Low magnesium levels have been associated with a number of adverse events, such as high risk for heart disease. However, little is understood about magnesium and kidney health. Here, we will discuss the potential benefits of magnesium on the kidneys. This is one of two articles on magnesium and kidneys. For more on how to test and treat kidney patients with magnesium deficiency, see part two, “Magnesium Deficiency: Assessment and Management for Better Kidney Health.”
Dietary sources of magnesium
A daily intake of 3.6 mg/kg is necessary to maintain magnesium balance in humans under normal conditions. This is estimated to be between 320 to 420 mg/day (13–17 mmol/day) for adults. Sadly, there has been a steady decline in magnesium content in cultivated fruits and vegetables over the past 100 years. This is due to depletion of magnesium in soil over time. This, along with the rise of ultra-processed food, sodas, and taking medications such as proton pump inhibitors and diuretics that deplete magnesium levels (polypharmacy), has led to rising prevalence of magnesium deficiency.
Traditionally, the highest food sources of magnesium are:
- Leafy greens (78 mg/serving on average)
- Nuts (80 mg/serving on average)
- Pumpkin seeds have the highest level of magnesium per serving (156 mg).
- Whole grains (46 mg/serving on average)
A complete list of foods high in magnesium can be found here.
Can Magnesium Help Kidney Function?
There are many potential benefits of magnesium for kidney health including improving blood pressure control, insulin sensitivity, bone health, vascular health, and preventing kidney stones. Let’s explore the data.
Magnesium and blood pressure control
Magnesium supplementation may help reduce blood pressure (BP) by increasing the production of nitric oxide. Nitric oxide acts as a signaling molecule that helps relax blood vessels, which lowers BP. In fact, a review of 34 studies showed that supplementing magnesium with an average dose of 368 mg per day for 3 months can decrease systolic BP by 2.00 mmHg and diastolic BP by 1.78 mmHg. This supplementation was accompanied by 0.05 mmol/L increase in serum magnesium levels.
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Magnesium and insulin sensitivity
Diabetes is one of the major risk factors for kidney disease worldwide. Higher dietary intake of magnesium has been correlated with lower diabetes incidence. A review of 18 studies in people with diabetes showed that magnesium supplements reduced fasting plasma glucose levels. In people who are at high risk for diabetes, magnesium supplementation significantly improved plasma glucose levels after a 2-hour oral glucose tolerance test. These effects are thought to be due to the effects of magnesium on insulin receptors and signaling that allows for improvement in glucose transport and utilization.
Magnesium and vascular health
Magnesium levels have been associated with a lower incidence of cardiovascular disease. In fact, supplementing with magnesium was associated with improvement in vascular flow and endothelial function. Endothelial function refers to the lining of the blood vessels, which is involved in regulating blood vessel health and blood clotting.
Studies in patients receiving dialysis have shown that having a lower serum magnesium level is a significant risk for cardiovascular mortality. Laboratory data show that magnesium inhibits high phosphate-induced calcification of vascular smooth muscle cells. Calcification of arteries is a strong predictor of heart disease and heart-disease-related death.
Magnesium and vitamin D
Magnesium is essential to vitamin D metabolism. Vitamin D that we eat or make in our skin from sun exposure circulates in the blood and is bound to vitamin D binding protein (VDBP). VDBP binding activity depends on adequate magnesium levels. In addition, magnesium is an essential cofactor for the enzymes that activate vitamin D. Studies have demonstrated that magnesium deficiency is associated with impaired vitamin D metabolism.
On the other hand, taking large doses of vitamin D can induce severe depletion of magnesium. This is thought to be due to the overutilization of magnesium. Therefore, adequate magnesium supplementation should be an important part of vitamin D therapy.
Adequate magnesium supplementation should be an important part of vitamin D therapy.
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Magnesium and bone health
Besides magnesium’s effects on vitamin D metabolism, it is an essential component of hydroxyapatite, an essential component of bone and teeth. In fact, 60% of total Mg is stored in the bone. Low magnesium intake was found to be associated with lower bone mineral density in postmenopausal women. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting the secretion and the activity of parathyroid hormone (PTH) and by promoting oxidative stress and inflammation.
In addition, a review of 8 studies looked at magnesium and chronic kidney disease (CKD). The study investigated magnesium supplementation on parameters of CKD-related mineral bone disease (CKD-MBD). Mg supplementation improved PTH levels and carotid intima-media thickness (CIMT). Low serum Mg levels were also found to impact PTH and worsen osteoporosis in CKD patients, particularly with diabetes.
Magnesium and kidney stones
Mg acts as an inhibitor of calcium oxalate crystallization and stone formation in the urine. It also decreases the absorption of dietary oxalate in the gut. Mg supplementation in patients with kidney stones was found to decrease the incidence of stone formation even in patients without signs of Mg deficiency.
Magnesium as a phosphate binder
Hyperphosphatemia (high phosphate level) is common in advanced kidney disease. Many kidney patients with stage 4 and above use binders that bind phosphate (or “phosphorus,” as it is commonly known) in the food and prevent it from getting absorbed. High phosphate levels have been associated with poor bone and vascular health in kidney patients. In fact, higher dietary phosphate load can be seen in earlier stages of CKD, and it can do harm even before it is detected.
Magnesium carbonate has been successfully used as a phosphate binder. Magnesium based phosphate binders were also found to reduce vascular calcifications in rats with kidney disease. Iron-magnesium hydroxycarbonate was also studied and found to be well tolerated and can effectively lower phosphate levels in dialysis patients. It is essential to know that most of the magnesium used as a phosphorus binder will not be absorbed.
The bottom line on magnesium and kidneys
Magnesium is essential to many biological functions. It has many health benefits for kidney, bone, and vascular health. Optimizing magnesium status is, therefore, an important step in the integrative approach to kidney health. In part two of this blog, “Magnesium Deficiency: Assessment and Management for Better Kidney Health,” we will discuss practical steps for figuring out a person’s actual magnesium status, the best form of magnesium to take, and the dose I recommend for each condition.
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By Majd Isreb, MD, FACP, FASN, IFMCP
What is vitamin A?
Vitamin A is an essential fat-soluble nutrient known for its role in good vision. It is also needed for cellular growth and differentiation. Since skin and gut cells are some of the fastest-growing cells in the human body, they are most sensitive to vitamin A deficiency. Vitamin A is also important for cells of the immune system. Vitamin A plays an important role in these processes:
- Growth and differentiation of all cells
- Embryonic development
- Organ formation in utero
- Normal immune function
- Eye development and vision
- Red blood cell production
Chemically, vitamin A is a group of organic compounds that share a beta-ionone ring with an isoprenoid chain. These compounds are often referred to as “retinoids.” The name of the retinoid depends on the number of the rings, the size of the isoprenoid chain, and the end group. These include -carotene, -carotene, retinal, retinol (which is vitamin A per se), all-trans-retinoic acid, all-trans-retinyl ester, 9-cis-retinoic acid, and 11-cis-retinal. Now, forget about all these different compounds, and let’s simplify things by calling them all vitamin A.
Diet and vitamin A
Vitamin A is consumed in the diet either as preformed vitamin A or as a precursor provitamin A carotenoid. Provitamin A carotenoids are converted to vitamin A in human intestinal cells. Sources of preformed vitamin A include eggs, liver, butter, milk, and fortified cereals. Provitamin A carotenoids are mainly found in vegetables such as carrots, spinach, collards, pumpkins, and squash. The most common type is beta-carotene. On average, the standard American diet provides approximately 700-800 micrograms of “retinol activity equivalents (RAE)” per day. Most of that comes as preformed vitamin A. The recommended dietary allowance of RAE for men and women is 900 and 700 micrograms/day, respectively. This makes deficiency of vitamin A rare. I will not discuss the complex absorption of vitamin A in the gut and storage in the liver and cellular mechanisms of action in detail here. These are described in detail elsewhere. However, it is important to remember that the presence of fat in the diet greatly enhances vitamin A absorption since it is fat-soluble. It is also worth noting that excessive intake of preformed vitamin A can cause elevated vitamin A levels. But elevated vitamin A does not usually occur after increased intake of provitamin A carotenoids. This is because the conversion of carotenoids to vitamin A is regulated by a negative feedback loop. When adequate levels of vitamin A are present, the body downregulates the production of vitamin A from carotenoids.
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Effects of vitamin A on the bone
Before we discuss the effects of vitamin A on bone in detail, we should review the processes of bone formation and maintenance.
Bone formation and maintenance
Our bones contain a small number of cells surrounded by a mesh of collagen fibers that provide a scaffolding for salt crystals. These salt crystals are made of calcium, phosphate, and carbonate which combine to create, the so-called, hydroxyapatite. The latter incorporates other salts like magnesium hydroxide, fluoride, and sulfate as it hardens, or calcifies, on the collagen scaffolding. Hydroxyapatite crystals give bones their hardness and strength, while collagen fibers give them flexibility. There are four types of cells that are found within the bone: osteoblasts, osteocytes, osteogenic cells, and osteoclasts. In adults, two processes are responsible for changes in the skeleton: modeling and remodeling. Bone modeling describes the process of new bone formation or bone resorption on a given bone surface. This process is important for bone growth and shaping during childhood and adolescence. Bone remodeling, on the other hand, is the process that is used to maintain and renew healthy bones during adulthood. In other words, in bone modeling either bone formation or bone resorption occurs, while in bone remodeling both bone resorption and bone formation occur together. For remodeling to occur the bone must be “dissolved,” and then a new bone is formed. In this process, osteoclasts dissolve old bone tissue at specific sites. This process is called resorption. Subsequently, new bone tissue is formed by the osteoblasts. Even though it may seem counterintuitive, bone resorption (breaking down old bone) is necessary for building new, healthy bone. So, in essence, modeling leads to the formation of new bone tissue where needed, while remodeling helps maintain and strengthen existing bone tissue.
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The role of vitamin A
Vitamin A has two different effects on bone depending on the dose. While adequate vitamin A intake was shown to maintain healthy bones, high levels of vitamin A have been shown to cause the opposite. Let me explain.
Good effects
Studies have shown that vitamin A is important for bone resorption. This is essential for maintaining healthy bone by remodeling as we discussed. In fact, adequate intake of vitamin A has been found to improve bone mineral density and decrease the risk of fractures.
Not-so-good effects
In the early 1900s, researchers found more osteoclasts in the bones of animals with high vitamin A levels. Later animal studies showed that excess vitamin A led to the formation of bones with a “moth-eaten appearance.” It was also demonstrated that vitamin A stimulated bone resorption. Recently, it was noted that vitamin A can stimulate mineral release and bone degradation in mouse bones. These effects were blocked by osteoclast inhibitors such as bisphosphonate and calcitonin. In essence, vitamin A can increase osteoclast formation and differentiation causing increased bone resorption. This is good for the maintenance of healthy bones but becomes harmful when there is excessive resorption at high levels of vitamin A. The evidence that supports this comes from studies that showed an increased risk of hip fractures in the lowest and highest vitamin A blood levels. There are other studies that also showed that a high daily intake of vitamin A was associated with decreased bone mineral density. In the NHANES study in the US, for example, daily vitamin A intake of more than 3,000 micrograms was associated with an increased risk of hip fracture. However, there was no increased risk of fractures with high beta-carotene intake. This low-dose versus high-dose phenomenon has been seen with other nutrients and is described as a U-shaped hormetic response. At low doses, there are symptoms of nutritional deficiency but at high doses, there are symptoms of toxicity.
The interaction between vitamin A & vitamin D3
As we noted before, nutrients don’t work solo. Optimal bone health requires optimization of vitamin D, vitamin K2, calcium, phosphorus, and magnesium. There have been reports of vitamins D and A opposing each other. Some studies showed that vitamin D protects against vitamin A toxicity. On the other side, excess vitamin A was also shown to reduce the effects of vitamin D toxicity. In humans, high vitamin A intake was found to decrease the ability of vitamin D to enhance calcium absorption in the gut. Studies have shown that the negative effects of excess vitamin A on bone mineral density and fracture risk are amplified when accompanied by vitamin D deficiency.
Vitamin A and kidney health
Several studies have shown that vitamin A levels increase with worsening kidney function and advanced CKD. This, along with the prevalence of vitamin D deficiency in this population, adds another layer of complexity to bone problems in kidney disease. This common complication of kidney disease is called chronic kidney disease-associated mineral bone disease (CKD-MBD). In CKD-MBD, there is abnormal bone turnover and increased vascular and soft tissue calcifications. Increasing intake of preformed vitamin A at the advanced stage of CKD can lead to worsening bone abnormality and elevated calcium levels in the blood. This, in turn, can increase the risk of vascular calcifications. Therefore, supplementing vitamin A in patients with advanced CKD is not generally recommended on a regular basis. Natural vitamin A intake through a diet high in carotenoids should be sufficient.
Assessing vitamin A status
Unfortunately, it is difficult to assess vitamin A status in an individual. This is because most vitamin A is stored in the liver and is released as needed to the blood. The two common ways to measure vitamin A status are measuring serum retinol and retinyl ester concentrations. There are also labs that measure beta-carotene levels. Serum retinol levels are only helpful if they are very low or very high. Levels < 1.05 micromol/L indicate vitamin A insufficiency. It has been suggested to use the ratio of serum retinyl esters to total serum vitamin A (retinol plus retinyl esters) as a marker for excess vitamin A. Serum retinyl ester levels exceeding 10% of total serum vitamin A may reflect excess vitamin A stores and potential toxicity.
How much vitamin A should I take?
Considering the above, we recommend our patients get most of their vitamin A from the diet (either as preformed vitamin A or provitamin A carotenoids). CKD patients can eat eggs, liver, butter, milk, carrots, spinach, collards, squash, and pumpkin with guidance from their dietitian/nutritionist and nephrologist. The following recommendations for CKD patients are based on anecdotal practice since the literature doesn’t support specific recommendations. Patients with stage I-IIIa CKD may take up to 2500-3000 IU of supplemental vitamin A (or RAE 900 microgram/day for men and 700 microgram/day for women.) Patients with stage IIIb-IV CKD should decrease their intake of vitamin A supplements by 50%. Supplementation with vitamin A is not recommended for patients with an estimated GFR of less than 20 ml/min. If supplementation is desired during periods of sickness (for example, a respiratory illness) to boost the immune system, we recommend using beta-carotene supplements instead of preformed vitamin A supplements.
The Bottom Line
Vitamin A has a great impact on bone health. It is essential for bone resorption and remodeling. However, excess vitamin A intake can lead to bone weakness and fractures. In patients with advanced CKD, vitamin A tends to accumulate, and supplementation is not recommended. If supplementation is desired to boost the mucosal immune system during periods of sickness and high demand, look for supplements that provide much of their vitamin A in the form of beta-carotene. The individualized integrative approach to CKD-MBD necessitates careful nutritional assessment and evaluation of vitamin A levels in addition to vitamins D, K, magnesium, calcium, and phosphorus. This can help develop a tailored lifestyle and nutrition plan that can be incorporated into the medical management of CKD.
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