-
Nephrology, Dialysis, Transplantation :... Jun 2024Magnesium (Mg2+) is essential for energy metabolism, muscle contraction, and neurotransmission. As part of the Mg-ATP complex, it is involved in over 600 enzymatic...
Magnesium (Mg2+) is essential for energy metabolism, muscle contraction, and neurotransmission. As part of the Mg-ATP complex, it is involved in over 600 enzymatic reactions. Serum Mg2+ levels are tightly regulated between 0.7 mmol/L and 1.1 mmol/L by interplay of intestinal absorption and renal excretion. In the small intestine, Mg2+ is absorbed paracellularly via claudin-2, and -12. In the colon, transcellular absorption of Mg2+ is facilitated by TRPM6/7 and CNNM4. In the kidney, the proximal tubule reabsorbs only 20% of the filtered Mg2+. The majority of the filtered Mg2+ is reabsorbed in the thick ascending limb (TAL), where the lumen-positive transepithelial voltage drives paracellular transport via claudin-16/-19. Fine-tuning of Mg2+ reabsorption is achieved in the distal convoluted tubule (DCT). Here, TRPM6/7 tetramers facilitate apical Mg2+ uptake, which is hormonally regulated by insulin and EGF. Basolateral Mg2+ extrusion is Na+ dependent and achieved by CNNM2 and/or SLC41A3. Hypomagnesemia (serum Mg2+ < 0.7 mmol/L) develops when intestinal and/or renal Mg2+ (re)absorption is disturbed. Common causes include alcoholism, type 2 diabetes mellitus, and the use of pharmacological drugs, such as proton-pump inhibitors (PPIs), calcineurin inhibitors (CNIs) and thiazide diuretics. Over the last decade, research on rare genetic and acquired Mg2+ disorders have identified Mg2+ channel and transporter activity, DCT length, mitochondrial function, and autoimmunity as mechanisms explaining hypomagnesemia. Classically, treatment of hypomagnesemia depended on oral or intravenous Mg2+ supplementation. Recently, prebiotic dietary fibers and SGLT2 inhibitors have been proposed as promising new therapeutic pathways to treat hypomagnesemia.
PubMed: 38871680
DOI: 10.1093/ndt/gfae134 -
American Journal of Physiology. Renal... Mar 2023Mg is essential for many cellular and physiological processes, including muscle contraction, neuronal activity, and metabolism. Consequently, the blood Mg concentration... (Review)
Review
Mg is essential for many cellular and physiological processes, including muscle contraction, neuronal activity, and metabolism. Consequently, the blood Mg concentration is tightly regulated by balanced intestinal Mg absorption, renal Mg excretion, and Mg storage in bone and soft tissues. In recent years, the development of novel transgenic animal models and identification of Mendelian disorders has advanced our current insight in the molecular mechanisms of Mg reabsorption in the kidney. In the proximal tubule, Mg reabsorption is dependent on paracellular permeability by claudin-2/12. In the thick ascending limb of Henle's loop, the claudin-16/19 complex provides a cation-selective pore for paracellular Mg reabsorption. The paracellular Mg reabsorption in this segment is regulated by the Ca-sensing receptor, parathyroid hormone, and mechanistic target of rapamycin (mTOR) signaling. In the distal convoluted tubule, the fine tuning of Mg reabsorption takes place by transcellular Mg reabsorption via transient receptor potential melastatin-like types 6 and 7 (TRPM6/TRPM7) divalent cation channels. Activity of TRPM6/TRPM7 is dependent on hormonal regulation, metabolic activity, and interacting proteins. Basolateral Mg extrusion is still poorly understood but is probably dependent on the Na gradient. Cyclin M2 and SLC41A3 are the main candidates to act as Na/Mg exchangers. Consequently, disturbances of basolateral Na/K transport indirectly result in impaired renal Mg reabsorption in the distal convoluted tubule. Altogether, this review aims to provide an overview of the molecular mechanisms of Mg reabsorption in the kidney, specifically focusing on transgenic mouse models and human hereditary diseases.
Topics: Animals; Mice; Humans; TRPM Cation Channels; Magnesium; Kidney Tubules, Distal; Kidney Tubules, Proximal; Signal Transduction; Protein Serine-Threonine Kinases
PubMed: 36633869
DOI: 10.1152/ajprenal.00298.2022 -
Annual Review of Physiology Feb 2024Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron.... (Review)
Review
Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.
Topics: Humans; Kidney Tubules; Bartter Syndrome; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria
PubMed: 38012047
DOI: 10.1146/annurev-physiol-042222-025000 -
Geriatrie Et Psychologie... Dec 2021Glucose and sodium tubular reabsorption inhibitors, or gliflozins, are a new therapeutic class. Their novel mechanism of action involves inhibition of a glucose and Na+...
Glucose and sodium tubular reabsorption inhibitors, or gliflozins, are a new therapeutic class. Their novel mechanism of action involves inhibition of a glucose and Na+ reabsorption co-transporter in the renal proximal tubule. They reduce blood glucose levels by reducing renal glucose reabsorption. They therefore cause glycosuria, which constitutes an energy loss and ultimately leads to a weight loss of around 2 to 3 kg. They reduce sodium load and lower blood pressure. This class improves HbA1c by about 0.7%. Empagliflozin has been shown to reduce all-cause mortality in type 2 diabetic patients at high cardiovascular risk and to reduce episodes of cardiac decompensation and is nephroprotective in diabetic and non-diabetic subjects. Empagliflozin, like other gliflozins, does not induce hypoglycaemia as it does not directly stimulate insulin secretion. Due to the high prevalence of type 2 diabetes, heart failure and renal failure in the elderly, gliflozins will become part of geriatric prescriptions. Their advantages and use must be known, especially as their role will be extended to numerous indications in the field of chronic diseases.
PubMed: 34933846
DOI: 10.1684/pnv.2021.0987 -
The Medical Clinics of North America Jan 2024Monogenic hypertension encompasses a group of conditions wherein single gene mutations result in increased renal sodium reabsorption manifesting as low renin... (Review)
Review
Monogenic hypertension encompasses a group of conditions wherein single gene mutations result in increased renal sodium reabsorption manifesting as low renin hypertension. As these diseases are rare, their contribution to hypertension in children and adolescents is often overlooked. Precise diagnosis is essential in those who have not been found to have more common identifiable causes of hypertension in adolescents, since treatment strategies for these rare conditions are specific and different from antihypertensive regimens for the other more common causes of hypertension in this age group. The objective of this review is to provide insight to the rare, monogenic forms of hypertension.
Topics: Child; Adolescent; Humans; Hypertension; Mutation; Causality
PubMed: 37951648
DOI: 10.1016/j.mcna.2023.06.005 -
The Journal of Clinical Endocrinology... Feb 2022In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.
METHODS
After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab.
RESULTS
Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity.
MAIN CONCLUSIONS
In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab.
CLINICALTRIALS.GOV
NCT02163577.
Topics: Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Dose-Response Relationship, Drug; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Humans; Male; Phosphates; Renal Reabsorption; Severity of Illness Index
PubMed: 34636899
DOI: 10.1210/clinem/dgab729 -
Reviews of Physiology, Biochemistry and... 2021Phosphate is a multivalent ion critical for a variety of physiological functions including bone formation, which occurs rapidly in the developing infant. In order to... (Review)
Review
Phosphate is a multivalent ion critical for a variety of physiological functions including bone formation, which occurs rapidly in the developing infant. In order to ensure maximal bone mineralization, young animals must maintain a positive phosphate balance. To accomplish this, intestinal absorption and renal phosphate reabsorption are greater in suckling and young animals relative to adults. This review discusses the known intestinal and renal adaptations that occur in young animals in order to achieve a positive phosphate balance. Additionally, we discuss the ontogenic changes in phosphotropic endocrine signalling as it pertains to intestinal and renal phosphate handling, including several endocrine factors not always considered in the traditional dogma of phosphotropic endocrine signalling, such as growth hormone, triiodothyronine, and glucocorticoids. Finally, a proposed model of how these factors may contribute to achieving a positive phosphate balance during development is proposed.
Topics: Animals; Homeostasis; Humans; Infant; Intestinal Absorption; Kidney; Phosphates; Renal Reabsorption
PubMed: 33398502
DOI: 10.1007/112_2020_52 -
Annales D'endocrinologie Jun 2021FGF23 is a protein secreted in the plasma by bone cells. In the kidney, FGF23 can activate an FGF receptor in the presence of its co-receptor αKlotho. FGF23 controls... (Review)
Review
FGF23 is a protein secreted in the plasma by bone cells. In the kidney, FGF23 can activate an FGF receptor in the presence of its co-receptor αKlotho. FGF23 controls the renal phosphate reabsorption and calcitriol metabolism. When renal function declines, plasma FGF23 concentration raises and FGF23 can stimulate FGFRs in the absence of αKlotho. This induces cardiac hypertrophy, modifies cardiomyocyte contractility and increases the risk of arrhythmic events in cardiac cells. There is still no evidence that decreasing FGF23 concentration in patients on dialysis could improve their survival. In different cardiac disorders cardiomyocyte can produce FGF23, which can reveal a way of adaptation to the stress.
Topics: Animals; Cardiovascular Diseases; Fibroblast Growth Factor-23; Heart Disease Risk Factors; Humans; Kidney; Phosphates; Renal Insufficiency; Risk Factors; Signal Transduction
PubMed: 32950228
DOI: 10.1016/j.ando.2020.03.007 -
Journal of Clinical Pathology Nov 2019Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between... (Review)
Review
Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.
Topics: Animals; Biomarkers; Bone and Bones; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Humans; Hyperphosphatemia; Hypophosphatemia; Intestinal Absorption; Parathyroid Hormone; Phosphates; Renal Reabsorption; Vitamin D
PubMed: 31467040
DOI: 10.1136/jclinpath-2018-205130