Altered vitamin K biodistribution may decrease the benefit of vitamin K2 supplementation in advance CKD
In this study, investigators sought to determine if there are other causes for vitamin K deficiency in advanced CKD beyond decreased dietary intake. They compared vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (MK-4 and MK-7) between patients on dialysis and healthy individuals.
They found that patients with uremia and advanced kidney disease don’t incorporate MK-7 well into HDL and LDL particles compared to healthy individuals. In addition, the combination of a statin and PPI was associated with signs of functional vitamin K2 deficiency in these patients.
In essence, patients with advanced kidney disease may not benefit as well from vitamin K2 supplementation. This highlights the importance of optimizing vitamin K2 status at earlier stages in CKD.
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Higher levels of deoxycholic acid were associated with a higher risk of progression in CKD
Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. Intestinal bacteria metabolize the primary bile acid, cholic acid, into deoxycholic acid (DCA).
Researchers studied 3,147 CRIC study participants who had fasting DCA levels. DCA levels above the median were independently associated with higher risks of ESKD and all-cause mortality.
This study highlights the importance of the microbiome and dysbiosis in the progression of kidney disease as we discussed in our blog.
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The higher number of medications a kidney patient takes the faster her kidney disease progresses
In a study performed in Japan of 1117 CKD patients under nephrological care, the use of a higher number of medications was associated with an increased risk of kidney failure, cardiovascular events, and all-cause mortality in patients with CKD. This is one of the major reasons we advocate for lifestyle modifications and coaching as the first and major step in the management of kidney disease.
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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.
The post Magnesium and kidneys appeared first on Integrative Kidney.]]>In this series we’re focusing on the integrative approach to preventing kidney stone formation.
Conventional approaches to kidney stones tend to focus on medications, surgical removal, and using ultrasonic waves to break up stone. It rarely approaches the root cause including risk factors to prevent stone formation.
We covered the impact of diet, the microbiome and gut health, and electrolyte imbalances on kidney stones in previous blogs. Here we will discuss the role genetics play in kidney stone formation.
The Genetics of Kidney Stones
There seems to be a familial link when it comes to the development of kidney stones. In fact, two thirds of patients with calcium-containing kidney stones have a relative with kidney stones. Recently, genome-wide association studies uncovered several genetic sequence variants (SNPs) that lead to increased risk of kidney stone development. Although we are still scratching the surface in understanding the contribution of genetic factors to stone formation, we do know that we can modulate these risks through environmental and dietary modifications.
Genetic Variations in Calcium Handling
In a previous blog, we discussed the role of the kidney filtration units (specifically the nephrons). The kidneys are responsible for filtering large volumes of blood daily. This function is crucial, and, the unique design of the nephrons make it able to adjust this filtrate and prevent dehydration. This intricate design also makes the kidneys crucial in the balance of water and many electrolytes.
Calcium is one of the electrolytes filtered and reabsorbed in the kidneys. Calcium sensing receptors (CaSR) are present in kidney cells and are essential for the reabsorption of calcium. These receptors increase and decrease the amount of calcium reabsorbed based on the calcium level in the blood. In other words, activating these receptors increases the amount of calcium lost in the urine.
Single nucleotide polymorphisms (SNPs) in CaSR have been found to alter the function of these receptors leading to increased urinary excretion of calcium. Of particular interest, SNPs in rs7652589 and rs1501899 were associated with kidney stones in patients with normal citrate excretion. SNPS in rs1801725, rs1042636 of the CaSR gene were also associated with kidney stones in various populations.
Another gene that has been associated with increased calcium in the urine is the gene coding for the protein Claudin-14, responsible for forming tight junctions. This protein helps connect adjacent cells to form a barrier which acts like a gate, separating blood from urine. Tight junctions are also responsible for ensuring that minerals don’t pass between the cells. SNPs in the genes that code Claudin-14 (CLDN14) alters the integrity of these “gates” and allows for calcium to “sneak” between cells into the urine, increasing the risk for kidney stone formation. Specifically, SNPs at the locations rs219778, and rs219780 of the CLDN14 gene were significantly associated with kidney stones.
Genetic Variations in Vitamin D Receptors (VDR)
Vitamin D plays a crucial role in calcium balance. Studies have shown that vitamin D increases the absorption of calcium from the gut and also increases calcium excretion in the urine. Vitamin D receptors are essential for vitamin D to exert its action on calcium balance.
Some mutations or SNPs in the VDR are associated with increased absorption and excretion of calcium, significantly increasing the risk of kidney stones. It is worth mentioning here that there is some controversy about the link between vitamin D supplementation and kidney stone formation. Vitamin D deficiency appears to be common among kidney stone formers. This is likely because low vitamin D causes calcium loss from the bone in order to maintain normal calcium range in the blood for cardiovascular protection. Even though vitamin D3 supplementation may increase calcium excretion in the urine, it has not been conclusively found to increase the risk of kidney stone formation.
Therefore, genetic assessment may be a key to identify patients who are at risk of kidney stone formation from taking vitamin D supplements.
Genetic Variations in the Handling of Other Minerals
The kidneys are crucial for balancing many minerals in our bodies such as magnesium, phosphate, oxalate and others. Genetic mutation or SNPs affecting the genes that code for the channels or receptors that regulate these minerals can also impact the risk of kidney stones. Some SNPs on the other hand can be protective against kidney stones such as SNPs in the UMOD gene. Discussion of this long list of SNPs requires details beyond the scope of this blog, but we summarized most of the genes that have been associated with kidney stones in the table below.
| Gene symbol | Gene name | Phenotype |
| ADCT10 | Adenylate cyclase 10 | Increased calcium excretion |
| AGXT | Alanine-glyoxylate aminotransferase | Increased oxalate excretion |
| CA2 | Carbonic anhydrase II | Osteoporosis + decreased acid excretion |
| CASR | Calcium-sensing receptor | Increased calcium excretion |
| CLCN5 | Chloride channel, voltage-sensitive 5 | Dent disease |
| CLCNKB | Chloride channel, voltage-sensitive Kb | Bartter Syndrome, type 3 |
| CLDN14 | Claudin 14 | Increased calcium excretion |
| CLDN16 | Claudin 16 | Increased calcium and magnesium excretion |
| CLDN19 | Claudin 19 | Increased calcium and magnesium excretion |
| CYP24A1 | Cytochrome P450 | Decreased breakdown of vitamin D3 |
| GRHPR | Glyoxylate reductase | Increased oxalate excretion |
| HOGA1 | 4-Hydroxy-2-oxoglutarate aldolase 1 | Increased oxalate excretion |
| HPRT1 | Hypoxanthine phosphoribosyltransferase 1 | Increased uric acid excretion |
| SLC12A1 | Solute carrier family 12, member 1 | Bartter syndrome, type 1 |
| SLC26A1 | Solute carrier family 26, member 1 | Calcium oxalate kidney stones |
| SLC22A12 | Solute carrier family 22, member 12 | Decrease uric acid excretion |
| SLC2A9 | Solute carrier family 2, member 9 | Decreased uric acid excretion |
| SLC34A1 | Solute carrier family 34, member 1 | Calcium phosphate kidney stones |
| SLC34A3 | Solute carrier family 34, member 3 | Calcium phosphate kidney stones |
| SCL3A1 | Solute carrier family 3, member 1 | Increased Cystine excretion |
| SLC4A1 | Solute carrier family 4, member 1 | Decrease acid excretion (dRTA) |
| SLC7A9 | Solute carrier family 7, member 9 | Increased Cystine excretion |
| SLC9A3R1 | Solute carrier family 9, subfamily A, member 3, regulator 1 | Calcium phosphate kidney stones |
| UMOD | Uromodulin (most common urine protein) | Protective against kidney stones |
| VDR | Vitamin D (1,25-dihydroxy D3) receptor | Increased calcium excretion |
| XDH | Xanthine dehydrogenase | Increased xanthine excretion |
The Bottom Line
There are many factors that impact the risk of kidney stone development. Although there are pure genetic diseases that are associated with kidney stones, often the increased risk is subtle or offset by other factors. Increased risk, when combined with other factors including nutrient depletion, dysbiosis, electrolyte imbalances and dehydration, may lead to the development of kidney stones in some. Assessing the genetic profile of kidney stone patients can help identify the root cause of the disease to tailor appropriate, personalized management. Practitioners working with individuals to prevent kidney stone formation should formulate a comprehensive and individualized intervention that modifies all relevant components in their integrative approach.
The post Genetics of Kidney Stones appeared first on Integrative Kidney.]]>
By Lara Zakaria, PharmD, CNS, CDN, IFMCP
Nutrients don’t work solo, they function as part of a symphony with other nutrients to help our body perform at its best and prevent disease, including kidney damage and chronic kidney disease (CKD).
Nutrients don’t work solo, they function as part of a symphony with other nutrients to help our body perform at its best and prevent disease
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Vitamin D Background
Vitamin D3, also known as cholecalciferol, is a fat-soluble vitamin that plays a role as a pro-hormone. It Is naturally found in some foods like fish, egg yolks, and beef liver, but humans rely on making it through a process in the skin that requires sunlight exposure. For a full review of vitamin D visit our previous blog.
Vitamin D play a role in multiple aspects of health including bone mineral balance, neuromuscular function, immunity and autoimmune disease, cognitive health, and insulin regulation. Maintaining adequate vitamin D levels can be beneficial when managing or treating many conditions, including:
- Back or musculoskeletal pain
- Osteoporosis
- Frequent colds or flu
- Cardiovascular disease
- Diabetes
- Fatigue
- Seasonal Affective Disorder (depression)
Vitamin D interaction with other nutrients
Calcium and Phosphorous
Vitamin D is necessary for absorption of calcium and phosphorous from food sources in the intestines into the blood as well as regulating the amount of those minerals in circulation. This is a delicate balance, these two minerals are essential for bone remineralization and remodeling (bone building), skeletal muscle contractility, as well as kidney and cardiovascular health.
Vitamin K: K1 vs K2
Vitamin K is a general term for a group of compounds that function as part of the coagulation (blood clotting) pathways that help us regulate blood thinning and prevent risk of bleeding from cuts or injuries. Vitamin K is typically thought of for bleeding disorders, but proper balance may also be useful in the management and treatment of the following conditions:
- Atherosclerosis and ischemic heart disease
- Cirrhosis, hepatitis, and liver disease
- Osteoporosis ad bone loss
- Cancer
Vitamin K naming and structure is one of the most misunderstood topics in nutritional medicine, so let’s spend a few minutes understanding these foundations. Vitamin K is the general term used to describe a group of compounds that share a common ring structure. There are 2 subcategories to keep in mind, K1 and K2.
Vitamin K naming and structure is one of the most misunderstood topics in nutritional medicine. There are 2 subcategories to keep in mind, K1 and K2
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K1, also known as phylloquinone or phytonadione, is the primary form found in plants. Leafy vegetables are the main source of vitamin K1. This is the form that is utilized in the liver and involved in clotting. This is also the form that interacts with blood thinners like warfarin and why patients on blood thinners are told to carefully monitor their intake of leafy greens.
K2, referred to menaquinones, describes a group of varying chemical structures that are used outside the liver (in the bone and vascular wall). The number of isoprenyl units determine the name of the structure. So, a K2 with 4-isoprenyl units is MK4, and MK7 means there are 7 isoprenyl units. This is the form that is involved in bone health and the focus of kidney-relevant associations of this vitamin.
Vitamin K2 can be found in the diet in multiple forms (for example MK4, MK7, MK8, and MK9) in egg yolks, meats, cheese and other dairy products, natto (fermented soybeans), and seems to be much more readily bioavailable than K1 sources. In addition, menaquinones are synthesized by bacteria in the colon.
Vitamin K2 can be found in egg yolks, meats, cheese and other dairy products, natto (fermented soybeans), and is more readily bioavailable than K1. It is also synthesized by bacteria in the colon
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Considering what we already know about the impact of the microbiome of kidney health and risk factors, menaquinone might play a larger role in the gut-kidney connection than we’ve been giving it credit for. Though there are multiple factors that contribute to the circulating level of vitamin K in the body, there is speculation that dysbiosis (imbalance of healthy gut bacteria in the gut) may be a significant contributing factor to inadequate circulating levels of K2 contributing to cardiovascular, kidney and bone disease.
Supplementing Vitamin K2
Supplements containing vitamin K are available commercially as K1, MK4, and MK7. However, it’s important to note that safety and efficacy of each form is not equal and has contributed to significant confusion and inaccurate recommendations.
There’s little evidence supporting the supplementation of phylloquinone, or K1. This may be due to poor bioavailability and low rate of conversion to active forms. K2 on the other hand seems to be the superior form, with more recent data supporting the use of MK7.
In older studies, MK4 form seemed to be established as the most efficacious form when it comes to certain conditions like osteoporosis and hepatocellular carcinoma. However, MK7 seems to be more bioavailable and have a steadier blood concentration when compared to MK4 (and K1), meaning more stable blood concentrations and requiring lower doses. Additionally, the added benefit of MK7, particularly in osteoporosis, may in part be related to MK7 inhibition of NF-kB, an inflammatory mediator known to increase disease progression.
Like Vitamin D3, K2 helps to manage calcium deposition. Adequate levels of Vitamin K2 are required to deposit calcium into the bone and to prevent calcium deposition into soft tissue like cardiovascular arteries and the kidneys. So, you see, depletion of K2 along with vitamin D3 can be a risk factor for bone loss, cardiovascular and kidney disease and supplementation of the two combined might yield the best health outcomes.
So depletion of K2 along with vitamin D3 can be a risk factor for bone loss, cardiovascular, and kidney disease and supplementation of the two combined might yield the best health outcomes
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Manufacturers and companies selling vitamin K supplements often do not reveal whether contains MK-4 or MK-7. Therefore, it’s important to use formulations with full transparency and quality control. This is important for ensuring the highest efficacy, but also for safety concerns surrounding vitamin K supplements and that they may interfere with the stability of anticoagulant medications such as warfarin. This is also why it’s very important to work with your nutritionist or doctor to choose the correct product and dose. If you’re on a blood thinner, never make changes to your diet or supplements without consulting with the healthcare provider monitoring your medication and INR (test for bleeding tendencies).
Studies that examine the benefit of MK-7 supplementation showed a positive effect on cardiovascular calcification. Although MK-7 did not prevent CKD-associated hypertension and hypertrophy, it did demonstrate prevention of calcification of blood vessels. The recommended dose of MK-7 is typically 45μg/d, though doses of 100μg/d have been suggested likely based on studies of the less potent form of MK-4 which, as explained above, is not equivalent.
Although further studies are still underway, it’s safe to say that considering the low risk and cost, it’s worth optimizing vitamin D3 and K2 (MK7) levels in patients with associated risk factors for or diagnosed with CKD. Work with your nutritionist and nephrologist to personalize your intake and optimize your nutrient levels safely and effectively.
The post Vitamin K in Vascular, Kidney and bone Health appeared first on Integrative Kidney.]]>Vitamin D as a hormone
Vitamin D is a term used to describe a family of compounds derived from cholesterol. There are two major forms to keep in mind. Vitamin D2, or ergocalciferol, mostly found in plants, and D3, or cholecalciferol, the form found in animal sources and produced naturally in our skin when we’re exposed to the sun. It is a “conditionally essential vitamin” because we need cholesterol precursors to produce it but we can also consume it with food.
Vitamin D is not only a vitamin, but it’s also considered a hormone because of its direct interaction with cell receptors in the body. We rely on our a “factory” in the skin to make Vitamin D when we are exposed to the sun. The UV rays stimulate the conversion of precursors derived from cholesterol into active vitamin D3. Like other hormones derived from cholesterol, such as estrogen and testosterone, not eating or producing enough cholesterol can contribute to a deficiency of vitamin D.
Foods that contain vitamin D
We typically think of vitamin D as “the sunshine vitamin.” However, various factors impact the ability of the body to produce adequate active vitamin D3, including average daily sun exposure, geographic location, skin color, and genetic variations that impact “the vitamin D factory.” Luckily, there are other options for meeting our needs, including consuming vitamin D-rich foods as well as taking a high-quality supplement.
Foods that naturally contain the active form of vitamin D3 include wild salmon, herring, sardines, cod liver oil, tuna, oysters, shrimp, and egg yolks. Surprisingly, mushrooms are the only plant-based source of natural vitamin D2. However, you can actually significantly increase the naturally occurring amount of D3 by laying mushrooms in the sun (learn more here). Since Vitamin D is a fat-soluble vitamin, absorption is best when eaten with a healthy fat or food naturally containing fat.
Many people associate milk with food sources of Vitamin D. However, milk is not naturally a good source of vitamin D. Beverage companies fortify milk and other drinks (like orange juice, and nut milk products) and market them as “a great sources of vitamin D” – in other words vitamin D is artificially added in during the manufacturing process.
Milk is not naturally a good source of vitamin D. Beverage companies fortify milk and other drinks (like orange juice, and nut milk products) and market them as “a great sources of vitamin D”
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Vitamin D receptors
Vitamin D is most commonly associated with bone health, because it’s necessary in bone formation process along with vitamins K, calcium, magnesium, and phosphorous. However, it’s vital beyond bone health. Receptors for vitamin D have been identified in almost all organs in the body. These genes are responsible for the calcium and phosphate balance, immune response, and cell growth and differentiation. The presence of vitamin D receptors in the blood vessels also indicates that vitamin D plays an important role in maintaining heart health.
The presence of vitamin D receptors in the blood vessels also indicates that vitamin D plays an important role in maintaining heart health
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Activation of Vitamin D by the kidneys (and the liver)
Vitamin D that is produced by our skin or consumed is transported to the liver as a “prohormone” by a protein called Vitamin D Binding Protein (DBP). In the liver, this precursory form is converted by an enzyme called 25-hydroxylase (or CYP2R1). The end-product is called 25-hydroxyvitamin D, abbreviated 25-(OH)D, and is the main circulating form of vitamin D.
Once produced, 25-(OH)D is eventually transported to the kidneys where another (-OH) group is added. The result is the active hormone called 1,25-Dihydroxyvitamin D (or 1,25-Dihydroxycalceferol, abbreviated 1,25-(OH)2D).
Vitamin D receptors are mainly activated by 1,25 (OH)2D, however, some cells may have a modest capacity to activate vitamin D locally. In addition, at a very high concentration the less active 25 (OH)D can bind with vitamin D receptors,
Genetic variations in the activating enzymes involved in this multi-step process are well documented and influence individual ability to activate the prohormone into the needed active product. This is why checking both the 25-(OH)D and the 1,25 (OH)2D levels may give us a better idea of the true level of bioavailable vitamin D.
Genetic variations in the activating enzymes involved in this process are well documented and influence individual ability to activate the prohormone. This is why checking both the 25-(OH)D and the 1,25 (OH)2D levels may give us a better…
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Vitamin D in Kidney Disease
In KD, the gradual loss of functional kidney tissue responsible for activation of vitamin D contributes to the deficiency of the active form 1,25 (OH)2D. Interestingly, more than 80% of KD patients also have a low level of the precursor form 25(OH)D when measured in the serum. Several factors have been implicated in the cause of this deficiency including inadequate outdoor physical activity, inadequate dietary intake, genetic variations, and impaired retention of the filtered 25(OH)D by the kidneys. There is also evidence that the accumulation of waste product, a common effect of KD, can decrease the production of 25(OH)D by the liver.
Remember, vitamin D circulates in the blood bound to DBP. Without this protein to provide transportation, vitamin D precursors will not reach the liver for the step of activation to 25(OH)D. Since some KD causes urinary protein loss, low levels of DBP may contribute to low 25(OH)D in kidney patients, however there’s conflicting evidence of the significance of this factor. There may be more to the story worth continued research especially surrounding the genetic variations in the gene that codes for DBP and its subsequent effect on production and binding capacity.
We can’t talk about vitamin D and KD without talking about the parathyroid glad (not to be confused with the thyroid gland). The main function of the parathyroid gland is to maintain blood levels of circulating calcium, a mineral very important in heart and bone health, as well as normal muscle function.
As kidney function declines, phosphate accumulation indirectly contributes to further reduction in vitamin D activation. These compounding factors promote production of parathyroid hormone (PTH) by the parathyroid gland. KD). PTH maintain calcium by influencing absorption from the gut as well as increasing its reabsorption during kidney filtration.
When calcium levels in the blood drop too low and endanger cardiac function, it triggers PTH to also mobilize calcium from the bone storage into the blood to normalize circulating levels. This is the contributing mechanism that leads to a high bone turnover, weakened bones, and increase the risk of fracture in kidney patients. In addition, vitamin D deficiency in kidney patients has been associated with muscle weakness, falls, insulin resistance, enlargement of heart muscles, blood vessel disease and calcifications.
vitamin D deficiency in kidney patients has been associated with muscle weakness, falls, insulin resistance, enlargement of heart muscles, blood vessel disease and calcifications
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The target level of vitamin D in kidney disease patients
There is controversy surrounding the ideal target goal of 25 (OH)D and 1,25(OH2)D for kidney patients. Studies showed that maximum benefit to decrease muscle weakness and fall risk in kidney patients is in the range between 24-44 ng/mL and that levels less than 15 ng/mL have been associated with increased risk for mortality and progression to dialysis in kidney patients. Conventionally, a target level of ~40 ng/mL but has been the standard of care, however, some practitioners argue that some patients may benefit from higher circulating levels.
Conventionally, a target level of ~40 ng/mL but has been the standard of care, however, some practitioners argue that some patients may benefit from higher circulating levels
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Conventional and Integrative approach to bone health in kidney disease
The conventional medicine approach to bone health in KD has been focused on correcting 1,25(OH)2D levels and decreasing PTH levels (though target levels in KD are unclear). Utilizing active vitamin D analogues has been linked to improved outcomes in KD and dialysis patients.
When addressing vitamin D’s impact on KD risk, we need to pay close attention to dietary factors that impact nutrient status (including calcium, magnesium, vitamin K and other relevant nutrients), as well as digestive issues that may reduce nutrient absorption from food. In addition, the role of genetic and epigenetic modifications in coding for factors that impact vitamin D activation and vitamin D receptors might mean that simple recommendations to “get more sun” or supplement may not be adequate for some individuals and warrant a more personalized approach to optimize kidney health.
References:
1. Holick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266–281.
2. Townsend, K.; Evans, K.N.; Campbell, M.J.; Colston, K.W.; Adams, J.S.; Hewison, M. Biological actions of extra-renal 25-hydroxyvitamin D-1alpha-hydroxylase and implications for chemoprevention and treatment.
3. J. Steroid Biochem. Mol. Biol. 2005, 97, 103–109. Souberbielle, J.C.; Body, J.J.; Lappe, J.M.; Plebani, M.; Shoenfeld, Y.; Wang, T.J.; Bischoff-Ferrari, H.A.; Cavalier, E.; Ebeling, P.R.; Fardellone, P.; et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 2010, 9, 709–715.
4. Eknoyan, G.; Levin, A.; Levin, N.W. Bone metabolism and disease in chronic kidney disease. Am. J. Kidney Dis. 2003, 42, S1–S201.
5. Ishimura, E.; Nishizawa, Y.; Inaba, M.; Matsumoto, N.; Emoto, M.; Kawagishi, T.; Shoji, S.; Okuno, S.; Kim, M.; Miki, T.; et al. Serum levels of 1,25-dihydroxyvitamin D, 24,25 dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure. Kidney Int. 1999, 55, 1019–1027.
6. Nguyen-Yamamoto, L.; Karaplis, A.C.; St-Arnaud, R.; Goltzman, D. Fibroblast Growth Factor 23 Regulation by Systemic and Local Osteoblast-Synthesized 1,25 Dihydroxyvitamin D. J. Am. Soc. Nephrol. 2017, 28, 586–597.
7. Slatopolsky, E.;Weerts, C.; Thielan, J.; Horst, R.; Harter, H.; Martin, K.J. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J. Clin. Investig. 1984, 74, 2136–2143.
8. Kim, S.M.; Choi, H.J.; Lee, J.P.; Kim, D.K.; Oh, Y.K.; Kim, Y.S.; Lim, C.S. Prevalence of vitamin D deficiency and effects of supplementation with cholecalciferol in patients with chronic kidney disease. J. Ren. Nutr. 2014, 24, 20–25.
9. Cankaya, E.; Bilen, Y.; Keles, M.; Uyanik, A.; Akbas, M.; Gungor, A.; Arslan, S.; Aydinli, B. Comparison of Serum Vitamin D Levels Among Patients With Chronic Kidney Disease, Patients in Dialysis, and Renal Transplant Patients. Transpl. Proc. 2015, 47, 1405–1407.
10. Kalousova, M.; Dusilova-Sulkova, S.; Zakiyanov, O.; Kostirova, M.; Safranek, R.; Tesar, V.; Zima, T. Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease. Biomed. Res. Int. 2015, 2015, 492365.
11. Garcia-Canton, C.; Bosch, E.; Ramirez, A.; Gonzalez, Y.; Auyanet, I.; Guerra, R.; Perez, M.A.; Fernandez, E.; Toledo, A.; Lago, M. Vascular calcification and 25-hydroxyvitamin D levels in non-dialysis patients with chronic kidney disease stages 4 and 5. Nephrol. Dial. Transpl. 2010, 26, 2250–2256.
12. Namir, Y.; Cohen, M.J.; Haviv, Y.S.; Slotki, I.; Shavit, L. Vitamin D levels, vitamin D supplementation, and prognosis in patients with chronic kidney disease. Clin. Nephrol. 2016, 86, 165–174.
13. Kendrick, J.; Cheung, A.K.; Kaufman, J.S.; Greene, T.; Roberts,W.L.; Smits, G.; Chonchol, M. Associations of plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with death and progression to maintenance dialysis in patients with advanced kidney disease. Am. J. Kidney Dis. 2012, 60, 567–575.
14. Yousefzadeh P, Shapses SA, Wang X. Vitamin D Binding Protein Impact on 25-Hydroxyvitamin D Levels under Different Physiologic and Pathologic Conditions. Int J Endocrinol. 2014;2014:981581.