Genetics, Methylation, Renal Disease & The Kidneys

Have you noticed how complex our lives have become over the last 20 years? Everything is go, go, go. We live fast, eat fast foods, expose ourselves to electromagnetic radiation each and every day, our vaccine schedules have tripled and then some, much of our soils are depleted of important minerals… and now we have more complex and difficult diseases to treat.

I don’t believe our increased exposure to potential toxins and the increased rate of chronic and debilitating disease is a coincidence. Do you?

Increased toxins from our day to day lives increase inflammatory mediators; increase stress from our hectic modern lives, suppresses our immune function; overuse of antibiotics has increased the prevalence of superbugs.

Then you combine this with poor dietary choices, full of processed foods and genetically modified organisms and we wonder why chronic diseases are on the rise?

So what does this all have to do with our genes?

A chronic disease is a multifactorial event, chronic disease is not just caused by one thing, it is a group of driving factors, an imperfect storm of events, if you will, that have to come together to create dis-ease in the body. Without a particular combination of genetic mutations, heavy metal toxicity, chronic viral and bacterial infections, chronic inflammation and excitotoxin damage then chronic disease would not manifest. It is never just one thing, so treatment must also address ALL the underlying factors, and that might mean looking at your bodies methylation cycle.

Epigenetics might provide some answers to questions like “Why do some children have a vaccine reaction and others don’t?” What is it that underpins HOW a disease will manifest from one person to another? I believe one of the answers to this lies in our genes.

Chronic diseases require us as practitioners to treat the individual. It is rule number one in our practitioner handbook; Treat the person, not the disease, Treat the cause not the effects of a disease. So does it not make sense that individual treatment requires the acknowledgement of an individual’s genetic predispositions? Does it not take our naturopathic guiding principles to the next level; Of ultimate individualised treatment protocols?

The beauty of accounting for individual genetic variances into a treatment plan not only makes for a more specific and more treatment targeted protocol but also optimises the health potential of the individual. As we move beyond the prevailing belief that each condition has a single cause and treatment, we come to recognise that our approach needs to be as unique and individual as we are. When our illnesses were simpler, we could address a sole factor and regain health. But now that they are more complex, we need to address multiple factors, and this means looking at an individual’s genetic makeup and tailoring our treatments as such.

Keeping it simple

The world of SNPs and genetics is a complex one. The biochemical pathways that each SNP governs and how each SNP interacts with another could be a year-long diploma in its self. Plus it’s full of technical jargon that you don’t need to know about!

Before I go on let me explain what an SNP actually is.

SNPs are essentially copying errors. To make new cells, an existing cell divides in two. But first, it copies its DNA so the new cells will each have a complete set of genetic instructions. Cells sometimes make mistakes during the copying process – kind of like typos. These typos lead to variations in the DNA sequence at particular locations, called single nucleotide polymorphisms, or SNPs. 

Methylation

In my clinical practice as a naturopath, I have a heavy focus on optimising methylation. This is because methylation is key in repairing and maintaining healthy DNA. Methylation is involved in almost every reaction in your body and occurs billions of times every second in your cells. 

Methylation is a simple biochemical process – it is the transfer of four atoms – one carbon atom and three hydrogen atoms (CH3) – from one substance to another.

Defects in methylation – due to a mutation in an SNP- lay the groundwork for further assault by environmental and infectious agents, resulting in a wide range of chronic health conditions. What makes the methylation cycle so unique and so critical for our health is that SNP mutations in this pathway also have secondary effects on genetic expression.

When optimal methylation occurs, it has a significant positive impact on many biochemical reactions in the body that regulate the activity of the cardiovascular, neurological, reproductive, and detoxification systems, including those relating to:

• Repairing and building RNA and DNA
• Immune function – without proper methylation, there is increased vulnerability to viruses and chronic bacterial infections
• Digestive Issues
• DNA silencing
• Neurotransmitter balance
• Heavy Metal Detoxification
• Inflammation
• Membrane fluidity
• Energy production
• Protein activity
• Myelination
• Cancer prevention
• Diabetes prevention
• Heart disease prevention

Image from – Great Plains Lab

Why is Methylation Important?

The body is a very complex machine, with various gears and switches that need to be all functioning properly to operate optimally. Think of methylation, and the opposite action, demethylation, as the mechanism that allows the gears to turn, and turns biological switches on and off for a host of systems in the body.

How Does Methylation Happen?

CH3 is provided to the body through a universal methyl donor known as SAMe (S-adenosylmethionine). SAMe readily gives away its methyl group to other substances in the body, which enables the cardiovascular, neurological, reproductive, and detoxification systems to perform their functions.

Unfortunately, the system that produces SAMe is reliant on one switch being turned on by a critical B vitamin, 5-MTHF (also known as active folate or methylfolate).

Simply put, if enough 5-MTHF is present, the methylation cycle will work efficiently.

Folic acid from the diet or supplements must be converted to this active form, 5-MTHF, before it can be used in the body in the methylation cycle.

Unfortunately, approximately 60% of people in the United States have a genetic mutation that makes it challenging for their bodies to create enough 5-MTHF.

Repairing and Building RNA and DNA

One extremely crucial function of methylation is its role in the synthesis of DNA. DNA carries the blueprint, or genetic coding, needed to build the components of living organisms. Every time your body needs to repair the gut lining or create an immune cell to respond to an immune threat or to heal when you have cut yourself, you need to synthesise new DNA. But without a functioning methylation cycle, your DNA is not going to replicate properly.

DNA is composed of building blocks called nucleotides, chemical compounds that contain four bases—cytosine, guanine, adenine, and thymidine. Several of the enzymes involved in the creation of these bases are a part of the methylation cycle. For instance, you might have heard of the gene called methylenetetrahydrofolate reductase (commonly abbreviated as MTHFR). As you can see from the beginning of its name, MTHFR contains a methyl group. That is why a mutation in the gene responsible for making this enzyme may impair the ability to make the necessary elements for DNA.

Digestive Issues

Since immune cells reside in the digestive tract, there’s a close relationship between methylation, immunity, and such digestive problems as leaky gut, allergies, and various forms of digestive distress such as IBS. Briefly, if methylation is low and T cell production is low, then histamine levels tend to be high. Histamine is linked to inflammation, a contributing factor to leaky gut as well as allergies and other chronic diseases.

With the under activity of T cells, B cell activity can take over, which can lead to autoimmune issues like allergies and food sensitivities. This is why gluten and dairy-free diets are so important in chronic health conditions, as we need to lower the immunogenic load on the body to optimise methylation function and DNA repair.

Inflammation

Inflammation has been implicated in a host of health conditions, and we often speak about it here at the kidney coach. There is a reciprocal relationship between methylation and inflammation, almost as if they were on a seesaw:

Increased inflammation will tend to decrease methylation and vice versa.

IL6 and TNF alpha are two bodily biochemicals that lead to inflammation. They frequently arise in response to stress. Higher levels of these inflammatory chemicals exacerbate low methylation status.

Energy Production

All cells need to produce energy to survive, and they produce it via a process called the Krebs cycle, also known as the citric acid cycle. This metabolic pathway produces the energy “currency” of the body, known as ATP. The Krebs cycle takes place within the cell’s mitochondria. The Krebs cycle is closely connected to the methylation cycle, and any impairment of one impacts the other. Essential to the action of the mitochondria are carnitine and CoQ10, both of which are dependent on the methylation pathway.

Methylation and Kidney Function

Now the bit that you are wondering about. Does methylation affect or contribute to a loss of kidney function and kidney disease? The short answer is yes.

The long answer…

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397141/

The table above shows all the ways in which changes to a healthy functioning methylation cycle can alter healthy kidney function and tissue repair. For example, we know that higher levels of homocysteine, a by-product of the methylation process of converting folic acid to its active form of 5 methyltetrahydrofolic acid increase the risk of cardiovascular disease, a disease often associated with a decline in kidney function.

Cardiovascular Disease

To understand why methylation plays such a key role in heart disease we first need to quickly cover what Homocysteine is. Homocysteine is a common amino acid found in your blood. The Methylation cycle is responsible for turning homocysteine into other amino acids for use by the body. B Vitamins play a pivotal role in helping your body to properly use homocysteine. Most people who have high homocysteine levels don’t get enough folate, vitamin B6, or vitamin B12 in their diet. Replacing these vitamins often helps return the homocysteine level to normal. 

Other possible causes of a high homocysteine level include:

• Low levels of thyroid hormone.
• Kidney disease.
• Psoriasis.
• Some medicines.
• When the condition is common in your family.

High levels of homocysteine are a major risk factor for heart disease. There does appear to be a relationship between high levels of homocysteine and artery damage, which may then lead to atherosclerosis and an increased risk of blood clots. 

If the methylation cycle is impaired via either environmental or genetic tendencies then the risk of cardiovascular disease may be increased. 

https://jamanetwork.com/journals/jamacardiology/article-abstract/2782550

https://cdnsciencepub.com/doi/10.1139/bcb-2019-0045

https://www.nature.com/articles/s41374-018-0104-x

Diabetic Kidney Disease

Diabetic kidney disease has multiple manifestations, such as structure changes, glomerulosclerosis and tubulointerstitial fibrosis, in addition to functional changes of albuminuria and kidney function (eGFR) changes. A study conducted in 2019 found that improper methylation significantly correlated with the degree of interstitial fibrosis, or the hardening of the tissue within the kidneys leading to a decline in kidney function. 

Another study published in the British Medical Journal found that patients with diabetic kidney disease with continual loss in kidney function may be caused by a specific DNA methylation change.

https://www.nature.com/articles/s41467-019-10378-8

https://drc.bmj.com/content/8/1/e001501

Klotho and Methylation

Proper methylation function is required for healthy Klotho levels and klotho expression. Klotho is fast becoming a major marker for kidney health and aging. Klotho expression is down-regulated in the renal tissues of chronic kidney disease animal models and patients with end-stage renal disease. The suppression of Klotho is associated with DNA hypermethylation and alterations to the methylation process.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397141/

DNA Methylation and Repair

DNA damage is caused by various stresses, including exogenous stress, such as UV radiation and chemicals, and endogenous stress, such as reactive oxygen species, DNA replication errors, spontaneous reactions, and mechanical stress. Chronic stimulation by these stresses induces DNA damage, which is linked to aging and various diseases.

Good functioning methylation is required to repair DNA, as I mentioned previously. Issues with the methylation pathway mean that DNA repair can be inhibited leading to further tissue damage in the kidneys, accelerating the progression of kidney disease and associated conditions.

https://www.karger.com/Article/FullText/501356

How to Improve Methylation

First, you can have a simple and easy genetic test to find out if you have a problem with your methylation cycle. This test looks at specific enzymes that are affected by your genetic makeup, including the enzyme MTHFR (methylenetetrahydrofolate reductase), which is the most important enzyme involved in creating 5-MTHF.

In addition to a healthy, whole-food, non-processed food diet which we recommend anyway if you have chronic kidney disease, make sure you are eating a lot of these foods:

• Asparagus
• Avocado (avoid if potassium levels are an issue)
• Broccoli
• Brussels sprouts
• Green, leafy vegetables
• Legumes (peas, beans, lentils)
• Rice

As well as dietary changes, basic lifestyle changes can also enhance the way in which your bodies methylation cycle works. The following is just a few ways in which you can make sure you are optimising your methylation cycle: 

• Engage in regular physical exercise
• Avoid excessive alcohol consumption
• Don’t smoke
• Avoid excessive coffee consumption (not more than two cups daily)
• Get enough quality sleep

Nutrients to Promote Healthy Methylation

There are many key nutrients that can help the methylation cycle work optimally, even if you have genetic mutations pertaining to the methylation cycle, these nutrients are still very useful. 

5-MTHF (Active Folate) 

Many individuals don’t get sufficient 5-MTHF (L-5-Methyltetrahydrofolate), the active form of folic acid, because they have intestinal or liver dysfunction, or because they are among the three out of five Americans whose genetic makeup makes it difficult to convert folic acid into active 5-MTHF. Folate deficiency has been implicated as a contributory factor in renal anaemia and hyporesponsiveness to rHuEPO treatment. Hyperhomocysteinemia (Hhcy) occurs in about 85% of chronic kidney disease patients because of impaired renal metabolism and reduced renal excretion. Folic acid, the synthetic form of vitamin B9, is critical in the conversion of homocysteine to methionine. If there is not enough intake of active folate, there is not enough conversion, and homocysteine levels are raised. Homocysteine is regarded as an independent predictor of cardiovascular morbidity and mortality in end-stage renal disease.

Since 5-MTHF also contributes to the production of serotonin, melatonin, dopamine, epinephrine, and norepinephrine, supplementation might also support a healthy mood.

Methylcobalamin – Vitamin B12

Many vitamin B12 supplements contain cyanocobalamin as the active ingredient, which the liver must first “detoxify” and modify to form methylcobalamin – an active form of vitamin B12 that is essential for processes involved in cardiac function, sleep, blood cell formation, and nerve function.

Methylcobalamin helps maintain normal circadian rhythms to promote normal sleep and supports healthy methylation processes in the body. Methylcobalamin is essential for the body to recycle homocysteine and to form the internal methyl donors involved in cardiovascular function, sleep, blood cell formation, and nerve function. Most vitamin B12 supplements contain cyanocobalamin; however, the liver must first “detoxify” the cyanide molecule in cyanocobalamin and then attach a methyl group to form methylcobalamin. Thus taking the active form in people suffering from chronic disease such as kidney disease is preferred, to bypass this step.

Pyridoxal 5′-Phosphate – Active B6

Vitamin B6 is necessary for the body’s transformation and utilization of amino acids in many functions in the body, including energy production, synthesizing important neurotransmitters, and metabolizing hormones. Pyridoxal 5′-phosphate (P5P) is also necessary for homocysteine recycling because it facilitates the break-down of homocysteine to taurine and cysteine. P5P is also involved in the body’s production of hemoglobin and intrinsic factor and is vital to the formation of the myelin sheath that surrounds nerve cells.

Supplementing with active B6 has also been shown to reduce the symptoms of peripheral polyneuropathy, often seen as a side effect in those on hemodialysis. 

https://pubmed.ncbi.nlm.nih.gov/10978399/

Riboflavin – Vitamin B2

Riboflavin, also known as vitamin B2, is necessary for the body to be able to activate vitamin B6. Riboflavin is also necessary for the body’s conversion of tryptophan to niacin and the conversion of folate to folate’s various active forms. In addition, riboflavin plays a crucial role in the metabolism of fats and glucose, the synthesis of red blood cells, healthy methylation, and the production and regulation of certain hormones.

To be utilized by the body, however, riboflavin must first be converted to its active form – riboflavin 5′-phosphate (R5P). A compromised digestive system, however, can adversely affect the body’s ability to convert riboflavin to R5P, and certain prescription medications can also compromise the absorption of riboflavin, putting it in a state of deficiency. 

Studies show that those with advanced kidney disease are often deficient in Vitamin B2 and that supplementation might be useful in slowing the progression of the disease and stopping deficiencies.

https://pubmed.ncbi.nlm.nih.gov/4096835/

Vitamin D

The prevalence of vitamin D deficiency increases with the progression of CKD and approaches 90% in people with stage 5 CKD. 

The other main factor linked to lower vitamin D levels in people with kidney disease has to do with a reduction in kidney function. Because the final stage of converting vitamin D into the active form (calcitriol) happens in the kidneys, as kidney function declines there is also a progressive decline in the activity of 1-alpha hydroxylase, the enzyme needed to convert vitamin D into its active form. 

Low levels of vitamin D in people with kidney disease have been associated with:

• Secondary hyperparathyroidism
• Low bone mineral density
• Low calcium levels
• Muscle weakness and risk of falls
• Metabolic syndrome, insulin resistance and obesity
• Enlargement of the left ventricle in the heart 
• Hardening of blood vessels
• Cognitive impairment
• Higher levels of protein in the urine
• Progression of kidney disease
• Higher mortality risk

When it comes to Methylation several studies have suggested that Vitamin D interplays with the methylation cycle and that a vitamin D deficiency has a negative impact on healthy methylation pathways

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010791/

You can read more about the role of vitamin D in kidney disease in a previous article we wrote – https://www.kidneycoach.com/anatomy-physiology/the-role-of-vitamin-d-in-kidney-disease/

Proper methylation influences so many systems in our bodies and it often gets overlooked, which can severely impact how well your body functions. Ask your healthcare practitioner for advice if you have any concerns about your methylation cycle, especially if you have kidney disease.

Final notes

I want to finish this somewhat technical article by letting you understand that while your genetics might seem like something that is hardwired and cannot be changed, that is not actually true. Science is beginning to understand that while genes might seem hardwired into us, it is the environment that signals gene expression, hence the expression epigenetics. That means that what you eat, how you move and even how you think all have the power to alter the way in which your genes function and code in the body. There are only a few genetic mutations that 100% lead to specific genetic diseases, they are in the minority of what causes disease, diet and lifestyle are far more important factors in the development of disease and something we all have control over

I will leave you with a great quote from Mehmet Oz

“Your genes load the gun; your lifestyle pulls the trigger”

So don’t underestimate the power of your dietary and lifestyle choices.

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