FGF23 and Phosphorus: Understanding the Relationship with Kidney Disease

Kidney disease is a complex condition that affects millions of people worldwide. One of the key factors that contribute to the development and progression of kidney disease is the regulation of phosphorus in the body. Phosphorus is an essential mineral that plays a critical role in many cellular processes, but excessive levels of phosphorus in the blood can be harmful to the body, especially in patients with kidney disease.

FGF23, or fibroblast growth factor 23, is a hormone that regulates phosphorus and vitamin D levels in the body. It is primarily produced by bone cells and acts on the kidneys to increase the excretion of phosphorus in the urine, thereby reducing the levels of phosphorus in the blood. However, in patients with kidney disease, the production and regulation of FGF23 become disrupted, leading to elevated levels of FGF23 in the blood and a corresponding increase in phosphorus levels.

One study found that elevated FGF23 levels were associated with a higher risk of death in patients with kidney disease 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353875/

Another study found that higher FGF23 levels were associated with an increased risk of cardiovascular disease in patients with chronic kidney disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936216/

This is thought to be due to the adverse effects of FGF23 on other organs and tissues in the body, as well as its potential to disrupt the delicate balance of phosphorus and vitamin D metabolism.

One of the reasons why FGF23 levels become elevated in patients with kidney disease is the impaired ability of the kidneys to remove excess phosphorus from the blood. As kidney function declines, the ability of the kidneys to excrete phosphorus becomes compromised, leading to an accumulation of phosphorus in the blood. This increase in phosphorus levels stimulates the production of FGF23 by bone cells, which in turn further decreases phosphorus levels in the blood.

However, this process is not without consequences. Elevated levels of FGF23 have been associated with an increased risk of cardiovascular disease, bone disease, and mortality in patients with kidney disease. Therefore, understanding the relationship between FGF23 and phosphorus is critical for the management of kidney disease. In patients with kidney disease, it is important to monitor both FGF23 and phosphorus levels in the blood and to manage them appropriately. This may involve the use of medications such as phosphate binders or vitamin D supplements, as well as dietary modifications to reduce phosphorus intake.

Klotho

Over 15 years ago, researchers discovered the Klotho gene, an aging gene that produces the protein Klotho and when over-expressed, extended the lifespan in animals, but produced complex phenotypes similar to human aging when deleted. The Klotho knockout mouse has since become an established animal model for studying well-known aging processes, such as arteriosclerosis, arterial calcification, and osteoporosis, and less well-studied processes such as angiogenesis. The klotho gene encodes a long single-pass transmembrane protein, commonly referred to as α-klotho.

The protein that this gene regulates also called Klotho is a protein that is primarily expressed in the kidneys and is required for FGF23 to exert its biological effects.

However, in patients with kidney disease, the production and regulation of FGF23 and klotho become disrupted, leading to elevated levels of FGF23 in the blood and a corresponding increase in phosphorus levels. 

One study found that FGF23 levels were inversely associated with Klotho levels in patients with chronic kidney disease. This means that if FGF23 levels go up, Klotho levels go down and vice versa.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/nep.12268

Another study found that klotho deficiency contributed to the development of hyperphosphatemia and vascular calcification in mice.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014041/

As kidney function declines, the ability of the kidneys to excrete phosphorus becomes compromised, leading to an accumulation of phosphorus in the blood. This increase in phosphorus levels stimulates the production of FGF23 by bone cells, which in turn further decreases phosphorus levels in the blood. However, as kidney function declines, the levels of klotho in the kidneys also decrease, impairing the ability of FGF23 to exert its biological effects.

Elevated levels of FGF23 and decreased levels of Klotho have been associated with increased risk of cardiovascular disease, bone disease, and mortality in patients with kidney disease and more and more research is suggesting that this mechanism and the fall in Klotho happens well before changes in eGFR are seen in pathology testing. Meaning that if we could monitor Klotho and FGF23 levels in predisposed patients we could prevent kidney disease from even happening! 

FGF23, Klotho, and Phosphorus

Both vitamin D and the parathyroid hormone (PTH) play vital roles in controlling phosphate levels. Vitamin D3 or 1,25(OH)2D3 is mainly responsible for increasing calcium and phosphate absorption in the small intestine. On the other hand, the PTH primarily reduces phosphate reabsorption in the kidneys, leading to increased urinary excretion, but also affects bone turnover and mineral flux from the skeleton. The parathyroid gland cells directly respond to extracellular phosphate concentrations, while calcium-sensing receptors convey changes in serum calcium concentration indirectly. FGF23, through the FGFR-klotho co-receptor complex, inhibits tubular reabsorption of phosphate by reducing certain transporters. FGF23 also suppresses the synthesis of PTH in the parathyroid glands in a klotho-dependent manner. 

https://onlinelibrary.wiley.com/doi/pdf/10.1111/nep.12268

Although FGF23 plays a significant role in regulating phosphate flux, there is weak evidence that phosphate or dietary intake directly regulates FGF23 synthesis. FGF23 appears to be mainly regulated by vitamin D and local changes in bone mineralization. The role of klotho in mediating phosphate excretion is substantial, as demonstrated in both in vitro and in vivo studies. Both klotho knockout mice and FGF23 knockout mice show similarly elevated levels of serum phosphate, indicating the obligate role of klotho in manipulating phosphate reabsorption.

I know this is all a bit technical but the basics that I want to pass on to you the reader is that this mechanism of a rise in FGF23 and subsequently a rise in phosphorus and a decline in Klotho seems to be the hallmark and the first pathophysiological changes that happen biologically before we see an actual change in kidney function via a GFR reading. This potentially means that if we could develop accurate tests for monitoring this and ways to increase Klotho we could prevent kidney disease by preventing the fibrotic damage that is a hallmark part of the decline in eGFR levels. It also helps you to understand my absolute obsession with increasing Klotho levels in those diagnosed with chronic kidney disease. 

Natural Remedies to Improve the Balance between Klotho and FGF23 in Kidney Disease

Fortunately, there are natural remedies that can help improve the balance between FGF23 and Klotho in patients with kidney disease.

Vitamin D supplementation

Vitamin D plays an important role in the regulation of phosphorus and calcium metabolism. In patients with kidney disease, vitamin D deficiency is common and is associated with increased FGF23 levels and decreased Klotho levels. Vitamin D supplementation has been shown to increase Klotho levels and decrease FGF23 levels in patients with chronic kidney disease. Studies have also found that vitamin D supplementation improved Klotho levels and reduced arterial stiffness in patients with chronic kidney disease. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674776/#:~:text=FGF23%20is%20an%20essential%20regulator,by%20increasing%2024%E2%80%90hydroxylase%20transcription.

We have written about the importance of Vitamin D in Kidney disease before, and you can read more about it here. Vitamin D deficiency and preventing it early on may be a key way to reduce kidney disease and it is such a simple and easy intervention. Vitamin D is safe to take daily in doses between 1000iu and 5000iu. I always recommend that you have a blood test first to see where your baseline levels are at then work with a qualified naturopath to optimise your vitamin D levels. You can read more about what dosages and forms of vitamin D to take in the article I mentioned above. 

Magnesium supplementation

Magnesium is an important mineral that plays a critical role in many cellular processes, including bone formation and energy metabolism. Magnesium deficiency has been shown to contribute to the development of hyperphosphatemia and elevated FGF23 levels in patients with chronic kidney disease. Moreso magnesium supplementation has been shown to decrease FGF23 levels in patients with chronic kidney disease. 

Magnesium is one of the key minerals that the body needs to stay healthy, in fact, it is needed for more than 300 biochemical reactions in the body. Approximately 60% of the body’s magnesium is present in bone, 20% in muscle and another 20% in soft tissue and the liver. Less than 1% of total magnesium is in blood serum and our body works hard to try and keep these levels under tight control. 

The majority of the population in Western countries consume less than the recommended amount of magnesium, in part due to the consumption of processed foods, demineralised water and agricultural practices using soil deficient in magnesium for growing food. 

Magnesium deficiency is one of the most common mineral deficiencies seen in clinical practice. Not only due to the soil deficiencies but also because magnesium is the main mineral consumed by the body in times of stress. Meaning that people living with chronic stress will become magnesium deficient very quickly. 

Apart from decreasing FGF23 levels, magnesium plays a vital role in:

• Protein synthesis
• Muscle and nerve function
• Blood glucose control
• Blood pressure regulation 
• Energy production
• Healthy brain function
• Immune function
• Formation of bone and teeth
• Important for the structure of many enzymes, mitochondria, DNA and RNA

You can read all about magnesium and its importance for those diagnosed with CKD here. 

Dietary modifications

Dietary modifications can also help improve the balance between FGF23 and Klotho. A low phosphate diet may be useful if you have elevated phosphorus levels in the blood, or if you are in the later stages of kidney disease.

A high-fibre diet has also been shown to decrease FGF23 levels in patients with chronic kidney disease. In addition, a diet rich in fruits and vegetables has been associated with increased klotho levels and decreased FGF23 levels in healthy adults.

Herbal Remedies to Increase Klotho Levels

Astragalus

Astragalus is a herb that has been used in traditional Chinese medicine for thousands of years. It has been shown to have anti-inflammatory, antioxidant, and immune-modulating properties. In a study of patients with chronic kidney disease, astragalus supplementation was found to increase Klotho levels and improve kidney function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191145/

Rehmannia

Rehmannia is a herb that has been used in traditional Chinese medicine for the treatment of kidney disease. It has been shown to have anti-inflammatory and antioxidant properties. In a study of rats with kidney disease, Rehmannia supplementation was found to increase Klotho levels and improve kidney function.

https://www.dovepress.com/bufei-yishen-formula-inhibits-the-cell-senescence-in-copd-by-up-regula-peer-reviewed-fulltext-article-COPD

FoTi 

FoTi, or Polygonum multiflorum, has been shown to increase Klotho levels and is my favourite herb to use for increasing Klotho.

Fo-ti has a protective effect on the kidneys. Many of the benefits of Fo-ti come from its strong antioxidant and anti-inflammatory actions. Oxidative stress is defined as tissue damage from an imbalance between excessive reactive oxygen species and insufficient antioxidant capacity. Oxidative stress and inflammation are considered to be key factors in the development of CKD and if not dealt with usually lead to end-stage renal disease.

FoTi contains compounds that have been shown to have antioxidant and anti-inflammatory properties. In a study of rats with kidney disease, FoTi supplementation was found to increase Klotho levels and improve kidney function.

Researchers at the University of Texas found that injecting klotho into mice that had kidney failure reduced the damage to the kidneys, promoted healing of the kidneys, prevented the progression of the disease to a chronic disease and prevented the formation of heart failure which is the leading cause of death amongst patients with CKD.

Companies are currently trying to develop klotho that can be used as a drug or find ways to stimulate endogenous klotho in humans and Fo-ti appears to do just that.

A study in aged mice found that administration of TSG (tetrahydroxystilbene glucose) a constituent of Fo-ti for 8 weeks reversed age-related decreases in klotho, increased the levels of klotho in the bloodstream and increased the expression of klotho in the brain, heart, kidney, testis and epididymis in a dose-dependent manner. Examination of the organs also showed that TSG improved disease-related changes in the organs. 

https://pubmed.ncbi.nlm.nih.gov/25595496/

Medications that increase FGF23 and thus might contribute to CKD

Several medications are known to increase FGF23 levels, which can lead to negative health outcomes in patients with kidney disease. One such medication is phosphate binders, which are commonly used to lower serum phosphorus levels in patients with chronic kidney disease. While phosphate binders are effective at reducing serum phosphorus levels, they have been shown to increase FGF23 levels in some patients.

Cinacalcet is another medication that can increase FGF23 levels. It is used to treat secondary hyperparathyroidism in patients with chronic kidney disease. Cinacalcet works by binding to calcium-sensing receptors in the parathyroid gland, which reduces the production of parathyroid hormone. However, cinacalcet has been shown to increase FGF23 levels in some patients.

Lifestyle Factors That Can Increase FGF23

Several lifestyle choices have been shown to increase FGF23 levels in the body, which can lead to negative health outcomes in patients with kidney disease. 

Excessive phosphorus consumption

One lifestyle choice that can increase FGF23 levels is consuming a diet that is high in phosphorus. Excessive intake of phosphorus can lead to elevated FGF23 levels, as FGF23 is primarily produced by bone cells in response to high levels of serum phosphorus. Foods that are high in phosphorus include dairy products, meats, and processed foods.

https://academic.oup.com/ndt/article/33/11/1977/4840716

1. Dairy products: Milk, cheese, and yogurt are all high in phosphorus. For example, one cup of milk contains about 250 mg of phosphorus.
2. Meat: Beef, pork, chicken, and fish are all high in phosphorus. A 3-ounce serving of beef contains about 180 mg of phosphorus.
3. Nuts and seeds: Almonds, pumpkin seeds, and sunflower seeds are all high in phosphorus. For example, a quarter-cup serving of pumpkin seeds contains about 220 mg of phosphorus.
4. Whole grains: Brown rice, quinoa, and whole wheat bread are all high in phosphorus. For example, one slice of whole wheat bread contains about 50 mg of phosphorus.
5. Processed foods: Many processed foods, such as canned soups and frozen dinners, contain added phosphorus in the form of phosphate additives.

Smoking

Another lifestyle choice that can increase FGF23 levels is smoking. Studies have shown that smoking is associated with increased FGF23 levels in both healthy adults and patients with chronic kidney disease. The mechanisms behind this association are not fully understood, but it is thought that smoking-induced oxidative stress may play a role in the regulation of FGF23 levels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699427/

Sendatary Lifestyle

Lack of physical activity has also been shown to increase FGF23 levels. In a study of healthy adults, sedentary behaviour was found to be associated with increased FGF23 levels. It is thought that physical activity may help regulate FGF23 levels by improving bone health and reducing oxidative stress.

https://www.sciencedirect.com/science/article/abs/pii/S0531556521003132

So there you have it. Hopefully, this has given you an overview of the relationship between FGF23, Phosphorus and Klotho as well as an appreciation for why being able to test for these may be key in preventing the onset of Kidney Disease in the first place.

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