Colchicine for CKD!
In a multi-center, nested, case-control study in three Korean hospitals, patients with CKD stage 3 and 4 who are using drugs including colchicine, allopurinol, and febuxostat for high uric acid or chronic gout were studied over a period of 10 years. The progression of CKD was compared between 3085 compared to 11715 control patients.
Colchicine use was associated with a lower risk of adverse kidney outcomes in CKD patients with hyperuricemia, or chronic gout.
Unlike a study published two years ago in NEJM which excluded patients with advanced CKD, this study included patients with kidney function as low as 15 ml/min. Colchicine is known to anti-inflammatory. It also protects against kidney fibrosis.
There are concerns about myopathy and neuropathy with the intake of colchicine. It is, therefore, important to adjust the dose with advanced kidney disease and to be cautious when using it with patients who are on other myopathy-inducing drugs such as statin drugs.
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Long sleep duration is associated with decline in kidney function
This study is retrospective, longitudinal cohort study included 82,001 participants who visited a primary care center in Japan. Patients were categorized into CKD risk groups and sleep duration categories according to their self-reported average nightly sleep duration. The relationship between average nightly sleep duration and the incidence of composite renal outcome was studied.
Researchers found that an average sleep durations ≥8 h/night were associated with an increased risk of kidney function decline over time.
There are many reasons that connect sleep problems with poor kidney function. We summarized these in this blog.
Risk of environmental heavy metal toxicity is higher in CKD
In a study of 5,638 NHANES participants, lead and cadmium levels were higher in patients with CKD than those without it. This was also associated with decreased urinary lead excretion. Each decrease in estimated GFR by 10 ml/min/1.73m2 was associated with 0.05 mcg/dL increase in lead levels and 0.02 mcg/dL of cadmium levels. This association was even stronger among black participants.
The study concluded that CKD increases the susceptibility to heavy metal environmental exposure by reducing its elimination.
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Breakfast Chia Apple Oatmeal
By Majd Isreb, MD, FACP, FASN, IFMCP
This is one of my favorite breakfast recipes. It is a healthy plant-based breakfast with 7 g protein and 10 g of fiber to start you day right.
Ingredients
Direction
- Boil 1 cup of water then add oats, chia seeds and chopped apple.
- Cook for 5 minutes, stirring over medium heat.
- Sprinkle cinnamon and nutmeg.
- Add raw stevia to taste
- Add 4 oz of almond milk if desired.
- Garnish with chopped apples and blueberries (optional)
Enjoy
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Root Causes of Itching in Kidney Disease
Uremic toxin-induced neurologic changes
Several studies showed that patients with CKD have an imbalance of opioid receptors in the central and peripheral nervous system. Interestingly, itching in CKD correlates better with the level of uremic toxins than with glomerular filtration rate (GFR, a measurement of how well the kidneys are working). These toxins play an important role in these neurologic changes that are common in CKD. Most of these toxins are generated by the gut microbiome and are excreted by the renal tubules and not by glomerular filtration (or GFR). Measuring these toxins can be helpful. This can be done by a metabolomic test such as Genova’s Metabolomix+.
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Inflammation
CKD is an inflammatory disorder. Elevated inflammatory markers have been found to be associated with itching in kidney disease. Measuring inflammatory markers such as hsCRP, Th-1 cells, and IL-6 can be helpful in the assessment of the root cause of itching in CKD.
Dehydration
Dehydration can also lead to dry skin and worsens itching in CKD patients. Correcting the dehydration can be important in the management of itching.
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Drug-induced itching
Many medications that are used in CKD have been associated with itching. These include calcium channel blockers, hydrochlorothiazide, and ACE inhibitors. In addition, other medications such as opioids, anticoagulants, and antibiotics can cause itching.
The itch-scratch-itch cycle
One of the major problems with itching is that it leads to scratching, and this can cause skin damage. The latter can cause further itching and the cycle continues.
Natural Treatments for itching in kidney disease
There are many steps you can take to get rid of itching in kidney disease and a kidney disease rash. The first step is to visit a healthcare provider to help you determine the root cause. You can download this two-page handout to guide you in the natural treatment of itching. There is hope that you’ll relieve this frustrating problem and have comfortable skin once again.
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Air pollution is linked to kidney disease
PM 2.5 refers to particulate matters that are up to 2.5 microns in size. Because of their small size, they are considered to be the worst of all air pollutants. They reach the alveoli and enter the blood stream. This study looked at the link between PM 2.5 and chronic kidney disease (CKD) in the Twin-cities area of Minnesota. Researchers found that the risk of CKD increases with higher levels of PM 2.5. This remained true after adjusting to all other variable.
It is, therefore, important to think of air pollution as a mediator of CKD and minimize exposure to it.
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A Study reaffirms the role of the gut kidney connection in diabetic kidney disease
You know we discussed the role of the gut-kidney connection in the progression of CKD. You can find many of our blogs discussing this here. Dysbiosis can be a predisposing factor or a mediator when it comes to kidney disease. This study looked at the contribution of impairment in the intestinal barrier (leaky gut) to kidney injury in diabetic kidney disease (DKD). In diabetic mice with impaired intestinal integrity intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation. This was associated with epithelial renal tubular injury and faster progression to kidney failure as compared to control.
So, always think about the gut when it comes to kidney disease. A personalized comprehensive gut restoration protocol is a must to heal the gut.
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A gut-derived uremic toxin is associated with inflammation
Speaking of the gut, we discussed monocyte to HDL ration (MHR) in a previous email. If you missed it, you can read about it on our Instagram page. This study looked at the connection between Indole-3-acetic acid which is a gut-derived uremic toxin and MHR in patients with kidney disease. The study was conducted on 67 patients with CKD. Researchers found that Indole-3-acetic acid levels are directly related to MHR levels. The latter was associated with higher levels of fibrinogen, arterial hypertension, CRP.
So, as they say, when in doubt think about the gut.
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Cold exposure
Cold exposure, such as cold showers, has many benefits for kidney patients. It increases endorphins and fights off depression. It improves metabolism and circulation. Most importantly, it stimulates the vagus nerve and improves renal circulation. It may also soothe itchy skin which is common in CKD patients. In addition, cold showers help with post-workout muscle soreness.
The benefits of a cold shower begin when the water temperature dips to 60 degrees Fahrenheit. This is 40 degrees lower than the typical steamy shower. To take a cold shower, start with your usual hot shower, then turn the knob to cold at the end of your shower. Lower the temperature gradually at the end of your shower every day. The benefits start with thirty seconds under the cold water. Maximum benefits are reached in three minutes.
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Vagus nerve breathing exercises
Deep and slow breathing can activate the parasympathetic system. In fact, deep breathing is one of the best ways to lower stress in the body. It sends messages to the brain to calm down and relax by activating the vagus nerve which helps lower heart rate and blood pressure. There are various ways to perform deep breathing. Here, I will discuss the 4-7-8 breathing technique.
This technique uses belly breathing. It can be performed sitting or lying down as follows:
- Start by putting one hand on the belly and the other one on the chest.
- Take a deep slow breath from the belly while silently counting to 4. The chest should not move.
- Hold the breath while silently counting to 7.
- Breathe out completely while silently counting to 8.
- The process can be repeated 5 to 10 times until feeling relaxed.
Singing, humming, chanting, and gargling
These activities have also been shown to improve heart rate variability and can also activate the vagus nerve because it is connected to the vocal cords. These benefits can be achieved by 10 minutes of singing, humming, chanting, or gargling every day.
Probiotics
The fact that probiotics have been found to support stimulation of the vagus nerve is another piece of evidence for the importance of the gut-brain axis. Healthy microbiota produce short-chain fatty acids, such as butyric acid, which can activate the vagus nerve and send messages from the gut to the brain. It is highly beneficial to get most probiotics through diet. However, if supplements are used, it is recommended to use good quality broad-spectrum probiotics.
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Meditation
Meditation has been found to increase vagal tone and positive emotions. Meditation for 10-15 minutes is a great way to start the day, manage stress, and stimulate the vagus nerve. There are many ways to meditate and many types of meditations. Mindfulness meditation is the most tested in kidney patients. It has been demonstrated to improve the quality of life, reduce anxiety and depression, reduce sympathetic overactivity,improve sleep, and improve blood pressure.
To practice mindfulness meditation such as Benson’s relaxation technique, follow these steps:
- Sit in a comfortable position or on a meditation cushion.
- Close your eyes.
- Relax your shoulders and muscles.
- Focus on breathing.
- Say a word with every exhalation. A positive word like “gratitude” can be used. As the mind starts racing, which distracts from the breath, the person returns to the word.
Practicing this every day will improve the experience and compound the benefits with consistency.
Omega-3 fatty acids
Among the many benefits of omega-3 fatty acids are increased vagal activity. The best way to reap the benefits of omega-3 fatty acids is by eating fatty fish twice per week, but if that is not an option due to protein restrictions or dietary choices, supplementation is an option. Other food sources include nuts and seeds such as walnuts and flaxseed. It is important that the supplement contains enough eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are the most powerful omega-3 fatty acids. The dose is at least 500-1,000 mg of EPA-DHA three times a day.
Exercise
One of the best vagal tone exercises is exercise itself. Exercise is linked to better mental health and stimulation of the vagus nerve. It may be one of the most underutilized yet effective interventions for the prevention and treatment of kidney disease. It has been shown to reduce the risk of CKD, help with blood pressure and glucose control, and improve health-related quality of life. Exercise also induces a positive influence on mental health, mood, and stress levels by stimulating the vagus nerve.
The best type of exercise is the one that you do. What I mean by that is don’t get discouraged by trying to find the perfect type of exercise and do anything that works best for you. Having said that, studies on exercise in CKD have included resistance training and aerobic activities that use large muscle groups continuously such as walking, cycling, and jogging.
High-intensity interval training (HIIT) offers superior benefits in individuals with metabolic diseases such as diabetic kidney disease. Studies of HIIT in CKD have shown that it is a safe and feasible option for individuals with CKD.
Those who are new to exercising should start slowly and gradually get to 20-30 minutes of strenuous exercises 5-6 days a week. It is best to alternate between aerobic exercises and resistance training. For those who are 50 years of age or older, it is important to check with your provider before engaging in strenuous exercises.
Massage therapy
Massage therapy has also been found to be associated with improved vagal tone. The stimulation of pressure receptors leads to an increased vagal activity which, in turn, seems to mediate the diverse benefits of massage therapy. Functional magnetic resonance imaging data suggested that moderate pressure massage was represented in the part of the brain involved in stress and emotion regulation.
Socializing and laughing
Finally, increased social connection and laughing have been linked to increased positive emotions. Increased
positive emotions, in turn, produced increases in vagal tone, which puts the body in a rest and repair state.
The bottom line
Stimulating the vagus nerve can turn on the parasympathetic nervous system, improve renal blood flow, and modulate inflammation in CKD. Improve kidney health using these natural techniques to turn on the vagus nerve and turn off stress: a cold shower, breathing exercises or meditation, singing or humming, probiotics, omega-3 fatty acids, exercise, massage, and social connection. Check out my 1-hour morning routine for kidney health that incorporates many of these techniques.
The post Nine Ways to Naturally Stimulate the Vagus Nerve, Lower Stress, and Promote Kidney Health appeared first on Integrative Kidney.]]>This routine should take no longer than an hour. Your kidneys and health deserve an hour from you every morning. I understand many of us have hectic lives, but if you are busy, try to go to bed early and wake up one hour earlier the next morning. Trust me, it is worth it. An hour morning routine beats dialysis any time. This could be the first step in how to heal your kidneys naturally.
Start with water
At night the body loses a lot of water due to sweat and breathing. In fact, in a small study presented at an Associated Professional Sleep Societies meeting in 2009, healthy young men were found to lose ¼ lbs. per hour while asleep. That is about 2 lbs. in eight hours of sleep.
This is why you should start your day with water. The rest of the routine can be done according to your judgment and comfort. Start with drinking two glasses of filtered water if you are not on any water restrictions. This is even more important for patients with polycystic kidney disease and kidney stones. If you are wondering how much water to drink in PKD, check out our calculator here.
Exercise
Exercise for about 20 minutes. The type and duration of exercise depend on an individual’s level of functioning, endurance, and preference. Studies on exercise in chronic kidney disease (CKD) have included resistance training and aerobic activities that use large muscle groups continuously such as walking, cycling, and jogging.
High-intensity interval training (HIIT) was shown to offer superior benefits in individuals with metabolic disease. In the few studies of HIIT in CKD, it was found to be a safe and feasible option for individuals with CKD.
If you are new to exercising, start slow and try to gradually get to 20 minutes of strenuous exercise five to six days a week. It is best to alternate between aerobic exercise and resistance training. If you absolutely can’t fit exercise into your morning routine, you can move it to whatever time that works for you. The benefits are all the same. Consistency is the key here.
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Meditation
Meditate for at least 10 minutes. Meditation is a great way to start your day, manage stress, and stimulate your vagus nerve, which connects the brain with many vital organs including the kidneys. There are many ways to meditate and many types of meditations. Mindfulness meditation is the most tested in kidney patients. It has been shown to improve the quality of life, reduce anxiety and depression, reduce sympathetic overactivity, improve sleep, and improve blood pressure.
To practice mindfulness meditation such as Benson’s relaxation technique, sit in a comfortable position or on a meditation cushion, close your eyes, relax your shoulders and muscles, and focus on your breathing. Say a word with every exhalation. Pick a positive word like “gratitude.” As your mind starts racing to distract you from your breath, try to return to the word you chose. Practicing this every day will make you better at it, and you will be able to reap all the benefits with consistency.
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Journaling
Journaling is a great way to write your thoughts and plan your day. It has similar benefits to meditation. In fact, journaling was found to reduce stress and depression, boost the immune system, and improve memory among many other benefits. You can write whatever comes to mind. Think of it as a thought download. This should also not take more than 10 minutes.
Meditation and journaling can also be moved to a different time of the day for busy individuals with similar benefits. If you are very busy, consider meditation in the morning and journaling in the evening.
Cold shower
Taking a cold shower has many benefits for kidney patients. It increases endorphins and fights off depression, and it improves metabolism and circulation. Most importantly, it stimulates the vagus nerve and improves renal circulation. It may also soothe itchy skin, which is common in CKD patients. Cold showers help with post-workout muscle soreness. The benefits of a cold shower begin when the water temperature dips to 60 degrees Fahrenheit. This is 40 degrees lower than the typical steamy shower.
Now, I know it will be hard to turn that shower knob from hot to cold in the morning. The way to do it is to start with your hot shower. Then gradually lower the temperature at the end of the shower every day by turning the knob to cold. Give your body time to adjust. You can start with 30 seconds under the cold and gradually increase it to a maximum of three minutes. A quick shower for kidney health takes 10 minutes.
Plant-based breakfast
A good plant-based breakfast can be a super healthy way to start your day. A plant-based or plant-dominant diet has been linked to better kidney health and to slow the progression of kidney disease. There are many options that you can prepare in less than 10 minutes or plan the day before. You can find a few recipes in this e-book.
The bottom line
Your kidneys and health deserve an hour from you every morning. This morning routine can improve kidney health and help slow the progression of early kidney disease. If you’re wondering how to heal kidneys, this routine could serve as the first step, or it could be all you need for heathier kidneys. You can modify it to fit your schedule so that you’re at least doing some of the suggested morning actions every day. If you’ve been wondering how to improve kidney function, this morning routine is an important step in the right direction.
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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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Lifestyle modifications do indeed prevent CKD and delay its progression
This study is coming from Japan. Researchers found that two years of healthy lifestyle choices prevent against the development of kidney disease and protein in the urine. Lifestyle modifications also slowed the decline in kidney function.
They studied 451,534 people (277,494 men and 174,040 women) aged 20–79 years. Healthy lifestyle choices in this study were defined as: 1. No smoking 2. Healthy eating habits, and 3. Low BMI
Now, we all know that there is more to lifestyle modifications than this but this is definitely a start.
Is Urea by itself toxic?
The authors in this study published in NDT definitely think so. They noted that the accumulation of uremic toxins is a risk factor for mortality and accelerated atherogenesis in patients with CKD. The researchers found that a post-translational protein modification called carbamylation is a predictor of CKD progression. They also noted that urea by itself promotes the carbamylation of proteins.
So urea is not just a benign marker and should be classified as a uremic toxin. The level of protein carbamylation may be used as a marker for risk stratification of CKD outcomes.
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Magnesium, bones, and kidneys… What?!
This study is coming from the dialysis world. It’s a meta-analysis that examined the effects of magnesium supplementation on chronic kidney disease mineral bone disease (CKD-MBD). As the researchers mentioned, magnesium supplementation in dialysis patients is controversial. However, this study showed that it helps by regulating calcium and parathyroid hormone and it decreases carotid intima-media thickness.
This is in the dialysis population. So paying attention to magnesium balance and supplementation may have a much better role in bone and vascular health in earlier stages of CKD. Optimizing vitamin D, vitamin K2, vitamin A, calcium, phosphorus , and magnesium is very important to improve bone and vascular health in CKD patients.
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By Megan Morrison, PharmD
Yoga and meditation are both considered mind-body interventions which the National Center for Complementary and Integrative Health defines as “a range of procedures or techniques focusing primarily on the connections between the mind, body and behavior and their resultant effects on one’s health”.
Yoga, which is said to have originated in India more than 5,000 years ago, literally means “union” and is a practice that aims to balance and harmonize the mind, body, and emotions. Various styles of yoga include regulated breathing techniques (pranayama), physical postures (asanas), hand gestures (mudras), yogic relaxation (yoga nidra), and more. Meditation encompasses several techniques that are used to influence the mind through mechanisms in the parasympathetic nervous system to bring about calm and relaxation.
Both yoga and meditation have been documented to have measurable positive impact on various chronic conditions, including type 2 diabetes and hypertension, two disease states that are major risk factors for the development of kidney disease. We’ll look at the research supporting the benefits of both for kidney health.
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Benefits of Yoga for Kidney Health
One study looked at the effects of a 6-month yoga program on renal function and quality of life in patients with chronic kidney disease. After 6 months, the yoga group saw a significant reduction in systolic and diastolic blood pressure, blood urea and serum creatinine levels, and significant improvement in quality of life. Furthermore, subjects in the yoga group had reduced need for dialysis than the control group although not statistically significant.
Another study looked at the effects of a 12-week yoga-based exercise program in hemodialysis patients. Significant improvements were seen for many of the variables measured including pain, fatigue, sleep disturbance, along with significant reductions in creatinine, blood urea, alkaline phosphatase, cholesterol, erythrocyte and hematocrit count.
Although the exact mechanism for many of the benefits of yoga have not been completely understood, they include:
- Improved blood pressure control
- Improved glycemic control
- More regulated eating patterns
- Improvement in markers for kidney function
- Significant reduction of the waste products associated with kidney damage, urea and serum creatinine
- Improved physical and psychological quality of life for kidney patients on dialysis
- Improved blood supply to muscles and increased muscle activity, strength, endurance, flexibility, and balance
- Favorable effects on body weight, adiposity, dyslipidemia, and insulin resistance
- Significant reduction in oxidative stress and increased antioxidant activity
- Improved parasympathetic tone, helping offset fight-or-flight response often associated with chronic disease
- Reduced need for dialysis
Benefits of Meditation for Kidney Health
In a study of 15 African American males with CKD and high blood pressure, there was a significantly greater reduction in systolic and diastolic blood pressures, mean arterial pressure, heart rate, and muscle sympathetic nerve activity during mindfulness meditation compared with the control.
Those with end-stage renal disease as well as mild CKD have been shown in multiple studies to have chronic activation and elevation of the sympathetic nervous system (SNS). Therefore, using a non-invasive, safe therapeutic intervention such as meditation to lower SNS activity in those with renal disease may mitigate long-term consequences.
One type of mindfulness meditation technique studied in kidney patients is called Benson’s relaxation technique which consists of “eye closing, muscle relaxation, breathing awareness, breathing out stating a word, and returning to the “word” when participants’ thoughts are distracted”. This technique has been shown to reduce levels of anxiety, depression, and improve sleep quality as well as improve quality of life in patients undergoing hemodialysis.
Benefits of meditation for those with kidney disease include:
- Improved quality of life for hemodialysis patients
- Reduced anxiety and depression
- Reduced sympathetic overactivity
- Better sleep
- Reduced blood pressure
- Less prone to various forms of stress
The Bottom Line
Research has demonstrated that yoga and meditation greatly improve measurable health outcomes and quality of life in those with kidney disease or those looking to protect their kidney health. Both modalities are generally safe for most people, but it’s best to consult your physician before initiating any exercise program including a yoga routine. When working with a clinician trained in Integrative or Functional Medicine, they will often suggest incorporating some type of mind-body intervention as part of your holistic therapeutic plan.
The post Yoga and Meditation for Kidney Health appeared first on Integrative Kidney.]]>Recently, there has been a growing interest in the gut-kidney axis, which refers to the overlapping relationship between gut integrity, microbiome diversity, resulting inflammatory process and kidney disease. The interaction between the gut and kidneys is very complex and can be divided into two major categories: the gut-derived uremic toxins that can worsen kidney disease, and the inflammatory autoimmune response that can trigger kidney disease. In this blog, we will focus on the gut-derived uremic toxins.
Uremic Retention Molecules (URMs)
Uremic toxins, accumulated waste products due to decreased renal clearance, have been linked to systemic inflammation. Recently, researchers have been successful at identifying many of these molecules thanks to a technique called metabolomic analysis. In general, URMs are divided into three categories:
- Small water-soluble molecules
- Middle size molecules
- Protein-bound uremic molecules
However, for our purpose, it is more helpful to divide these toxins according to their origin:
- Endogenous uremic toxins: toxins or waste that naturally and normally occur during metabolism or catabolism
- Exogenous uremic toxins: related to dietary intake
- Gut-derived uremic toxins: generated by pathogenic gut microbiota in the presence of dysbiosis
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Gut-derived uremic toxins
The human gut contains trillions of microorganisms, collectively referred to as the gut microbiota or microbiome . The composition of the gut microbiome varies from person to person due to genetics, environmental factors, dietary, and disease state. These microorganisms are in constant communication with the body. They also produce multiple metabolites, nutrients, and cell signals for various physiological functions. [read more about the microbiome here]
Dysbiosis describes a state where “bad” bacteria (or other organisms like yeast or parasites) outgrow the “good” bacteria. In dysbiosis, we see a rise in inflammatory markers that interact with the lining of the gut and result in damage and increased intestinal permeability (“leaky gut”). This causes shifts in the breakdown of nutrients, including amino acids, which leads to the formation of many gut-derived uremic toxins.
Thanks to recent advances in metabolomic analysis, researchers have identified more than 60 uremic toxins that are derived from the gut. A number of studies have demonstrated that URMs are associated with high cardiovascular burden and mortality in CKD. There are four major gut-derived uremic toxins associated with CKD: Indoxyl sulfate (IS), para-Cresyl sulfate (pCS), Trimethylamine-N-oxide (TMAO), and Indole acetic acid (IAA).
Indoxyl sulfate (IS)
IS is a protein-bound uremic toxin. Gut microbiota produce indole from the breakdown of dietary tryptophan, which is then further metabolized to IS in the liver. The majority of IS circulates bound to albumin in the blood. It is excreted by the kidney tubules through organic anion transporters.
IS is one of the most studied uremic toxins. It has been associated with vascular calcifications and increased risk of death from heart disease in patients with advanced kidney disease. Higher levels of circulating IS have also been associated with faster progression of CKD.
para-Cresyl sulfate (pCS)
This is another protein-bound uremic toxin that is produced by the metabolism of amino acids tyrosine and phenylalanine by intestinal bacteria. This leads to the formation of p-cresol which is metabolized in the liver to pCS. pCS also circulates in the blood bound to albumin and is excreted by the kidneys in the same mechanism as IS.
Serum pCS levels increase with worsening kidney function. Similarly to IS, pCS was also found to predict the progression of kidney disease and is associated with an increased risk of death from heart disease in kidney disease patients.
Trimethylamine-N-oxide (TMAO)
TMAO is one of the small water-soluble URMs. It is produced by the metabolism of dietary L-carnitine and choline. The latter two compounds are metabolized into trimethylamine by gut bacteria, which is then absorbed by the gut and oxidized in the liver to form TMAO. The kidneys are the primary source for eliminating TMAO from the body. Dysbiosis and decreased kidney function have been documented to lead to elevated levels of TMAO.
TMAO levels increase with worsening kidney function and are associated with increased progression of kidney disease, increased risk of heart disease and all-cause mortality in kidney patients.
The L-carnitine controversy
L-carnitine is a relatively small water-soluble compound that is found abundantly in food sources including in red meat, dairy, poultry, and fish. Lysine, methionine, ascorbate, niacin, pyridoxine, and iron are among the major sources of endogenous carnitine production.
There is evidence that patients with kidney disease are deficient in L-carnitine and that supplementation leads to improved outcomes. However, there’s seemingly contradictory evidence that, the metabolism of L-carnitine by gut bacteria leads to the production of TMAO which, as described above, is associated with increased mortality in kidney patients.
One explanation for this discrepancy is that research on L-carnitine often fails to distinguish CKD patients who are not on dialysis with those on dialysis. In fact, one study showed L-carnitine levels are actually high in patients with CKD but are low in dialysis patients. Another reason for the confusion is that most research on L-carnitine supplementation uses intravenous L-carnitine which bypasses the gut microbiota and liver and, therefore, may not lead to the production of TMAO. Another important consideration is the composition of the microbiome and intestinal integrity of the gut. Those with certain dysbiotic markers might be at higher risk for producing TMAO and failing to break it down sufficiently, leading increased kidney injury.
The literature seems to support the need for restricting oral intake of dietary or supplement sources of L-carnitine in patients with kidney disease who are not on dialysis. This might also explain why CKD patients benefit from diets that are dairy-free and low in red meat.
Indole acetic acid (IAA)
IAA is yet another protein-bound uremic toxin that results from the metabolism of tryptophan by gut bacteria. Levels of IAA are proportional with CKD stage progression and normalize after kidney transplantation. IAA is linked to vascular inflammation and oxidative stress and has been associated with mortality and increased risk of death from heart disease in patients with CKD.
The role of diet
Dietary habits play an important role in gut microbiota composition. Diets high in animal protein are associated with increased dysbiosis and intestinal hyperpermeability and also contain a higher amount of amino acids precursors of uremic toxins. Meanwhile, whole-food and fiber-dense plant-based diets are associated with the growth of healthy gut microbiota, leading to decreased inflammation and better intestinal integrity.
Levels of protein intake have been studied in relation to CKD. Interestingly, it is not the amount but the type of protein that is associated with kidney disease. In fact, a large study of 12,000 adults with normal kidney function found no significant association between total protein intake and the incidence of CKD. The same study found that individuals consuming more red and processed meat were at higher risk for CKDcompared to those consuming more vegetable protein. Red meat intake has also been reported to increase the risk of worsening kidney function requiring dialysis.
There are various additional factors that should be considered as well, including consumption of processed carbohydrates, simple sugars, and reduced consumption of whole fruits, vegetables, and other fiber sources like whole grains. These nutrient-poor dietary habits can lead to dysbiosis which in turn produce inflammatory molecules that can lead to kidney disease. This can cause further accumulation of inflammatory uremic toxins.
Furthermore, the worsening of kidney function and accumulation of URMs can lead to further dysbiosis,and so on the cycle repeats. This is what we describe as the dysbiosis cycle in kidney disease.
To date, unfortunately, there are no studies that measure the effectiveness of dietary interventions on URM levels in kidney disease and subsequent prognosis. Studies focusing on the use of prebiotics and probiotics to improve gut health and reduce inflammation and CKD risk have had mixed results. However, a major weakness is that these studies only look at a single intervention that impacts kidney disease when in reality the process is much more complex. Future studies should take into consideration the complex interplay of the dietary and lifestyle factors on GI integrity, microbiome balance, genetics, and kidney outcomes.
The bottom line
There is a significant link between the microbiome, gut integrity, genetics, diet, lifestyle, and kidney disease. Most of this can be traced back to the accumulation of URMs in CKD causing a vicious cycle. The conventional approaches to improve gut health and slow the progression of CKD have yielded mixed results. Casting a wider net to include considerations for all factors that contribute to gut integrity, inflammation, and CKD risk must also be examined, including environmental exposures, genetic risk factors, metabolic factors and changes in body fluid volume, and overlapping factors which contribute to diabetes and hypertension, collectively contribute to increased CKD risk. Hence, we advocate for a comprehensive approach that starts with a gut restoration protocol and addresses the above factors in patients with CKD.
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