Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats

Díaz-Tocados, Juan Miguel; Peralta-Ramírez, Alan; Rodríguez‐Ortiz, María E.; Raya, Ana I.; López, Ignacio; Pineda, Carmen; Herencia, Carmen; de, Addy Montes; Vergara, Noemí; Steppan, Sonja; Mier, M. Victoria Pendón-Ruiz de; Buendía, Paula; Carmona, Andrés; Carracedo, Julia; Alcalá‐Díaz, Juan F.; Frazão, João; Martínez-Moreno, Julio M.; Canalejo, Antonio; Felsenfeld, Arnold J.; Rodriguez, Mariano; Aguilera–Tejero, Escolástico; Almadén, Yolanda; Muñoz‐Castañeda, Juan R.

doi:10.1016/j.kint.2017.04.011

Cited by 91 publications

(76 citation statements)

References 59 publications

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“…In any case, hypomagnesemia compounds the deficiency of serum fetuin-A, a crystal growth inhibitor. Like in this study, magnesium supplementation prevented calcification in a mouse model of pseudoxanthoma elasticum (PXE), Abcc6-/-mice [13], and reduced nephrocalcinosis [43] as well as vascular and soft tissue calcifications in a rat CKD model [44]. Serum Mg is considered a poor marker of Mg deficiency and is not routinely monitored in CKD patients [37].…”

Section: Discussionmentioning

confidence: 74%

Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate

et al. 2020

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Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.

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Section: Discussionmentioning

confidence: 74%

Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate

et al. 2020

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“…In any case, hypomagnesemia compounds the deficiency of serum fetuin-A, a crystal growth inhibitor. Magnesium supplementation prevented calcification in a mouse model of pseudoxanthoma elasticum (PXE), Abcc6-/-mice [14], and reduced nephrocalcinosis [40] as well as vascular and soft tissue calcifications in a CKD rat model [41]. Serum Mg is considered a poor marker of Mg deficiency and is not routinely monitored in CKD patients [35].…”

Section: Discussionmentioning

confidence: 99%

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

Babler

Schmitz

Büscher

et al. 2019

Preprint

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Objective -Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic target that could be influenced by dietary of parenteral supplementation.Approach and Results -We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement.Conclusions -We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.

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“…27 Hyperphosphatemia is a well-recognized risk factor in feline CKD, 6,7 and our results might suggest that higher tMg mitigates the risk of death associated with hyperphosphatemia, as a significantly increased risk was observed only in HP cats with plasma tMg below the median value. A possible explanation could be an inhibitory role of magnesium on phosphate-induced vascular calcification, 21,71 although only scant reports exist on soft tissue and vascular calcification in cats with CKD. 2,72,73 In addition, both phosphate and magnesium could influence plasma FGF23, which has been identified as an important prognostic factor in cats with CKD.…”

Section: Discussionmentioning

confidence: 99%

Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease

Broek

Chang

Elliott

et al. 2018

Veterinary Internal Medicne

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BackgroundHypomagnesemia is associated with increased mortality and renal function decline in humans with chronic kidney disease (CKD). Magnesium is furthermore inversely associated with fibroblast growth factor 23 (FGF23), an important prognostic factor in CKD in cats. However, the prognostic significance of plasma magnesium in cats with CKD is unknown.ObjectivesTo explore associations of plasma total magnesium concentration (tMg) with plasma FGF23 concentration, all‐cause mortality, and disease progression in cats with azotemic CKD.AnimalsRecords of 174 client‐owned cats with IRIS stage 2‐4 CKD.MethodsCohort study. Cats with azotemic CKD were identified from the records of two London‐based first opinion practices (1999–2013). Possible associations of baseline plasma tMg with FGF23 concentration and risks of death and progression were explored using, respectively, linear, Cox, and logistic regression.ResultsPlasma tMg (reference interval, 1.73–2.57 mg/dL) was inversely associated with plasma FGF23 when controlling for plasma creatinine and phosphate concentrations (partial correlation coefficient, −0.50; P < .001). Hypomagnesemia was observed in 12% (20/174) of cats, and independently associated with increased risk of death (adjusted hazard ratio, 2.74; 95% confidence interval [CI], 1.35–5.55; P = .005). The unadjusted associations of hypermagnesemia (prevalence, 6%; 11/174 cats) with survival (hazard ratio, 2.88; 95% CI, 1.54–5.38; P = .001), and hypomagnesemia with progressive CKD (odds ratio, 17.7; 95% CI, 2.04–154; P = .009) lost significance in multivariable analysis.Conclusions and Clinical ImportanceHypomagnesemia was associated with higher plasma FGF23 concentrations and increased risk of death. Measurement of plasma tMg augments prognostic information in cats with CKD, but whether these observations are associations or causations warrants further investigation.

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Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats

Cited by 91 publications

References 59 publications

Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate

Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease

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