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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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.
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Causes of magnesium deficiency
Poor dietary choices
There has been a steady decline in magnesium content in cultivated fruits and vegetables over the past 100 years. This is caused by the depletion of magnesium in soil over time. In addition, utilizing phosphate-based fertilizers leads to the formation of magnesium phosphate salts that are not soluble. This means the soil is deprived of both components: magnesium and phosphorus.
On top of that, the rise of ultra-processed food and drinks have also contributed to the depletion of magnesium in the modern standard American diet. Grain bleaching and vegetable cooking and adding preservatives can lead to a significant loss of magnesium content. Preservatives such as various forms of phosphate and oxalate can bind with magnesium and prevent its absorption. Phosphoric acid in soft drinks has similar effects.
The addition of fluoride to drinking water also prevents magnesium absorption by binding to it and forming insoluble complexes. Finally, drinking caffeine and alcohol can also lead to an increase in the excretion of magnesium by the kidneys, causing magnesium deficiency.
Drug-induced magnesium deficiency
Many medications can interfere with magnesium absorption or increase its excretion, leading to deficiency. Most of the medications leading to magnesium deficiency are summarized in the following table:
| Medication class | Example | Mechanism |
| Anti-diabetic medications | Insulin, insulin mimetics | Interferes with Na/Mg exchange leading to renal loss |
| Antimicrobial | Gentamicin, pentamidine, foscarnet, amphotericin B | Increased renal loss |
| Beta agonists | Salbutamol | Renal loss and cellular shifts |
| Bisphosphonate | Pamidronate | Renal loss |
| Cardiac glycoside | Digoxin | Increased renal loss |
| Chemotherapy agents | Cisplatin | Renal loss |
| Diuretics | Thiazide diuretics | Renal loss |
| Proton-pump inhibitors | Omeprazole | Decreased GI absorption |
Measuring magnesium status
Simply put, there is no ideal test for assessing magnesium status in the body. Mg blood levels are tightly controlled and represent only 0.8% of total body stores (0.5% in red blood cells and 0.3% in the serum). Red blood cell Mg levels have been used as an alternative method, but this too does not represent total body stores and is not well validated. Measuring urine Mg requires measuring a 24-hour urine specimen. This too has been found to be imperfect due to large variations from day to day.
The Mg retention test has been proposed as a more accurate way to assess Mg status. Here, the patient receives an intravenous Mg load (0.25 mmol magnesium/kg body weight at a rate of 2.5 mmol/hour), and a 24-hour urine specimen is collected before and after the load. The percentage of administered magnesium that is retained by the body (not excreted in urine) determines magnesium status. This test is not standardized yet, but retention of 25%-50% may indicate a moderate deficiency, and retention of more than that may indicate severe deficiency.
Ideally, measuring muscle or bone magnesium may be more reflective of accurate magnesium stores but this is obviously not practical. Combining a serum Mg test, a 24-hour urinary Mg, and assessing dietary Mg intake is the most comprehensive and practical evaluation of a patient’s magnesium status.
Combining a serum Mg test, a 24-hour urinary Mg, and assessing dietary Mg intake is the most comprehensive and practical evaluation of a patient’s magnesium status
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Patients at high risk for magnesium deficiency include:
- Diabetics
- Heart disease patients
- Osteoporosis patients
- People who eat a diet high in processed food and soda
- People who suffer from leg cramps
- People with metabolic syndrome
- People who take certain medications
Those patients at risk of magnesium deficiency should be targeted for additional testing and supplementation.
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What type of magnesium should I take?
The type of magnesium supplement used depends on the exact indication. Magnesium supplements are available as oxide, hydroxide, gluconate, chloride, citrate, lactate, malate, taurate, L-threonate, sulfate, glycinate, orotate, and carbonate salts. In addition to magnesium citrate’s direct effects on kidney stones, magnesium benefits the person with kidney disease through its effects on blood pressure, insulin sensitivity, vascular health, and bone. The following indications are listed with the recommended types of magnesium supplements and doses. These doses are for prevention only. Patients who are deficient may need higher doses. Magnesium supplements should be discontinued or decreased in kidney patients if the serum magnesium level is higher than 2.6.
| Indication | Mg type | Dose |
| Prevention of kidney stones | Magnesium citrate | 400 mg daily |
| Bone health | Magnesium citrate or chloride | 400 mg daily |
| Improving blood pressure | Magnesium taurate | 400 mg once or twice daily |
| Improving insulin sensitivity | Magnesium taurate | 400 mg once or twice daily |
| Improving vascular health | Magnesium glycinate or orotate | 200-400 mg daily |
| Phosphate binder | Magnesium carbonate | 250 mg with meals |
We recommend using high-quality supplements. This article can be a useful guide.
The bottom line
Magnesium is essential to many biological functions, as I described in part one, “Magnesium and Kidneys.” It has many health benefits for kidney, bone, and vascular health. Assessing magnesium status is difficult but magnesium deficiency is very common and underrecognized. Supplementing magnesium may be important for patients with kidney disease. The type of supplement used depends on the indication. As always, it is recommended that you check with a Functional or Integrative Medicine provider and nephrologist before taking any new supplement.
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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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We would love to hear your feedback. Let us know what you think of these educational materials and if you like us to focus on certain topics. Email us at info@inkidney.com
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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 Majd Isreb, MD, FACP, FASN, IFMCP
The nervous system and kidney health
The autonomic nervous system describes the system that controls involuntary actions, such as heartbeat and the widening or narrowing of blood vessels. It has two components: the sympathetic system (fight or flight system), and the parasympathetic system (or the rest and digest system).
It has been long established that the sympathetic system innervates all segments of the kidneys including the blood vessels and tubules. Stimulating the sympathetic system (fight or flight) can affect blood flow to the kidneys and lead to sodium retention at the level of the tubules, resulting in the progression of kidney disease. The kidneys are also innervated by small branches of the parasympathetic (rest and digest) vagus nerve.
What is the vagus nerve?
The vagus nerve is the longest nerve in the body. The word “vagus” means “wanderer” in Latin. This nerve is described as such because it connects the brain with many vital organs including the heart, lungs, gut, liver, spleen, and kidneys. It, therefore, affects breathing, digestion, and heart rate. Early studies also demonstrated that it also affects kidney blood flow.
Fascinating new evidence shows that the vagus nerve plays an important role in modulating inflammation in the body. When foreign particles are identified in various organs, “inflammatory signals” or neural messages are conveyed to the brain by the vagus nerve. The vagus nerve, then, transmits reflex signals back. These signals end up activating the splenic (spleen) nerve, which leads to a decreased inflammatory response and reduced inflammatory cytokines.
Simply put, the vagus nerve identifies triggers for inflammation and helps the brain regulate the inflammatory response. This is an evolving field called the cholinergic anti-inflammatory pathway (CAP).
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Stress worsens kidney disease
Our increasingly stressful lives can lead to increased cortisol levels, insulin resistance, and inflammation. Stress has been linked to imbalances between the sympathetic and parasympathetic systems. This is often described as autonomic dysfunction. These imbalances can also lead to the development and progression of kidney disease. Genetics, environment, and nutrition play important roles in augmenting these changes.
Autonomic dysfunction is a common finding in CKD. It is often measured by what is called heart rate variability (HRV).
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Heart rate variability as a measure of vagus nerve activity
HRV is simply a measure of the variation in time between each heartbeat. Because this variation is controlled by the autonomic system, HSV can be used to measure changes in this system. The vagus nerve plays an essential role here since it controls heart rate. Therefore, stimulation of the vagus nerve can affect HRV.
HRV can be measured by analyzing a long strip of electrocardiogram (EKG). However, several companies created “apps” and heart rate monitors that can measure it. Unfortunately, the accuracy of these apps and wearable devices is not yet clear. The easiest way to check HRV is to buy a chest strap heart monitor (Polar, Wahoo) and download a free app such as Elite HRV to analyze the data. Chest straps tend to be more accurate than wrist or finger wearables.
Finally, decreased HRV has been linked to bad outcomes in hypertension, systemic inflammation, depression, and CKD. Low HRV can increase the risk of sudden cardiac death. Therefore, there is increasing interest in manipulating heart rate variability by stimulating the vagus nerve.
Activate the vagus nerve to calm inflammation in CKD
Vagus Nerve Stimulation
CKD is a state of chronic inflammation that is associated with heart disease and poor outcomes. As mentioned above, the vagus nerve plays an important role in detecting and calming inflammation in the body. It identifies sources of inflammation and helps the brain modulate the inflammatory response appropriately. The vagus nerve may play an anti-inflammatory role in conditions such as endotoxin-induced sepsis, arthritis, and acute kidney injury.
Electrical stimulation of the vagus nerve is the most common method to modulate the inflammatory response and other functions of the vagus nerve. Pharmacological methods are also being studied for that purpose. However, there are many simple and natural ways to stimulate the vagus nerve.
Natural ways to stimulate the vagus nerve
Stimulating the vagus nerve can improve the response to emotional and physiological stress, thereby improving kidney health. It can also help decrease inflammation. In fact, the FDA approved a surgically implanted device that stimulates the vagus nerve to treat resistant depression. However, there are many ways to stimulate it naturally. I will mention them briefly here.
Activate the Vagus Nerve Naturally to Improve Kidney Disease:
- Cold exposure such as cold showers.
- Deep and slow breathing can activate the parasympathetic system.
- Singing, humming, chanting, and gargling can also activate the vagus nerve because it is connected to the vocal cords.
- Probiotics, interestingly, can be beneficial in activating the gut-brain axis and stimulating the vagus nerve.
- Meditation has been found to increase vagal tone and positive emotions.
- Omega-3 fatty acids have yet another great benefit- increasing vagal activity.
- Exercise is of course linked to better mental health and stimulation of the vagus nerve.
- Massage therapy has also been found to be associated with improved vagal tone.
- Socializing and laughing can also be beneficial.
The Bottom Line
Emotional stress can be associated with faster progression of CKD. The kidneys have both sympathetic and parasympathetic innervation. Acute stress can worsen kidney function, while relaxation practices can promote kidney health. Stimulating the vagus nerve can turn on the parasympathetic nervous system, improving renal blood flow and modulating inflammation in CKD. Stress reduction and the natural stimulation of the vagus nerve can help delay the progression of kidney disease.
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There are practical steps that you can take to improve your sleep. These include creating a relaxing sleep environment, lowering the temperature in the bedroom, making sure it is dark, and having a comfortable mattress, etc. Yet, many people don’t realize that a good sleep is more about what we do away from the bed than what we do in bed.
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In the era of social media, technology, and 24-hour news that are always available in the palm of our hands, our minds are going a million miles per hour. Many of us are juggling so many things and have even more worries. We worry about work, about the kids, emails, social media reactions, finances and many other things. Some of us get to bed with exhausted bodies but minds that are still going at full speed.
So, what do you need to do to help the brain shut down? Here are the five steps to help you unwind your brain and get a better sleep.
Step 1: Don’t carry today’s problems into bed
Your mind is not going to stop thinking about today’s problems and worries unless you help it clean up. You must tie up all the loose ends from the day. The best way to do that is by allowing your mind to settle down two hours before bedtime. Simply, write down ALL your thoughts and worries on a paper or in a notebook. It does not matter how or what. Think of it as a thought download or a brain dump.
Do this process outside the bedroom and leave the notebook or paper there. This will train your brain to leave the worrying thoughts outside the bedroom. It allows space for positive thoughts. Positive thoughts are calming and will help you to go to sleep.
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Step 2: Plan your tomorrow
After you downloaded your thoughts, look at your plan for the next day. Look at your calendar and prepare for that early meeting, pick workout clothes, prepare and pack for lunch. Your attention to details will help your mind avoid the worry about tomorrow. This will set you up for success and give you control. The control that will help you settle your mind.
Step 3: Keep your phone outside of the bedroom
In fact, keep all electronics out of the bedroom. The bedroom is for two things, sleep and intimacy. I actually recommend that you stop looking at your phone, social media, emails or any other projects for two hours before going to bed. Trust me, I know it is hard and I am guilty of this too.
I also get that some of you may be in a profession like me where you take calls at night and may need a phone nearby. But in the era of smartphones, it is easy for the mind to wander at night. These types of phones bring your worries and the whole world with you to the bedroom. Do you want the world to be in your bedroom when you’re trying to sleep?
So, if your profession requires it, get a landline or cheap flip phone to be by your bed for emergencies. No texting, no social media, and no news in the bedroom. Research found that one third of people wake up at night and check their smartphones.
Step 4: Create a bedtime restorative ritual
A restorative ritual signals your brain that you’re going into a relaxed state. These rituals include things like taking a bath or a hot shower, drinking hot green tea, lighting up candles, dimming the lights, praying or meditating. You can also read a fiction book to take your mind out of your own story into the story of the book.
Step 5: Think happy thoughts
Pick a location of your dreams. If you love to be on the beach in Hawaii or on top of mount Everest immerse yourself in the experience. Feel it, smell it, see it and dream it. Visualize it as if you are living in it. This powerful way will calm your mind and set it up for dreaming. The goal is to feel calm, safe, quiet and “tucked in.”
Bonus: what if you wake up in the middle of the night
Waking up in the middle of the night is not unusual. Researchers found that 31% of people wake up in the middle of the night at least 3 times a week. So, if you wake and you can’t go back to sleep, use the 15 minute rule. If you wake up in the middle of the night and after 15 minutes you don’t drift back into sleep, you should get out of bed. Do not lay there and start thinking about going to sleep. Do not look at the time, do not check your phone, and do not make a cup of coffee.
Get up and go to another room. Sit in a comfortable chair, read that novel, light up a candle. If your mind is racing again. Go back to that piece of paper or notebook and write down your thoughts and worries again. Do not do these things in bed because that will train your mind to associate your bed with wakefulness instead of sleep. When you feel drowsy again, go back to your bed and go to sleep.
The Bottom Line
Here is the trick though, you have to do these steps every night. You may feel like you want to stay up watching a movie on your favorite app or stay on your phone or catch up on a project instead of your bedtime ritual. But your health and your mind deserve a good sleep. So, this simple promise to yourself will help you establish the good habit of sleep and set you up for better health and success.
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The Role of Dietary Fiber Supplementation in Regulating Uremic Toxins in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials
Gut-derived uremic toxins, including indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are waste products that accumulate in the body due to decreased clearance by the failing kidneys. These accumulated uremic toxins are a risk factor associated with cardiovascular disease, progression of kidney dysfunction, mineral bone disorders, and increased mortality in patients with CKD. This meta-analysis showed that dietary fiber supplementation could decrease IS and PCS levels in patients with CKD.
https://www.jrnjournal.org/article/S1051-2276(20)30291-0/fulltext
Causal effects of physical activity or sedentary behaviors on kidney function: an integrated population-scale observational analysis and Mendelian randomization study
The health benefits of exercise and regular physical activity are vast. Using Mendelian randomization (MR) to assess causality, this study found that “the genetic predisposition to a higher degree of physical activity was associated with a lower risk of CKD and a higher eGFR, while the genetically predicted television watching duration was associated with a higher risk of CKD and a lower eGFR.”
https://academic.oup.com/ndt/advance-article/doi/10.1093/ndt/gfab153/6214515?login=true
Prevalence of Inflammatory Bowel Disease and Celiac Disease in Patients with IgA Nephropathy over Time
Poor gut health and a lack of intestinal wall integrity is linked to many diseases, including IgA nephropathy (IgAN). The results of this Finnish study showed an increase in the prevalence of inflammatory bowel disease (IBD) in patients with newly diagnosed IgAN over a 36-year period.
https://www.karger.com/Article/Abstract/511555
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Genetic testing for patients with kidney disease can have a remarkable impact on their care. The availability of “broad-panel genetic testing” for kidney patients ushers in a new era of nephrology and patient care. Tests that used to cost thousands of dollars and took months for results can now be done for a fraction of the cost in just a few weeks. New commercially available genetic tests utilize next-generation sequencing to identify multiple gene variants simultaneously. These tests can help in the management of kidney disease in multiple ways. In this blog, we will focus on the clinical utility of genetic testing for kidney transplant evaluation.
Genetic Testing for Kidney Transplant Evaluation
During the evaluation of a patient for a kidney transplant (the recipient), the assessment usually focuses on answering these questions:
- Can the recipient survive elective transplant surgery?
- Can the recipient tolerate immunosuppression after the transplant?
- Can the recipient have a good outcome?
In addition, evaluation of living donors try to answer questions about their suitability for donation and their risk of developing kidney failure in the future.
Living Donor Evaluation
One of the most pressing questions when evaluating a living donor is: Will this donor develop kidney disease in the future if s/he donates a kidney now? Several studies have shown an increased risk of the donor developing kidney disease after donation. This risk is higher if the donor and the recipient are related. This may indicate that genetic factors play a role in this risk.
In 2017, the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines suggested that “transplant programs should have a strategy for evaluating for inherited kidney disease in donor candidates when there is a family history of kidney failure and the recipient’s cause of kidney failure is uncertain.”
These guidelines suggested genetic testing of living related donors with specific diseases such as focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome, Alport disease, sickle cell trait, and autosomal dominant tubulointerstitial kidney disease.
Genetic testing of a living relative donor can be especially important if the recipient has polycystic kidney disease. If this mutation is identified in the recipient, the donor can then be tested and excluded if s/he has the mutation. This can give greater assurance to both the donor and recipient.
Other genetic variants are associated with increased risk of chronic kidney disease (CKD) such as APOL1 gene variants that are associated with increased risk for nephropathy in patients of African ancestry. Incorporating testing for these genetic risk variants in the evaluation of the donor may help replace race for calculation of the so-called Kidney Donor Risk Index that is used to predict the longevity of the transplant graft.
While it is still too early to incorporate the genetic risk variants for diabetic kidney disease and IgA nephropathy in transplant evaluation, getting more clarity on the utility of the risk variants can have a tremendous impact on the care of current patients.
Recipient Evaluation
Kidney disease is silent in its progression and symptoms do not develop until the advanced stages of CKD. One in 10 patients with advanced kidney diseases presents with end-stage kidney disease (ESKD). In many of these cases, the laboratory workup is inconclusive, and their kidneys are often too atrophic to biopsy. Unlike kidney biopsies, genetic data can be informative even after ESKD has developed.
Genetic evaluation of the recipient is, therefore, helpful in identifying the causative mutation that could have led to the disease. Using targeted gene testing, researchers were able to identify pathogenic mutations in 19% of waitlisted transplant patients under the age of 40. Broad panel genetic testing can likely have an even higher yield. Indeed, broad panel genetic testing has been shown to identify the cause of CKD in up to one-third of the patients with an unknown cause.
Genetic testing of the recipient can also help in providing individualized post-transplant care. Finding a specific mutation that leads to a localized disease in the kidneys can decrease concerns about the recurrence of the disease after transplantation.
Also, a genetic diagnosis can often point to the likelihood of disease in another organ and can prompt referral and evaluation.
Currently, researchers are collecting phenotypic and genetic information on patients receiving transplants in the iGeneTRAiN consortium. Analyzing this data in the future may have a significant impact on our understanding of transplant graft outcome.
Pharmacogenomics
Wouldn’t it be a relief to be able to predict in advance how someone might respond to a medication? This would save time, eliminate guesswork, and improve patient outcomes. Thanks to advances in a field of genetics called pharmacogenomics (PGx), clinicians have begun to use genetic information to personalize drug therapy.
Accurate pharmacogenomics data are now available on two transplant medications: tacrolimus and azathioprine. Although the latter is not commonly used, the former is used often. Tacrolimus is metabolized by the enzyme encoded in the gene CYP3A5. Variants in this gene can classify the patient into one of three phenotypes: extensive metabolizer, intermediate metabolizer, and poor metabolizer. Indeed, pharmacogenomic data can now be used to optimize the initial dose of tacrolimus.
Many other medications commonly used by patients have pharmacogenomic data which can also be used to optimize their dosing. Medications such as clopidogrel, voriconazole, and allopurinol are a few of these. We discussed these medications in-depth in our previous blog about pharmacogenomics.
The Bottom Line
Genetic testing is gradually becoming a significant part of the transplant evaluation of the donor and the recipient. It is particularly useful in the evaluation of living donors with a family history of kidney disease. This data has the potential to transform the care of kidney transplant patients and improve their outcomes.
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Exercise may be one of the most underutilized yet effective interventions for the prevention and treatment of chronic disease. It has been shown to reduce the risk of complex chronic disease, help with blood pressure and glucose control and improve health-related quality of life. Other benefits of exercise include positive influence on mental health, mood and stress levels, important factors to overall health and wellness. In this blog, we will discuss the benefits of exercise in kidney health.
By Megan Morrison, PharmD
The implications of kidney disease are vast. It is an extremely costly disease, with many people progressing to end stage renal disease (ESRD) requiring dialysis or a kidney transplant, a significant physical and financial burden. Often the disease dramatically reduces an individual’s quality of life, the ability to perform activities of daily living, and independence.
Furthermore, kidney disease is associated with a high symptom burden, cardiovascular disease and increased mortality rates. With the prevalence of chronic kidney disease (CKD) on the rise, along with diabetes and hypertension, it’s imperative that prevention and an integrative medicine approach to kidney health become the norm along with exercise, a modifiable lifestyle factor.
Benefits of exercise in kidney disease
Physical inactivity is associated with a decline in kidney function in CKD. Exercise has the ability to markedly improve numerous health parameters associated with the disease, including:
- Cardiovascular health
- Systemic inflammation
- Muscle mass
- Gut health
- Mortality rate
- Risk factors associated with CKD, including diabetes and high blood pressure.
Exercise improves cardiovascular health and vascular function
Patients with CKD have an increased risk of cardiovascular disease (CVD). In fact, rates are estimated to be 10-20 times higher among ESRD patients than the general population. High blood pressure, the second leading cause of kidney failure in the US after diabetes, is closely related to adverse kidney and cardiovascular outcomes in CKD. This is why reducing blood pressure is imperative.
Benefits of exercise on blood pressure management are well-established. One study in pre-dialysis patients showed reductions in both systolic and diastolic blood pressure in participants who engaged in 1-hour of acute aerobic exercise such as walking. Another study found that 1 hour of supervised, home-based exercise reduced arterial stiffness over 3-months and improved outcomes in pre-dialysis patients.
Exercise positively effects inflammatory markers
Chronic inflammation has detrimental effects on health and is associated with increased cardiovascular events, the leading reason for mortality in CKD. Plasma inflammatory markers have been found to be positively affected by exercise. A study found that a 30-minute bout of exercise increased plasma IL-10 levels and regular walking 5 days a week for 6 months reduced the plasma IL-6:IL-10 ratio favorably. IL-10 is an anti-inflammatory cytokine, while IL-6 is inflammatory. The reduction in the IL-6:IL-10 ratio seen in the regular exercisers reflects a decrease in overall inflammation.
Exercise increases muscle mass
Muscle wasting, which promotes a sedentary lifestyle and increases morbidity and mortality, is another complication associated with CKD. An 8-week resistance training program (3 times a week) for pre-dialysis patients increased muscle mass, with similar findings in dialysis and transplant patients.
Exercise favorably impacts the gut microbiome
In a previous blog post, we discussed the close relationship between the quality of the microbiome and the health of the kidney, known as the gut-kidney axis. Those with a healthy microbiome balance, defined as an abundance of “good” bacteria, and the absence of pathogenic species or overgrowth, are less likely to develop CKD.
One study that compared active women and sedentary controls found that women who performed at least 3 hours of exercise per week had increased levels of beneficial bacteria. Additional studies have shown that exercise increases fecal butyrate concentrations and the relative abundance of butyrate-producing taxa. Butyrate is a short-chain fatty acid produced by bacteria that positively impacts intestinal health by supporting a favorable environment for commensal growth.
Exercise significantly reduces mortality rate in ESRD
ESRD is associated with considerable morbidity and mortality. A study of dialysis patients found that those who regularly exercised (2-5 times per week) had significantly lower all-cause and cardiovascular mortality rates than less active peers.
Type and Duration of Exercise
The type and duration of exercise depends on an individual’s level of functioning, endurance, and preference. 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), which has gained popularity in recent years, has shown to offer superior benefits in individuals with metabolic disease. In the few studies of HIIT in CKD, HIIT was found to be a safe and feasible option for individuals with CKD, including those undergoing hemodialysis. Regardless of type, duration, or intensity, regular exercise is beneficial in CKD patients.
Considerations & Contraindications
Individuals with CKD should consult their healthcare provider before beginning any type of new exercise routine. Certain subgroups of the CKD population need special considerations including those with known or suspected cardiac disease and dialysis patients.
It’s important to note that patients with kidney disease have identified certain barriers to exercise which include fear of injury or aggravating their condition, poor physical condition as a result of both co-morbid conditions and CKD-related symptoms, a lack of guidance from health professionals, and a lack of facilities and social support. Exercise facilities are less defined and less accessible to the CKD population in comparison to services provided for cardiac and pulmonary patients, resulting in fewer opportunities to develop peer support groups, which can significantly effect exercise adherence. It is our responsibility as integrative clinicians to discuss exercise with patients and include physical therapists and trainers in our protocols for management of CKD.
The Bottom Line
The majority of risk factors for CKD are related to lifestyle factors or conditions related to lifestyle disease. Exercise is an intervention that has the ability to positively impact a large number of those risk factors. Integrative and Functional Medicine prioritizes the vital role that physical activity plays in overall health and wellbeing, including exercise as part of the holistic therapeutic plan. There are benefits to any level of exercise, it’s important to guide patients to choose activities that are safe, meet them where they are, are appropriate to their level of physical activity, and are enjoyable.
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