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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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.
The post Vitamin A in Bone Disease Associated with Chronic Kidney Disease 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.
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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.
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