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Matias PJ, Ávila G, Domingos D, Gil C, Ferreira A. Lower serum magnesium levels are associated with a higher risk of fractures and vascular calcifications in hemodialysis patients. Clin Kidney J 2025; 18:sfae381. [PMID: 40008355 PMCID: PMC11852323 DOI: 10.1093/ckj/sfae381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Indexed: 02/27/2025] Open
Abstract
Background Magnesium (Mg) deficiency seems to be associated with altered bone metabolism and vascular calcifications (VC). This study aimed to evaluate the association between serum Mg levels and incident bone fragility fractures and VC in a cohort of prevalent hemodialysis (HD) patients. Methods We performed a retrospective study of 206 patients, with a mean age of 68.3 ± 13.1 years; 121 (59%) were male, and the median follow-up time was 58 months. Results Thirty-seven episodes of fragility fractures were identified with a median HD vintage of 42 months-an incidence rate of 29 per 1000 person-years. Patients with fractures showed lower Mg levels compared with those without fractures (P < .001) and more VC (P = .01). In a Cox regression analysis, time to fragility fracture was independently associated with serum Mg <2.2 mg/dL (P < .001), in a model adjusted to age, female gender, HD vintage, diabetes mellitus, body mass index, albumin, parathyroid hormone, active vitamin D therapy and the presence of VC. Patients with Mg serum levels <2.2 mg/dL had a 1.32-fold higher risk of fragility fractures (P < .001). Conclusions This study showed that the incidence of bone fragility fractures in HD patients is high and is significantly associated with lower Mg levels and with the presence of more VC.
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Affiliation(s)
- Patrícia João Matias
- Dialverca – Dialysis clinic, Forte da Casa, Portugal
- NephroCare Carregado – Dialysis clinic, Carregado, Portugal
- NOVA Medical School and Centro Clínico Académico de Lisboa, Lisboa, Portugal
| | - Gonçalo Ávila
- Dialverca – Dialysis clinic, Forte da Casa, Portugal
| | | | - Célia Gil
- Dialverca – Dialysis clinic, Forte da Casa, Portugal
- NephroCare Carregado – Dialysis clinic, Carregado, Portugal
| | - Aníbal Ferreira
- Dialverca – Dialysis clinic, Forte da Casa, Portugal
- NephroCare Carregado – Dialysis clinic, Carregado, Portugal
- NOVA Medical School and Centro Clínico Académico de Lisboa, Lisboa, Portugal
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Sadeghpour M, Bejani A, Kupaei MH, Majd SJA, Najafi A, Fakhari S, Abdolizadeh A, Mohammadi K. Unraveling the Mechanisms of Magnesium Supplementation in Alleviating Chronic Kidney Disease Complications and Progression: Balancing Risks and Benefits. Biol Trace Elem Res 2024:10.1007/s12011-024-04368-1. [PMID: 39256329 DOI: 10.1007/s12011-024-04368-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 09/03/2024] [Indexed: 09/12/2024]
Abstract
Chronic kidney disease (CKD) is a major cause of death and disability worldwide. It is usually diagnosed at early levels because of its slow progression. Treatment should consider CKD complications (such as electrolyte level imbalance, vascular calcification, and bone mineral disorders), as well as the development of CKD itself. Large-scale studies have shown that current treatment guidelines are nearly ineffective and fail to achieve treatment goals. Guidelines have not paid as much attention to magnesium (Mg) as the other electrolytes, while Mg has a significant role in the treatment goals of CKD. Hypomagnesemia is the only electrolyte imbalance that is equally prevalent in all stages of CKD. A lower plasma Mg level in each stage of CKD is associated with a higher risk of CKD progression and cardiac events. Magnesium exerts its effects both directly and via other ions. Mg supplementation increases insulin sensitivity while reducing proteinuria and inflammation. It lowers blood pressure and inhibits vascular calcification primarily because of its effects on calcium and phosphate, respectively. Vitamin D supplementation for low-active vitamin D in CKD patients increases vascular calcification and cardiac events, but magnesium supplementation enhances vitamin D levels and activity without increasing the risk of cardiac events. However, careful attention is required due to the potential threats of hypermagnesemia, particularly in advanced CKD stages. Starting magnesium supplementation early in patients' treatment plans will result in fewer side effects and more advantages. More original research is needed to determine its optimal dose and serum levels.
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Affiliation(s)
- Majid Sadeghpour
- Department of General Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Ali Bejani
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Seyed Jafar Amini Majd
- Department of General Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Afshin Najafi
- Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shiva Fakhari
- Department of Physical Medicine and Rehabilitation, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Abdolizadeh
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Keivan Mohammadi
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Shahid Chamran Heart Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Siddiqui IA, Masood A, Chandagiri S, Kumar RV, Mir AA. Beyond Numbers: How Biochemical Parameters Can Predict Outcomes in Chronic Kidney Disease Patients on Maintenance Hemodialysis. Cureus 2024; 16:e67349. [PMID: 39310569 PMCID: PMC11413472 DOI: 10.7759/cureus.67349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction The treatment and management of patients undergoing maintenance hemodialysis (MHD) requires constant evaluation through the assessment of biochemical markers. This is necessary for treatment, to prevent progression to complications such as mineral bone disease, and to improve quality of life. We aimed to study the biochemical profile of patients with chronic kidney disease (CKD) grades 4 and 5 on MHD, identify markers altered due to different etiologies, duration of illness, and duration of hemodialysis, and create a panel of markers that can be useful in planning better management. Methods All consecutive patients attending the dialysis unit of ESIC Super Speciality Hospital with CKD grade 4 or grade 5 on MHD between 2019 and 2020 were recruited. A detailed clinical history and demographic profile were taken, and blood samples were collected from the patients during follow-up visits in plain and EDTA (ethylenediamine tetraacetic acid) tubes for analysis. Results A total of 312 patients (22.1% females and 77.9% males.) with a mean age of 49.74 ± 11.49 years were recruited. In the study population, diabetic nephropathy (DN) (17%) and hypertensive nephropathy (48.7%) were the two most prevalent causes of CKD. The majority (64%) of the patients were on MHD three times a week. The range of estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) at the time of initiation of MHD was 2.9-26.8 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The mean duration of MHD was 51.58 months, with a mortality rate of 5.9% during the follow-up period (3-108 months). Conclusion Optimal selection and combination of biochemical tests will help in ascertaining the adequacy of management, progress of disease, or complications in MHD patients. This in turn will help guide the clinicians in effectively using these markers in their day-to-day practice.
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Affiliation(s)
- Imran A Siddiqui
- Biochemistry, ESIC Medical College and Superspeciality Hospital, Sanathnagar, Hyderabad, IND
| | - Afshan Masood
- Biochemistry, Obesity Research Centre, College of Medicine, King Saud University, Riyadh, SAU
| | - Sushmita Chandagiri
- Nephrology, ESIC Medical College and Superspeciality Hospital, Sanathnagar, Hyderabad, IND
| | - Raichur V Kumar
- Nephrology, ESIC Medical College and Superspeciality Hospital, Sanathnagar, Hyderabad, IND
| | - Altaf A Mir
- Biochemistry, All India Institute of Medical Sciences, Raebareli, IND
- Biochemistry, ESIC Medical College and Superspeciality Hospital, Sanathnagar, Hyderabad, IND
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Gheorghe AM, Ciobica ML, Nistor C, Gurzun MM, Sandulescu BA, Stanciu M, Popa FL, Carsote M. Inquiry of the Metabolic Traits in Relationship with Daily Magnesium Intake: Focus on Type 2 Diabetic Population. Clin Pract 2024; 14:1319-1347. [PMID: 39051301 PMCID: PMC11270223 DOI: 10.3390/clinpract14040107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/27/2024] Open
Abstract
Magnesium (Mg), an essential nutrient with a wide area of physiological roles, stands as a cofactor in over 600 enzymatic reactions involved in the synthesis of proteins and nucleic acids, DNA repair, neuromuscular functions, neuronal transmission, cardiac rhythm regulation, and the modulation of metabolic pathways, as well as acting as a natural blocker for the calcium channels. Our objective was to highlight the most recent clinical data with respect to daily Mg intake (DMI) and metabolic traits, particularly type 2 diabetes mellitus (DM). This was a PubMed-based review of the English-language medical papers across different key terms of search; the time frame was from January 2019 until April 2024. We included (clinically relevant) original studies and excluded cases reports, series, reviews, editorials, opinion, experimental studies, and non-human data as well as studies that did not specifically assessed DMI and only provided assays of serum Mg, studies on patients diagnosed with type 1 or secondary DM. A total of 30 studies were included and we organized the key findings into several sections as follows. Studies investigating DMI in relationship with the adherence to local recommendations in diabetic subjects (n = 2, one transversal and another retrospective cohort; N = 2823) found that most of them had lower DMI. Deficient DMI was correlated with the risk of developing/having DM across five studies (n = 5, one prospective and four of cross-sectional design; N = 47,166). An inverse correlation between DMI and DM prevalence was identified, but these data are presented amid a rather heterogeneous spectrum. Four novel studies (N = 7279) analysed the relationship between DMI and DM control according to various methods (HbA1c, fasting and postprandial glycaemia, and insulin); the association may be linear in diabetic subjects only at certain levels of DMI; additionally, the multifactorial influence on HBA1c should take into consideration this dietary determinant, as well, but there are no homogenous results. Three studies concerning DMI and diabetic complications (one cross-sectional, one prospective, and another case-control study) in terms of retinopathy (n = 1, N = 3794) and nephropathy (n = 2, N = 4805) suggested a lower DMI was associated with a higher risk of such complications. Additionally, two other studies (one prospective and one retrospective cohort) focused on mortality (N = 6744), which, taking only certain mortality indicators into consideration, might be decreased in the subgroups with a higher DMI. Seven studies (N = 30,610) analysed the perspective of DMI in the general population with the endpoint of different features amid glucose profile, particularly, insulin resistance. Concerning HOMA-IR, there were three confirmatory studies and one non-confirmatory, while fasting plasma glucose was highlighted as inversely correlated with a DMI (n = 1). The highest level of evidence regarding Mg supplementation effects on glucose metabolism stands on seven randomised controlled trials (N = 350). However, the sample size was reduced (from 14 to 86 individuals per study, either diabetic or pre-diabetic) and outcomes were rather discordant. These clinical aspects are essential from a multidisciplinary perspective and further trials are mandatory to address the current areas of discordant results.
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Affiliation(s)
- Ana-Maria Gheorghe
- PhD Doctoral School, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.-M.G.); (B.-A.S.)
- Department of Clinical Endocrinology V, “C.I. Parhon” National Institute of Endocrinology, 011863 Bucharest, Romania;
| | - Mihai-Lucian Ciobica
- Department of Internal Medicine and Gastroenterology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine I and Rheumatology, “Dr. Carol Davila” Central Military University Emergency Hospital, 010825 Bucharest, Romania
| | - Claudiu Nistor
- Department 4-Cardio-Thoracic Pathology, Thoracic Surgery II Discipline, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Thoracic Surgery Department, “Dr. Carol Davila” Central Military University Emergency Hospital, 010242 Bucharest, Romania
| | - Maria-Magdalena Gurzun
- Cardiology Discipline, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Laboratory of Non-Invasive Cardiovascular Exploration, “Dr. Carol Davila” Central Military University Emergency Hospital, 010242 Bucharest, Romania
| | - Bianca-Andreea Sandulescu
- PhD Doctoral School, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.-M.G.); (B.-A.S.)
- Department of Internal Medicine and Gastroenterology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Internal Medicine I and Rheumatology, “Dr. Carol Davila” Central Military University Emergency Hospital, 010825 Bucharest, Romania
| | - Mihaela Stanciu
- Department of Endocrinology, Faculty of Medicine, Lucian Blaga University of Sibiu, 550024 Sibiu, Romania;
| | - Florina Ligia Popa
- Department of Physical Medicine and Rehabilitation, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania;
| | - Mara Carsote
- Department of Clinical Endocrinology V, “C.I. Parhon” National Institute of Endocrinology, 011863 Bucharest, Romania;
- Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Panta R, Regmi S. Role of Magnesium, Effects of Hypomagnesemia, and Benefits of Magnesium Supplements in Cardiovascular and Chronic Kidney Diseases. Cureus 2024; 16:e64404. [PMID: 39130977 PMCID: PMC11317063 DOI: 10.7759/cureus.64404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Cardiovascular diseases (CVDs) account for nearly half of chronic kidney disease (CKD)-related deaths. Hypomagnesemia has been associated with various cardiovascular conditions and predicts a decline in renal function leading to end-stage renal disease (ESRD). The objective of this review is to delve into and discuss the significance of magnesium (Mg) in cardiovascular and renal functions, the clinical consequences of hypomagnesemia on CVD and CKD, and the benefits of Mg supplementation in managing CVD and CKD. This review is the result of an extensive search for pertinent articles in databases like PubMed, Medline, PubMed Central, and Google Scholar. Based on the literature search conducted in this review, we concluded that Mg protects against various CVDs and delays the progression of CKD. Mg can regulate pathways associated with inflammation, oxidative stress, and fibrosis. Therefore, maintaining slightly elevated Mg levels and timely Mg supplementation may benefit patients with CVD and CKD. There is a need for additional prospective randomized controlled trials to fully comprehend the therapeutic effects of Mg on CVD and CKD along with setting individualized target levels for serum Mg in such patients.
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Affiliation(s)
- Raju Panta
- Physiology and Pathology, Burrell College of Osteopathic Medicine, Melbourne, USA
| | - Subash Regmi
- Critical Care Medicine, University of Southern Carolina, Columbia, USA
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Kudryavtseva O, Lyngsø KS, Jensen BL, Dimke H. Nitric oxide, endothelium-derived hyperpolarizing factor, and smooth muscle-dependent mechanisms contribute to magnesium-dependent vascular relaxation in mouse arteries. Acta Physiol (Oxf) 2024; 240:e14096. [PMID: 38258597 DOI: 10.1111/apha.14096] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/27/2023] [Accepted: 01/01/2024] [Indexed: 01/24/2024]
Abstract
AIM Magnesium (Mg2+ ) is a vasorelaxant. The underlying physiological mechanisms driving this vasorelaxation remain unclear. Studies were designed to test the hypothesis that multiple signaling pathways including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in endothelial cells as well as Ca2+ antagonization and TRPM7 channels in vascular smooth muscle cells mediate Mg2+ -dependent vessel relaxation. METHODS To uncover these mechanisms, force development was measured ex vivo in aorta rings from mice using isometric wire myography. Concentration responses to Mg2+ were studied in intact and endothelium-denuded aortas. Key findings were confirmed in second-order mesenteric resistance arteries perfused ex vivo using pressure myography. Effects of Mg2+ on NO formation were measured in Chinese Hamster Ovary (CHO) cells, isolated mesenteric vessels, and mouse urine. RESULTS Mg2+ caused a significant concentration-dependent relaxation of aorta rings. This relaxation was attenuated significantly in endothelium-denuded aortas. The endothelium-dependent portion was inhibited by NO and cGMP blockade but not by cyclooxygenase inhibition. Mg2+ stimulated local NO formation in CHO cells and isolated mesenteric vessels without changing urinary NOx levels. High extracellular Mg2+ augmented acetylcholine-induced relaxation. SKCa and IKCa channel blockers apamin and TRAM34 inhibited Mg2+ -dependent relaxation. The endothelium-independent relaxation in aorta rings was inhibited by high extracellular Ca2+ . Combined blockade of NO, SKCa , and IKCa channels significantly reduced Mg2+ -dependent dilatation in mesenteric resistance vessels. CONCLUSIONS In mouse conductance and resistance arteries Mg2+ -induced relaxation is contributed by endothelial NO formation, EDHF pathways, antagonism of Ca2+ in smooth muscle cells, and additional unidentified mechanisms.
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Affiliation(s)
- Olga Kudryavtseva
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Kristina S Lyngsø
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Boye L Jensen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Henrik Dimke
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
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Zaslow SJ, Oliveira-Paula GH, Chen W. Magnesium and Vascular Calcification in Chronic Kidney Disease: Current Insights. Int J Mol Sci 2024; 25:1155. [PMID: 38256228 PMCID: PMC10816532 DOI: 10.3390/ijms25021155] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/12/2024] [Accepted: 01/14/2024] [Indexed: 01/24/2024] Open
Abstract
Magnesium (Mg) plays crucial roles in multiple essential biological processes. As the kidneys are the primary organ responsible for maintaining the blood concentration of Mg, people with chronic kidney disease (CKD) may develop disturbances in Mg. While both hyper- and hypomagnesemia may lead to adverse effects, the consequences associated with hypomagnesemia are often more severe and lasting. Importantly, observational studies have shown that CKD patients with hypomagnesemia have greater vascular calcification. Vascular calcification is accelerated and contributes to a high mortality rate in the CKD population. Both in vitro and animal studies have demonstrated that Mg protects against vascular calcification via several potential mechanisms, such as inhibiting the formation of both hydroxyapatite and pathogenic calciprotein particles as well as limiting osteogenic differentiation, a process in which vascular smooth muscle cells in the media layer of the arteries transform into bone-like cells. These preclinical findings have led to several important clinical trials that have investigated the effects of Mg supplementation on vascular calcification in people with CKD. Interestingly, two major clinical studies produced contradictory findings, resulting in a state of equipoise. This narrative review provides an overview of our current knowledge in the renal handling of Mg in health and CKD and the underlying mechanisms by which Mg may protect against vascular calcification. Lastly, we evaluate the strength of evidence from clinical studies on the efficacy of Mg supplementation and discuss future research directions.
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Affiliation(s)
- Shari J. Zaslow
- Department of Medicine, Nephrology Division, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- The Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, USA
| | - Gustavo H. Oliveira-Paula
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Wei Chen
- Department of Medicine, Nephrology Division, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Ferrè S, Liu YL, Lambert JW, Katz R, Gianella FG, Drew DA, Shlipak MG, Moe OW, Ix JH, Toto RD, Neyra JA. Serum Magnesium Levels and Cardiovascular Outcomes in Systolic Blood Pressure Intervention Trial Participants. Kidney Med 2023; 5:100634. [PMID: 37235044 PMCID: PMC10206180 DOI: 10.1016/j.xkme.2023.100634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
Abstract
Rationale and Objective Serum magnesium levels have been inversely yet inconsistently associated with cardiovascular (CV) outcomes. In this study, we examined the association of serum magnesium levels with CV outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT) participants. Study Design Case-control post hoc analysis of SPRINT. Setting & Participants A total of 2,040 SPRINT participants with available serum samples at baseline level were included in this study. Case participants (n = 510) who experienced a CV event during the SPRINT observation period (median follow-up of 3.2 years) and control participants (n = 1,530) without CV events were sampled in a 1:3 ratio for measurements of serum magnesium level at baseline and 2-year follow-up. Predictors Baseline serum magnesium levels and 2-year percentage change in serum magnesium levels (ΔSMg). Outcome SPRINT primary composite CV outcome. Analytical Approach Multivariable conditional logistic regression analysis, accounting for matching factors, was used to evaluate the association of baseline and ΔSMg with CV outcomes. Individual matching of cases and controls was based on the SPRINT treatment arm allocation (standard vs intensive) and prevalence of chronic kidney disease (CKD). Results The median serum magnesium level at baseline was similar among the case and control groups. In a fully adjusted model, each standard deviation (SD) (0.18 mg/dL) higher of the baseline serum magnesium level was independently associated with a lower risk for composite CV outcomes in all study participants (adjusted odds ratio 95% CI, 0.79 [0.70-0.89]). This association was similar when serum magnesium levels were analyzed in quartiles but dissipated in the standard (vs intensive) arm of SPRINT (0.88 [0.76-1.02] vs 0.65 [0.53-0.79], respectively; Pinteraction = 0.06). The presence or absence of CKD at baseline did not modify this association. ΔSMg was not independently associated with CV outcomes occurring after 2 years. Limitations ΔSMg was small in magnitude, limiting effect size. Conclusions Higher baseline serum magnesium levels were independently associated with reduced risk for CV outcomes in all study participants, but ΔSMg was not associated with CV outcomes.
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Affiliation(s)
- Silvia Ferrè
- Department of Scientific Activities, National Kidney Foundation, New York, NY
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Yu-Lun Liu
- Peter O’Donnell Jr School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Ronit Katz
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA
| | - Fabiola G. Gianella
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX
| | - David A. Drew
- Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Michael G. Shlipak
- Kidney Health Research Collaborative, San Francisco VA Health Care System, San Francisco, CA
| | - Orson W. Moe
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Joachim H. Ix
- Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, CA
- Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA
| | - Robert D. Toto
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX
| | - Javier A. Neyra
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
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Macías Ruiz MDC, Cuenca Bermejo L, Veronese N, Fernández Villalba E, González Cuello AM, Kublickiene K, Raparelli V, Norris CM, Kautzky-Willer A, Pilote L, Barbagallo M, Dominguez L, Herrero MT. Magnesium in Kidney Function and Disease-Implications for Aging and Sex-A Narrative Review. Nutrients 2023; 15:1710. [PMID: 37049550 PMCID: PMC10097335 DOI: 10.3390/nu15071710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Magnesium (Mg) has a vital role in the human body, and the kidney is a key organ in the metabolism and excretion of this cation. The objective of this work is to compile the available evidence regarding the role that Mg plays in health and disease, with a special focus on the elderly population with chronic kidney disease (CKD) and the eventual sex differences. A narrative review was carried out by executing an exhaustive search in the PubMed, Scopus, and Cochrane databases. Ten studies were found in which the role of Mg and sex was evaluated in elderly patients with CKD in the last 10 years (2012-2022). The progression of CKD leads to alterations in mineral metabolism, which worsen as the disease progresses. Mg can be used as a coadjuvant in the treatment of CKD patients to improve glomerular filtration, but its use in clinical applications needs to be further characterized. In conclusion, there's a need for well-designed prospective clinical trials to advise and standardize Mg supplementation in daily clinical practice, taking age and sex into consideration.
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Affiliation(s)
- María del Carmen Macías Ruiz
- Clinical and Experimental Neuroscience (NiCE), Institute for Aging Research, Biomedical Institute of Murcia (IMIB-Pascual Parrilla), School of Medicine, Campus Mare Nostrum, UniWell, University of Murcia, 30100 Murcia, Spain
| | - Lorena Cuenca Bermejo
- Clinical and Experimental Neuroscience (NiCE), Institute for Aging Research, Biomedical Institute of Murcia (IMIB-Pascual Parrilla), School of Medicine, Campus Mare Nostrum, UniWell, University of Murcia, 30100 Murcia, Spain
| | - Nicola Veronese
- Geriatric Unit, Department of Medicine, University of Palermo, 90100 Palermo, Italy
| | - Emiliano Fernández Villalba
- Clinical and Experimental Neuroscience (NiCE), Institute for Aging Research, Biomedical Institute of Murcia (IMIB-Pascual Parrilla), School of Medicine, Campus Mare Nostrum, UniWell, University of Murcia, 30100 Murcia, Spain
| | - Ana María González Cuello
- Clinical and Experimental Neuroscience (NiCE), Institute for Aging Research, Biomedical Institute of Murcia (IMIB-Pascual Parrilla), School of Medicine, Campus Mare Nostrum, UniWell, University of Murcia, 30100 Murcia, Spain
| | - Karolina Kublickiene
- Department of Renal Medicine, Institution for Clinical Science, Intervention and Technology, Karolinska Institute, 17177 Stockholm, Sweden
| | - Valeria Raparelli
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Colleen M. Norris
- Faculty of Nursing, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Cardiovascular and Stroke Strategic Clinical Network, Alberta Health Services, Edmonton, AB T5J 3E4, Canada
| | - Alexandra Kautzky-Willer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Louise Pilote
- Research Institute of McGill University Health Centre, Divisions of General Internal Medicine and Clinical Epidemiology, McGill University, Montreal, QC H4A 3J1, Canada
| | - Mario Barbagallo
- Geriatric Unit, Department of Medicine, University of Palermo, 90100 Palermo, Italy
| | - Ligia Dominguez
- Geriatric Unit, Department of Medicine, University of Palermo, 90100 Palermo, Italy
- Faculty of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy
| | - María Trinidad Herrero
- Clinical and Experimental Neuroscience (NiCE), Institute for Aging Research, Biomedical Institute of Murcia (IMIB-Pascual Parrilla), School of Medicine, Campus Mare Nostrum, UniWell, University of Murcia, 30100 Murcia, Spain
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Kanbay M, Copur S, Tanriover C, Yavuz F, Galassi A, Ciceri P, Cozzolino M. The pathophysiology and management of vascular calcification in chronic kidney disease patients. Expert Rev Cardiovasc Ther 2023; 21:75-85. [PMID: 36716079 DOI: 10.1080/14779072.2023.2174525] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Vascular calcification (VC) which is the pathological mineral deposition in the vascular system, predominantly at the intimal and medial layer of the vessel wall, is an important comorbidity in patients with chronic kidney disease (CKD) leading to significant morbidity and mortality while necessitating appropriate treatment. Our review aims to provide an in-depth analysis of the current understanding of VC. AREAS COVERED In this review, we first discuss the pathophysiology of VC in CKD patients, then we explain the methods to predict and assess VC. Afterwards, we provide the currently available as well as the potential therapeutic approaches of VC. We finally discuss our understanding regarding the current situation surrounding VC in our expert opinion section. EXPERT OPINION Predicting, assessing and treating VC is crucial and the future advances in the field of research surrounding VC will potentially occur in one or more of these three areas of clinical management. There is a current lack of evidence and consensus regarding specific therapeutic options for alleviating VC and this situation may not necessitate VC to be determined, detected, and documented before the available options are implemented. Regardless, the prediction and assessment of VC is still important and requires further improvement together with the developments in therapeutic alternatives. The future has the potential to bring better research which would guide and improve the management of this patient group. A more specialized approach consisting of targeted therapies and more tailored management plans for patients with CKD and VC is on the horizon.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.,Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Furkan Yavuz
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Andrea Galassi
- Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Paola Ciceri
- Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, 20142 Milan, Italy
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Magnesium Administration in Chronic Kidney Disease. Nutrients 2023; 15:nu15030547. [PMID: 36771254 PMCID: PMC9920010 DOI: 10.3390/nu15030547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/24/2023] Open
Abstract
Awareness of the clinical relevance of magnesium in medicine has increased over the last years, especially for people with chronic kidney disease (CKD), due to magnesium's role in vascular calcification and mineral metabolism. The inverse association between serum magnesium and clinically relevant, adverse outcomes is well-established in people with CKD. Subsequent intervention studies have focused on the effect of magnesium administration, mainly in relation to cardiovascular diseases, mineral bone metabolism, and other metabolic parameters. The most commonly used routes of magnesium administration are orally and by increasing dialysate magnesium. Several oral magnesium formulations are available and the daily dosage of elemental magnesium varies highly between studies, causing considerable heterogeneity. Although data are still limited, several clinical studies demonstrated that magnesium administration could improve parameters of vascular function and calcification and mineral metabolism in people with CKD. Current clinical research has shown that magnesium administration in people with CKD is safe, without concerns for severe hypermagnesemia or negative interference with bone metabolism. It should be noted that there are several ongoing magnesium intervention studies that will contribute to the increasing knowledge on the potential of magnesium administration in people with CKD.
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Vermeulen EA, Eelderink C, Hoekstra T, van Ballegooijen AJ, Raijmakers P, Beulens JW, de Borst MH, Vervloet MG. Reversal Of Arterial Disease by modulating Magnesium and Phosphate (ROADMAP-study): rationale and design of a randomized controlled trial assessing the effects of magnesium citrate supplementation and phosphate-binding therapy on arterial stiffness in moderate chronic kidney disease. Trials 2022; 23:769. [PMID: 36096824 PMCID: PMC9465140 DOI: 10.1186/s13063-022-06562-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 07/18/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Arterial stiffness and calcification propensity are associated with high cardiovascular risk and increased mortality in chronic kidney disease (CKD). Both magnesium and phosphate are recognized as modulators of vascular calcification and chronic inflammation, both features of CKD that contribute to arterial stiffness. In this paper, we outline the rationale and design of a randomized controlled trial (RCT) investigating whether 24 weeks of oral magnesium supplementation with or without additional phosphate-binding therapy can improve arterial stiffness and calcification propensity in patients with stage 3–4 CKD.
Methods
In this multi-center, placebo-controlled RCT, a total of 180 participants with an estimated glomerular filtration rate of 15 to 50 ml/min/1.73 m2 without phosphate binder therapy will be recruited. During the 24 weeks intervention, participants will be randomized to one of four intervention groups to receive either magnesium citrate (350 mg elemental magnesium/day) or placebo, with or without the addition of the phosphate binder sucroferric oxyhydroxide (1000 mg/day). Primary outcome of the study is the change of arterial stiffness measured by the carotid-femoral pulse wave velocity over 24 weeks. Secondary outcomes include markers of calcification and inflammation, among others calcification propensity (T50) and high-sensitivity C-reactive protein. As explorative endpoints, repeated 18F-FDG and 18F-NaF PET-scans will be performed in a subset of participants (n = 40). Measurements of primary and secondary endpoints are performed at baseline, 12 and 24 weeks.
Discussion
The combined intervention of magnesium citrate supplementation and phosphate-lowering therapy with sucroferric oxyhydroxide, in stage 3–4 CKD patients without overt hyperphosphatemia, aims to modulate the complex and deregulated mineral metabolism leading to vascular calcification and arterial stiffness and to establish to what extent this is mediated by T50 changes. The results of this combined intervention may contribute to future early interventions for CKD patients to reduce the risk of CVD and mortality.
Trial registration
Netherlands Trial Register, NL8252 (registered December 2019), EU clinical Trial Register 2019-001306-23 (registered November 2019).
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Ashitomi Y, Konta T, Motoi F, Watanabe M, Kayama T, Ueno Y. Association between Serum Magnesium Levels and Mortality in a Community-Based Population: The Yamagata (Takahata) Study. J Nutr Sci Vitaminol (Tokyo) 2022; 68:270-275. [PMID: 36047098 DOI: 10.3177/jnsv.68.270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The element magnesium (Mg) is involved in various metabolic reactions within the human body, and its deficiency is considered a risk factor for several diseases. In this study, we investigated the relationship between serum Mg levels and mortality in a community-based population. We prospectively assessed the association between serum Mg levels at enrollment and all-cause mortality in 1,314 participants who underwent a community health examination. The mean serum Mg level was 2.4 (±0.2) mg/dL. Patients with serum Mg levels ≤2.3 mg/dL constituted the low Mg group, while those with serum Mg ≥2.4 mg/dL constituted the high Mg group. Ninety-three (7.1%) patients died during the 10-y follow-up period. Kaplan-Meier analysis revealed that all-cause mortality was significantly higher in the low Mg group (log-rank p<0.05). Cox proportional hazards analysis revealed a significant association in the unadjusted model (hazard ratio [HR] 1.72, 95% confidence intervals [CI] 1.14-2.58, p<0.01) and in the fully adjusted model (HR 1.73, 95% CI 1.09-2.76, p<0.05). This association was particularly strong in males (HR 2.08, 95% CI 1.19-3.63, p<0.05). Low serum Mg levels were significantly associated with the risk of all-cause mortality among males in a community-based Japanese population.
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Affiliation(s)
- Yuya Ashitomi
- First Department of Surgery, Yamagata University Faculty of Medicine
| | - Tsuneo Konta
- Global Center of Excellence Program Study Group, Yamagata University Faculty of Medicine.,Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science
| | - Fuyuhiko Motoi
- First Department of Surgery, Yamagata University Faculty of Medicine
| | - Masahumi Watanabe
- Global Center of Excellence Program Study Group, Yamagata University Faculty of Medicine
| | - Takamasa Kayama
- Global Center of Excellence Program Study Group, Yamagata University Faculty of Medicine
| | - Yoshiyuki Ueno
- Global Center of Excellence Program Study Group, Yamagata University Faculty of Medicine
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14
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New Therapeutics Targeting Arterial Media Calcification: Friend or Foe for Bone Mineralization? Metabolites 2022; 12:metabo12040327. [PMID: 35448514 PMCID: PMC9027727 DOI: 10.3390/metabo12040327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 01/27/2023] Open
Abstract
The presence of arterial media calcification, a highly complex and multifactorial disease, puts patients at high risk for developing serious cardiovascular consequences and mortality. Despite the numerous insights into the mechanisms underlying this pathological mineralization process, there is still a lack of effective treatment therapies interfering with the calcification process in the vessel wall. Current anti-calcifying therapeutics may induce detrimental side effects at the level of the bone, as arterial media calcification is regulated in a molecular and cellular similar way as physiological bone mineralization. This especially is a complication in patients with chronic kidney disease and diabetes, who are the prime targets of this pathology, as they already suffer from a disturbed mineral and bone metabolism. This review outlines recent treatment strategies tackling arterial calcification, underlining their potential to influence the bone mineralization process, including targeting vascular cell transdifferentiation, calcification inhibitors and stimulators, vascular smooth muscle cell (VSMC) death and oxidative stress: are they a friend or foe? Furthermore, this review highlights nutritional additives and a targeted, local approach as alternative strategies to combat arterial media calcification. Paving a way for the development of effective and more precise therapeutic approaches without inducing osseous side effects is crucial for this highly prevalent and mortal disease.
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15
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ter Braake AD, Vervloet MG, de Baaij JHF, Hoenderop JGJ. Magnesium to prevent kidney disease-associated vascular calcification: crystal clear? Nephrol Dial Transplant 2022; 37:421-429. [PMID: 33374019 PMCID: PMC8875474 DOI: 10.1093/ndt/gfaa222] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Indexed: 12/11/2022] Open
Abstract
Vascular calcification is a prognostic marker for cardiovascular mortality in chronic kidney disease (CKD) patients. In these patients, magnesium balance is disturbed, mainly due to limited ultrafiltration of this mineral, changes in dietary intake and the use of diuretics. Observational studies in dialysis patients report that a higher blood magnesium concentration is associated with reduced risk to develop vascular calcification. Magnesium prevents osteogenic vascular smooth muscle cell transdifferentiation in in vitro and in vivo models. In addition, recent studies show that magnesium prevents calciprotein particle maturation, which may be the mechanism underlying the anti-calcification properties of magnesium. Magnesium is an essential protective factor in the calcification milieu, which helps to restore the mineral-buffering system that is overwhelmed by phosphate in CKD patients. The recognition that magnesium is a modifier of calciprotein particle maturation and mineralization of the extracellular matrix renders it a promising novel clinical tool to treat vascular calcification in CKD. Consequently, the optimal serum magnesium concentration for patients with CKD may be higher than in the general population.
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Affiliation(s)
- Anique D ter Braake
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marc G Vervloet
- Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Kawai Y, Banshodani M, Moriishi M, Shizukawa H, Sato T, Shintaku S, Masaki T, Kawanishi H. Penile calciphylaxis in patients with end-stage kidney disease undergoing dialysis: invasive treatment and pain management. Ther Apher Dial 2022; 26:950-959. [PMID: 34984854 DOI: 10.1111/1744-9987.13789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/26/2021] [Accepted: 12/29/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Penile calciphylaxis is rarely reported in dialysis patients. METHODS We experienced cases of dialysis patients who had penile calciphylaxis between 2003 and 2020. RESULTS Seven patients undergoing dialysis were treated for penile necrosis (hemodialysis [HD], 5; peritoneal dialysis [PD], 1; hybrid therapy comprising PD and HD, 1). Their mean age was 62.8 years and their mean dialysis vintage 116.1 months. All had severe penile pain and were clinically diagnosed with calciphylaxis. Four received partial penectomy and three received percutaneous transluminal angioplasty (PTA) due to rapid aggravation. The number of analgesia types and the critical-care pain observation tool score significantly decreased after invasive treatment (both, P = 0.008). The 90-day and 1-year survival rates after onset were 85.7% and 57.1%, respectively. CONCLUSION In dialysis patients, penile calciphylaxis has poor prognosis; however, invasive treatments for pain management are effective. PTA may be beneficial in dialysis patients in poor condition. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yusuke Kawai
- Artificial Organs, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
| | - Masataka Banshodani
- Artificial Organs, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
| | - Misaki Moriishi
- Artificial Organs, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
| | - Hiroko Shizukawa
- Dermatology, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
| | - Tomoyasu Sato
- Radiology, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
| | - Sadanori Shintaku
- Artificial Organs, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital 1-2-3, Kasumi, Minami-ku, Hiroshima, Japan
| | - Hideki Kawanishi
- Artificial Organs, Akane Foundation, Tsuchiya General Hospital 3-30, Nakajimacho, Naka-ku, Hiroshima, Japan
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17
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Salem RM, Zhang C, Chou L. Effect of Magnesium on Dentinogenesis of Human Dental Pulp Cells. Int J Biomater 2021; 2021:6567455. [PMID: 34840576 PMCID: PMC8616686 DOI: 10.1155/2021/6567455] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 10/27/2021] [Indexed: 11/23/2022] Open
Abstract
Introducing therapeutic ions into pulp capping materials has been considered a new approach for enhancing regeneration of dental tissues. However, no studies have been reported on its dentinogenic effects on human dental pulp cells (HDPCs). This study was designed to investigate the effects of magnesium (Mg2+) on cell attachment efficiency, proliferation, differentiation, and mineralization of HDPCs. HDPCs were cultured with 0.5 mM, 1 mM, 2 mM, 4 mM, and 8 mM concentrations of supplemental Mg2+ and 0 mM (control). Cell attachment was measured at 4, 8, 12, 16, and 20 hours. Cell proliferation rate was evaluated at 3, 7, 10, 14, and 21 days. Crystal violet staining was used to determine cell attachment and proliferation rate. Alkaline phosphatase (ALP) activity was assessed using the fluorometric assay at 7, 10, and 14 days. Mineralization of cultures was measured by Alizarin red staining. Statistical analysis was done using multiway analysis of variance (multiway ANOVA) with Wilks' lambda test. Higher cell attachment was shown with 0.5 mM and 1 mM at 16 hours compared to control (P < 0.0001). Cells with 0.5 mM and 1 mM supplemental Mg2+ showed significantly higher proliferation rates than control at 7, 10, 14, and 21 days (P < 0.0001). However, cell proliferation rates decreased significantly with 4 mM and 8 mM supplemental Mg2+ at 14 and 21 days (P < 0.0001). Significantly higher levels of ALP activity and mineralization were observed in 0.5 mM, 1 mM, and 2 mM supplemental Mg2+ at 10 and 14 days (P < 0.0001). However, 8 mM supplemental Mg2+ showed lower ALP activity compared to control at 14 days (P < 0.0001), while 4 mM and 8 mM supplemental Mg2+showed less mineralization compared to control (P < 0.0001). The study indicated that the optimal (0.5-2 mM) supplemental Mg2+ concentrations significantly upregulated HDPCs by enhancing cell attachment, proliferation rate, ALP activity, and mineralization. Magnesium-containing biomaterials could be considered for a future novel dental pulp-capping additive in regenerative endodontics.
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Affiliation(s)
- Rania M. Salem
- Department of Restorative Sciences & Biomaterials, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
- Department of Endodontics, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
| | - Chang Zhang
- Department of Restorative Sciences & Biomaterials, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
| | - Laisheng Chou
- Department of Restorative Sciences & Biomaterials, Goldman School of Dental Medicine, Boston University, Boston, MA 02118, USA
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Donato M, Faggin E, Cinetto F, Felice C, Lupo MG, Ferri N, Rattazzi M. The Emerging Role of Nutraceuticals in Cardiovascular Calcification: Evidence from Preclinical and Clinical Studies. Nutrients 2021; 13:nu13082603. [PMID: 34444763 PMCID: PMC8401694 DOI: 10.3390/nu13082603] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/22/2021] [Accepted: 07/27/2021] [Indexed: 02/03/2023] Open
Abstract
Cardiovascular calcification is the ectopic deposition of calcium-phosphate crystals within the arterial wall and the aortic valve leaflets. This pathological process leads to increased vascular stiffness, reduced arterial elasticity, and aortic valve stenosis, increasing the risk of cardiovascular diseases. Although cardiovascular calcification is an increasing health care burden, to date no medical therapies have been approved for treating or preventing it. Considering the current lack of therapeutic strategies and the increasing prevalence of cardiovascular calcification, the investigation of some nutraceuticals to prevent this pathological condition has become prevalent in recent years. Recent preclinical and clinical studies evaluated the potential anti-calcific role of nutraceuticals (including magnesium, zinc, iron, vitamin K, and phytate) in the progression of vascular calcification, providing evidence for their dietary supplementation, especially in high-risk populations. The present review summarizes the current knowledge and latest advances for nutraceuticals with the most relevant preclinical and clinical data, including magnesium, zinc, iron, vitamin K, and phytate. Their supplementation might be recommended as a cost-effective strategy to avoid nutritional deficiency and to prevent or treat cardiovascular calcification. However, the optimal dose of nutraceuticals has not been identified and large interventional trials are warranted to support their protective effects on cardiovascular disease.
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Affiliation(s)
- Maristella Donato
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padua, Italy; (M.D.); (M.G.L.); (N.F.)
| | - Elisabetta Faggin
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
| | - Francesco Cinetto
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
- Medicina Generale I^, Ca’ Foncello Hospital, 31100 Treviso, Italy
| | - Carla Felice
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
- Medicina Generale I^, Ca’ Foncello Hospital, 31100 Treviso, Italy
| | - Maria Giovanna Lupo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padua, Italy; (M.D.); (M.G.L.); (N.F.)
| | - Nicola Ferri
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padua, Italy; (M.D.); (M.G.L.); (N.F.)
| | - Marcello Rattazzi
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
- Medicina Generale I^, Ca’ Foncello Hospital, 31100 Treviso, Italy
- Correspondence: ; Tel.: +39-04-9821-1867 or +39-04-2232-2207
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High Intakes of Bioavailable Phosphate May Promote Systemic Oxidative Stress and Vascular Calcification by Boosting Mitochondrial Membrane Potential-Is Good Magnesium Status an Antidote? Cells 2021; 10:cells10071744. [PMID: 34359914 PMCID: PMC8303439 DOI: 10.3390/cells10071744] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/23/2021] [Accepted: 06/29/2021] [Indexed: 12/23/2022] Open
Abstract
Chronic kidney disease is characterized by markedly increased risk for cardiovascular mortality, vascular calcification, and ventricular hypertrophy, and is associated with increased systemic oxidative stress. Hyperphosphatemia, reflecting diminished glomerular phosphate (Pi) clearance, coupled with a compensatory increase in fibroblast growth factor 23 (FGF23) secretion are thought to be key mediators of this risk. Elevated serum and dietary Pi and elevated plasma FGF23 are associated with increased cardiovascular and total mortality in people with normal baseline renal function. FGF23 may mediate some of this risk by promoting cardiac hypertrophy via activation of fibroblast growth factor receptor 4 on cardiomyocytes. Elevated serum Pi can also cause a profound increase in systemic oxidative stress, and this may reflect the ability of Pi to act directly on mitochondria to boost membrane potential and thereby increase respiratory chain superoxide production. Moreover, elevated FGF23 likewise induces oxidative stress in vascular endothelium via activation of NADPH oxidase complexes. In vitro exposure of vascular smooth muscle cells to elevated Pi provokes an osteoblastic phenotypic transition that is mediated by increased mitochondrial oxidant production; this is offset dose-dependently by increased exposure to magnesium (Mg). In vivo, dietary Mg is protective in rodent models of vascular calcification. It is proposed that increased intracellular Mg opposes Pi’s ability to increase mitochondrial membrane potential; this model could explain its utility for prevention of vascular calcification and predicts that Mg may have a more global protective impact with regard to the direct pathogenic effects of hyperphosphatemia.
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20
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Ito M, Yamaguchi M, Katsuno T, Nobata H, Iwagaitsu S, Sugiyama H, Kinashi H, Banno S, Ando M, Kubo Y, Ishimoto T, Ito Y. Association between serum magnesium levels and abdominal aorta calcification in patients with pre-dialysis chronic kidney disease stage 5. PLoS One 2021; 16:e0253592. [PMID: 34143857 PMCID: PMC8213142 DOI: 10.1371/journal.pone.0253592] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/08/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Several studies have revealed the relationship between serum magnesium levels and vascular calcification in chronic kidney disease patients. Despite excellent predictability of abdominal aorta calcification for cardiovascular disease events, the relationship between serum magnesium levels and abdominal aorta calcification, as evaluated by quantitative methods, in pre-dialysis patients remains unclear. This study aimed to determine the abdominal aorta calcification volume using computerized tomography and its association with serum magnesium levels in pre-dialysis chronic kidney disease stage 5 patients. METHODS This single-center cross-sectional study included 100 consecutive patients with pre-dialysis chronic kidney disease stage 5 between January 2016 and May 2020 at Aichi Medical University Hospital, Japan. The relationships between serum magnesium levels and the abdominal aorta calcification volume were assessed using multiple linear regression models after adjusting for clinically relevant factors. We also assessed clinical factors that affect serum magnesium levels. RESULTS The mean serum magnesium level was 2.0 mg/dL (interquartile range, 1.8 to 2.3). Multivariate analyses revealed that a higher serum magnesium level (stand. β = -0.245, p = 0.010) was significantly associated with a reduced abdominal aorta calcification volume, and that a history of cardiovascular disease (stand. β = 0.3792, p < 0.001) and older age (stand. β = 0.278, p = 0.007) were significantly associated with an increased abdominal aorta calcification volume. Moreover, multivariate analysis showed that the use of proton pump inhibitor or potassium-competitive acid blocker was significantly associated with lower serum magnesium levels (stand. β = -0.246, p = 0.019). CONCLUSIONS The present study revealed that the higher Mg level was significantly associated with lower volume of abdominal aorta calcification in pre-dialysis chronic kidney disease stage 5 patients. Further studies should be undertaken to determine the appropriate magnesium level to suppress vascular calcification.
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Affiliation(s)
- Mayumi Ito
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Makoto Yamaguchi
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Takayuki Katsuno
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Hironobu Nobata
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Shiho Iwagaitsu
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Hirokazu Sugiyama
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Hiroshi Kinashi
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Shogo Banno
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Masahiko Ando
- Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yoko Kubo
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takuji Ishimoto
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiko Ito
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
- * E-mail:
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21
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McCarty MF. Nutraceutical, Dietary, and Lifestyle Options for Prevention and Treatment of Ventricular Hypertrophy and Heart Failure. Int J Mol Sci 2021; 22:ijms22073321. [PMID: 33805039 PMCID: PMC8037104 DOI: 10.3390/ijms22073321] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
Although well documented drug therapies are available for the management of ventricular hypertrophy (VH) and heart failure (HF), most patients nonetheless experience a downhill course, and further therapeutic measures are needed. Nutraceutical, dietary, and lifestyle measures may have particular merit in this regard, as they are currently available, relatively safe and inexpensive, and can lend themselves to primary prevention as well. A consideration of the pathogenic mechanisms underlying the VH/HF syndrome suggests that measures which control oxidative and endoplasmic reticulum (ER) stress, that support effective nitric oxide and hydrogen sulfide bioactivity, that prevent a reduction in cardiomyocyte pH, and that boost the production of protective hormones, such as fibroblast growth factor 21 (FGF21), while suppressing fibroblast growth factor 23 (FGF23) and marinobufagenin, may have utility for preventing and controlling this syndrome. Agents considered in this essay include phycocyanobilin, N-acetylcysteine, lipoic acid, ferulic acid, zinc, selenium, ubiquinol, astaxanthin, melatonin, tauroursodeoxycholic acid, berberine, citrulline, high-dose folate, cocoa flavanols, hawthorn extract, dietary nitrate, high-dose biotin, soy isoflavones, taurine, carnitine, magnesium orotate, EPA-rich fish oil, glycine, and copper. The potential advantages of whole-food plant-based diets, moderation in salt intake, avoidance of phosphate additives, and regular exercise training and sauna sessions are also discussed. There should be considerable scope for the development of functional foods and supplements which make it more convenient and affordable for patients to consume complementary combinations of the agents discussed here. Research Strategy: Key word searching of PubMed was employed to locate the research papers whose findings are cited in this essay.
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Affiliation(s)
- Mark F McCarty
- Catalytic Longevity Foundation, 811 B Nahant Ct., San Diego, CA 92109, USA
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22
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Düsing P, Zietzer A, Goody PR, Hosen MR, Kurts C, Nickenig G, Jansen F. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. J Mol Med (Berl) 2021; 99:335-348. [PMID: 33481059 PMCID: PMC7900031 DOI: 10.1007/s00109-021-02037-7] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 12/14/2020] [Accepted: 01/05/2021] [Indexed: 12/13/2022]
Abstract
Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.
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Affiliation(s)
- Philip Düsing
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Andreas Zietzer
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Philip Roger Goody
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Mohammed Rabiul Hosen
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Christian Kurts
- Institute of Experimental Immunology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany
| | - Georg Nickenig
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Felix Jansen
- Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
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23
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Ter Braake AD, Govers LP, Peeters MJ, van Zuilen AD, Wetzels JFM, Blankenstijn PJ, Hoenderop JGJ, de Baaij JHF, van den Brand JAJG. Low plasma magnesium concentration and future abdominal aortic calcifications in moderate chronic kidney disease. BMC Nephrol 2021; 22:71. [PMID: 33632150 PMCID: PMC7905862 DOI: 10.1186/s12882-021-02267-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/09/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Higher plasma magnesium concentrations are associated with reduced cardiovascular disease risk in chronic kidney disease (CKD) patients. The importance of plasma magnesium concentration for vascular calcification in earlier stages of CKD remains underexplored. This study investigated whether plasma magnesium is a determinant for the presence and severity of vascular calcification in moderate CKD. METHODS Retrospective analysis was performed using abdominal aortic calcification (AAC) scores in 280 patients with stage 3 and 4 CKD enrolled in the MASTERPLAN trial. Lateral abdominal X-ray was used to evaluate AAC. Plasma magnesium concentration were measured over time. A zero-inflated Poisson model determined the association between plasma magnesium concentration and AAC. RESULTS 79 out of 280 patients did not have AAC, and in patients with AAC the median calcification score was 3.5 (interquartile range: 0.0-8.6). The mean plasma magnesium concentration was 0.76 ± 0.10 mmol/L at baseline. A 0.1 mmol/L higher plasma magnesium concentration was associated with lower AAC of 0.07 point (95% CI -0.28 - 0.14). A 0.1 mmol/L higher plasma magnesium lowered the odds of detecting any AAC by 30% (OR = 0.63; 95% CI 0.29-1.37). After 1 year and 4 years (at time of X-ray) of follow-up this association was attenuated (OR = 0.93; 95% CI 0.61-1.43 and 0.93; 95% CI 0.60-1.45, respectively). None of these associations reached statistical significance. CONCLUSIONS Plasma magnesium concentration at baseline is not associated with the risk for future AAC. Interventions increasing magnesium to avoid vascular calcification may have greatest potential in early CKD stages prior to onset of vascular calcification.
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Affiliation(s)
- Anique D Ter Braake
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Larissa P Govers
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mieke J Peeters
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, PO box 9101, 6500, HB, Nijmegen, The Netherlands
| | - Arjan D van Zuilen
- Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jack F M Wetzels
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, PO box 9101, 6500, HB, Nijmegen, The Netherlands
| | - Peter J Blankenstijn
- Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jan A J G van den Brand
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, PO box 9101, 6500, HB, Nijmegen, The Netherlands.
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24
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Wu H, Li Q, Fan L, Zeng D, Chi X, Guan B, Hu B, Lu Y, Yun C, Krämer B, Hocher B, Liu F, Yin L. Prognostic Value of Serum Magnesium in Mortality Risk among Patients on Hemodialysis: A Meta-Analysis of Observational Studies. KIDNEY DISEASES 2021; 7:24-33. [PMID: 33614731 PMCID: PMC7879293 DOI: 10.1159/000510513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/26/2020] [Indexed: 12/19/2022]
Abstract
Background Previous studies have reported that serum magnesium (Mg) deficiency is involved in the development of heart failure, particularly in patients with end-stage kidney disease. The association between serum Mg levels and mortality risk in patients receiving hemodialysis is controversial. We aimed to estimate the prognostic value of serum Mg concentration on all-cause mortality and cardiovascular mortality in patients receiving hemodialysis. Methods We did a systematic literature search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify eligible studies that reported the prognostic value of serum Mg levels in mortality risk among patients on hemodialysis. We performed a meta-analysis by pooling and analyzing hazard ratios (HRs) and 95% confidence intervals (CIs). Results We identified 13 observational studies with an overall sample of 42,967 hemodialysis patients. Higher all-cause mortality (adjusted HR 1.58 [95% CI: 1.31–1.91]) and higher cardiovascular mortality (adjusted HR 3.08 [95% CI: 1.27–7.50]) were found in patients with lower serum Mg levels after multivariable adjustment. There was marked heterogeneity (I<sup>2</sup> = 79.6%, p < 0.001) that was partly explained by differences in age stratification and study area. In addition, subgroup analysis showed that a serum Mg concentration of ≤1.1 mmol/L might be the vigilant cutoff value. Conclusion A lower serum Mg level was associated with higher all-cause mortality and cardiovascular mortality in patients receiving hemodialysis.
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Affiliation(s)
- Hongwei Wu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Qiang Li
- Department of Nephrology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, China
| | - Lijing Fan
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Dewang Zeng
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Department of Nephrology, Huadu District People's Hospital, Guangzhou, China
| | - Xianggeng Chi
- Department of Nephrology, The First Affiliated Xiaolan Hospital of Southern Medical University, Zhongshan, China
- Department of Medicine Nephrology, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
| | - Baozhang Guan
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Bo Hu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
| | - Yongping Lu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Department of Medicine Nephrology, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
| | - Chen Yun
- Department of Medicine Nephrology, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
| | - Bernhard Krämer
- Department of Medicine Nephrology, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
| | - Berthold Hocher
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- Department of Medicine Nephrology, Medical Faculty Mannheim Heidelberg University, Mannheim, Germany
| | - Fanna Liu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- **Fanna Liu, Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, 613 West Huangpu Avenue, Guangzhou 510632 (China),
| | - Lianghong Yin
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China
- *Lianghong Yin, Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, 613 West Huangpu Avenue, Guangzhou 510632 (China),
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25
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Dominguez LJ, Veronese N, Barbagallo M. Magnesium and Hypertension in Old Age. Nutrients 2020; 13:E139. [PMID: 33396570 PMCID: PMC7823889 DOI: 10.3390/nu13010139] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
Hypertension is a complex condition in which various actors and mechanisms combine, resulting in cardiovascular and cerebrovascular complications that today represent the most frequent causes of mortality, morbidity, disability, and health expenses worldwide. In recent decades, there has been an exceptional number of experimental, epidemiological, and clinical studies confirming a close relationship between magnesium deficit and high blood pressure. Multiple mechanisms may help to explain the bulk of evidence supporting a protective effect of magnesium against hypertension and its complications. Hypertension increases sharply with advancing age, hence older persons are those most affected by its negative consequences. They are also more frequently at risk of magnesium deficiency by multiple mechanisms, which may, at least in part, explain the higher frequency of hypertension and its long-term complications. The evidence for a favorable effect of magnesium on hypertension risk emphasizes the importance of broadly encouraging the intake of foods such as vegetables, nuts, whole cereals and legumes, optimal dietary sources of magnesium, and avoiding processed foods, which are very poor in magnesium and other fundamental nutrients, in order to prevent hypertension. In some cases, when diet is not enough to maintain an adequate magnesium status, magnesium supplementation may be of benefit and has been shown to be well tolerated.
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Affiliation(s)
| | | | - Mario Barbagallo
- Geriatric Unit, Department of Medicine, University of Palermo, 90100 Palermo, Italy; (L.J.D.); (N.V.)
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26
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Rodelo-Haad C, Pendón-Ruiz de Mier MV, Díaz-Tocados JM, Martin-Malo A, Santamaria R, Muñoz-Castañeda JR, Rodríguez M. The Role of Disturbed Mg Homeostasis in Chronic Kidney Disease Comorbidities. Front Cell Dev Biol 2020; 8:543099. [PMID: 33282857 PMCID: PMC7688914 DOI: 10.3389/fcell.2020.543099] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 10/09/2020] [Indexed: 12/19/2022] Open
Abstract
Some of the critical mechanisms that mediate chronic kidney disease (CKD) progression are associated with vascular calcifications, disbalance of mineral metabolism, increased oxidative and metabolic stress, inflammation, coagulation abnormalities, endothelial dysfunction, or accumulation of uremic toxins. Also, it is widely accepted that pathologies with a strong influence in CKD progression are diabetes, hypertension, and cardiovascular disease (CVD). A disbalance in magnesium (Mg) homeostasis, more specifically hypomagnesemia, is associated with the development and progression of the comorbidities mentioned above, and some mechanisms might explain why low serum Mg is associated with negative clinical outcomes such as major adverse cardiovascular and renal events. Furthermore, it is likely that hypomagnesemia causes the release of inflammatory cytokines and C-reactive protein and promotes insulin resistance. Animal models have shown that Mg supplementation reverses vascular calcifications; thus, clinicians have focused on the potential benefits that Mg supplementation may have in humans. Recent evidence suggests that Mg reduces coronary artery calcifications and facilitates peripheral vasodilation. Mg may reduce vascular calcification by direct inhibition of the Wnt/β-catenin signaling pathway. Furthermore, Mg deficiency worsens kidney injury induced by an increased tubular load of phosphate. One important consequence of excessive tubular load of phosphate is the reduction of renal tubule expression of α-Klotho in moderate CKD. Low Mg levels worsen the reduction of Klotho induced by the tubular load of phosphate. Evidence to support clinical translation is yet insufficient, and more clinical studies are required to claim enough evidence for decision-making in daily practice. Meanwhile, it seems reasonable to prevent and treat Mg deficiency. This review aims to summarize the current understanding of Mg homeostasis, the potential mechanisms that may mediate the effect of Mg deficiency on CKD progression, CVD, and mortality.
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Affiliation(s)
- Cristian Rodelo-Haad
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain.,Nephrology Service, Reina Sofia University Hospital, Córdoba, Spain.,Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain
| | - M Victoria Pendón-Ruiz de Mier
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain.,Nephrology Service, Reina Sofia University Hospital, Córdoba, Spain.,Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain
| | - Juan Miguel Díaz-Tocados
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain
| | - Alejandro Martin-Malo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain.,Nephrology Service, Reina Sofia University Hospital, Córdoba, Spain.,Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain
| | - Rafael Santamaria
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain.,Nephrology Service, Reina Sofia University Hospital, Córdoba, Spain.,Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain
| | - Juan Rafael Muñoz-Castañeda
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain.,Nephrology Service, Reina Sofia University Hospital, Córdoba, Spain.,Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain
| | - Mariano Rodríguez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.,University of Córdoba, Córdoba, Spain.,Nephrology Service, Reina Sofia University Hospital, Córdoba, Spain.,Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain
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27
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Ter Braake AD, Eelderink C, Zeper LW, Pasch A, Bakker SJL, de Borst MH, Hoenderop JGJ, de Baaij JHF. Calciprotein particle inhibition explains magnesium-mediated protection against vascular calcification. Nephrol Dial Transplant 2020; 35:765-773. [PMID: 31605492 PMCID: PMC7203562 DOI: 10.1093/ndt/gfz190] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/27/2019] [Indexed: 12/20/2022] Open
Abstract
Background Phosphate (Pi) toxicity is a strong determinant of vascular calcification development in chronic kidney disease (CKD). Magnesium (Mg2+) may improve cardiovascular risk via vascular calcification. The mechanism by which Mg2+ counteracts vascular calcification remains incompletely described. Here we investigated the effects of Mg2+ on Pi and secondary crystalline calciprotein particles (CPP2)-induced calcification and crystal maturation. Methods Vascular smooth muscle cells (VSMCs) were treated with high Pi or CPP2 and supplemented with Mg2+ to study cellular calcification. The effect of Mg2+ on CPP maturation, morphology and composition was studied by medium absorbance, electron microscopy and energy dispersive spectroscopy. To translate our findings to CKD patients, the effects of Mg2+ on calcification propensity (T50) were measured in sera from CKD patients and healthy controls. Results Mg2+ supplementation prevented Pi-induced calcification in VSMCs. Mg2+ dose-dependently delayed the maturation of primary CPP1 to CPP2 in vitro. Mg2+ did not prevent calcification and associated gene and protein expression when added to already formed CPP2. Confirmatory experiments in human serum demonstrated that the addition of 0.2 mmol/L Mg2+ increased T50 from healthy controls by 51 ± 15 min (P < 0.05) and CKD patients by 44 ± 13 min (P < 0.05). Each further 0.2 mmol/L addition of Mg2+ led to further increases in both groups. Conclusions Our results demonstrate that crystalline CPP2 mediates Pi-induced calcification in VSMCs. In vitro, Mg2+ delays crystalline CPP2 formation and thereby prevents Pi-induced calcification.
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Affiliation(s)
- Anique D Ter Braake
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Coby Eelderink
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Lara W Zeper
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Andreas Pasch
- Calciscon AG, Nidau, Switzerland.,Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
| | - Stephan J L Bakker
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Martin H de Borst
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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28
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Ogawa C, Tsuchiya K, Maeda K. High serum magnesium levels are associated with favorable prognoses in diabetic hemodialysis patients, retrospective observational study. PLoS One 2020; 15:e0238763. [PMID: 32941454 PMCID: PMC7498072 DOI: 10.1371/journal.pone.0238763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/24/2020] [Indexed: 11/23/2022] Open
Abstract
Background Recent studies have found hypomagnesemia is linked to a heightened risk of cardiovascular events and mortality in hemodialysis (HD) patients; however, the level of serum magnesium (s-Mg) necessary for promoting overall health in these patients and the effects of s-Mg in diabetes HD patients remains to be clarified. Methods HD outpatients (n = 148 under, age ≤ 70 y) were followed over a 6-y period. They were divided into four groups according to their average s-Mg during the first year (L; low level, H; high level) and if they had DM or not (non-DM). The endpoint was mortality and hospitalization for decline of Activities of Daily Living (death/hospitalization). A receiver operating characteristics curve was used in diagnostic tests to identify s-Mg associated with this endpoint. Kaplan–Meier, log-rank test, and a Cox proportional hazards model were used to evaluate prognoses. Fisher's exact test and multiple regressions examined the causes of the endpoints between the four groups and the factors predictive of s-Mg. Results s-Mg at 2.7 mg/dL was associated with death/hospitalization. The 5-y survival rate was 38.1%, 86.7%, 73.2% and 87.5%, in the DM/Mg(L), DM/Mg(H), non-DM/Mg(L) and non-DM/Mg(H) groups, respectively (P < 0.001). The Cox proportional hazards model showed significantly lower risk in other groups compared with that in the DM/Mg(L) group [DM/Mg(H); hazard ratio (HR): 0.22, 95% confidence interval (CI): 0.05–0.97, P = 0.046, non-DM/Mg(L); HR: 0.32, 95% CI: 0.15–0.68, P = 0.003, non-DM/Mg(H); HR: 0.17, 95% CI: 0.06–0.44, P < 0.001]. The frequency of the different causes of the endpoints for each group was not significant; s-Mg only associated with age in the DM group. Conclusions s-Mg greater than 2.7 mg/dL associated with a favorable prognosis in HD patients with DM, suggesting that s-Mg is a factor independent of diabetes.
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Affiliation(s)
- Chie Ogawa
- Maeda Institute of Renal Research, Kawasaki, Kanagawa, Japan
- Biomarker Society, INC, Kawasaki, Kanagawa, Japan
- * E-mail:
| | - Ken Tsuchiya
- Biomarker Society, INC, Kawasaki, Kanagawa, Japan
- Department of Blood Purification, Tokyo Women’s Medical University, Tokyo, Japan
| | - Kunimi Maeda
- Maeda Institute of Renal Research, Kawasaki, Kanagawa, Japan
- Biomarker Society, INC, Kawasaki, Kanagawa, Japan
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29
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Nakagawa Y, Komaba H, Fukagawa M. Magnesium as a Janus-faced inhibitor of calcification. Kidney Int 2020; 97:448-450. [PMID: 32087884 DOI: 10.1016/j.kint.2019.11.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/12/2019] [Accepted: 11/13/2019] [Indexed: 12/14/2022]
Abstract
Vascular calcification is a life-threatening complication in patients with chronic kidney disease. Magnesium is a potent inhibitor of calcification and attracting attention as a new therapeutic candidate. ter Braake and colleagues demonstrate that magnesium supplementation strikingly prevents vascular calcification in Klotho knockout mice. However, these mice also show osteomalacia, indicating that magnesium has a Janus face. Maximizing the beneficial effects of magnesium without causing bone mineralization defects is an important next challenge.
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Affiliation(s)
- Yosuke Nakagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Hirotaka Komaba
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan; Interactive Translational Research Center for Kidney Diseases, Tokai University School of Medicine, Isehara, Japan; The Institute of Medical Sciences, Tokai University, Isehara, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.
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30
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Villa-Bellosta R. Dietary magnesium supplementation improves lifespan in a mouse model of progeria. EMBO Mol Med 2020; 12:e12423. [PMID: 32875720 PMCID: PMC7539193 DOI: 10.15252/emmm.202012423] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 01/11/2023] Open
Abstract
Aging is associated with redox imbalance according to the redox theory of aging. Consistently, a mouse model of premature aging (LmnaG609G/+) showed an increased level of mitochondrial reactive oxygen species (ROS) and a reduced basal antioxidant capacity, including loss of the NADPH‐coupled glutathione redox system. LmnaG609G/+ mice also exhibited reduced mitochondrial ATP synthesis secondary to ROS‐induced mitochondrial dysfunction. Treatment of LmnaG609G/+ vascular smooth muscle cells with magnesium‐enriched medium improved the intracellular ATP level, enhanced the antioxidant capacity, and thereby reduced mitochondrial ROS production. Moreover, treatment of LmnaG609G/+ mice with dietary magnesium improved the proton pumps (complexes I, III, and IV), stimulated extramitochondrial NADH oxidation and enhanced the coupled mitochondrial membrane potential, and thereby increased H+‐coupled mitochondrial NADPH and ATP synthesis, which is necessary for cellular energy supply and survival. Consistently, magnesium treatment reduced calcification of vascular smooth muscle cells in vitro and in vivo, and improved the longevity of mice. This antioxidant property of magnesium may be beneficial in children with HGPS.
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Affiliation(s)
- Ricardo Villa-Bellosta
- Fundación Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
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Sakaguchi Y, Hamano T, Matsui I, Oka T, Yamaguchi S, Kubota K, Shimada K, Matsumoto A, Hashimoto N, Isaka Y. Low magnesium diet aggravates phosphate-induced kidney injury. Nephrol Dial Transplant 2020; 34:1310-1319. [PMID: 30535376 DOI: 10.1093/ndt/gfy358] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 10/11/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Magnesium is known to protect against phosphate-induced tubular cell injuries in vitro. We investigated in vivo effects of magnesium on kidney injuries and phosphate metabolism in mice exposed to a high phosphate diet. METHODS Heminephrectomized mice were maintained on a high phosphate/normal magnesium diet or a high phosphate/low magnesium diet for 6 weeks. We compared renal histology, phosphaturic hormones and renal α-Klotho expression between the two diet groups. RESULTS High phosphate diet-induced tubular injuries and interstitial fibrosis were remarkably aggravated by the low-magnesium diet. At 1 week after high phosphate feeding when serum creatinine levels were similar between the two groups, the low magnesium diet suppressed not only fecal phosphate excretion but also urinary phosphate excretion, resulting in increased serum phosphate levels. Parathyroid hormone (PTH) levels were not appropriately elevated in the low magnesium diet group despite lower 1,25-dihydroxyvitamin D and serum calcium levels compared with the normal magnesium diet group. Although fibroblast growth factor 23 (FGF23) levels were lower in the low magnesium diet group, calcitriol-induced upregulation of FGF23 could not restore the impaired urinary phosphate excretion. The low magnesium diet markedly downregulated α-Klotho expression in the kidney. This downregulation of α-Klotho occurred even when mice were fed the low phosphate diet. CONCLUSIONS A low magnesium diet aggravated high phosphate diet-induced kidney injuries. Impaired PTH secretion and downregulation of renal α-Klotho were likely to be involved in the blunted urinary phosphate excretion by the low magnesium diet. Increasing dietary magnesium may be useful to attenuate phosphate-induced kidney injury.
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Affiliation(s)
- Yusuke Sakaguchi
- Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takayuki Hamano
- Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Isao Matsui
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tatsufumi Oka
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Yamaguchi
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Keiichi Kubota
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Karin Shimada
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ayumi Matsumoto
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Nobuhiro Hashimoto
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
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Magnesium and calciprotein particles in vascular calcification: the good cop and the bad cop. Curr Opin Nephrol Hypertens 2020; 28:368-374. [PMID: 31045659 DOI: 10.1097/mnh.0000000000000509] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Vascular calcification is a major contributor to increased cardiovascular mortality in chronic kidney disease (CKD). Recently, calciprotein particles (CPP) were identified to drive the calcification process. CPP may explain the effects of high phosphate on vascular calcification. Magnesium is a promising novel therapeutic approach to halt vascular calcification, because it inhibits CPP maturation and is associated with reduced cardiovascular mortality in CKD. We aim to examine the current evidence for the role of CPP in the calcification process and to explain how magnesium prevents calcification. RECENT FINDINGS A recent meta-analysis concluded that reducing high phosphate levels in CKD patients does not associate with lowering cardiovascular mortality. Inhibition of CPP formation prevents phosphate-induced calcification in vitro. Consequently, delaying CPP formation and maturation may be a clinical approach to reduce calcification. Magnesium inhibits CPP maturation and vascular calcification. Clinical pilot studies suggest that magnesium is a promising intervention strategy against calcification in CKD patients. SUMMARY CPP induce vascular calcification and are modulated by serum phosphate and magnesium concentrations. Magnesium is a strong inhibitor of CPP maturation and therefore, a promising therapeutic approach to reduce vascular calcification in CKD. Currently, several studies are being performed to determine the clinical outcomes of magnesium supplementation in CKD.
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Quaglino D, Boraldi F, Lofaro FD. The biology of vascular calcification. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 354:261-353. [PMID: 32475476 DOI: 10.1016/bs.ircmb.2020.02.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Vascular calcification (VC), characterized by different mineral deposits (i.e., carbonate apatite, whitlockite and hydroxyapatite) accumulating in blood vessels and valves, represents a relevant pathological process for the aging population and a life-threatening complication in acquired and in genetic diseases. Similarly to bone remodeling, VC is an actively regulated process in which many cells and molecules play a pivotal role. This review aims at: (i) describing the role of resident and circulating cells, of the extracellular environment and of positive and negative factors in driving the mineralization process; (ii) detailing the types of VC (i.e., intimal, medial and cardiac valve calcification); (iii) analyzing rare genetic diseases underlining the importance of altered pyrophosphate-dependent regulatory mechanisms; (iv) providing therapeutic options and perspectives.
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Affiliation(s)
- Daniela Quaglino
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
| | - Federica Boraldi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Nelson AJ, Raggi P, Wolf M, Gold AM, Chertow GM, Roe MT. Targeting Vascular Calcification in Chronic Kidney Disease. JACC Basic Transl Sci 2020; 5:398-412. [PMID: 32368697 PMCID: PMC7188874 DOI: 10.1016/j.jacbts.2020.02.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/24/2020] [Accepted: 02/03/2020] [Indexed: 12/22/2022]
Abstract
Cardiovascular (CV) disease remains an important cause of morbidity and mortality for patients with chronic kidney disease (CKD). Although clustering of traditional risk factors with CKD is well recognized, kidney-specific mechanisms are believed to drive the disproportionate burden of CV disease. One perturbation that is frequently observed at high rates in patients with CKD is vascular calcification, which may be a central mediator for an array of CV sequelae. This review summarizes the pathophysiological bases of intimal and medial vascular calcification in CKD, current strategies for diagnosis and management, and posits vascular calcification as a risk marker and therapeutic target.
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Key Words
- CAC, coronary artery calcification
- CI, confidence interval
- CKD, chronic kidney disease
- CT, computed tomography
- CV, cardiovascular
- CVD, cardiovascular disease
- ESKD, end-stage kidney disease
- FGF, fibroblast growth factor
- HR, hazard ratio
- LDL-C, low-density lipoprotein cholesterol
- MGP, matrix Gla protein
- PTH, parathyroid hormone
- VSMC, vascular smooth muscle cell
- chronic kidney disease
- dialysis
- eGFR, estimated glomerular filtration rate
- medial calcification
- vascular calcification
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Affiliation(s)
- Adam J. Nelson
- Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
| | - Paolo Raggi
- Division of Cardiology, Department of Medicine, University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Alexander M. Gold
- Research and Development, Sanifit Therapeutics, San Diego, California
- Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Glenn M. Chertow
- Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Matthew T. Roe
- Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
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Potier J, Dolley-Hitze T, Hamel D, Landru I, Cardineau E, Queffeulou G, Zagdoun E, Renaudineau E, Molinari N, Gamon L, Morena M, Cristol JP, Canaud B. Long-term effects of citric acid-based bicarbonate haemodialysis on patient outcomes: a survival propensity score–matched study in western France. Nephrol Dial Transplant 2020; 35:1228-1236. [DOI: 10.1093/ndt/gfz274] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 10/22/2019] [Indexed: 12/23/2022] Open
Abstract
Abstract
Background
Citric acid–based bicarbonate haemodialysis (CIT-HD) has gained more clinical acceptance over the last few years in France and is a substitute for other acidifiers [e.g. acetic acid (CH3COOH) and hydrochloric acid (HCl)]. This trend was justified by several clinical benefits compared with CH3COOH as well as the desire to avoid the consequences of the corrosive action of HCl, but a nationwide clinical report raised concerns about the long-term safety of CIT-HD. The aim of this study was to assess the long-term effects of CIT-HD exposure on patient outcomes in western France.
Methods
This is a population-based retrospective multicentre observational study performed in 1132 incident end-stage kidney disease patients in five sanitary territories in western France who started their renal replacement therapy after 1 January 2008 and followed up through 15 October 2018. Relevant data, collected prospectively with the same medical software, were anonymously aggregated for the purposes of the study. The primary goal of this study was to investigate the effects of citrate exposure on all-cause mortality. To provide a control group to CIT-HD one, propensity score matching (PSM) at 2:1 was performed in two steps: the first analysis was intended to be exploratory, comparing patients who received citrate ≤80% of the time (CIT-HD ≤80) versus those who received citrate >80% of the time (CIT-HD >80), while the second analysis was intended to be explanatory in comparing patients with 0% (CIT-HD0) versus 100% citrate time exposure (CIT-HD100).
Results
After PSM, in the exploratory part of the analysis, 432 CIT-HD ≤80 patients were compared with 216 CIT-HD >80 patients and no difference was found for all-cause mortality using the Kaplan–Meier model (log-rank 0.97), univariate Cox regression analysis {hazard ratio [HR] 1.01 [95% confidence interval (CI) 0.71–1.40]} and multivariate Cox regression analysis [HR 1.11 (95% CI 0.76–1.61)] when adjusted for nine variables with clinical pertinence and high statistical relevance in the univariate analysis. In the explanatory part of the analysis, 316 CIT-HD0 patients were then compared with 158 CIT-HD100 patients and no difference was found using the Kaplan–Meier model (log-rank 0.06), univariate Cox regression analysis [HR 0.69 (95% CI 0.47–1.03)] and multivariate Cox regression analysis [HR 0.87 (95% CI 0.57–1.33)] when adjusted for seven variables with clinical pertinence and high statistical relevance in the univariate analysis.
Conclusions
Findings of this study support the notion that CIT-HD exposure ≤6 years has no significant effect on all-cause mortality in HD patients. This finding remains true for patients receiving high-volume online haemodiafiltration, a modality most frequently prescribed in this cohort.
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Affiliation(s)
- Jacky Potier
- Department of Nephrology and Hemodialysis, Centre Hospitalier Public du Cotentin, Cherbourg, France
| | | | | | - Isabelle Landru
- Department of Nephrology and Hemodialysis, Centre Hospitalier Robert Bisson, Lisieux, France
| | - Erick Cardineau
- Department of Nephrology and Hemodialysis, Centre Hospitalier Intercommunal Alencon-Mamers, Alençon, France
| | - Guillaume Queffeulou
- Department of Nephrology and Hemodialysis, Centre Hospitalier Public du Cotentin, Cherbourg, France
| | - Elie Zagdoun
- Department of Nephrology and Hemodialysis, Centre Hospitalier Mémorial France Etats-Unis, Saint-Lô, France
| | - Eric Renaudineau
- Department of Nephrology and Hemodialysis, Centre Hospitalier Broussais, Saint-Malo, France
| | - Nicolas Molinari
- IMAG, CNRS, Centre Hospitalier Universitaire de Montpellier, University of Montpellier, Montpellier, France
| | - Lucie Gamon
- Clinical Research and Epidemiology Unit, Centre Hospitalier Universitaire de Montpellier, University of Montpellier, Montpellier, France
| | - Marion Morena
- PhyMedExp. INSERM, CNRS, Université de Montpellier, Montpellier, France
| | - Jean-Paul Cristol
- PhyMedExp. INSERM, CNRS, Université de Montpellier, Montpellier, France
- Département de Biochimie et Hormonologie, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Bernard Canaud
- School of Medicine, Montpellier University, Montpellier, France
- FMC, Global Medical Office, Bad Homburg, Germany
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Levy J, Miranda AAM, De Carli E, Bittencourt MS, Benseñor IJ, Lotufo PA, Marchioni DM. Ingestion of magnesium was not associated with coronary calcium score in a cross-sectional study. INT J VITAM NUTR RES 2019; 91:217-223. [PMID: 31711405 DOI: 10.1024/0300-9831/a000618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background and aims: Magnesium plays a key role in glucose metabolism, vascular tone, and inflammation. Therefore, it might be a dietary risk factor for cardiovascular diseases. In vitro and animal studies have suggested a decrease in vascular calcification with an increase in the magnesium intake. The objective of the present study was to investigate the association between magnesium intake and coronary artery calcium (CAC) score among participants of the ELSA-Brasil. Methods: This is an observational, cross-sectional study undertaken with a sub-sample from the ELSA-Brasil baseline data. In this sub-sample, only participants with CAC examination data were included (n = 4,306). Dietary intake was assessed by a validated food frequency questionnaire. The association between magnesium intake and presence of CAC (0 versus > 0) was investigated using multiple logistic regression models. Results: The participants were predominantly female (54.4 %), with self-reported white skin color (59.1 %), no smoking habit (53.7 %) and undergraduate or postgraduate education (44.4 %). The range of magnesium consumption was 37.24 - 1266.31 mg/day. CAC prevalence was 28.4 %. No significant association was found between magnesium intake and CAC after adjustments for diet, lifestyle, and clinical characteristics. In a first univariate model, the fifth quintile of magnesium intake, in comparison to the first quintile (lowest intake), resulted in an OR = 1.25, 95 % CI: 1.01 - 1.54 (P-linear trend = 0.005). However, in the last fully adjusted model, the fifth quintile of magnesium intake resulted in OR = 0.86, 95 % CI: 0.64 - 1.17 (P-linear trend = 0.239). Conclusions: In ELSA-Brasil, the intake of magnesium was not associated with the presence of coronary artery calcification.
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Affiliation(s)
- Jéssica Levy
- School of Public Health/University of São Paulo, Brazil
| | | | | | - Marcio Sommer Bittencourt
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, Brazil
| | - Isabela Judith Benseñor
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, Brazil
| | - Paulo Andrade Lotufo
- Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, Brazil
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Ter Braake AD, Smit AE, Bos C, van Herwaarden AE, Alkema W, van Essen HW, Bravenboer N, Vervloet MG, Hoenderop JGJ, de Baaij JHF. Magnesium prevents vascular calcification in Klotho deficiency. Kidney Int 2019; 97:487-501. [PMID: 31866113 DOI: 10.1016/j.kint.2019.09.034] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/20/2019] [Accepted: 09/27/2019] [Indexed: 01/08/2023]
Abstract
Klotho knock-out mice are an important model for vascular calcification, which is associated with chronic kidney disease. In chronic kidney disease, serum magnesium inversely correlates with vascular calcification. Here we determine the effects of serum magnesium on aortic calcification in Klotho knock-out mice treated with a minimal or a high magnesium diet from birth. After eight weeks, serum biochemistry and aorta and bone tissues were studied. Protective effects of magnesium were characterized by RNA-sequencing of the aorta and micro-CT analysis was performed to study bone integrity. A high magnesium diet prevented vascular calcification and aortic gene expression of Runx2 and matrix Gla protein found in such mice on the minimal magnesium diet. Differential expression of inflammation and extracellular matrix remodeling genes accompanied the beneficial effects of magnesium on calcification. High dietary magnesium did not affect serum parathyroid hormone, 1,25-dihydroxyvitamin D3 or calcium. High magnesium intake prevented vascular calcification despite increased fibroblast growth factor-23 and phosphate concentration in the knock-out mice. Compared to mice on the minimal magnesium diet, the high magnesium diet reduced femoral bone mineral density by 20% and caused excessive osteoid formation indicating osteomalacia. Osteoclast activity was unaffected by the high magnesium diet. In Saos-2 osteoblasts, magnesium supplementation reduced mineralization independent of osteoblast function. Thus, high dietary magnesium prevents calcification in Klotho knock-out mice. These effects are potentially mediated by reduction of inflammatory and extracellular matrix remodeling pathways within the aorta. Hence magnesium treatment may be promising to prevent vascular calcification, but the risk for osteomalacia should be considered.
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Affiliation(s)
- Anique D Ter Braake
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Anna E Smit
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Caro Bos
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Antonius E van Herwaarden
- Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wynand Alkema
- Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Huib W van Essen
- Department of Clinical Chemistry, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands
| | - Marc G Vervloet
- Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
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Disthabanchong S, Srisuwarn P. Mechanisms of Vascular Calcification in Kidney Disease. Adv Chronic Kidney Dis 2019; 26:417-426. [PMID: 31831120 DOI: 10.1053/j.ackd.2019.08.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/18/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023]
Abstract
The increase in prevalence and severity of vascular calcification in chronic kidney disease is a result of complex interactions between changes in the vascular bed, mineral metabolites, and other uremic factors. Vascular calcification can occur in the intima and the media of arterial wall. Under permissive conditions, vascular smooth muscle cells (VSMCs) can transform to osteoblast-like phenotype. The membrane-bound vesicles released from transformed VSMCs and the apoptotic bodies derived from dying VSMCs serve as nucleating structures for calcium crystal formation. Alterations in the quality and the quantity of endogenous calcification inhibitors also give rise to an environment that potentiates calcification.
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Affiliation(s)
- Sinee Disthabanchong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
| | - Praopilad Srisuwarn
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Machado AD, Andrade GRG, Levy J, Ferreira SS, Marchioni DM. Association between Vitamins and Minerals with Antioxidant Effects and Coronary Artery Calcification in Adults and Older Adults: A Systematic Review. Curr Pharm Des 2019; 25:2474-2479. [DOI: 10.2174/1381612825666190722101954] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 07/20/2019] [Indexed: 12/19/2022]
Abstract
Background:
Coronary Artery Calcification (CAC) is considered an important cardiovascular risk
factor. There is evidence that CAC is associated with an increased risk of atherosclerosis, coronary events and
cardiovascular mortality. Inflammation is one of the factors associated with CAC and despite the interest in antioxidant
compounds that can prevent CAC, its association with antioxidants remains unclear.
Objective:
This study aimed to systematically review the association between vitamins and minerals with antioxidant
effects and CAC in adults and older adults.
Methods:
We conducted a systematic review using PubMed for articles published until October 2018. We included
studies conducted in subjects aged 18 years and older with no previous cardiovascular disease. Studies
involving animal or in vitro experiments and the ones that did not use reference methods to assess the CAC, dietary
intake or serum levels of vitamin or mineral were excluded.
Results:
The search yielded 390 articles. After removal of duplicates, articles not related to the review, review
articles, editorials, hypothesis articles and application of the inclusion and exclusion criteria, 9 articles remained.
The results of the studies included in this systematic review suggest that magnesium is inversely associated with
CAC and results on the association between CAC and vitamin E have been conflicting.
Conclusion:
Additional prospective studies are needed to elucidate the role of these micronutrients on CAC.
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Affiliation(s)
- Alisson Diego Machado
- Department of Nephrology, Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Jéssica Levy
- Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo, Brazil
| | - Sara Silva Ferreira
- Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo, Brazil
| | - Dirce Maria Marchioni
- Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo, Brazil
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Yang Y, Ye H, He Q, Zhang X, Yu B, Yang J, Chen J. Association between predialysis hypermagnesaemia and morbidity of uraemic restless legs syndrome in maintenance haemodialysis patients: a retrospective observational study in Zhejiang, China. BMJ Open 2019; 9:e027970. [PMID: 31292178 PMCID: PMC6624039 DOI: 10.1136/bmjopen-2018-027970] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE The aim of the present study was to determine whether the predialysis serum magnesium level was associated with morbidity of uraemic restless legs syndrome (RLS) in maintenance haemodialysis patients. DESIGN A retrospective observational study of morbidity of uraemic RLS was conducted. SETTING Patients on maintenance haemodialysis three times a week. PARTICIPANTS We reviewed 578 patients receiving maintenance haemodialysis for >1 year as our cohort. OUTCOME MEASURES Uraemic RLS was diagnosed according to International RLS Study Group criteria, and hypermagnesaemia was defined as serum magnesium level >1.02 mmol/L. RESULTS The prevalence of uraemic RLS was 14.4% in our study cohort. Univariate analysis indicated that patients with uraemic RLS differed significantly from non-RLS ones in certain demographic and clinical characteristics, including younger age, longer dialysis duration, higher serum parathyroid hormone level and higher prevalence of predialysis hyperphosphataemia and hypermagnesaemia. Binary logistic-regression model analysis indicated that predialysis hypermagnesaemia was independently associated with uraemic RLS and conferred an increase in morbidity of the syndrome (OR=2.024; 95% CI 1.160 to 3.532; p=0.013). Moreover, we found that dialysis duration and predialysis hyperphosphataemia were independently associated with morbidity of uraemic RLS. CONCLUSIONS Our data indicated that the predialysis serum magnesium level was associated with morbidity of uraemic RLS in maintenance haemodialysis patients and that predialysis hypermagnesaemia might serve as an independent risk factor for the syndrome.
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Affiliation(s)
- Yi Yang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hongying Ye
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Nephrology, Jinhua Municipal Central Hospital, Jinhua, China
| | - Qien He
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Nephrology, Beilun People’s Hospital, Ningbo, China
| | - Xiaohui Zhang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Nephrology, Yiwu Municipal Central Hospital, Yiwu, China
| | - Biying Yu
- Department of Nephrology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, China
| | - Jingjuan Yang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Nephrology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Shimohata H, Yamashita M, Ohgi K, Tsujimoto R, Maruyama H, Takayasu M, Hirayama K, Kobayashi M. The relationship between serum magnesium levels and mortality in non-diabetic hemodialysis patients: A 10-year follow-up study. Hemodial Int 2019; 23:369-374. [PMID: 31037843 DOI: 10.1111/hdi.12759] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 03/15/2019] [Accepted: 04/12/2019] [Indexed: 11/28/2022]
Abstract
Introduction Recently, although there are many reports showing that serum magnesium concentration is a predictor of mortality in dialysis patients, the observation periods of those reports were of short duration, typically around 12 months. Thus, we investigated this relationship over a longer follow-up period. Methods This retrospective, observational study included a total of 83 non-diabetic hemodialysis patients. The follow-up period was 120 months. Patients were divided into two groups, those with serum magnesium ≥2.5 mg/dL (Mg ≥2.5 mg/dL group) and serum magnesium <2.5 mg/dL (Mg <2.5 mg/dL group), and Kaplan-Meier analysis and Cox proportional hazards analysis were conducted. In addition to the above analysis, single and multiple regression analysis were performed at baseline to reveal the relationship between serum magnesium and clinical parameters. Findings During the follow-up period, 31 out of 83 patients died. Kaplan-Meier analysis showed a significantly higher incidence of death in the Mg <2.5 mg/dL group (log-rank test 4.951, P = 0.026). Multivariate Cox proportional hazards analysis showed a 62% decreased risk of mortality in the Mg ≥2.5 mg/dL group compared to the Mg <2.5 mg/dL group after adjustment for several confounding factors. Simple correlation coefficient analysis showed positive correlations of serum magnesium levels with serum creatinine, phosphorus, high-density lipoprotein, ankle-brachial index and KT/V, and a negative correlation with age. Multiple linear regression analysis showed that the ankle-brachial index was the only parameter that had a positive and significant correlation with the serum magnesium level. Conclusion Our study demonstrated that higher serum magnesium levels were associated with improved survival in non-diabetic hemodialysis patients.
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Affiliation(s)
- Homare Shimohata
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Marina Yamashita
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Kentaro Ohgi
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Ryuji Tsujimoto
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Hiroshi Maruyama
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Mamiko Takayasu
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Kouichi Hirayama
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Masaki Kobayashi
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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Sakaguchi Y, Hamano T, Obi Y, Monden C, Oka T, Yamaguchi S, Matsui I, Hashimoto N, Matsumoto A, Shimada K, Takabatake Y, Takahashi A, Kaimori JY, Moriyama T, Yamamoto R, Horio M, Yamamoto K, Sugimoto K, Rakugi H, Isaka Y. A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD. J Am Soc Nephrol 2019; 30:1073-1085. [PMID: 31036759 DOI: 10.1681/asn.2018111150] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 02/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Developing strategies for managing coronary artery calcification (CAC) in patients with CKD is an important clinical challenge. Experimental studies have demonstrated that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. METHODS To assess the efficacy of magnesium oxide (MgO) and/or the oral carbon adsorbent AST-120 for slowing CAC progression in CKD, we conducted a 2-year, open-label, randomized, controlled trial, enrolling patients with stage 3-4 CKD with risk factors for CAC (diabetes mellitus, history of cardiovascular disease, high LDL cholesterol, or smoking). Using a two-by-two factorial design, we randomly assigned patients to an MgO group or a control group, and to an AST-120 group or a control group. The primary outcome was percentage change in CAC score. RESULTS We terminated the study prematurely after an interim analysis with the first 125 enrolled patients (of whom 96 completed the study) showed that the median change in CAC score was significantly smaller for MgO versus control (11.3% versus 39.5%). The proportion of patients with an annualized percentage change in CAC score of ≥15% was also significantly lower for MgO compared with control (23.9% versus 62.0%). However, MgO did not suppress the progression of thoracic aorta calcification. The MgO group's dropout rate was higher than that of the control group (27% versus 17%), primarily due to diarrhea. The percentage change in CAC score did not differ significantly between the AST-120 and control groups. CONCLUSIONS MgO, but not AST-120, appears to be effective in slowing CAC progression. Larger-scale trials are warranted to confirm these findings.
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Affiliation(s)
- Yusuke Sakaguchi
- Departments of Inter-Organ Communication Research in Kidney Disease
| | - Takayuki Hamano
- Departments of Inter-Organ Communication Research in Kidney Disease,
| | - Yoshitsugu Obi
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine, Orange, California
| | - Chikako Monden
- Department of Internal Medicine, Kisei Hospital, Osaka, Japan; and
| | | | | | | | | | | | | | | | | | | | - Toshiki Moriyama
- Health Care Division, Health and Counseling Center, Osaka University, Toyonaka, Japan
| | - Ryohei Yamamoto
- Health Care Division, Health and Counseling Center, Osaka University, Toyonaka, Japan
| | | | - Koichi Yamamoto
- Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ken Sugimoto
- Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hiromi Rakugi
- Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
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Magnesium: A Magic Bullet for Cardiovascular Disease in Chronic Kidney Disease? Nutrients 2019; 11:nu11020455. [PMID: 30813254 PMCID: PMC6412491 DOI: 10.3390/nu11020455] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/17/2019] [Accepted: 02/19/2019] [Indexed: 12/19/2022] Open
Abstract
Magnesium is essential for many physiological functions in the human body. Its homeostasis involves dietary intake, absorption, uptake and release from bone, swifts between the intra- and extracellular compartment, and renal excretion. Renal excretion is mainly responsible for regulation of magnesium balance. In chronic kidney disease (CKD), for a long time the general policy has been limiting magnesium intake. However, this may not be appropriate for many patients. The reference ranges for magnesium are not necessarily optimal concentrations, and risks for insufficient magnesium intake exist in patients with CKD. In recent years, many observational studies have shown that higher (in the high range of “normal” or slightly above) magnesium concentrations are associated with better survival in CKD cohorts. This review gives an overview of epidemiological associations between magnesium and overall and cardiovascular survival in patients with CKD. In addition, potential mechanisms explaining the protective role of magnesium in clinical cardiovascular outcomes are described by reviewing evidence from in vitro studies, animal studies, and human intervention studies with non-clinical endpoints. This includes the role of magnesium in cardiac arrhythmia, heart failure, arterial calcification, and endothelial dysfunction. Possible future implications will be addressed, which will need prospective clinical trials with relevant clinical endpoints before these can be adopted in clinical practice.
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Zhou Y, Liu X, Huang N, Chen Y. Magnesium ion leachables induce a conversion of contractile vascular smooth muscle cells to an inflammatory phenotype. J Biomed Mater Res B Appl Biomater 2018; 107:988-1001. [PMID: 30270501 DOI: 10.1002/jbm.b.34192] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 05/27/2018] [Accepted: 06/12/2018] [Indexed: 12/29/2022]
Abstract
Phenotype switching is a characteristic response of vascular smooth muscle cells (vSMCs) to the dynamic microenvironment and contributes to all stages of atherosclerotic plaque. Here, we immersed pure magnesium and AZ31 alloy in the completed medium under cell culture condition, applied the resultant leaching extracts to the isolated contractile rat aortic vSMCs and investigated how vSMCs phenotypically responded to the degradation of the magnesium-based stent materials. vSMCs became more proliferative and migratory but underwent more apoptosis when exposed to the degradation products of pure magnesium; while the AZ31 extracts caused less cell division but more apoptosis, thus slowing cell moving and growing. Noticeably, both leaching extracts dramatically downregulated the contractile phenotypic genes at mRNA and protein levels while significantly induced the inflammatory adhesive molecules and cytokines. Exogenously added Mg ions excited similar transformations of vSMCs. With the liberation or supplementation of Mg2+ , the expression patterns of the pro-contractile transactivator myocardin and the pro-inflammatory transcriptional factor kruppel-like factor 4 (KLF4) were reversed. Overall, the degradation of the Mg-based materials would evoke a shift of the contractile vSMCs to an inflammatory phenotype via releasing Mg ions to induce a transition from the phenotypic control of vSMCs by the myocardin to that by the KLF4. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 988-1001, 2019.
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Affiliation(s)
- Yuehua Zhou
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Xing Liu
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Nan Huang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
| | - Yuping Chen
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmacy, University of South China, Hengyang, Hunan, 421001, China.,Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, 610031, China
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Okamoto T, Hatakeyama S, Hosogoe S, Tanaka Y, Imanishi K, Takashima T, Saitoh F, Suzuki T, Ohyama C. Proton pump inhibitor as an independent factor of progression of abdominal aortic calcification in patients on maintenance hemodialysis. PLoS One 2018; 13:e0199160. [PMID: 29969455 PMCID: PMC6029762 DOI: 10.1371/journal.pone.0199160] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 06/02/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUNDS Proton pump inhibitors (PPIs) can be associated with vascular calcification in patients undergoing dialysis through hypomagnesemia. However, only few studies have demonstrated the influence of PPIs on vascular calcification in patients on maintenance hemodialysis (HD). This study aimed to investigate whether the use of PPIs accelerates vascular calcification in patients on HD. MATERIALS AND METHODS We retrospectively evaluated 200 HD patients who underwent regular blood tests and computed tomography (CT) between 2016 and 2017. The abdominal aortic calcification index (ACI) was measured using abdominal CT. The difference in the ACI values between 2016 and 2017 was evaluated as ΔACI. Patients were divided into PPI and non-PPI groups, and variables, such as patient background, medication, laboratory data, and ΔACI were compared. Factors independently associated with higher ΔACI progression (≥ third tertile value of ΔACI in this study) were determined using multivariate logistic regression analysis. RESULTS The PPI and non-PPI groups had 112 (56%) and 88 (44%) patients, respectively. Median and third tertile value of ΔACIs were 4.2% and 5.8%, respectively. Serum magnesium was significantly lower in the PPI (2.1 mg/dL) than in the non-PPI (2.3 mg/dL) group (P <0.001). Median ΔACI was significantly higher in the PPI (5.0%) than in the non-PPI (3.8%) group (P = 0.009). A total of 77 (39%) patients had a higher ΔACI. Multivariate analysis revealed that PPIs (odds ratio = 2.23; 95% confidence interval = 1.11-4.49), annual mean calcium phosphorus product, ACI in 2016, baseline serum magnesium levels, and HD vintage were independent factors associated with higher ΔACI progression after adjusting for confounders. CONCLUSION PPI use may accelerate vascular calcification in patients on HD. Further studies are necessary to elucidate their influence on vascular calcification.
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Affiliation(s)
- Teppei Okamoto
- Department of Urology, Oyokyo Kidney Research Institute Aomori Hospital, Aomori, Japan
- * E-mail:
| | - Shingo Hatakeyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Shogo Hosogoe
- Department of Urology, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Yoshimi Tanaka
- Department of Urology, Oyokyo Kidney Research Institute Aomori Hospital, Aomori, Japan
| | - Kengo Imanishi
- Department of Urology, Oyokyo Kidney Research Institute Aomori Hospital, Aomori, Japan
| | - Toru Takashima
- Department of Urology, Oyokyo Kidney Research Institute Aomori Hospital, Aomori, Japan
| | - Fumitada Saitoh
- Department of Urology, Oyokyo Kidney Research Institute Aomori Hospital, Aomori, Japan
| | - Tadashi Suzuki
- Department of Urology, Oyokyo Kidney Research Institute, Aomori, Japan
| | - Chikara Ohyama
- Department of Urology, Hirosaki University Graduate School of Medicine, Aomori, Japan
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Tohno Y, Tohno S, Quiggins R, Minami T, Mahakkanukrauh P. Scarce Occurrence of Calcification in Human Sinoatrial Nodal Arteries in Old Age. Biol Trace Elem Res 2018; 184:24-32. [PMID: 28986768 DOI: 10.1007/s12011-017-1173-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 09/27/2017] [Indexed: 10/18/2022]
Abstract
To elucidate age-related changes of the sinoatrial (sinuatrial) nodal (SAN) artery, the authors investigated age-related changes of elements in the SAN artery by direct chemical analysis. In addition, the effects of different arterial origins, arterial sizes, and genders on element accumulation were investigated in the SAN artery. Fifty-nine formalin-fixed adult Thai hearts were dissected, and the following three types of the SAN artery were found: The first type was a single SAN artery arising from the right coronary artery (RCA). The second type was a single SAN artery arising from the proximal segment of the left circumflex artery (LCX). The third type was dual SAN artery arising from both the RCA and the LCX. For element analysis, both 41 single SAN arteries arising from the RCA and the LCX and 18 larger branches of dual SAN artery were used. After the arteries were incinerated with nitric acid and perchloric acid, element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that seven element contents such as Ca, P, S, Mg, Zn, Fe, and Na did not change significantly in the SAN arteries with aging. Regarding the relationships among seven elements in the SAN arteries, extremely significant direct correlations were found among P, S, Mg, and Fe contents with one exception. However, no significant correlations were found between Ca and either P or Mg contents in the SAN arteries. To examine an effect of the different arterial origins on element accumulation, the SAN arteries were separated into the RCA and the LCX groups by the arterial origin and age-related changes of element contents were compared between two groups. It was found that there were no significant differences between the RCA and the LCX groups in age-related changes of Ca and P contents. No gender differences were found in age-related changes of Ca and P contents in the SAN arteries. To elucidate whether calcification occurred in the SAN arteries in old age, both the mass ratios of Ca/P and Mg/Ca were estimated in the SAN arteries. The mass ratio of Ca/P increased progressively in the SAN arteries with Ca increase, being not constant. The mass ratio of Mg/Ca decreased gradually in the SAN arteries with Ca increase, but the average mass ratio of Mg/Ca was very high, being 49.4 ± 16.5%. These results indicated that calcification scarcely occurred in the SAN arteries in old age, independently of the arterial origin and gender.
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Affiliation(s)
- Yoshiyuki Tohno
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Setsuko Tohno
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Ranida Quiggins
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Takeshi Minami
- Laboratory of Environmental Biology, Department of Life Science, Faculty of Science and Technology, Kinki University, Higashi-Osaka, Osaka, 577-8502, Japan
| | - Pasuk Mahakkanukrauh
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
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Vanholder R, Van Laecke S, Glorieux G, Verbeke F, Castillo-Rodriguez E, Ortiz A. Deleting Death and Dialysis: Conservative Care of Cardio-Vascular Risk and Kidney Function Loss in Chronic Kidney Disease (CKD). Toxins (Basel) 2018; 10:E237. [PMID: 29895722 PMCID: PMC6024824 DOI: 10.3390/toxins10060237] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 05/11/2018] [Indexed: 02/07/2023] Open
Abstract
The uremic syndrome, which is the clinical expression of chronic kidney disease (CKD), is a complex amalgam of accelerated aging and organ dysfunctions, whereby cardio-vascular disease plays a capital role. In this narrative review, we offer a summary of the current conservative (medical) treatment options for cardio-vascular and overall morbidity and mortality risk in CKD. Since the progression of CKD is also associated with a higher cardio-vascular risk, we summarize the interventions that may prevent the progression of CKD as well. We pay attention to established therapies, as well as to novel promising options. Approaches that have been considered are not limited to pharmacological approaches but take into account lifestyle measures and diet as well. We took as many randomized controlled hard endpoint outcome trials as possible into account, although observational studies and post hoc analyses were included where appropriate. We also considered health economic aspects. Based on this information, we constructed comprehensive tables summarizing the available therapeutic options and the number and kind of studies (controlled or not, contradictory outcomes or not) with regard to each approach. Our review underscores the scarcity of well-designed large controlled trials in CKD. Nevertheless, based on the controlled and observational data, a therapeutic algorithm can be developed for this complex and multifactorial condition. It is likely that interventions should be aimed at targeting several modifiable factors simultaneously.
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Affiliation(s)
- Raymond Vanholder
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Steven Van Laecke
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Griet Glorieux
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Francis Verbeke
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | | | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain.
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Sakaguchi Y, Hamano T, Isaka Y. Magnesium and Progression of Chronic Kidney Disease: Benefits Beyond Cardiovascular Protection? Adv Chronic Kidney Dis 2018; 25:274-280. [PMID: 29793667 DOI: 10.1053/j.ackd.2017.11.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 11/12/2017] [Accepted: 11/15/2017] [Indexed: 12/16/2022]
Abstract
Experimental and clinical studies have demonstrated that magnesium deficiency leads to hypertension, insulin resistance, and endothelial dysfunction, and is associated with an increased risk of cardiovascular events. Given that cardiovascular disease and CKD share similar risk factors, the low magnesium status may also contribute to CKD progression. In fact, lower serum magnesium levels and lower dietary magnesium intake are associated with an increased risk of incident CKD and progression to end-stage kidney disease. Because these associations are independent of traditional risk factors, other pathways might be involved in the relationship between magnesium deficiency and the risk of CKD progression. Recent evidence has shown that magnesium suppresses phosphate-induced vascular calcification. Magnesium impairs the crystallization of calcium phosphate-more specifically, the maturation of calciprotein particles. Considering that phosphate overload causes kidney damage, magnesium might counteract the phosphate toxicity to the kidney, as in the case of vascular calcification. This hypothesis is supported by an in vitro observation that magnesium alleviates proximal tubular cell injury induced by high phosphate. Potential usefulness of magnesium as a treatment option for phosphate toxicity in CKD should be further investigated by intervention studies.
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Microwave assisted coating of bioactive amorphous magnesium phosphate (AMP) on polyetheretherketone (PEEK). MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2018; 85:107-113. [DOI: 10.1016/j.msec.2017.12.025] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 08/25/2017] [Accepted: 12/19/2017] [Indexed: 12/21/2022]
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Gant CM, Soedamah-Muthu SS, Binnenmars SH, Bakker SJL, Navis G, Laverman GD. Higher Dietary Magnesium Intake and Higher Magnesium Status Are Associated with Lower Prevalence of Coronary Heart Disease in Patients with Type 2 Diabetes. Nutrients 2018; 10:E307. [PMID: 29510564 PMCID: PMC5872725 DOI: 10.3390/nu10030307] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 02/24/2018] [Accepted: 03/01/2018] [Indexed: 02/07/2023] Open
Abstract
In type 2 diabetes mellitus (T2D), the handling of magnesium is disturbed. Magnesium deficiency may be associated with a higher risk of coronary heart disease (CHD). We investigated the associations between (1) dietary magnesium intake; (2) 24 h urinary magnesium excretion; and (3) plasma magnesium concentration with prevalent CHD in T2D patients. This cross-sectional analysis was performed on baseline data from the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 ± 9 years, 57% men, and diabetes duration of 11 (7-18) years). Prevalence ratios (95% CI) of CHD by sex-specific quartiles of magnesium indicators, as well as by magnesium intake per dietary source, were determined using multivariable Cox proportional hazard models. CHD was present in 100 (22%) subjects. Adjusted CHD prevalence ratios for the highest compared to the lowest quartiles were 0.40 (0.20, 0.79) for magnesium intake, 0.63 (0.32, 1.26) for 24 h urinary magnesium excretion, and 0.62 (0.32, 1.20) for plasma magnesium concentration. For every 10 mg increase of magnesium intake from vegetables, the prevalence of CHD was, statistically non-significantly, lower (0.75 (0.52, 1.08)). In this T2D cohort, higher magnesium intake, higher 24 h urinary magnesium excretion, and higher plasma magnesium concentration are associated with a lower prevalence of CHD.
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Affiliation(s)
- Christina M Gant
- Department of Internal Medicine/Nephrology, ZGT Hospital, 7609 PP Almelo, The Netherlands.
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, 9713EZ Groningen, The Netherlands.
| | - Sabita S Soedamah-Muthu
- Centre of Research on Psychology in Somatic Diseases (CORPS), Department of Medical and Clinical Psychology, Tilburg University, 5037 AB Tilburg, The Netherlands.
- Institute for Food, Nutrition and Health, University of Reading, Reading RG1 5EX, UK.
| | - S Heleen Binnenmars
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, 9713EZ Groningen, The Netherlands.
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, 9713EZ Groningen, The Netherlands.
| | - Gerjan Navis
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, 9713EZ Groningen, The Netherlands.
| | - Gozewijn D Laverman
- Department of Internal Medicine/Nephrology, ZGT Hospital, 7609 PP Almelo, The Netherlands.
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