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Chenchula S, Sharma P, Ghanta MK, Amerneni KC, Rajakarunakaran P, Saggurthi P, Chandra MB, Gupta R, Chavan M. Association and Mechanisms of Proton Pump Inhibitors Use with Type-2Diabetes Mellitus Incidence in Adults: A Systemic Review andMeta-Analysis. Curr Diabetes Rev 2024; 20:e120124225581. [PMID: 38243950 DOI: 10.2174/0115733998254869231101095222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/09/2023] [Accepted: 09/28/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are an extensively prescribed class of anti-ulcer drugs. This systematic review aimed to investigate the association between PPI use and the risk of new-onset diabetes mellitus or type 2 diabetes (T2DM) incidence. METHODS A comprehensive literature search was conducted in PubMed, Scopus, Cochrane Library, and ClinicalTrials.gov using the search terms "proton pump inhibitor," "proton pump inhibitors," "PPIs," "diabetes mellitus," and "type 2 diabetes" from inception to February 2023. Statistical analyses were performed using the "Review Manager 5.4" version, and a statistically highly significant P-value <0.05 was set. RESULTS This systematic review identified 12 studies (8 cohort, 1 RCT, and 3 case-control) with a total of 12, 64, 816 population, and the median age ranged from ≥18 yrs to ≤ 75 yrs. The pooled relative risk (RR) observations of a random-effects meta-analysis model showed that chronic exposure to PPI use has a significant association with T2DM risk incidence (RR, 2.44; 95% confidence interval, 1.31-4.54; I2 = 99%, P < 0.00001). The systematic review findings of the three case-control studies also supported an association of dose-dependent and chronic use of PPIs with an incidence of T2DM among chronic users. CONCLUSION The systematic review concludes that chronic PPI exposure increases the risk of T2DM incidence. The authors recommend the shortest possible duration of PPI use and not prescribing PPIs to high-risk prediabetics and those without a compelling indication for PPI use. Regular education to patients regarding adverse reactions with prolonged use may decrease the risk of adverse effects associated with PPIs. The authors suggest that gut dysbiosis, hypergastrinemia, hypomagnesemia, decreased pancreatic secretions and IGF-1 levels, and PXR activation associated with chronic acid suppression among chronic PPI users and the potency of PPIs might explain the association between abnormal glucose metabolism and T2DM incidence. Finally, the authors recommend further randomized controlled trials to investigate the association between PPIs and the risk of new-onset T2DM incidence.
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Affiliation(s)
- Santenna Chenchula
- Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, India
| | - Phulen Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Mohan Krishna Ghanta
- Department of Pharmacology, MVJ Medical College and Research Hospital, Bangalore, Karnataka, India
| | | | | | - Pavani Saggurthi
- Department of Pharmacology, Pharmacovigilance Associate, All India Institute of Medical Sciences, Mangalagiri, India
| | | | - Rupesh Gupta
- Department of Internal Medicine, Government Medical College, Shahdol, Madhya Pradesh, India
| | - Madhavrao Chavan
- Department of Pharmacology, Pharmacovigilance Associate, All India Institute of Medical Sciences, Mangalagiri, India
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Malinowska J, Małecka-Giełdowska M, Pietrucha K, Górska G, Kogut D, Ciepiela O. Massive Transfusion Increases Serum Magnesium Concentration. J Clin Med 2023; 12:5157. [PMID: 37568557 PMCID: PMC10419839 DOI: 10.3390/jcm12155157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/03/2023] [Accepted: 08/05/2023] [Indexed: 08/13/2023] Open
Abstract
(1) Background: The massive transfusion of packed red blood cells (RBCs) is a lifesaving procedure, but it is associated with complications, e.g., dysmagnesemia. Since magnesium is an intracellular ion, the transfused RBCs can significantly influence the magnesium concentration in the recipient's blood. (2) Methods: A retrospective study was performed among 49 patients hospitalized in the Central Clinical Hospital of the Medical University of Warsaw who received a massive blood transfusion (≥4 units/h). Data on laboratory results and patient history were collected from the hospital database. The intracellular RBCs magnesium concentration was measured in 231 samples using the colorimetric method. (3) Results: There were statistically significant changes in the mean serum magnesium concentration preoperatively and 24 h postoperatively (0.87 ± 0.13 vs. 1.03 ± 0.14, p < 0.00001) and 48 h postoperatively (0.87 ± 0.13 vs. 1.06 ± 0.15, p < 0.00001). Patients who died had significantly higher serum magnesium concentrations (p < 0.05). The median intracellular magnesium concentration in RBCs was 0.91 (0.55-1.8) mmol/L, which is below the reference values of 1.65-2.65 mmol/L. (4) Conclusions: Transfused RBCs significantly increased the serum magnesium concentration 24 h and 48 h postoperatively. It could be a result of mild hemolysis, as the median intracellular magnesium concentration in RBCs was below the reference values.
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Affiliation(s)
- Justyna Malinowska
- Department of Laboratory Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland;
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Milena Małecka-Giełdowska
- Department of Laboratory Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland;
- Central Laboratory, Central Teaching Hospital of University Clinical Center, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Katarzyna Pietrucha
- Students Scientific Group of Laboratory Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Gabriela Górska
- Students Scientific Group of Laboratory Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Dagmara Kogut
- Central Laboratory, Central Teaching Hospital of University Clinical Center, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Olga Ciepiela
- Department of Laboratory Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland;
- Central Laboratory, Central Teaching Hospital of University Clinical Center, Medical University of Warsaw, 02-097 Warsaw, Poland
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3
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Doboszewska U, Sawicki J, Sajnóg A, Szopa A, Serefko A, Socała K, Pieróg M, Nieoczym D, Mlyniec K, Nowak G, Barałkiewicz D, Sowa I, Wlaź P. Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy—The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene. Cells 2022; 11:cells11131987. [PMID: 35805072 PMCID: PMC9265460 DOI: 10.3390/cells11131987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/14/2022] [Indexed: 12/10/2022] Open
Abstract
Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a chronic, pentylenetetrazole (PTZ)-induced kindling model of epilepsy. MES seizures and PTZ kindling, unlike 6 Hz seizures, increased serum magnesium concentration. In turn, Gpr39-KO mice that underwent PTZ kindling displayed decreased concentrations of this element in serum, compared to WT mice subjected to this procedure. However, the levels of expression of TRPM7 and SlC41A1 proteins—which are responsible for magnesium transport into and out of cells, respectively—did not differ in the hippocampus between Gpr39-KO and WT mice. Furthermore, laser ablation inductively coupled plasma mass spectrometry applied to hippocampal slices did not reveal differences in magnesium levels between the groups. These data show the relationship between magnesium homeostasis and certain types of acute or chronic seizures (MES seizures or PTZ kindling, respectively), but do not explicitly support the role of GPR39 in mediating magnesium balance in the hippocampus in the latter model. However, decreased expression of TRPM7 and increased expression of SLC41A1—which were observed in the hippocampi of Gpr39-KO mice treated with TC-G 1008, in comparison to WT mice that received the same treatment—implicitly support the link between GPR39 and hippocampal magnesium homeostasis.
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Affiliation(s)
- Urszula Doboszewska
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland; (K.S.); (M.P.); (D.N.); (P.W.)
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; (K.M.); (G.N.)
- Correspondence: or ; Tel.: +48-81-537-50-10; Fax: +48-81-537-59-01
| | - Jan Sawicki
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, PL 20-093 Lublin, Poland; (J.S.); (I.S.)
| | - Adam Sajnóg
- Department of Trace Analysis, Adam Mickiewicz University, Uniwersytetu Poznanskiego 8, PL 61-614 Poznan, Poland; (A.S.); (D.B.)
| | - Aleksandra Szopa
- Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, Chodźki 1, PL 20-093 Lublin, Poland; (A.S.); (A.S.)
| | - Anna Serefko
- Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, Chodźki 1, PL 20-093 Lublin, Poland; (A.S.); (A.S.)
| | - Katarzyna Socała
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland; (K.S.); (M.P.); (D.N.); (P.W.)
| | - Mateusz Pieróg
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland; (K.S.); (M.P.); (D.N.); (P.W.)
| | - Dorota Nieoczym
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland; (K.S.); (M.P.); (D.N.); (P.W.)
| | - Katarzyna Mlyniec
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; (K.M.); (G.N.)
| | - Gabriel Nowak
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; (K.M.); (G.N.)
- Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland
| | - Danuta Barałkiewicz
- Department of Trace Analysis, Adam Mickiewicz University, Uniwersytetu Poznanskiego 8, PL 61-614 Poznan, Poland; (A.S.); (D.B.)
| | - Ireneusz Sowa
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, PL 20-093 Lublin, Poland; (J.S.); (I.S.)
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland; (K.S.); (M.P.); (D.N.); (P.W.)
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Ota R, Hirata A. Relationship between renal dysfunction and electrolyte abnormalities in hematopoietic stem cell transplant patients treated with foscarnet. J Chemother 2021; 33:539-546. [PMID: 34060436 DOI: 10.1080/1120009x.2021.1915074] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
This study aimed to investigate the relationship between renal dysfunction and electrolyte abnormalities, which are adverse events of foscarnet used for cytomegalovirus infection. Of the Ninety hematopoietic stem cell transplantation patients, 32 who met the selection criteria were enrolled in this retrospective study. The study patients were divided into two groups according to whether they developed renal dysfunction. The incidences of hypocalcemia, hypokalemia, and hypomagnesemia with an increase of grade 2 or higher in the renal dysfunction group were 45.5%, 18.2%, and 27.3%, respectively. Additionally, in the renal dysfunction group, a significant correlation was observed between creatinine and calcium (r = -0.458, p = 0.0244) and between creatinine and potassium (r = -0.520, p = 0.0092). This study shows that renal dysfunction and electrolyte abnormalities may be closely related in HSCT patients receiving foscarnet; thus, it is a report that may contribute to the safety of continuous foscarnet treatment.
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Affiliation(s)
- Ryosuke Ota
- Department of Pharmacy, Kindai University Nara Hospital, Ikoma, Japan
| | - Atsushi Hirata
- Department of Pharmacy, Kindai University Nara Hospital, Ikoma, Japan
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5
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Affiliation(s)
- Leo Monnens
- Department of Physiology Radboud University Nijmegen The Netherlands
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6
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Workeneh BT, Uppal NN, Jhaveri KD, Rondon-Berrios H. Hypomagnesemia in the Cancer Patient. KIDNEY360 2020; 2:154-166. [PMID: 35368816 PMCID: PMC8785729 DOI: 10.34067/kid.0005622020] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/11/2020] [Indexed: 02/04/2023]
Abstract
Hypomagnesemia is a common medical problem that contributes to the morbidity and mortality of patients with cancer. This review summarizes magnesium physiology and highlights the mechanisms underlying magnesium disturbances due to cancer and cancer treatment. The causes of hypomagnesemia can be categorized according to the pathophysiologic mechanism: decreased intake, transcellular shift, gastrointestinal losses, and kidney losses. Patients with cancer are at risk for opportunistic infections, frequently experience cardiovascular complications, and often receive classes of medications that cause or exacerbate hypomagnesemia. Also, cancer-specific therapies are responsible for hypomagnesemia, including platinum-based chemotherapy, anti-EGF receptor mAbs, human EGF receptor-2 target inhibitors (HER2), and calcineurin inhibitors. Urinary indices, such as the fractional excretion of magnesium, can provide useful information about the etiology. The management of hypomagnesemia depends on the magnitude of hypomagnesemia and the underlying cause. We recommended checking serum magnesium at the beginning of treatment and as part of routine monitoring throughout cancer treatment. Opportunities exist for potential research and practice improvement, including further characterization of hypomagnesemia regarding the clinical effect on cancer outcomes, preventing hypomagnesemia in patients receiving high-risk anticancer agents, and developing effective therapeutic strategies.
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Affiliation(s)
- Biruh T. Workeneh
- Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nupur N. Uppal
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, New York
| | - Kenar D. Jhaveri
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, New York
| | - Helbert Rondon-Berrios
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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7
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Ray EC. Evolving understanding of cardiovascular protection by SGLT2 inhibitors: focus on renal protection, myocardial effects, uric acid, and magnesium balance. Curr Opin Pharmacol 2020; 54:11-17. [PMID: 32682281 DOI: 10.1016/j.coph.2020.06.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 05/08/2020] [Accepted: 06/02/2020] [Indexed: 12/19/2022]
Abstract
Robust clinical data indicate that inhibitors of the sodium/glucose cotransporter 2 (SGLT2) dramatically improve clinical outcomes in diabetes, especially heart failure and progression of kidney disease. Factors that may contribute to these findings include: 1) improved glycemic control, 2) diuresis and reduced extracellular fluid volume, 3) reduced serum uric acid levels, 3) direct myocardial effects, 4) reduction in proteinuria and preservation of kidney function, and 5) correction of diabetic magnesium deficiency. Understanding the mechanisms by which SGLT2 inhibitors improve cardiovascular outcomes has the potential to improve clinical management not only of diabetes, but also of other cardiovascular disorders such as heart failure and chronic kidney disease.
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Affiliation(s)
- Evan C Ray
- University of Pittsburgh School of Medicine, Renal-Electrolyte Division, A915 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261, United States.
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8
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Safaryan AS, Sargsyan VS, Nebieridze DV. The Role of Magnesium in the Development of Cardiovascular Diseases and the Possibility of their Prevention and Correction with Magnesium Preparations (Part 2). RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2020. [DOI: 10.20996/1819-6446-2020-02-16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Data on the effect of magnesium on the homeostasis of the body and on the cardiovascular system, are presented in the article. These data supplement information on studies of the role of magnesium in many body processes. The influence of lifestyle on magnesium metabolism, the pathological processes that cause its deficiency, and the clinical picture of hypomagnesemia are presented in the article. The necessary daily amount of magnesium, ways to restore the magnesium deficiency, both nutritional and with the help of magnesium-containing pharmacological preparations, their form, bioavailability and dosage regimen are discussed. Diseases that occur and/or worsen with hypomagnesemia are considered. Data on the iatrogenic effect of many drugs, including cardiological, removing magnesium from the body and ways to solve this issue, are also presented. Hypomagnesemia exacerbates the course of cardiovascular disease. Elimination of magnesium deficiency can contribute a lot to the prevention of morbidity and the optimization of treatment of patients.
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Affiliation(s)
- A. S. Safaryan
- National Medical Research Center for Therapy and Preventive Medicine
| | - V. S. Sargsyan
- National Medical Research Center for Therapy and Preventive Medicine
| | - D. V. Nebieridze
- National Medical Research Center for Therapy and Preventive Medicine
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9
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Gratreak BDK, Swanson EA, Lazelle RA, Jelen SK, Hoenderop J, Bindels RJ, Yang C, Ellison DH. Tacrolimus-induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a role for calcineurin. Physiol Rep 2020; 8:e14316. [PMID: 31908154 PMCID: PMC6944708 DOI: 10.14814/phy2.14316] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Calcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may contribute to new-onset diabetes mellitus, and hypercalciuria, which may contribute to post-transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off-target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previously generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus-treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRNA abundance of key magnesium and calcium transport proteins (NCX-1 and Calbindin-D28k ). However, qPCR also showed decreased mRNA expression of NCX-1 and Calbindin-D28k , and TRPM6. In contrast, KS-FKBP12-/- mice treated with tacrolimus were completely protected from these effects. These results indicate that tacrolimus affects calcium and magnesium transport along the distal convoluted tubule and strongly suggests that inhibition of the phosphatase, calcineurin, is directly involved.
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Affiliation(s)
- Brittany D. K. Gratreak
- Division of Nephrology and HypertensionDepartment of MedicineOregon Health and Science UniversityPortlandORUSA
| | - Elizabeth A. Swanson
- Division of Nephrology and HypertensionDepartment of MedicineOregon Health and Science UniversityPortlandORUSA
| | - Rebecca A. Lazelle
- Division of Nephrology and HypertensionDepartment of MedicineOregon Health and Science UniversityPortlandORUSA
| | - Sabina K. Jelen
- Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenNetherlands
| | - Joost Hoenderop
- Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenNetherlands
| | - René J. Bindels
- Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenNetherlands
| | - Chao‐Ling Yang
- Division of Nephrology and HypertensionDepartment of MedicineOregon Health and Science UniversityPortlandORUSA
| | - David H. Ellison
- Division of Nephrology and HypertensionDepartment of MedicineOregon Health and Science UniversityPortlandORUSA
- Renal SectionVeterans Affairs Portland Health Care SystemPortlandORUSA
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10
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Factors Affecting the Environmentally Induced, Chronic Kidney Disease of Unknown Aetiology in Dry Zonal Regions in Tropical Countries—Novel Findings. ENVIRONMENTS 2019. [DOI: 10.3390/environments7010002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A new form of chronic tubulointerstitial kidney disease (CKD) not related to diabetes or hypertension appeared during the past four decades in several peri-equatorial and predominantly agricultural countries. Commonalities include underground stagnation of drinking water with prolonged contact with rocks, harsh climatic conditions with protracted dry seasons, and rampant poverty and malnutrition. In general, the cause is unknown, and the disease is therefore named CKD of unknown aetiology (CKDu). Since it is likely caused by a combination of factors, a better term would be CKD of multifactorial origin (CKDmfo). Middle-aged malnourished men with more than 10 years of exposure to environmental hazards are the most vulnerable. Over 30 factors have been proposed as causative, including agrochemicals and heavy metals, but none has been properly tested nor proven as causative, and unlikely to be the cause of CKDmfo/CKDu. Conditions such as, having favourable climatic patterns, adequate hydration, and less poverty and malnutrition seem to prevent the disease. With the right in vivo conditions, chemical species such as calcium, phosphate, oxalate, and fluoride form intra-renal nanomineral particles initiating the CKDmfo. This article examines the key potential chemical components causing CKDmfo together with the risk factors and vulnerabilities predisposing individuals to this disease. Research findings suggest that in addition to drinking water from stagnant sources that contain high ionic components, more than 10 years of exposure to environmental nephrotoxins and micronutrient malnutrition are needed to contract this fatal disease.
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11
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van der Wijst J, Belge H, Bindels RJM, Devuyst O. Learning Physiology From Inherited Kidney Disorders. Physiol Rev 2019; 99:1575-1653. [PMID: 31215303 DOI: 10.1152/physrev.00008.2018] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The identification of genes causing inherited kidney diseases yielded crucial insights in the molecular basis of disease and improved our understanding of physiological processes that operate in the kidney. Monogenic kidney disorders are caused by mutations in genes coding for a large variety of proteins including receptors, channels and transporters, enzymes, transcription factors, and structural components, operating in specialized cell types that perform highly regulated homeostatic functions. Common variants in some of these genes are also associated with complex traits, as evidenced by genome-wide association studies in the general population. In this review, we discuss how the molecular genetics of inherited disorders affecting different tubular segments of the nephron improved our understanding of various transport processes and of their involvement in homeostasis, while providing novel therapeutic targets. These include inherited disorders causing a dysfunction of the proximal tubule (renal Fanconi syndrome), with emphasis on epithelial differentiation and receptor-mediated endocytosis, or affecting the reabsorption of glucose, the handling of uric acid, and the reabsorption of sodium, calcium, and magnesium along the kidney tubule.
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Affiliation(s)
- Jenny van der Wijst
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands ; Institute of Physiology, University of Zurich , Zurich , Switzerland ; and Division of Nephrology, Institute of Experimental and Clinical Research (IREC), Medical School, Université catholique de Louvain, Brussels, Belgium
| | - Hendrica Belge
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands ; Institute of Physiology, University of Zurich , Zurich , Switzerland ; and Division of Nephrology, Institute of Experimental and Clinical Research (IREC), Medical School, Université catholique de Louvain, Brussels, Belgium
| | - René J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands ; Institute of Physiology, University of Zurich , Zurich , Switzerland ; and Division of Nephrology, Institute of Experimental and Clinical Research (IREC), Medical School, Université catholique de Louvain, Brussels, Belgium
| | - Olivier Devuyst
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen , The Netherlands ; Institute of Physiology, University of Zurich , Zurich , Switzerland ; and Division of Nephrology, Institute of Experimental and Clinical Research (IREC), Medical School, Université catholique de Louvain, Brussels, Belgium
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12
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Cardiovascular and non-cardiovascular concerns with proton pump inhibitors: Are they safe? Trends Cardiovasc Med 2019; 29:353-360. [DOI: 10.1016/j.tcm.2018.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/09/2018] [Accepted: 10/16/2018] [Indexed: 12/11/2022]
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13
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van Orten-Luiten ACB, Janse A, Verspoor E, Brouwer-Brolsma EM, Witkamp RF. Drug use is associated with lower plasma magnesium levels in geriatric outpatients; possible clinical relevance. Clin Nutr 2018; 38:2668-2676. [PMID: 30581015 DOI: 10.1016/j.clnu.2018.11.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 11/04/2018] [Accepted: 11/26/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND Hypomagnesemia has been associated with diabetes, cardiovascular disease, and other disorders. Drug use has been suggested as one of the risk factors for low magnesium (Mg) levels. In the elderly population, prone to polypharmacy and inadequate Mg intake, hypomagnesemia might be relevant. Therefore, we aimed to investigate associations between drug use and plasma Mg. METHODS Cross-sectional data of 343 Dutch geriatric outpatients were analysed by Cox and linear regression, while adjusting for covariates. Drug groups were coded according to the Anatomical Therapeutic Chemical classification system; use was compared to non-use. Hypomagnesemia was defined as plasma Mg < 0.75 mmol/l and <0.70 mmol/l. RESULTS Prevalence of hypomagnesemia was 22.2% (Mg < 0.75 mmol/l) or 12.2% (Mg < 0.70 mmol/l); 67.6% of the patients used ≥5 medications (polypharmacy). The number of different drugs used was inversely linearly associated with Mg level (beta -0.01; p < 0.01). Fully adjusted Cox regression showed significant associations of polypharmacy with hypomagnesemia (Mg < 0.75 mmol/l) (prevalence ratio (PR) 1.81; 95%CI 1.08-3.14), proton pump inhibitors (PR 1.80; 95%CI 1.20-2.72), and metformin (PR 2.34; 95%CI 1.56-3.50). Moreover, stratified analyses pointed towards associations with calcium supplements (PR 2.26; 95%CI 1.20-4.26), insulins (PR 3.88; 95%CI 2.19-6.86), vitamin K antagonists (PR 2.01; 95%CI 1.05-3.85), statins (PR 2.44; 95%CI 1.31-4.56), and bisphosphonates (PR 2.97; 95%CI 1.65-5.36) in patients <80 years; selective beta blockers (PR 2.01; 95%CI 1.19-3.40) if BMI <27.0 kg/m2; and adrenergic inhalants in male users (PR 3.62; 95%CI 1.73-7.56). Linear regression supported these associations. CONCLUSION As polypharmacy and several medications are associated with hypomagnesemia, Mg merits more attention, particularly in diabetes, cardiovascular disease, and in side-effects of proton pump inhibitors and calcium supplements.
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Affiliation(s)
- A C B van Orten-Luiten
- Division of Human Nutrition and Health, Wageningen University and Research Centre, P.O. Box 17, 6700 AA Wageningen, the Netherlands; Nutrition & Healthcare Alliance, Willy Brandtlaan 10, 6716 RP Ede, the Netherlands.
| | - A Janse
- Nutrition & Healthcare Alliance, Willy Brandtlaan 10, 6716 RP Ede, the Netherlands; Department of Geriatric Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716 RP Ede, the Netherlands.
| | - E Verspoor
- Division of Human Nutrition and Health, Wageningen University and Research Centre, P.O. Box 17, 6700 AA Wageningen, the Netherlands.
| | - E M Brouwer-Brolsma
- Division of Human Nutrition and Health, Wageningen University and Research Centre, P.O. Box 17, 6700 AA Wageningen, the Netherlands.
| | - R F Witkamp
- Division of Human Nutrition and Health, Wageningen University and Research Centre, P.O. Box 17, 6700 AA Wageningen, the Netherlands; Nutrition & Healthcare Alliance, Willy Brandtlaan 10, 6716 RP Ede, the Netherlands.
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14
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Ozcaliskan Ilkay H, Sahin H, Tanriverdi F, Samur G. Association Between Magnesium Status, Dietary Magnesium Intake, and Metabolic Control in Patients with Type 2 Diabetes Mellitus. J Am Coll Nutr 2018; 38:31-39. [PMID: 30160617 DOI: 10.1080/07315724.2018.1476194] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hypomagnesemia could worsen glycemic control by impairing insulin release and promoting insulin resistance. On the contrary, type 2 diabetes mellitus (T2DM) may induce and/or exacerbate low serum magnesium levels, and this could, in turn, worsen glycemic control of diabetes. OBJECTIVE The aim of this study was to investigate the relationship between serum magnesium level, dietary magnesium intake, and metabolic control parameters in patients with T2DM. METHODS The study included 119 patients with T2DM (26 male, 93 female; mean age 54.7 ± 8.4 years). Serum magnesium level was measured by spectrophotometric method. Magnesium intake was assessed by food frequency questionnaire. Anthropometric measurements were taken. The General Linear Model procedure was applied to determine the relationship of serum magnesium with quantitative variables. RESULTS Of the 119 patients, 23.5% of the patients had inadequate magnesium intake (lower than 67% of the recommended daily allowance), and 18.5% had hypomagnesemia. In patients with hypomagnesemia (< 0.75 mmol/l), serum levels of fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and serum glycosylated hemoglobin (HbA1c) were higher compared to patients with normomagnesemia. FPG levels were significantly higher in patients with hypomagnesemia in Model 1 (179.0 ± 64.9 vs. 148.7 ± 52.0 mg/dl, p = 0.009) but the significance disappeared in other models. PPG levels were significantly higher in patients with hypomagnesemia in all models (287.9 ± 108.4 vs. 226.8 ± 89.4 mg/dl, p = 0.006 for Model 1, p = 0.027 for Model 2, p = 0.016 for Model 3). Serum HbA1c levels were significantly higher in patients with hypomagnesemia, and this significance proceeded (8.0 ± 1.9% vs. 6.5 ± 1.2%, p = 0.000 for all models). Body fat mass was significantly higher in patients with hypomagnesemia as compared to patients with normomagnesemia in model 3 (35.4 ± 9.4 kg, 34.6 ± 10.2 kg; p = 0.034). Dietary magnesium intake was not significantly associated with either metabolic parameters or anthropometric measurements. CONCLUSION Hypomagnesemia in T2DM is directly associated with poor metabolic control. Clinical assessment should, therefore, focus on augmentation of magnesium status and adequate magnesium intake in patients with T2DM.
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Affiliation(s)
| | - Habibe Sahin
- a Department of Nutrition and Dietetics , Erciyes University , Melikgazi, Kayseri , Turkey
| | - Fatih Tanriverdi
- b Department of Endocrinology and Metabolism , Erciyes University , Melikgazi, Kayseri , Turkey
| | - Gulhan Samur
- c Department of Nutrition and Dietetics , Hacettepe University , Sıhhiye, Ankara , Turkey
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15
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Ledeganck KJ, Anné C, De Monie A, Meybosch S, Verpooten GA, Vinckx M, Van Hoeck K, Van Eyck A, De Winter BY, Trouet D. Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors. Nutrients 2018; 10:677. [PMID: 29861470 PMCID: PMC6024309 DOI: 10.3390/nu10060677] [Citation(s) in RCA: 7] [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: 04/30/2018] [Revised: 05/17/2018] [Accepted: 05/21/2018] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND It was shown in animal models and adults that the epidermal growth factor (EGF) is involved in the pathophysiology of calcineurin inhibitor (CNI) induced renal magnesium loss. In children, however, the exact mechanism remains unclear, which was set as the purpose of the present study. METHODS Children with nephrotic syndrome and renal transplant children treated with CNI (n = 50) and non-CNI treated children (n = 46) were included in this study. Urine and serum samples were collected at three time points to determine magnesium, creatinine, and EGF. The magnesium intake was calculated from a food frequency questionnaire. RESULTS Serum Mg2+ and urinary EGF/creatinine were significantly lower in the CNI treated children, with significantly more CNI-treated children developing hypomagnesaemia. In the latter patients, the fractional excretion of magnesium (FE Mg2+) was significantly higher. Urinary EGF, age, renal function, and serum magnesium were independent predictors of the FE Mg2+. Only 29% of the children reached the recommended daily intake of magnesium. The magnesium intake did not differ between hypomagnesemic and normomagnesemic patients and was not a predictor of the FE Mg2+. CONCLUSIONS In CNI-treated children who developed hypomagnesemia, the FE Mg2+ was increased. The urinary EGF concentration, age, and renal function are independent predictors of the FE Mg2+.
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Affiliation(s)
- Kristien J Ledeganck
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Charlotte Anné
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Amandine De Monie
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Sarang Meybosch
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Gert A Verpooten
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Marleen Vinckx
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Koen Van Hoeck
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
- Department of Pediatric Nephrology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
| | - Annelies Van Eyck
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
| | - Dominique Trouet
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.
- Department of Pediatric Nephrology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
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Ozturk Z, Genc GE, Gumuslu S. Minerals in thalassaemia major patients: An overview. J Trace Elem Med Biol 2017; 41:1-9. [PMID: 28347454 DOI: 10.1016/j.jtemb.2017.01.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 12/19/2016] [Accepted: 01/09/2017] [Indexed: 01/19/2023]
Abstract
Thalassaemia major (TM) is a hereditary blood disease characterised by reduced or absent production of beta globin chains. Erythrocyte transfusions are given to raise the haemoglobin level in patients with thalassaemia major. However, transfusions have been related to increased risk of iron overload and tissue damage related to excess iron. Both elevated oxidative stress due to iron overload and increased hemolysis lead to over utilisation of minerals required for antioxidant enzymes activities. Iron chelators have been used to prevent iron overload in thalassaemia major patients, but these chelators have the possibility of removing minerals from the body. Thalassaemia patients are more at risk for mineral deficiency because of increased oxidative stress and iron chelation therapies. Growth and maturational delay, cardiomyopathy, endocrinopathies and osteoporosis are the complications of thalassaemia. Minerals may play a particular role to prevent these complications. In the current review, we provide an overview of minerals including zinc (Zn), copper (Cu), selenium (Se), magnesium (Mg) and calcium (Ca) in thalassaemia major patients. We, also, underline that some complications of thalassaemia can be caused by an increased need for minerals or lack of the minerals.
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Affiliation(s)
- Zeynep Ozturk
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya, 07070, Turkey.
| | - Gizem Esra Genc
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya, 07070, Turkey.
| | - Saadet Gumuslu
- Department of Medical Biochemistry, Faculty of Medicine, Akdeniz University, Antalya, 07070, Turkey.
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Kurstjens S, de Baaij JHF, Bouras H, Bindels RJM, Tack CJJ, Hoenderop JGJ. Determinants of hypomagnesemia in patients with type 2 diabetes mellitus. Eur J Endocrinol 2017; 176:11-19. [PMID: 27707767 DOI: 10.1530/eje-16-0517] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 09/13/2016] [Accepted: 10/04/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hypomagnesemia (plasma magnesium (Mg2+) concentration <0.7 mmol/L) has been described in patients with type 2 diabetes. Polypharmacy is inevitable when treating a complex disease such as type 2 diabetes and could explain disturbances in the plasma Mg2+ concentration. In this study, we aimed to establish the extent of hypomagnesemia in a cohort of type 2 diabetes patients and to identify the determinants of plasma Mg2+ levels. METHODS Patient data and samples of 395 type 2 diabetes patients were investigated. Plasma Mg2+ concentrations were measured using a spectrophotometric assay. Using Pearson correlation analyses, variables were correlated to plasma Mg2+ levels. After excluding confounding variables, all parameters correlating (P < 0.1) with plasma Mg2+ were included in a stepwise backward regression model. RESULTS The mean plasma Mg2+ concentration in this cohort was 0.74 ± 0.10 mmol/L. In total, 121 patients (30.6%) suffered from hypomagnesemia. Both plasma triglyceride (r = -0.273, P < 0.001) and actual glucose levels (r = -0.231, P < 0.001) negatively correlated with the plasma Mg2+ concentration. Patients using metformin (n = 251, 62%), proton pump inhibitors (n = 179, 45%) or β-adrenergic receptor agonists (n = 31, 8%) displayed reduced plasma Mg2+ levels. Insulin use (n = 299, 76%) positively correlated with plasma Mg2+ levels. The model predicted (R2) 20% of all variance in the plasma Mg2+ concentration. CONCLUSIONS Hypomagnesemia is highly prevalent in type 2 diabetes patients. Plasma triglycerides and glucose levels are major determinants of the plasma Mg2+ concentration, whereas only a minor part (<10%) of hypomagnesemia can be explained by drug intake, excluding polypharmacy as a major cause for hypomagnesemia in type 2 diabetes.
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Affiliation(s)
| | | | | | | | - Cees J J Tack
- Internal MedicineRadboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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18
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Brent J, Burkhart K, Dargan P, Hatten B, Megarbane B, Palmer R, White J. Adverse Drug Reactions in the Intensive Care Unit. CRITICAL CARE TOXICOLOGY 2017. [PMCID: PMC7153447 DOI: 10.1007/978-3-319-17900-1_33] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Adverse drug reactions (ADRs) are undesirable effects of medications used in normal doses [1]. ADRs can occur during treatment in an intensive care unit (ICU) or result in ICU admissions. A meta-analysis of 4139 studies suggests the incidence of ADRs among hospitalized patients is 17% [2]. Because of underreporting and misdiagnosis, the incidence of ADRs may be much higher and has been reported to be as high as 36% [3]. Critically ill patients are at especially high risk because of medical complexity, numerous high-alert medications, complex and often challenging drug dosing and medication regimens, and opportunity for error related to the distractions of the ICU environment [4]. Table 1 summarizes the ADRs included in this chapter.
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Affiliation(s)
- Jeffrey Brent
- Department of Medicine, Division of Clinical Pharmacology and Toxicology, University of Colorado, School of Medicine, Aurora, Colorado USA
| | - Keith Burkhart
- FDA, Office of New Drugs/Immediate Office, Center for Drug Evaluation and Research, Silver Spring, Maryland USA
| | - Paul Dargan
- Clinical Toxicology, St Thomas’ Hospital, Silver Spring, Maryland USA
| | - Benjamin Hatten
- Toxicology Associates, University of Colorado, School of Medicine, Denver, Colorado USA
| | - Bruno Megarbane
- Medical Toxicological Intensive Care Unit, Lariboisiere Hospital, Paris-Diderot University, Paris, France
| | - Robert Palmer
- Toxicology Associates, University of Colorado, School of Medicine, Denver, Colorado USA
| | - Julian White
- Toxinology Department, Women’s and Children’s Hospital, North Adelaide, South Australia Australia
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19
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Costello RB, Elin RJ, Rosanoff A, Wallace TC, Guerrero-Romero F, Hruby A, Lutsey PL, Nielsen FH, Rodriguez-Moran M, Song Y, Van Horn LV. Perspective: The Case for an Evidence-Based Reference Interval for Serum Magnesium: The Time Has Come. Adv Nutr 2016; 7:977-993. [PMID: 28140318 PMCID: PMC5105038 DOI: 10.3945/an.116.012765] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The 2015 Dietary Guidelines Advisory Committee indicated that magnesium was a shortfall nutrient that was underconsumed relative to the Estimated Average Requirement (EAR) for many Americans. Approximately 50% of Americans consume less than the EAR for magnesium, and some age groups consume substantially less. A growing body of literature from animal, epidemiologic, and clinical studies has demonstrated a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders; osteoporosis; hypertension; cardiovascular diseases; metabolic syndrome; and diabetes. Studies have also demonstrated that magnesium deficiency is associated with several chronic diseases and that a reduced risk of these diseases is observed with higher magnesium intake or supplementation. Subclinical magnesium deficiency can exist despite the presentation of a normal status as defined within the current serum magnesium reference interval of 0.75-0.95 mmol/L. This reference interval was derived from data from NHANES I (1974), which was based on the distribution of serum magnesium in a normal population rather than clinical outcomes. What is needed is an evidenced-based serum magnesium reference interval that reflects optimal health and the current food environment and population. We present herein data from an array of scientific studies to support the perspective that subclinical deficiencies in magnesium exist, that they contribute to several chronic diseases, and that adopting a revised serum magnesium reference interval would improve clinical care and public health.
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Affiliation(s)
| | - Ronald J Elin
- Department of Pathology and Laboratory Medicine, University of Louisville, KY
| | | | - Taylor C Wallace
- Department of Nutrition and Food Studies, George Mason University, Fairfax, VA
| | | | - Adela Hruby
- Nutritional Epidemiology Program, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
| | - Pamela L Lutsey
- School of Public Health, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | | | | | - Yiqing Song
- Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN; and
| | - Linda V Van Horn
- Division of Nutrition, Department of Preventive Medicine, Northwestern University, Chicago, IL
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20
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de Baaij JHF, Arjona FJ, van den Brand M, Lavrijsen M, Lameris ALL, Bindels RJM, Hoenderop JGJ. Identification of SLC41A3 as a novel player in magnesium homeostasis. Sci Rep 2016; 6:28565. [PMID: 27349617 PMCID: PMC4923877 DOI: 10.1038/srep28565] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 06/02/2016] [Indexed: 01/08/2023] Open
Abstract
Regulation of the body Mg(2+) balance takes place in the distal convoluted tubule (DCT), where transcellular reabsorption determines the final urinary Mg(2+) excretion. The basolateral Mg(2+) extrusion mechanism in the DCT is still unknown, but recent findings suggest that SLC41 proteins contribute to Mg(2+) extrusion. The aim of this study was, therefore, to characterize the functional role of SLC41A3 in Mg(2+) homeostasis using the Slc41a3 knockout (Slc41a3(-/-)) mouse. By quantitative PCR analysis it was shown that Slc41a3 is the only SLC41 isoform with enriched expression in the DCT. Interestingly, serum and urine electrolyte determinations demonstrated that Slc41a3(-/-) mice suffer from hypomagnesemia. The intestinal Mg(2+) absorption capacity was measured using the stable (25)Mg(2+) isotope in mice fed a low Mg(2+) diet. (25)Mg(2+) uptake was similar in wildtype (Slc41a3(+/+)) and Slc41a3(-/-) mice, although Slc41a3(-/-) animals exhibited increased intestinal mRNA expression of Mg(2+) transporters Trpm6 and Slc41a1. Remarkably, some of the Slc41a3(-/-) mice developed severe unilateral hydronephrosis. In conclusion, SLC41A3 was established as a new factor for Mg(2+) handling.
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Affiliation(s)
- Jeroen H F de Baaij
- Department of Physiology Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Francisco J Arjona
- Department of Physiology Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Michiel van den Brand
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Marla Lavrijsen
- Department of Physiology Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Anke L L Lameris
- Department of Physiology Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - René J M Bindels
- 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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William JH, Danziger J. Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms. World J Nephrol 2016; 5:152-157. [PMID: 26981439 PMCID: PMC4777786 DOI: 10.5527/wjn.v5.i2.152] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 11/20/2015] [Accepted: 01/04/2016] [Indexed: 02/06/2023] Open
Abstract
Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia (PPIH) has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective, controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the field of PPIH and the proposed mechanisms of this effect.
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Management of Epidermal Growth Factor Receptor Inhibitor-Induced Hypomagnesemia: A Systematic Review. Clin Colorectal Cancer 2016; 15:e117-23. [PMID: 26961757 DOI: 10.1016/j.clcc.2016.02.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 12/21/2015] [Accepted: 02/03/2016] [Indexed: 11/21/2022]
Abstract
BACKGROUND Despite occurring in 30% of patients, there are no evidence-based guidelines on the management of epidermal growth factor receptor inhibitor (EGFRI)-induced hypomagnesemia. Based on expert opinion, severe hypomagnesemia should be treated by intravenous magnesium replacement. A systematic review of published data of intervention on EGFRI-induced hypomagnesemia was performed. METHODS Articles from 1960 to March 2015 were identified from Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed using a peer-reviewed systematic search strategy. Eligible studies included randomized controlled trials or observational studies that evaluated management of hypomagnesemia in adult patients treated with EGFRIs. Risk factors for severe hypomagnesemia were also assessed. The quality of included studies was rated using Jadad scores. RESULTS A total of 1327 references were identified, and 6 studies, involving 486 patients, met inclusion criteria for analysis. There were no randomized controlled trials, and all included studies were of poor quality. From the studies included in this review, severity of EGFRI-induced hypomagnesemia was associated with length of EGFRI treatment, concomitant platinum chemotherapy, increasing age, and baseline magnesium concentration. In most patients with grade 3 or 4 hypomagnesemia, high-dose intravenous magnesium replacement did not achieve sustainable magnesium repletion beyond 72 hours. Oral magnesium supplementation was not effective or tolerable. Severe hypomagnesemia has been associated with tachycardia and mental alteration. After discontinuation of EGFRI therapy, hypomagnesemia generally resolves within weeks to months. CONCLUSIONS There is an absence of high-quality evidence for the management of EGFRI-induced hypomagnesemia. As hypomagnesemia is often refractory to frequent intravenous or oral replacement, there is a need for prospective trials of new interventions for this common toxicity.
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Osborn KE, Shytle RD, Frontera AT, Soble JR, Schoenberg MR. Addressing potential role of magnesium dyshomeostasis to improve treatment efficacy for epilepsy: A reexamination of the literature. J Clin Pharmacol 2015; 56:260-5. [PMID: 26313363 DOI: 10.1002/jcph.626] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 08/25/2015] [Indexed: 01/08/2023]
Abstract
Magnesium (Mg(2+) ) is an abundant mineral in the body serving many biochemical functions. Magnesium supplementation has been shown to raise seizure threshold in animal and human studies, but the etiological contribution of magnesium deficiency to the onset and maintenance of epilepsy, as well as the degree to which it impacts antiepileptic drug efficacy, remains poorly understood. This may be due, at least in part, to the inherent limitations of commonly used serum levels as a measure of functional magnesium status, as well as insufficient data regarding relative bioavailabilities of various magnesium salts and chelates for use with humans. To date, 1 randomized clinical trial has been conducted assessing Mg(2+) supplementation in epilepsy, and findings yielded promising results. Yet a notable dearth in the literature remains, and more studies are needed. To better understand the potential role of magnesium deficiency as a causal factor in epilepsy, more convenient and accurate measurement methods should to be developed and employed in randomized, controlled trials of oral magnesium supplementation in epilepsy. Findings from such studies have the potential to facilitate far-reaching clinical and economic improvements in epilepsy treatment standards.
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Affiliation(s)
- Katie E Osborn
- Department of Psychiatry & Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - R Douglas Shytle
- Center for Excellence in Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Alfred T Frontera
- Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Jason R Soble
- Psychology Service, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Mike R Schoenberg
- Department of Psychiatry & Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Center for Excellence in Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, FL, USA
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25
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Abstract
There is increasing evidence and case reports regarding proton pump inhibitor (PPI)-induced hypomagnesemia. Our study aimed to clarify the relationship between PPI use and serum magnesium levels and to specify high-risk patients. We retrospectively studied 112 consecutive patients aged 20 years or older who were treated with PPI for ≥30 days and whose serum magnesium levels were available for the PPI treatment period. We compared the mean level of serum magnesium of the enrolled patients with PPI treatment with matched controls. There were no significant differences between the matched PPI users (n = 105) and nonusers (n = 210) in the magnesium levels (0.85 ± 0.09 vs. 0.86 ± 0.16 mM, P = 0.297). In a subgroup analysis of a PPI user group, hypomagnesemia could be observed in 32 patients but not in 80 patients. In multivariate analyses, PPI use for >1 year, age less than 45 years, and concurrent cisplatin or carboplatin use were significantly associated with PPI-induced hypomagnesemia {P = 0.042, odds ratio [OR; 95% confidence interval (CI)]: 5.388 [1.056-27.493]; P = 0.007, OR [95% CI]: 4.710 [1.523-14.571]; P = 0.007, OR [95% CI]: 13.404 [2.066-86.952], respectively} after adjusting for confounders. This study shows that long-term PPI use is associated with hypomagnesemia in hospitalized adult patients. Therefore, serum magnesium levels should be checked before the initiation of PPI treatment and during the treatment period in patients, particularly those concurrently using platinum-based chemotherapy or who are expected to use PPI for long periods.
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Li L, Somerset S. Dietary intake and nutritional status of micronutrients in adults with cystic fibrosis in relation to current recommendations. Clin Nutr 2015; 35:775-82. [PMID: 26159903 DOI: 10.1016/j.clnu.2015.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 05/25/2015] [Accepted: 06/12/2015] [Indexed: 01/29/2023]
Abstract
An increased prevalence of cystic fibrosis (CF) related complications such as impaired bone health and diabetes has accompanied increased survival of patients with CF. This review was conducted to determine the extent to which adults with CF are meeting current nutrition recommendations for micronutrients in association with CF-related complications management. Although dietary intake and nutritional status in CF has improved significantly in recent decades, micronutrient status seems to have diverged. While vitamin A and E intakes appear adequate, frequent vitamin D and K deficiency/insufficiency and compromised bone health in CF, occurs despite supplementation. Although deficiency of water-soluble vitamins and minerals is uncommon, ongoing surveillance will enhance overall health outcomes, particularly in cases of CF-related liver disease and deteriorated lung function and bone health. Salt and fluid status in CF may also need attention due to diminished thirst sensation and voluntary rehydration. Further investigation in micronutrient status optimisation in CF will inform the development of more effective and targeted nutrition therapies to enable integration of more refined recommendations for micronutrient intakes in CF based on individual needs and disease progression.
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Affiliation(s)
- Li Li
- School of Medicine, Griffith Health Institute, Griffith University, Brisbane, Queensland, Australia
| | - Shawn Somerset
- School of Medicine, Griffith Health Institute, Griffith University, Brisbane, Queensland, Australia; School of Allied Health, Faculty of Health Sciences, Australian Catholic University, Brisbane, Queensland, Australia.
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Atkinson NSS, Reynolds DJM, Travis SPL. 'Lemonade Legs': Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? Intest Res 2015; 13:227-32. [PMID: 26130997 PMCID: PMC4479737 DOI: 10.5217/ir.2015.13.3.227] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 04/30/2015] [Accepted: 04/30/2015] [Indexed: 12/14/2022] Open
Abstract
Proton pump inhibitors (PPIs) are widely used though an association with hypomagnesaemia and hypocalcaemia has only been described since 2006. Patients typically present after years of stable dosing with musculoskeletal, neurological or cardiac arrhythmic symptoms, but it is likely that many cases are under-recognised. Magnesium levels resolve rapidly on discontinuation of PPI therapy and hypomagnesaemia recurs rapidly on rechallenge with any agent in the class. The cellular mechanisms of magnesium homeostasis are increasingly being understood, including both passive paracellular absorption through claudins and active transcellular transporters, including the transient receptor potential channels (TRPM6) identified in the intestine and nephron. PPIs may alter luminal pH by modulating pancreatic secretions, affecting non-gastric H+K+ATPase secretion, altering transporter transcription or channel function. A small reduction in intestinal absorption appears pivotal in causing cumulative deficiency. Risk factors have been associated to help identify patients at risk of this effect but clinical vigilance remains necessary for diagnosis.
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Affiliation(s)
- Nathan S S Atkinson
- Translational Gastroenterology Unit and Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
| | - D John M Reynolds
- Department of Acute General Medicine, Oxford University Hospitals Trust, University of Oxford, Oxford, UK
| | - Simon P L Travis
- Translational Gastroenterology Unit and Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
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de Baaij JHF, Dorresteijn EM, Hennekam EAM, Kamsteeg EJ, Meijer R, Dahan K, Muller M, van den Dorpel MA, Bindels RJM, Hoenderop JGJ, Devuyst O, Knoers NVAM. Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia. Nephrol Dial Transplant 2015; 30:952-7. [PMID: 25765846 DOI: 10.1093/ndt/gfv014] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 12/15/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Magnesium (Mg(2+)) is an essential ion for cell growth, neuroplasticity and muscle contraction. Blood Mg(2+) levels <0.7 mmol/L may cause a heterogeneous clinical phenotype, including muscle cramps and epilepsy and disturbances in K(+) and Ca(2+) homeostasis. Over the last decade, the genetic origin of several familial forms of hypomagnesaemia has been found. In 2000, mutations in FXYD2, encoding the γ-subunit of the Na(+)-K(+)-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis. However, no additional patients have been identified since then. METHODS Here, two families with hypomagnesaemia and hypocalciuria were screened for mutations in the FXYD2 gene. Moreover, the patients were clinically and genetically characterized. RESULTS We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria. Interestingly, this is the same mutation as was described in the original study. As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy. Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect. CONCLUSIONS The recurrent p.Gly41Arg FXYD2 mutation in two new families with IDH confirms that FXYD2 mutation causes hypomagnesaemia. Until now, no other FXYD2 mutations have been reported which could indicate that other FXYD2 mutations will not cause hypomagnesaemia or are embryonically lethal.
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Affiliation(s)
- Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eiske M Dorresteijn
- Pediatric Nephrology, Erasmus MC, Sophia Childrens Hospital, Rotterdam, The Netherlands
| | - Eric A M Hennekam
- Department of Medical Genetics, University Medical Centre Utrecht, Utrecht 3508 AB, The Netherlands
| | - Erik-Jan Kamsteeg
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rowdy Meijer
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Karin Dahan
- Institut de Génétique et de Pathologie, IPG, Gosselies, Belgium
| | | | | | - René J M Bindels
- 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
| | - Olivier Devuyst
- Institute of Physiology, ZIHP, University of Zurich, Zürich, Switzerland
| | - Nine V A M Knoers
- Department of Medical Genetics, University Medical Centre Utrecht, Utrecht 3508 AB, The Netherlands
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Piezzi V, Kullak-Ublick GA, Glisenti P. [A 78-year-old female patient with dizziness, apraxia and seizure under proton pump inhibitor therapy]. Internist (Berl) 2014; 55:199-205. [PMID: 24419536 DOI: 10.1007/s00108-013-3419-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We report about a female patient with severe hypomagnesemia under therapy with proton pump inhibitors (PPI) who presented with a cerebral seizure. Chronic use of PPIs can cause hypomagnesemia. Because of mostly unspecific symptoms which become symptomatic only with severe deficiency, the disease pattern is underdiagnosed. Hypomagnesemia is currently coming increasingly more to the forefront of medical literature.
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Affiliation(s)
- V Piezzi
- Klinik für Innere Medizin, Spital Oberengadin, Via Nouva 3, 7503, Samedan, Schweiz
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Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 2014; 10:1257-72. [PMID: 25287933 DOI: 10.2215/cjn.09750913] [Citation(s) in RCA: 439] [Impact Index Per Article: 39.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.
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Affiliation(s)
- Judith Blaine
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Moshe Levi
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Maggio M, De Vita F, Lauretani F, Nouvenne A, Meschi T, Ticinesi A, Dominguez LJ, Barbagallo M, Dall'Aglio E, Ceda GP. The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men. Int J Endocrinol 2014; 2014:525249. [PMID: 24723948 PMCID: PMC3958794 DOI: 10.1155/2014/525249] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 01/20/2014] [Accepted: 01/20/2014] [Indexed: 02/01/2023] Open
Abstract
The role of nutritional status as key factor of successful aging is very well recognized. Among the different mechanisms by which nutrients may exert their beneficial effects is the modulation of the hormonal anabolic milieu, which is significantly reduced with aging. Undernutrition and anabolic hormonal deficiency frequently coexist in older individuals determining an increased risk of mobility impairment and other adverse outcomes. Mineral assessment has received attention as an important determinant of physical performance. In particular, there is evidence that magnesium exerts a positive influence on anabolic hormonal status, including Testosterone, in men. In this review we summarize data from observational and intervention studies about the role of magnesium in Testosterone bioactivity and the potential underlying mechanisms of this relationship in male subjects. If larger studies will confirm these pivotal data, the combination of hormonal and mineral replacements might be adopted to prevent or delay the onset of disability in the elderly.
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Affiliation(s)
- Marcello Maggio
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
- Geriatric Rehabilitation Department, University-Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Francesca De Vita
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Fulvio Lauretani
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Antonio Nouvenne
- Geriatric Rehabilitation Department, University-Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Tiziana Meschi
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
- Geriatric Rehabilitation Department, University-Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Andrea Ticinesi
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Ligia J. Dominguez
- Department of Internal Medicine and Medical Specialties (DIMIS), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
| | - Mario Barbagallo
- Department of Internal Medicine and Medical Specialties (DIMIS), University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
| | - Elisabetta Dall'Aglio
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
- Geriatric Rehabilitation Department, University-Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy
| | - Gian Paolo Ceda
- Section of Geriatrics, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43100 Parma, Italy
- Geriatric Rehabilitation Department, University-Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy
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P2X4 receptor regulation of transient receptor potential melastatin type 6 (TRPM6) Mg2+ channels. Pflugers Arch 2014; 466:1941-52. [DOI: 10.1007/s00424-014-1440-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 12/13/2013] [Accepted: 01/03/2014] [Indexed: 12/27/2022]
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de Baaij JHF, Groot Koerkamp MJ, Lavrijsen M, van Zeeland F, Meijer H, Holstege FCP, Bindels RJM, Hoenderop JGJ. Elucidation of the distal convoluted tubule transcriptome identifies new candidate genes involved in renal Mg2+ handling. Am J Physiol Renal Physiol 2013; 305:F1563-73. [DOI: 10.1152/ajprenal.00322.2013] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The kidney plays a key role in the maintenance of Mg2+ homeostasis. Specifically, the distal convoluted tubule (DCT) is instrumental in the fine-tuning of renal Mg2+ handling. In recent years, hereditary Mg2+ transport disorders have helped to identify important players in DCT Mg2+ homeostasis. Nevertheless, several proteins involved in DCT-mediated Mg2+ reabsorption remain to be discovered, and a full expression profile of this complex nephron segment may facilitate the discovery of new Mg2+-related genes. Here, we report Mg2+-sensitive expression of the DCT transcriptome. To this end, transgenic mice expressing enhanced green fluorescent protein under a DCT-specific parvalbumin promoter were subjected to Mg2+-deficient or Mg2+-enriched diets. Subsequently, the Complex Object Parametric Analyzer and Sorter allowed, for the first time, isolation of enhanced green fluorescent protein-positive DCT cells. RNA extracts thereof were analyzed by DNA microarrays comparing high versus low Mg2+ to identify Mg2+ regulatory genes. Based on statistical significance and a fold change of at least 2, 46 genes showed differential expression. Several known magnesiotropic genes, such as transient receptor potential cation channel, subfamily M, member 6 ( Trpm6), and Parvalbumin, were upregulated under low dietary Mg2+. Moreover, new genes were identified that are potentially involved in renal Mg2+ handling. To confirm that the selected candidate genes were regulated by dietary Mg2+ availability, the expression levels of solute carrier family 41, member 3 ( Slc41a3), pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1α ( Pcbd1), TBC1 domain family, member 4 ( Tbc1d4), and uromodulin ( Umod) were determined by RT-PCR analysis. Indeed, all four genes show significant upregulation in the DCT of mice fed a Mg2+-deficient diet. By elucidating the Mg2+-sensitive DCT transcriptome, new candidate genes in renal Mg2+ handling have been identified.
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Affiliation(s)
- Jeroen H. F. de Baaij
- Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and
| | | | - Marla Lavrijsen
- Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands
| | - Femke van Zeeland
- Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and
| | - Hans Meijer
- Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and
| | | | - René J. M. Bindels
- Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and
| | - Joost G. J. Hoenderop
- Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and
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Maggio M, De Vita F, Lauretani F, Buttò V, Bondi G, Cattabiani C, Nouvenne A, Meschi T, Dall’Aglio E, Ceda GP. IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty. Nutrients 2013; 5:4184-205. [PMID: 24152751 PMCID: PMC3820068 DOI: 10.3390/nu5104184] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 10/01/2013] [Accepted: 10/01/2013] [Indexed: 12/11/2022] Open
Abstract
The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects.
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Affiliation(s)
- Marcello Maggio
- Geriatric Rehabilitation Department, University Hospital of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (F.V.); (F.L.); (A.N.); (G.P.C.)
- Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (V.B.); (G.B.); (T.M.); (E.D.A.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +0039-0521-703-916; Fax: +0039-0521-987-562
| | - Francesca De Vita
- Geriatric Rehabilitation Department, University Hospital of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (F.V.); (F.L.); (A.N.); (G.P.C.)
| | - Fulvio Lauretani
- Geriatric Rehabilitation Department, University Hospital of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (F.V.); (F.L.); (A.N.); (G.P.C.)
| | - Valeria Buttò
- Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (V.B.); (G.B.); (T.M.); (E.D.A.)
| | - Giuliana Bondi
- Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (V.B.); (G.B.); (T.M.); (E.D.A.)
| | - Chiara Cattabiani
- Azienda USL Piacenza, Via Taverna, 49, Piacenza (PC) 23121, Italy; E-Mail:
| | - Antonio Nouvenne
- Geriatric Rehabilitation Department, University Hospital of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (F.V.); (F.L.); (A.N.); (G.P.C.)
| | - Tiziana Meschi
- Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (V.B.); (G.B.); (T.M.); (E.D.A.)
| | - Elisabetta Dall’Aglio
- Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (V.B.); (G.B.); (T.M.); (E.D.A.)
| | - Gian Paolo Ceda
- Geriatric Rehabilitation Department, University Hospital of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (F.V.); (F.L.); (A.N.); (G.P.C.)
- Department of Clinical and Experimental Medicine, Section of Geriatrics, Food Sciences Unit and Endocrinology of Aging Unit, University of Parma, Via Gramsci, 14, Parma (PR) 43126, Italy; E-Mails: (V.B.); (G.B.); (T.M.); (E.D.A.)
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The relationship between hypomagnesemia, metformin therapy and cardiovascular disease complicating type 2 diabetes: the Fremantle Diabetes Study. PLoS One 2013; 8:e74355. [PMID: 24019966 PMCID: PMC3760872 DOI: 10.1371/journal.pone.0074355] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Accepted: 08/02/2013] [Indexed: 12/15/2022] Open
Abstract
Background Low serum magnesium concentrations have been associated with cardiovascular disease risk and outcomes in some general population studies but there are no equivalent studies in diabetes. Metformin may have cardiovascular benefits beyond blood glucose lowering in type 2 diabetes but its association with hypomagnesemia appears paradoxical. The aim of this study was to examine relationships between metformin therapy, magnesium homoeostasis and cardiovascular disease in well-characterized type 2 patients from the community. Methods and Findings We studied 940 non-insulin-treated patients (mean±SD age 63.4±11.6 years, 49.0% males) from the longitudinal observational Fremantle Diabetes Study Phase I (FDS1) who were followed for 12.3±5.3 years. Baseline serum magnesium was measured using stored sera. Multivariate methods were used to determine associates of prevalent and incident coronary heart disease (CHD) and cerebrovascular disease (CVD) as ascertained from self-report and linked morbidity/mortality databases. 19% of patients were hypomagnesemic (serum magnesium <0.70 mmol/L). Patients on metformin, alone or combined with a sulfonylurea, had lower serum magnesium concentrations than those on diet alone (P<0.05). There were no independent associations between serum magnesium or metformin therapy and either CHD or CVD at baseline. Incident CVD, but not CHD, was independently and inversely associated with serum magnesium (hazard ratio (95% CI) 0.28 (0.11–0.74); P = 0.010), but metformin therapy was not a significant variable in these models. Conclusions Since hypomagnesemia appears to be an independent risk factor for CVD complicating type 2 diabetes, the value of replacement therapy should be investigated further, especially in patients at high CVD risk.
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Cunha AR, Medeiros F, Umbelino B, Oigman W, Touyz RM, Neves MF. Altered vascular structure and wave reflection in hypertensive women with low magnesium levels. ACTA ACUST UNITED AC 2013; 7:344-52. [DOI: 10.1016/j.jash.2013.04.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 04/03/2013] [Accepted: 04/21/2013] [Indexed: 11/15/2022]
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Lameris ALL, Hess MW, van Kruijsbergen I, Hoenderop JGJ, Bindels RJM. Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6. Pflugers Arch 2013; 465:1613-20. [PMID: 23756852 DOI: 10.1007/s00424-013-1306-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 05/13/2013] [Accepted: 05/29/2013] [Indexed: 02/06/2023]
Abstract
Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, used by millions of patients suffering from gastric acid-related complaints. Although PPIs have an excellent safety profile, an increasing number of case reports describe patients with severe hypomagnesemia due to long-term PPI use. As there is no evidence of a renal Mg²⁺ leak, PPI-induced hypomagnesemia is hypothesized to result from intestinal malabsorption of Mg²⁺. The aim of this study was to investigate the effect of PPIs on Mg ²⁺homeostasis in an in vivo mouse model. To this end, C57BL/6J mice were treated with omeprazole, under normal and low dietary Mg²⁺ availability. Omeprazole did not induce changes in serum Mg²⁺ levels (1.48 ± 0.05 and 1.54 ± 0.05 mmol/L in omeprazole-treated and control mice, respectively), urinary Mg²⁺ excretion (35 ± 3 μmol/24 h and 30 ± 4 μmol/24 h in omeprazole-treated and control mice, respectively), or fecal Mg²⁺ excretion (84 ± 4 μmol/24 h and 76 ± 4 μmol/24 h in omeprazole-treated and control mice, respectively) under any of the tested experimental conditions. However, omeprazole treatment did increase the mRNA expression level of the transient receptor potential melastatin 6 (TRPM6), the predominant intestinal Mg²⁺ channel, in the colon (167 ± 15 and 100 ± 7 % in omeprazole-treated and control mice, respectively, P < 0.05). In addition, the expression of the colonic H⁺,K⁺-ATPase (cHK-α), a homolog of the gastric H⁺,K⁺-ATPase that is the primary target of omeprazole, was also significantly increased (354 ± 43 and 100 ± 24 % in omeprazole-treated and control mice, respectively, P < 0.05). The expression levels of other magnesiotropic genes remained unchanged. Based on these findings, we hypothesize that omeprazole inhibits cHK-α activity, resulting in reduced extrusion of protons into the large intestine. Since TRPM6-mediated Mg²⁺absorption is stimulated by extracellular protons, this would diminish the rate of intestinal Mg²⁺ absorption. The increase of TRPM6 expression in the colon may compensate for the reduced TRPM6 currents, thereby normalizing intestinal Mg²⁺ absorption during omeprazole treatment in C57BL/6J mice, explaining unchanged serum, urine, and fecal Mg²⁺ levels.
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Affiliation(s)
- A L L Lameris
- Department of Physiology, Nijmegen Centre for Molecular Life Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Muradov JM, Hagg T. Intravenous infusion of magnesium chloride improves epicenter blood flow during the acute stage of contusive spinal cord injury in rats. J Neurotrauma 2013; 30:840-52. [PMID: 23302047 PMCID: PMC3660110 DOI: 10.1089/neu.2012.2670] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Vasospasm, hemorrhage, and loss of microvessels at the site of contusive or compressive spinal cord injury lead to infarction and initiate secondary degeneration. Here, we used intravenous injection of endothelial-binding lectin followed by histology to show that the number of perfused microvessels at the injury site is decreased by 80-90% as early as 20 min following a moderate T9 contusion in adult female rats. Hemorrhage within the spinal cord also was maximal at 20 min, consistent with its vasoconstrictive actions in the central nervous system (CNS). Microvascular blood flow recovered to up to 50% of normal volume in the injury penumbra by 6 h, but not at the epicenter. A comparison with an endothelial cell marker suggested that many microvessels fail to be reperfused up to 48 h post-injury. The ischemia was probably caused by vasospasm of vessels penetrating the parenchyma, because repeated Doppler measurements over the spinal cord showed a doubling of total blood flow over the first 12 h. Moreover, intravenous infusion of magnesium chloride, used clinically to treat CNS vasospasm, greatly improved the number of perfused microvessels at 24 and 48 h. The magnesium treatment seemed safe as it did not increase hemorrhage, despite the improved parenchymal blood flow. However, the treatment did not reduce acute microvessel, motor neuron or oligodendrocyte loss, and when infused for 7 days did not affect functional recovery or spared epicenter white matter over a 4 week period. These data suggest that microvascular blood flow can be restored with a clinically relevant treatment following spinal cord injury.
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Affiliation(s)
- Johongir M. Muradov
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky
- Department of Neurological Surgery, University of Louisville, Louisville, Kentucky
| | - Theo Hagg
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky
- Department of Neurological Surgery, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
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Luk CP, Parsons R, Lee YP, Hughes JD. Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? Ann Pharmacother 2013; 47:773-80. [PMID: 23632281 DOI: 10.1345/aph.1r556] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid-related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs. OBJECTIVE To address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypo magnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database. METHODS We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. χ² analysis was conducted to investigate the association of PPI-associated hypomagnesemia with hypocalcemia and hypokalemia. RESULTS Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3-5.7; p < 0.001). The risk of female subjects having hypo magnesemia (OR 0.83; 95% CI 0.71-0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI-associated hypomagnesemia (OR 1.5; 95% CI 1.2-1.7; p < 0.001). χ² analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001). CONCLUSIONS All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia.
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Affiliation(s)
- Chee Phun Luk
- School of Pharmacy, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia
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