In its early stages, kidney disease has no symptoms and isn’t easily detected which makes it difficult to make an early and accurate diagnosis. Frequently, people aren’t aware they have kidney disease until they have already reached the later stages and a lot of kidney damage has already occurred.
Today I want to introduce you to something that has the potential to change the face of kidney disease. There’s a new protein in town (and by new I really mean twenty years old!) that researchers are hoping will provide a new (and more effective) treatment for both acute and chronic kidney disease.
What is klotho?
Klotho is a protein found in mammals that is produced by the klotho gene. The discovery of klotho was made in 1997 and it was initially identified as an anti-ageing gene.
Like many scientific breakthroughs the discovery of the Klotho gene was a happy accident.
Klotho was originally identified as a gene in mice when a defect in klotho gene expression resulted in effects that resembled human aging, such as cognitive impairment, osteoporosis, atherosclerosis (hardening of the arteries), hearing loss and a shortened life span.
So, while a reduction of the klotho protein in mice were shown to shorten their lifespan, higher levels of klotho actually extended their lifespan. Pretty cool, huh!
Image from: klotho.com
Klotho takes its name from the Greek goddess of destiny. Klotho (or Clotho) is one of the Three Fates of Greek mythology who spun the thread of the lives of all mortals, deciding when they were born and when they died. Once you learn a bit more about the klotho gene you will see that this aptly named gene really is intertwined with lifespan (pun intended!).
Klotho levels are closely related to age. Its serum level is low in the first decade; it then increases and reaches its peak in the 20-40 age groups and gradually decreases thereafter.
In humans, klotho deficiency has been associated with the development of atherosclerosis, diabetes, high blood pressure, chronic kidney disease, osteoporosis, anaemia, and various cancers.
Buendia, P., Ramirez, R., Aljama, P. & Carracedo, J. (2016). Klotho prevents translocation of NF-kB. Vitamins and Hormones, 101, 119-150.
The role of Klotho in Kidney Disease
There is unequivocal evidence in experimental animals that both acute kidney injury (AKI) and CKD are states of systemic klotho deficiency.
Most of the klotho in the body is produced in the kidneys which means that the more kidney damage you have, the less klotho they can make which then results in further damage which becomes a bit of a vicious cycle.
Soluble Klotho is the main functional form in the circulation and is detected in the blood, urine and CSF (cerebrospinal fluid).
Evidence shows that klotho deficiency develops in very early stages of CKD as a response to albuminuria (albumin in urine), kidney inflammation or even inflammation elsewhere in the body.
Having a reliable method of measuring klotho levels could potentially be a game changing development that allows for earlier diagnosis of kidney disease which is desperately needed because the earlier we know about a problem, the sooner we can do something about it.
(A) αKlotho was measured by the IP-IB assay in human sera from normal healthy volunteers and patients from a CKD clinic and dialysis unit using the conventional numerical staging (B) Barker et al. (2015). The demonstration of aKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrology Dialysis Transplantation, 30(2), 223-233.
The actions of klotho in the kidneys include:
- Protection of the cells in the kidney
- Reduction in oxidative stress
- Anti-fibrosis- renal fibrosis is like scarring in the kidneys which results in progressive loss of kidney function and can ultimately lead to end-stage renal failure
- Reduces inflammation
- Protection against vascular calcification and mineral bone disease (a consequence of later stages of kidney disease)
- Inhibits phosphate absorption and promotes excretion of phosphate in urine
Klotho doesn’t just play a role in kidney disease but has also been implicated as a key molecule in the development of cardiovascular disease and diabetes which we know are the two primary causes of CKD.
Clinical studies have shown that low levels of klotho correlate with both the occurrence and severity of cardiovascular disease and animal studies have shown that administration of klotho resulted in lowering blood pressure and protecting against kidney damage caused by high blood pressure.
Klotho has also been shown to improve B-cell function in the pancreas and protects against the development of type 2 diabetes.
What this means is that low levels of klotho contribute to the progression of kidney disease not only by directly effecting the kidneys themselves but also by contributing to the development of cardiovascular disease, high blood pressure and diabetes.
Considering all of the evidence around the role of klotho in numerous chronic diseases, including kidney disease, you might be asking why testing of klotho levels hasn’t been made available?
One of the reasons for this is that any sort of testing first needs to be conducted in research settings to ensure its accuracy and reproducibility and while there are numerous published research studies involving klotho expression in animals, there is still a great need for more human research.
Klotho as a potential treatment strategy for CKD
Hu, M., Kuro-o, M. & Moe, O. (2012). The emerging role of klotho in clinical nephrology. Nephrology Dialysis Transplantation, 27(7), 2650-2657.
Studies in mice have shown that restoring Klotho levels either by supplementing with exogenous klotho and/or upregulating production of the animal’s own klotho can improve kidney disease and its associated complications.
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.
Animal studies have shown that the bolus administration of Klotho protein is a safe and effective way to protect against kidney injury and preserve kidney function.
When you think about the ramifications this may have for humans with CKD, you can see why interest in this protein is growing.
Companies are currently trying to develop klotho that can be used as a drug or find ways to stimulate endogenous klotho in humans.
Factors that decrease klotho in humans:
- Chronic stress
- Oxidative stress
- Indoxyl sulfate
- Alcohol consumption
So, what does this tell us?
Well, if we know some of the things that have been shown to reduce klotho levels, this will give us some good information about what we may be able to do to increase our own endogenous klotho.
How can we do this?
There are a number of strategies we can use to manage stress levels including exercise, meditation, yoga, breathing exercises, making sure we get enough sleep and herbal and nutritional supplements just to name a few.
Inflammation and oxidative stress are implicated in the development and progression of ageing and all chronic diseases and reducing inflammation and oxidative stress in our bodies will have widespread benefits beyond just raising klotho levels.
Eating a diet rich in antioxidants and low in inflammatory foods such as sugar, refined carbohydrates, dairy, gluten, processed meat, saturated and trans fats is a must when it comes to treating kidney disease. Supplementing with anti-oxidant and anti-inflammatory herbs and nutrients is also likely to be necessary.
Indoxyl sulfate is uremic toxin produced by bacteria in the gut following breakdown of animal proteins. One way to reduce production of this toxin is to reduce the intake of animal protein and eat more vegetarian protein sources and ensure a healthy balance of bacteria in your gut through increasing dietary fibres, prebiotics and probiotics.
I think reducing alcohol consumption is pretty self-explanatory!
Can you increase your own klotho levels?
There are some drugs that have been shown to increase klotho levels although they’re not prescribed for this purpose and more research needs to be conducted in this area.
These include HMG-CoA reductase inhibitor (statin drugs) that are used to lower cholesterol, Angiotensin II receptor blockers that are used to reduce blood pressure and PPAR agonists which are used to lower triglycerides and blood sugar levels.
Even more exciting, there are some studies showing that the Chinese Medicine herb Polygonum multiflorum or Fo-ti and the mushroom Cordyceps sinensis increase klotho levels in animals.
Fo-ti for increasing klotho levels
Polyonum multiflorum (Fo-ti) is one of the most popular herbs in Chinese medicine. One of the main constituents in Fo-ti is Tetrahydroxystilbene glucoside (TSG for short!) which is a strong antioxidant and free radical scavenger.
A study in aged mice found that administration of TSG from Fo-ti for 8 weeks reversed age related decreases in klotho, increased the levels of klotho in their 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.
Cordyceps sinensis for increasing klotho levels
The mushroom Cordyceps sinensis was given to rats with high blood pressure, after treatment with Cordyceps, klotho expression was increased, and kidney damage was reduced.
Exercise increases klotho levels
A great way to increase our own klotho levels is through exercise. One study showed that doing 150 minutes of moderate aerobic exercise per week or 40-65 minutes of high intensity interval training both increased klotho levels by the same amount.
I hope this blog has taught you something about this exciting protein which may just change the way kidney disease is managed in the (hopefully not too distant!) future and given you some tips to work on increasing your own klotho levels. Now, I’d love to know what you thought of this article, give us a share or a “LIKE” on the button below if you have found this article useful and/or interesting.
Until next time, take care of yourself.