Magnesium- protects against vascular calcification

Summary - Calcification is damaging throughout the body, not just in the kidneys, and magnesium can help reverse calcification but intestinal absorption of the magnesium may be a problem, increased urinary or sweat losses may also be a problem, and/or low protein and low phospholipids in the diet or inability to make the chemicals endogenously may limit the amount of back stock of magnesium that the body can store. Background info: We can not have excess magnesium in the electrically active ionic form (or other ions). Extra magnesium is held in a non-electrically active form on protein transport molecules and the phospho-chemical ribonucleotide ATP. Other nutrients and bitter tasting plant phytonutrients may also be needed to prevent calcification - vitamins D and K, magnesium, iodine, selenium, zinc are discussed in this post.

Magnesium, in particular, is a nutrient essential for vascular health & prevention or reversal of vascular calcification (VC).

Magnesium helps for prevention and reversal of vascular calcification (VC) - plaque build up along vessel walls of deposits of calcium and cholesterol which leads to stiffening and dysfunction of the vessels. Cholesterol buildup in the blood vessels was wrongly blamed exclusively on fat in the diet and cholesterol from eggs initially and people were instructed to not eat eggs and other cholesterol rich foods but we can make our own cholesterol too, and eventually it was recognized that excess carbohydrates was also a causal factor of vascular calcification. It has also been shown that excess calcium (or phosphorus) in ratio to magnesium availability may also be a primary causal factor of VC; and lack of other trace minerals, zinc, iodine, selenium, or vitamin D (12) can also be risk factors for vascular calcification.

Calcification in renal tissue or other organs of the body would cause dysfunction in different ways - disrupting the function of that organ type. transcendingsquare.com/calcification. Calcification of soft tissue and blood vessels is typically a problem associated with aging but it is seen early in life for young patients with chronic kidney disease on dialysis treatments and greatly increases risk of early death due to heart disease. (17)

"Medial calcification is associated with increased vascular stiffening and cardiac workload, poor coronary perfusion, and sudden cardiac death and is thought to be responsible for the high cardiovascular mortality observed in [Chronic Kidney Disease] CKD patients.4 Significantly, even children and adolescents on dialysis develop vascular calcification and have a vastly elevated risk for cardiovascular mortality when compared with the normal age-matched population. Strikingly, the risk in adolescence is equivalent to that of the very elderly in the general population. 2, 5" (17) *Medial calcification causes stiffening of the vessel wall but does not include plaque deposits that obstruct the interior of the blood vessel. (18)

"Chronic kidney disease (CKD) afflicts more than 10% population and is becoming a major public health problem worldwide (Denic et al., 2016; Yang et al., 2020). The prevalence of CKD in the elderly reaches to 14.3–41.3% in some countries (Susnik et al., 2017). CKD is also an independent risk factor for cardiovascular complications and all-cause mortality." (19)

Both calcium and magnesium are electrically active minerals and the body has many methods to try to keep the levels of the minerals in a narrow range within the blood or cell fluid. Magnesium is kept at higher levels within cells and calcium has higher levels within the blood stream and extracellular fluid. Magnesium within cells helps inhibit calcium ion channels from opening and allowing calcium to enter from the surrounding tissue fluid.

Magnesium has inhibitory roles for several types of receptors and ion channels and within the brain. Other plant phytonutrients and vitamins, minerals, free amino acids, and nucleotides like ATP can also act as signals to cells and receptors on the cell surfaces, such as bitter taste receptors. Taste receptors can be found on the surface of immune cells, not just on the tongue, they are also found within the kidney and in the cells of the intestinal lining.

Membrane receptors can act like a lever - activate the lever on the outside of the cell and changes occur in the shape of the protein on the inside of the cell that lead to other actions occurring such as gene transcription of a specific protein type - so bitter taste receptors found in areas of the body besides on the tongue tend to be functioning as biologic machines that cause action besides a nerve signal to the brain saying "tastes bitter, don't eat too much". Within the kidneys bitter taste receptors can be activated by bitter tasting alkaloid phytonutrients and cause more uptake of calcium for removal in the urine output, more is included later in the post on this topic.

Cytokine types can lead to inflammatory actions or anti-inflammatory actions depending on the type. Cytokines are chemical signals that can be released by one cell to cause a change in another cell or in the original cell. Cytokines can act as signals to immune cells to activate a change in the function or type of cytokines it releases.

"Magnesium prevents osteogenic vascular smooth muscle cell transdifferentiation in in vitro and in vivo models." (1)

"Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a key mechanism of VC. Recent studies show that IL-18 (interleukin-18) favors VC while TRPM7 (transient receptor potential melastatin 7) channel upregulation inhibits VC. However, the relationship between IL-18 and TRPM7 is unclear." [Vascular calcification (VC)] (2) .

TRPM7 is a magnesium membrane ion channel that is involved in embryologic development of the heart and kidneys. The TRPM7 ion channels also are involved in regulation of gene expression with the actions of an intracellular protein kinase domain. (3, 5)

Interleukin-18 is a cytokine that may be released by macrophages, dendritic cells, or the adrenal gland. It is involved in fighting infection and preventing cancerous tumor cell growth and may be increased by other stress conditions that activate the adrenal gland. Elevated levels of IL-18 lead to longer episodes of non-REM sleep which is deeper sleep and may help reduce stress effects on the body. Osteoblast produced IL-18 suppresses osteoclast bone cells, which break down bone. (7) The role of IL-18 in inflammation does seem unclear.

Renal cellular senescence (alive but stop cell division and growth of new cells) and premature aging theory of early kidney disease.

"Increasing evidence indicates that there is a striking similarity between the manifestations of progressive [Chronic Kidney Disease] CKD and aging kidney (Docherty et al., 2020; Goligorsky, 2020; Zhou et al., 2020). As such, CKD is often viewed as a form of premature and accelerated aging. Aging and CKD also share many common triggers and underlying mechanisms, such as cellular senescence, oxidative stress, inflammation, mitochondrial dysfunction, RAAS activation and hyperactive Wnt/β-catenin (Sturmlechner et al., 2017; Xiong and Zhou, 2019). In various animal models and human kidney biopsies, accumulation of senescent cells in different renal compartments is increasingly recognized as a common pathway leading to premature aging and CKD (Docherty et al., 2019; Docherty et al., 2020)." (19)

Children receiving renal dialysis treatment were found to have DNA damage, reduced repair of damaged DNA, and faster than normal cellular senescence in samples of their vascular smooth muscle cells. Increased calcification and osteogenic cell differentiation was also found. Medications that blocked a type of DNA damage signaling reduced both the inflammation and the calcification. Question - why are they having DNA damage and reduced repair, and accelerated cellular senescence?

"Vascular smooth muscle cells cultured from children on dialysis exhibited persistent DNA damage, impaired DNA damage repair, and accelerated senescence. Under calcifying conditions vascular smooth muscle cells from children on dialysis showed increased osteogenic differentiation and calcification. These changes correlated with activation of the senescence-associated secretory phenotype (SASP), an inflammatory phenotype characterized by the secretion of proinflammatory cytokines and growth factors. Blockade of ataxia-telangiectasia mutated (ATM)-mediated DNA damage signaling reduced both inflammation and calcification. Clinically, children on dialysis had elevated circulating levels of osteogenic SASP factors that correlated with increased vascular stiffness and coronary artery calcification. These data imply that dysregulated mineral metabolism drives vascular “inflammaging” by promoting oxidative DNA damage, premature senescence, and activation of a pro-inflammatory SASP." (17)

Zinc deficiency causes problems with repair of DNA damage in an animal based study. "Zinc is an essential component of numerous proteins involved in the defense against oxidative stress and DNA damage repair. Studies in vitro have shown that zinc depletion causes DNA damage." (20) Zinc has a variety of roles in renal health and in gene transcription and will be discussed more later in the post.

Hyperphosphatemia is more common in aging, and is a risk of Chronic Kidney Disease and dialysis treatment -- it is also a cause of cellular senescence in muscle cells in an animal based study. "Hyperphosphatemia is an aging-related condition involved in several pathologies. ... Knocking-down ILK expression increased autophagy and protected cells from senescence induced by hyperphosphatemia." (21) Hyperphosphatemia in renal health and calcification will also be discussed more later in the post. Hypothyroidism and iodine are also discussed. Thyroid hormone is involved in the control of phosphorus levels in blood serum and excretion or retention within the kidneys. Either hypo or hyperthyroidism can affect phosphorus levels. (22) Perhaps a combination of nutrient related problems is leading to early kidney disease.

The Thyroid Hormone Receptor when activated by T3 Thyroid hormone can increase DNA damage, seen with hyperthyroidism in an animal based study. T3 hormone also activated the ATM/PRKAA protein kinase (23) of the same type that was elevated in the children with early kidney disease, mentioned in the earlier excerpt, (17) , though the actions then performed by the kinase may be different. Interesting - noted.

"T3 induces a rapid activation of ATM (ataxia telangiectasia mutated)/PRKAA (adenosine monophosphate–activated protein kinase) signal transduction and recruitment of the NRF1 (nuclear respiratory factor 1) and THRB to the promoters of genes with a key role on mitochondrial respiration." (23)

Magnesium sulfate - Epsom salt can inhibit inflammatory cytokine production that can lead to bone matrix breakdown.

Adequate magnesium sulfate (MgSO4, Epsom salt) can help inhibit IL-6 and TNF-alpha production and was found to be linked to lower Nf-Kb levels. The magnesium working intracellularly seemed to be the causal factor for the reduction in inflammatory cytokine production rather than the sulfate (prenatal/preterm birth study). (4)

Vitamin K2 is also helpful with magnesium & calcium balance and reducing stress related bone loss.

When bone cells differentiate into osteoblasts or osteoclasts it is telling the bone matrix to either release calcium and magnesium and break down bone tissue, or to store more of it in new bone tissue (osteogenesis). So chronic low magnesium levels along with calcification of vascular and other soft tissue may also be due to inflammatory cytokines signaling more release of calcium and magnesium from the bones. Stress increases chemical stress on the body and can lead to weakening of the bones with increased osteoporosis changes. Adequate Vitamin K2 can help with calcium, vitamin D and magnesium metabolism and with bone health.

Vitamin K2 supplementation did help reduce calcification in an animal based study. "Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD." (16)

Vascular calcification can also involve plaque deposits that obstruct the blood vessel.

Cholesterol and fatty deposits within the blood vessels may be more like the body trying to scab over excess calcium in a form that is no longer electrically active within the blood stream, rather than primarily or exclusively a problem of too much cholesterol or other fats in the diet. Calcium deposits and fatty deposits can be found in other tissue besides blood vessels, such as renal tubules and in vascular skin conditions such as calciphylaxis (previous posts/calciphylaxis) or calcinosis.

Screening for calcium in blood vessels may help predict who is more at risk for severe heart disease:

"Analysing 52 previous studies, the international team of researchers found that people who have abdominal aortic calcification (AAC) have a two to four times higher risk of a future cardiovascular event. The study also found the more extensive the calcium in the blood vessel wall, the greater the risk of future cardiovascular events and people with AAC and chronic kidney disease were at even greater risk than those from the general population with AAC. Calcium can build up in the blood vessel wall and harden the arteries, blocking blood supply or causing plaque rupture, which is a leading cause of heart attacks and strokes."

New research reveals early warning sign for heart disease. 14 January 2021 (24)

Causes of chronically low magnesium: certain diuretic medications, reduced kidney function, increased sweat loss, poor intestinal absorption, and low dietary intake.

Magnesium levels tend to be low in patients with kidney disease because of use of certain diuretics that cause magnesium wasting by the renal tubules, reduced function of the renal tubules at reabsorbing magnesium, and by low dietary intake. (1, previouspost) Patients with chronic kidney disease may be recommended to take a magnesium supplement three times per day equaling 1200 mg/day (15) which is about three times the RDA recommendation for normal health - chronic kidney disease is not normal health however.

Thiazide diuretics are a worse risk for magnesium wasting in the urine output (14) than "potassium-sparing diuretics such as amiloride." (15)

"Maintenance therapy may require oral administration of Mg2+ oxide (400 mg twice daily or three times daily) for as long as the risk factors for Mg2+ deficiency exist. Oral Mg2+ gluconate (500 mg twice daily or three times daily) can also be used. In addition, there are several slow-release Mg2+ preparations. As noted, is also important to address the underlying cause, and if diuretic therapy is being used, consideration should be given to the use of potassium-sparing diuretics such as amiloride, which can increase Mg2+ reabsorption in the cortical collecting duct. " (15)

“Subpopulations known to be particularly susceptible to the toxic effects of calcium include individuals with renal failure, those using thiazide diuretics (Whiting and Wood, 1997), and those with low intakes of minerals that interact with calcium (for example, iron, magnesium, zinc).”)

from: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, Jan 1, 1997 (14) (nih-reports/previouspost)

Poor intestinal absorption of magnesium can be another reason for someone having low magnesium even though there is good magnesium sources in the diet.

Use of magnesium sulfate (Epsom salt) foot-soaks or baths might be a gentle and effective way to increase magnesium absorption for kidney or prenatal patients (or heart disease, diabetic, or cognitive patients) in a form that bypasses any intestinal malabsorption of magnesium. Calcium may be preferentially absorbed, especially if hormone/vitamin D levels are elevated. Posts on magnesium sources and role in health: 1) Epsom Salt Foot-soaks, 2) Magnesium – essential for eighty percent of our body’s chemistry. , 3) To have optimal Magnesium needs Protein and Phospholipids too., 4) Hypomagnesemia symptoms and causes list

Health requires all of the nutrients in a good balance with each other.

Excess calcium or excess vitamin D can lead to lower magnesium absorption and various negative symptoms. (previous post) Low magnesium may also be involved in the fatigue and mitochondrial dysfunction seen in fibromyalgia, as magnesium along with NAD+ is essential for mitochondria function. (6)

Patients with diabetes are more at risk for renal damage over time and also tend to be low in magnesium. Opioid pain killers do not provide pain relief for patients with diabetes unless magnesium was also given and a larger dose of magnesium reduced pain as much or more than the opioid plus magnesium intravenous dose. See post: G3.6.1.8: If magnesium deficiency is cause of a diabetic patient’s pain, why give opioids instead?. - excerpt from effectivecare.info/G3. Stress & Relaxation a webpage that includes more information about TRP channels, magnesium and calcium, and their role in creating or reducing oxidative stress damage.

Renal health - kidney health - is a combination of adequate water, magnesium, potassium, and not too much total protein on average, and not excess sodium, calcium and phosphorus on average; as well as avoiding other kidney damaging toxins or chronically elevated blood sugar levels. Post: Make every day Kidney Appreciation Day. Other nutrients are also important for renal health including zinc, iodine, selenium, and vitamin D. For more on the topic of calcification, heart disease & magnesium, and vitamin D, zinc, iodine, and selenium see post: Links on heart disease, calcium and iodine, and/or transcendingsquare.com/calcification.

Iodine, Hypothyroidism, & the goitrogenic halides: fluoride, bromide, and chloride.

Excess fluoride, bromide, perchlorate, can interfere with iodine levels or replace it in a molecule if we have too little iodine. The fluoride, bromide, or chloride atom within the molecule wouldn't function correctly. (effectivecare.info/G9. Iodine & Thyroid) The imbalance in iodine to other halide minerals (fluoride, bromide, or chloride) could increase hypothyroid symptoms without showing up as low levels of thyroid hormone so the problem might remain undiagnosed.

Hypothyroidism is more common among patients with chronic kidney disease than on average. "Hypothyroidism is highly prevalent in chronic kidney disease (CKD) patients..." (12) Trace mineral deficiency can affect other nutrients or minerals absorption or actions on the body. Selenium and iodine need to be in balance for optimal health. Deficiency of selenium is linked to increased risk of kidney disease. (11)

Phosphorus in excess can be damaging to kidney health.

Excess phosphorus intake whether from the diet (carbonated beverages would be a source) or from some types of dialysis treatments can increase vascular calcification, and also deficiency of vitamin D by reducing Sirt1 protein which has beneficial anti-inflammatory effects. (12)

"Hyperphosphatemia induces [vascular calcification] VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC." (12)

"FoxO's transcription factors are downstream signals of Sirt1, and activation of Sirt1 induces FoxO3a expression to suppresses cellular ROS..." (12)

Zinc is needed for gene transcription of bitter taste receptors & other proteins.

Trace minerals share some mineral transport proteins which is why some minerals have more impact on the level of another one such as copper and zinc.

Zinc may also be important for healthy kidneys (and body) because of involvement in gene transcription as well as in enzymes. Zinc sulfate helped prevent renal calcification in an animal based study. "ZnSO4 increased the abundance of zinc-finger protein TNF-a–induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-kB pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression." (10)

Zinc is also necessary for the body to transcribe the gene for the protein that is made into bitter taste receptors (or other types of taste and odor receptors), so if a person has poor taste and smell sensation then they may also have low zinc levels and low levels of bitter taste receptors in the kidneys (and other areas of the body). See post: Zinc, cancer, and bitter taste receptors.

Bitter taste receptors in the kidneys & plant alkaloids

Why do we have bitter taste receptors in the kidneys? because when activated they increase the removal of calcium. Alkaloid plant phytonutrients ("phellodendrine and coptisine") have been found to activate the renal taste receptors and increase uptake of calcium as a result. (8) Caffeine is also an alkaloid phytonutrient. (9)

"Plants are the major sources of alkaloids, especially certain families of flowering plants, including Papaveraceae (poppy - [poppy seeds are a source]), Amaryllidaceae (amaryllis), Ranunculaceae (buttercups), Solanaceae (nightshades), and Stemonaceae." (9)

The Solanaceae (nightshades) plants include tomatoes, white potatoes, eggplant, Bell peppers, tobacco, and several plants that have seeds or other plant material with toxic effects - Belladonna, Jimson weed, Nightshade, Datura, and Bittersweet. (images search results)

Phytonutrients used medicinally in Traditional Chinese Medicine and other herbal care practices are listed in this document with a few excerpts and notes: TCM and other phytonutrients for kidney health. Many medicinal herbs contain bitter tasting phytonutrients and often extracts of medicinal plants are made into medicines such as chloroquine from quinine tree bark. "Quinine is an alkaloid derived from the bark of the Cinchona tree (Fig. 7.1). " (13)

Baking to do list - make lemon zest poppy seeds muffins because I love them and they may be good for my renal health.

Team - magnesium sulfate, zinc, iodine, selenium, Vitamin D, protein, phospholipids.

Secondary take home point - while magnesium, and particularly topical Epsom salts (magnesium sulfate) may help reverse or prevent vascular calcification within the kidneys (and rest of the body) - other nutrients may also be essential to help in that process such as zinc, iodine, and selenium. Adequate vitamin D is also essential while excess may increase calcium excess and add to problems with poor intestinal absorption. Adequate protein and phospholipids are also necessary to maintain a surplus supply of magnesium within cells.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

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24. New research reveals early warning sign for heart disease. 14 January 2021, ecu.edu.au, https://www.ecu.edu.au/news/latest-news/2021/01/new-research-reveals-early-warning-sign-for-heart-disease

From a previous post "Pomegranate peel/extract is also a source of EGCG. Pomegranate preparation tips and more information about health benefits is able on page effectivecare.info/G13. Pomegranate. It may have anti-inflammatory activity through down regulation of Fox03a (4) which is a protein that can increase oxidative stress damage in mitochondria (5) where the NAD+ chemical reactions are taking place."

• 4. Liu S, Zhang X, Sun M, Xu T and Wang A: FoxO3a plays a key role in the protective effects of pomegranate peel extract against amikacin-induced ototoxicity. Int J Mol Med 40: 175-181, 2017 https://www.spandidos-publications.com/10.3892/ijmm.2017.3003

• 5. Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013 Oct;63:222-34. doi: 10.1016/j.freeradbiomed.2013.05.002. Epub 2013 May 7. PMID: 23665396. https://pubmed.ncbi.nlm.nih.gov/23665396/

12. Chien-Lin Lu, Min-Tser Liao, Yi-Chou Hou, et al., Sirtuin-1 and Its Relevance in Vascular Calcification. Int. J. Mol. Sci. 2020, 21, 1593; doi:10.3390/ijms21051593 "FoxO's transcription factors are downstream signals of Sirt1, and activation of Sirt1 induces FoxO3a expression to suppresses cellular ROS..." (12)

Addition, new research about factors that indicate senescence occurring in cells after starvation time period rather than remaining in the quiescent stage of ongoing cell division: Same difference: Predicting divergent paths of genetically identical cells. Jan 11, 2021, utsouthwestern.edu https://www.utsouthwestern.edu/newsroom/articles/year-2021/predicting-divergent-paths-of-genetically-identical-cells.html