ultrafiltration coefficient >20 mL/h.[9]Dialysis dose was defined by Kt/V for urea, which was calculated according to the formula of Daugirdas.[10]Patients were exclu- ded if they had Kt/V for urea <1.2.

Thirty-five of the enrolled patients excreted up to 100 mL of urine per day. Calcium chan- nel blockers, beta-blockers or a-MEA were included in the receiving medications by our patients. None of the enrolled patients was re- ceiving statins and only calcium and magne- sium-free phosphate binders were prescribed. The total of the studied patients was on ery- thropoietin-a or-ß therapy and on individual dose of Vitamin D. Fifteen of the studied sub- jects underwent parathyroidectomy, due to uncontrolled secondary hyperparathyroidism. The underlying renal disease was hyperten- sive nephrosclerosis (n = 31), chronic glome- rulonephritis (n = 28), polycystic kidney disease (n = 12), diabetic nephropathy (n = 11), and other/unknown (n = 14).

Blood collection

Blood samples were drawn just before the start of the mean weekly dialysis session in a 12 h fasting state from the vascular access. At the end of the treatment, the blood pump speed was reduced to <80 mL/min and blood sam- ples was obtained at 2 min postdialysis from the arterial dialysis tubing for the calculation of the adequacy of dialysis by Kt/V for urea.

Laboratory measurements

Albumin, calcium (Ca) corrected for the al- bumin levels, phosphate (P), magnesium (Mg), total cholesterol, triglycerides, high-density lipoproteins (HDLs), and LDLs were mea- sured by biochemical analysis and hemoglobin values were also measured. The ratio of LDL/ HDL and Ca × P products were calculated.

The concentrations of beta2M and intact- parathormone (i-PTH) were measured by radio- immunoassays (Immunotech by Beckman, Czech Republic, and CIS Bio International/ France respectively). High-sensitivity C- reactive protein (hsCRP) and ox-LDL serum con-centrations were also measured by ΕLISA (Immundiagnostik AG, Germany, Immundiag- nostik AG. Stubenwald-Allee, Bensheim res- pectively).

Metabolic acidosis status was defined by serum bicarbonate levels, which were mea- sured in the gas machine (Roche, combas b 121) taking care of the blood specimens.[11]Normalized protein catabolic rate for dry body mass was calculated from the urea generation rate.[12]Body mass index was obtained from height and postdialysis body weight.

Hemodynamic measurements

Predialysis peripheral systolic and diastolic blood pressures (SBP and DBP, respectively) were calculated as the mean of 10 measure- ments during a treatment month using an automatic sphygmomanometer OMRON M4-I (Co Ltd Kyoto Japan). Mean peripheral pre- dialysis BP (MBP) was calculated as: MBP = DBP + 1/3 (SBP - DBP).

Approval and consent

The study was approved by the ethics com- mittee of the Hospitals "Laiko, University General Hospital of Athens" and Renal Unit of "Diagnostic and Therapeutic Center of Athens Hygeia SA." Informed consent was obtained from all subjects.

Data analysis

Data were analyzed using Statistical Package (SPSS) 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA) and expressed as a mean ± stan- dard deviation or as median value ± interquartile range for data that showed skewed distri- butions; correlations between variables were defined by Pearson and Spearman co-efficient and P <0.05 were considered significant. We performed logistic regression analysis models to investigate Mg serum concentrations as an important independent predictor of high ox- LDL and high beta2M concentrations in the serum of patients, after adjustment to tradi- tional and specific factors for dialysis patients, such as age, hypertension, smoking, diabetes, i-PTH and dialysis adequacy defined by Kt/V for urea.


   Results Top


Characteristics of studied patients are listed in [Table 1] and [Table 2]. Mean value of serum magnesium was 2.47 ± 0.4 mg/dL, (normal - 1.8-2.9 mg/dL).
Table 1. Demographic characteristics of studied patients, n=96 (62 males/34 females)

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Table 2. Characteristics of studied patients, n=96 (62 males/34 females)

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In enrolled patients, we observed a positive correlation of Mg with ox-LDL (r = 0.383, P = 0.001), but the correlation of Mg with beta2M, hsCRP and serum bicarbonate levels was significantly inverse (r = −0.252, P = 0.01, r = −0.292, P = 0.004, and r = −0.282, P = 0.04 respectively). On the other hand, serum bicarbonate levels were inversely associated to ox-LDL (r = −0.290, P = 0.01).

The built logistic-regression analysis showed that serum concentrations of Mg act as a signi- ficantly positive independent factor for the elevated ox-LDL serum concentrations (up to the median value of ox-LDL = 60.6 ng/mL) adjusting to the age, hypertension, diabetes, smoking, i-PTH and Kt/V for urea [Table 3].
Table 3. Magnesium as a significant independent predictor of elevated oxidized-low density lipoprotein serum concentrations (using the median value = 60.6 ng/mL as the divided value)

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Also, in a multivariate model Mg was shown as a significantly inverse independent factor for the increased beta2M serum concentrations (up to the median value of beta2M = 25.9 mg/L) after adjustment to the age, hypertension and Kt/V for urea [Table 4].
Table 4. Magnesium as a significant independent predictors of elevated beta2-microglobulin serum concentrations (using the median value = 25.9mg/L as divided value)

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   Discussion Top


In general, magnesium serum concentrations in a population is regulated by the balance between dietary intake, intestinal absorption and renal excretion.[13]However, in patients on hemodialysis, it is the dialysate magnesium concentration that mainly affects magnesium balance, in combination with the dietary intake and gastrointestinal absorption. About ten to fifteen percent of hemodialysis patients have been reported to have hypermagnesemia, defined as a serum magnesium more than 2.9 mg/dL (1.15mmol/L).

The previous study reported no change in serum magnesium using a 1.5 mEq/L (0.75 mmol/L) dialysate.[14]In this study, we used a dialysate concentration of 1 mEq/L (0.5 mmol/ L), similar to the normal ionized serum mag- nesium of 0.5 mmol/L, in agreement with another study,[15]thus the mean value of serum Mg in our patients was in the reference range of normal subjects. Moreover, our patients had a normal dietary Mg intake according to our recommendations.

Magnesium is a dominant intracellular cation and it acts as a catalyst or activator for many intracellular enzymatic reactions, then both hyper- and hypo-magnesemia could have effects on intracellular metabolism. Mg is in- volved in metabolic pathways such as energy- dependent transport, glycolysis, and phospho- rylation;[16]it regulates ion channels and can act as the calcium antagonist.[17]Hypomagnesemia has been linked with increased comorbidity and cardiovascular risk factors, including elevated C-reactive protein levels, atheroscle- rosis, hypertension, and dyslipidemia.[15]In agreement, in this study, we observed a signi- ficant inverse association between Mg and hsCRP. In addition, in the present study using both, bivariate analysis and multivariate model, we observed significantly positive rela- tionship between Mg and ox-LDL concentra- tions in the serum of studied dialysis patients, adjusting to traditional and specific factors for these patients. Contrary to this, previous studies using healthy subjects or patients with type 1 diabetes reported that elevated ox-LDL was associated with low Mg status.[5],[6]It has been already found that Mg plays a protective role in the development of oxidative stress in healthy subjects, controversially to the above finding of present study.[4],[18]

Dialysis patients is a different group of pa- tients with disturbances in metabolic path- ways and with an unstable metabolic acidosis status resulting in increased oxidative stress. Metabolic acidosis is a common condition particularly in ESRD patients resulting in overproduction of reactive oxygen species, inflammatory stimulation, lipids oxidation, and oxidative stress.[19]Maintenance dialysis therapies are often not able to completely correct the base deficit. Moreover, the mineral metabolism disturbances act through the exis- ting metabolic acidosis in dialysis patients.[20]Indeed, in this study, we observed signi- ficantly positive association between acidosis state and both, ox-LDL and Mg concentrations in the serum of our patients, as ox-LDL and Mg serum concentrations were inversely asso- ciated with serum bicarbonate levels.

It could be hypothesized that although the normal action of Mg is the regulation of the activity of antioxidant enzymes reducing the oxidative stress, in a uremic acidosis environ- ment Mg may participate in intracellular enzy- matic reactions resulting in upregulation of metabolic acidosis state. This could be an explanation for the found positive impact of Mg serum concentrations on the increased ox- LDL concentrations in the serum of our pa- tients, in contrast to the findings of previous studies in healthy subjects or in patients with Type 1 diabetes. However, more studies are needed to confirm such a hypothesis.

On the other hand, in the present study, we observed an inverse association between Mg serum concentrations and increased beta2M serum concentrations. Previously, it has been reported that uremic toxins contribute substan- tially to the disturbances of mineral homeos- tasis, due partly to their role on the bone and cardiovascular systems.[21]It has been already established that beta2M serves as a surrogate marker of other middle-molecular weight ure- mic toxins, and predialysis beta2M serum con- centrations may provide dual information, on dialysis efficacy and on internal bioactivity.[22]Stimulated internal bioactivity, as could be demonstrated by the elevated beta2M serum concentrations, may be connected to low Mg serum concentrations, highlighting the possi- ble importance of Mg on immunity. Therefore, Mg serum concentrations can influence the immunological activity of these patients.

Based on the findings of the present study, one could postulate that elevated Mg serum concentrations may stimulate metabolic aci- dosis pathways in dialysis patients resulting in increased oxidative stress and high lipid oxida- tion, compared to general population. How- ever, Mg serum concentrations may impact on the immunological response of these patients as it was associated with reduced beta2M serum concentrations.

Conclusion

We observed a positive relationship between magnesium and acidosis status-related ox-LDL concentrations, but inverse association bet- ween magnesium and beta2M serum concen- trations in hemodialysis patients.

Conflict of interest: None.

 
   References Top

1.
de Jager DJ, Grootendorst DC, Jager KJ, et al. Cardiovascular and noncardiovascular morta- lity among patients starting dialysis. JAMA 2009;302:1782-9.  Back to cited text no. 1
    
2.
Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral meta- bolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004;15: 2208-18.  Back to cited text no. 2
    
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Van Laecke S, Van Biesen W, Vanholder R. Hypomagnesaemia, the kidney and the vessels. Nephrol Dial Transplant 2012;27:4003-10.  Back to cited text no. 3
[PUBMED]    
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Bo S, Durazzo M, Guidi S, et al. Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clin Nutr 2006;84:1062-9.  Back to cited text no. 4
    
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Cocate PG, Natali AJ, Oliveira AD, et al. Fruit and vegetable intake and related nutrients are associated with oxidative stress markers in middle-aged men. Nutrition 2014;30:660-5.  Back to cited text no. 5
    
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Okuno S, Ishimura E, Kohno K, et al. Serum beta2-microglobulin level is a significant predictor of mortality in maintenance haemo- dialysis patients. Nephrol Dial Transplant 2009;24:571-7.  Back to cited text no. 7
    
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Wilson AM, Kimura E, Harada RK, et al. Beta2-microglobulin as a biomarker in peri- pheral arterial disease: Proteomic profiling and clinical studies. Circulation 2007;116:1396- 403.  Back to cited text no. 8
    
9.
Chauveau P, Nguyen H, Combe C, et al. Dialyzer membrane permeability and survival in hemodialysis patients. Am J Kidney Dis 2005;45:565-71.  Back to cited text no. 9
    
10.
Daugirdas JT. Second generation logarithmic estimates of single-pool variable volume Kt/V: An analysis of error. J Am Soc Nephrol 1993; 4:1205-13.  Back to cited text no. 10
    
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Kirschbaum B. Spurious metabolic acidosis in hemodialysis patients. Am J Kidney Dis 2000; 35:1068-71.  Back to cited text no. 11
    
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Daugirdas JT. Simplified equations for moni- toring Kt/V, PCRn, eKt/V, and ePCRn. Adv Ren Replace Ther 1995;2:295-304.  Back to cited text no. 12
    
13.
Ayuk J, Gittoes NJ. Contemporary view of the clinical relevance of magnesium homeostasis. Ann Clin Biochem 2014;51(Pt 2):179-88.  Back to cited text no. 13
    
14.
Kelber J, Slatopolsky E, Delmez JA. Acute effects of different concentrations of dialysate magnesium during high-efficiency dialysis. Am J Kidney Dis 1994;24:453-60.  Back to cited text no. 14
    
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Courivaud C, Davenport A. Magnesium and the risk of all-cause and cardiac mortality in hemodialysis patients: Agent provocateur or innocent bystander? Kidney Int 2014;85:17-20.  Back to cited text no. 15
    
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Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev 2003;24:47- 66.  Back to cited text no. 16
    
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Curiel-García JA, Rodríguez-Morán M, Guerrero-Romero F. Hypomagnesemia and mortality in patients with type 2 diabetes. Magnes Res 2008;21:163-6.  Back to cited text no. 17
    
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Barbagallo M, Belvedere M, Dominguez LJ. Magnesium homeostasis and aging. Magnes Res 2009;22:235-46.  Back to cited text no. 18
    
19.
Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnu- trition-inflammation complex syndrome in chronic renal failure. Semin Dial 2004;17: 455-65.  Back to cited text no. 19
    
20.
Al-Aly Z. Vascular calcification in uremia: What is new and where are we going? Adv Chronic Kidney Dis 2008;15:413-9.  Back to cited text no. 20
    
21.
Tanaka H, Komaba H, Koizumi M, Kakuta T, Fukagawa M. Role of uremic toxins and oxidative stress in the development of chronic kidney disease-mineral and bone disorder. J Ren Nutr 2012;22:98-101.  Back to cited text no. 21
    
22.
Canaud B, Morena M, Cristol JP, Krieter D. Beta2-microglobulin, a uremic toxin with a double meaning. Kidney Int  Back to cited text no. 22
    

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Correspondence Address:
Despina Kyriaki
1st Department of Medicine - Propaedaetic, School of Medicine, National and Kapodistrian University of Athens, Athens
Greece
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DOI: 10.4103/1319-2442.182396

PMID: 27215248

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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