The root cause of IgA nephropathy
IgA nephropathy is a kidney disease that is defined by the pathologic appearance of glomerular deposition of IgA immune complexes. However, this definition does not address the root cause of the disease.
It has been increasingly recognized that IgA immune complex that deposit in the kidneys predominantly contain polymeric IgA1 lacking galactose within its O-glycosylated hinge region.
In this study, researchers found that patients with IgA nephropathy have elevated levels of certain B cells that are enriched for λ light chains. These cells are predestined for homing to upper respiratory and digestive tract mucosal tissues. In the mucosal tissues, these B cells mature and excrete abnormal IgA in the setting of upper respiratory or digestive infection. You can read more IgA nephropathy by reading our blog here.
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Metformin: Some people love it and some people hate it… But it sure is getting a lot of attention lately
This study was done in rats with “non-diabetic kidney disease.” CKD was established in these rats by feeding them high adenine diet. Then they were randomized to receive either metformin or canagliflozin (an SGLT-2 inhibitor).
Metformin, but not canagliflozin, halted the decline in kidney function. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group.
Metformin is increasingly being studied in humans for various kidney diseases. If used judiciously it may be a cheap alternative to preserving kidney function.
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Tremor + gum disease + nephrotic Syndrome = ?
In this study, investigators in Beijing looked into the manifestation of mercury poisoning in 172 patients. 26.74% of these patients had kidney injury (3/4 were women) and most of them had nephrotic syndrome. The most common finding on the biopsy was membranous nephropathy.
Other findings of chronic mercury poisoning were neurotoxicity and gingivitis. Chelation with DMPS alone was as effective as chelation and prednisone in reversing kidney injury.
The most common source of exposure without kidney disease was industrial exposure. Interestingly, the most common source of exposure leading to kidney disease was cosmetics containing ionic mercury (mercury concentration in one of the patients cosmetic was 4600 mg/kg – national standards are < 1 mg/kg).
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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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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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3 years of lifestyle interventions improved exercise capacity and decreased the losses in neuromuscular and cardiorespiratory fitness in CKD patients
In this study, researchers randomized 161 patients with stage 3-4 CKD to either get usual care or usual care plus lifestyle “intervention” for 3 years.
The lifestyle intervention comprised of care from a multidisciplinary team, including a nephrologist, nurse practitioner, exercise physiologist, dietitian, diabetes educator, psychologist, and social worker.
The patients were coached for 8 weeks and then followed for 34 months with a home-based program.
The study did not look at the progression of CKD but it found that a 3-year lifestyle intervention doubled the percentage of CKD patients meeting physical activity guidelines, improved exercise capacity, and decreased the losses in neuromuscular and cardiorespiratory fitness.
It appears that the study mainly focused on exercise. So imagine the benefit of a comprehensive lifestyle modification plan that includes nutrition, exercise, stress management, sleep improvement, and attention to toxin exposure and gut-kidney connection. That’s what we focus on.
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Curcumin powder did not improve markers of vascular dysfunction in PKD
This is essentially a negative study.
It demonstrated that Curcumin powder did not improve markers of vascular dysfunction in children and young adults with PKD. The study was conducted for only one year using a dose of 25 mg/kg per day of curcumin.
This is a classic supplement or nutrient study that is usually underpowered or conducted for short periods of time for a disease that takes years or even decades to evolve. Nevertheless, the study proved that short-term use of curcumin is not beneficial for vascular health for young patients with polycystic kidney disease.
Low serum zinc levels were associated with infections in CKD patients
This did not really need research but it is now studied and it is official: Low zinc levels in patients with CKD lead to infection (..well among other things).
This retrospective study analyzed data from 299 CKD patients who had serum zinc levels checked to evaluate anemia. They used the level of 50 mcg/dl as the cutoff between low or “high” zinc values.
Low serum zinc values remained an independent risk factor for infection-related hospitalization. This was especially true for patients taking proton pump inhibitors (PPIs) medications.
Read about the effect of Zinc on kidney health in this blog.
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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.
The post Magnesium Deficiency: Assessment and Management for Better Kidney Health appeared first on Integrative Kidney.]]>Low magnesium levels have been associated with a number of adverse events, such as high risk for heart disease. However, little is understood about magnesium and kidney health. Here, we will discuss the potential benefits of magnesium on the kidneys. This is one of two articles on magnesium and kidneys. For more on how to test and treat kidney patients with magnesium deficiency, see part two, “Magnesium Deficiency: Assessment and Management for Better Kidney Health.”
Dietary sources of magnesium
A daily intake of 3.6 mg/kg is necessary to maintain magnesium balance in humans under normal conditions. This is estimated to be between 320 to 420 mg/day (13–17 mmol/day) for adults. Sadly, there has been a steady decline in magnesium content in cultivated fruits and vegetables over the past 100 years. This is due to depletion of magnesium in soil over time. This, along with the rise of ultra-processed food, sodas, and taking medications such as proton pump inhibitors and diuretics that deplete magnesium levels (polypharmacy), has led to rising prevalence of magnesium deficiency.
Traditionally, the highest food sources of magnesium are:
- Leafy greens (78 mg/serving on average)
- Nuts (80 mg/serving on average)
- Pumpkin seeds have the highest level of magnesium per serving (156 mg).
- Whole grains (46 mg/serving on average)
A complete list of foods high in magnesium can be found here.
Can Magnesium Help Kidney Function?
There are many potential benefits of magnesium for kidney health including improving blood pressure control, insulin sensitivity, bone health, vascular health, and preventing kidney stones. Let’s explore the data.
Magnesium and blood pressure control
Magnesium supplementation may help reduce blood pressure (BP) by increasing the production of nitric oxide. Nitric oxide acts as a signaling molecule that helps relax blood vessels, which lowers BP. In fact, a review of 34 studies showed that supplementing magnesium with an average dose of 368 mg per day for 3 months can decrease systolic BP by 2.00 mmHg and diastolic BP by 1.78 mmHg. This supplementation was accompanied by 0.05 mmol/L increase in serum magnesium levels.
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Magnesium and insulin sensitivity
Diabetes is one of the major risk factors for kidney disease worldwide. Higher dietary intake of magnesium has been correlated with lower diabetes incidence. A review of 18 studies in people with diabetes showed that magnesium supplements reduced fasting plasma glucose levels. In people who are at high risk for diabetes, magnesium supplementation significantly improved plasma glucose levels after a 2-hour oral glucose tolerance test. These effects are thought to be due to the effects of magnesium on insulin receptors and signaling that allows for improvement in glucose transport and utilization.
Magnesium and vascular health
Magnesium levels have been associated with a lower incidence of cardiovascular disease. In fact, supplementing with magnesium was associated with improvement in vascular flow and endothelial function. Endothelial function refers to the lining of the blood vessels, which is involved in regulating blood vessel health and blood clotting.
Studies in patients receiving dialysis have shown that having a lower serum magnesium level is a significant risk for cardiovascular mortality. Laboratory data show that magnesium inhibits high phosphate-induced calcification of vascular smooth muscle cells. Calcification of arteries is a strong predictor of heart disease and heart-disease-related death.
Magnesium and vitamin D
Magnesium is essential to vitamin D metabolism. Vitamin D that we eat or make in our skin from sun exposure circulates in the blood and is bound to vitamin D binding protein (VDBP). VDBP binding activity depends on adequate magnesium levels. In addition, magnesium is an essential cofactor for the enzymes that activate vitamin D. Studies have demonstrated that magnesium deficiency is associated with impaired vitamin D metabolism.
On the other hand, taking large doses of vitamin D can induce severe depletion of magnesium. This is thought to be due to the overutilization of magnesium. Therefore, adequate magnesium supplementation should be an important part of vitamin D therapy.
Adequate magnesium supplementation should be an important part of vitamin D therapy.
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Magnesium and bone health
Besides magnesium’s effects on vitamin D metabolism, it is an essential component of hydroxyapatite, an essential component of bone and teeth. In fact, 60% of total Mg is stored in the bone. Low magnesium intake was found to be associated with lower bone mineral density in postmenopausal women. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting the secretion and the activity of parathyroid hormone (PTH) and by promoting oxidative stress and inflammation.
In addition, a review of 8 studies looked at magnesium and chronic kidney disease (CKD). The study investigated magnesium supplementation on parameters of CKD-related mineral bone disease (CKD-MBD). Mg supplementation improved PTH levels and carotid intima-media thickness (CIMT). Low serum Mg levels were also found to impact PTH and worsen osteoporosis in CKD patients, particularly with diabetes.
Magnesium and kidney stones
Mg acts as an inhibitor of calcium oxalate crystallization and stone formation in the urine. It also decreases the absorption of dietary oxalate in the gut. Mg supplementation in patients with kidney stones was found to decrease the incidence of stone formation even in patients without signs of Mg deficiency.
Magnesium as a phosphate binder
Hyperphosphatemia (high phosphate level) is common in advanced kidney disease. Many kidney patients with stage 4 and above use binders that bind phosphate (or “phosphorus,” as it is commonly known) in the food and prevent it from getting absorbed. High phosphate levels have been associated with poor bone and vascular health in kidney patients. In fact, higher dietary phosphate load can be seen in earlier stages of CKD, and it can do harm even before it is detected.
Magnesium carbonate has been successfully used as a phosphate binder. Magnesium based phosphate binders were also found to reduce vascular calcifications in rats with kidney disease. Iron-magnesium hydroxycarbonate was also studied and found to be well tolerated and can effectively lower phosphate levels in dialysis patients. It is essential to know that most of the magnesium used as a phosphorus binder will not be absorbed.
The bottom line on magnesium and kidneys
Magnesium is essential to many biological functions. It has many health benefits for kidney, bone, and vascular health. Optimizing magnesium status is, therefore, an important step in the integrative approach to kidney health. In part two of this blog, “Magnesium Deficiency: Assessment and Management for Better Kidney Health,” we will discuss practical steps for figuring out a person’s actual magnesium status, the best form of magnesium to take, and the dose I recommend for each condition.
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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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The root causes of my sleep problems go far back, with mild symptoms of pregnancy insomnia in my third trimester. After giving birth, I became an extremely light sleeper who could be awakened by hearing anyone tiptoeing nearby. I became hyper-vigilant. I thought it was driven by me being a new mom. I was getting up multiple times through the night to heed to my newborn baby, and then staying wide awake the rest of the night. However, that chronotype of light sleeping continued throughout the following years.
My journey with suboptimal sleep.
In 2016, when I was a victim of a chronic job, I was drained by a huge workload and long hours. I was assailed with onerous functional, technical, and humanitarian ethical commitments. My job required crossing several time zones. My social life was badly affected and my social circle narrowed significantly. I was severely sleep deprived, barely getting 2-3 hours a night for days in a row and occasionally getting 5 hours once in a blue moon.
In the beginning, I didn’t feel the negative effects of poor sleep. I was getting up early in the morning feeling energetic, motivated, and looking forward to my day as if I had good sleep the night before. That made me wrongly think that I might be blessed; my body doesn’t need long hours of sleep for me to be able to fully function. Having the extra hours in my day seemed to help me perform at a high level, deliver more, and enjoy my time.
Consequently, I stopped obsessing about getting enough sleep and started to adjust to my insomnia, telling myself I’m lucky that I’m unfettered and not wasting my time with unnecessary sleep. When I was in bed trying to sleep every night, my brain was hyper alert; I was not able to stop the thoughts circulating in my mind, and when I awoke in the morning, I felt like my brain had been racing while I was sleeping.
The fatigue began to catch up, causing my mental and emotional state to shake. I was gradually running out of energy. Any energy I did have to socialize or practice my hobbies was diminishing day by day. The fatigue also stirred my vitality and my mood disorder was on the rise.
I started to look for remedies to beat my sleep disorder. I tried melatonin supplements, sought advice from sleep therapists, heard about acupuncture, listened to alpha waves tones, drank herbal tea and had amber/rose aromatic baths pre- bedtime. The last thing I tried was based on advice from a colleague of mine, who recommended that I wipe my eyes with the water of soaked jasmine petals so that I could fall asleep.
Unfortunately, none of these worked for me.
Deep dive into our brain circuits.
As a science-oriented person, I was interested in decoding the chemistry of the brain and the Cognitive Neuroscience of Sleep to understand how to use neuroscience to improve my sleep and how stress and worrying affect sleep. I learned that my daily routine, along with managing my reaction to stress, can change the activity of the neurotransmitter systems in my brain, and can therefore positively impact my insomnia. I read the article published on InKidney titled “Sleep and Kidney Health”, in addition to the book The Upward Spiral by Alex Korb, PhD which helped me understand the biological basis of sleep disorders and adopt practical tips to improve my sleep cycle. One caveat of the aforementioned book is that it focuses more on how to get out of the downward spiral of depression; thankfully, I was not suffering from any course of depression. The book also illustrated how the circuits inside our brains are connected to each other (for example, the changes to my daily routine that reduced stress levels, improved mood, and provided me more energy to exercise, significantly contributed to the improvement of my sleep circuit by releasing more norepinephrine, oxytocin, endocannabinoids, dopamine, and melatonin).
The magic of sleep.
To improve sleep, we must first understand what I call “the magic of sleep.” I became familiar with the sleep architecture of our brains. That was key to understanding the stages of sleep and the governance the brain has on hormones/neurotransmitters and quality of sleep cycle. The circadian rhythm, controlled by the hypothalamus, also plays a role . The hypothalamus governs a large number of our daily activities including hunger, alertness, and body temperature. It also made me aware of the fact that circadian rhythms cause a variety of daily neuro-hormone fluctuations, including melatonin which helps with falling asleep. This biological system can be restored and maintained by sticking to a sleep schedule and making small changes like minimizing light exposure at night.
Figure 1: The Cycle of Melatonin- (Matthew Walker, 2017)
Figure 2: Sleep Architecture- when experts chart sleep on a hypnogram, the different levels resemble a drawing of a city skyline. This pattern is known as sleep architecture. The hypnogram above shows a typical night’s sleep of a healthy young adult.
(the editors of Harvard Health Publishing in consultation with Lawrence Epstein & Program Director, 2019)
Optimizing my sleep hygiene.
Because habits are triggered by stress, I have come to understand the fundamental importance of controlling stress and anxiety. Additionally, I’ve followed a number of tips and strategies that made me feel an immediate lift in the quality and duration of my sleep. The tips to improve sleep are summarized as follows:
Day-time activities:
- Exercise, which is a great part of my daily life, gives me an enormous sense of well-being, and makes me more energetic and positive throughout the day. This translates to more productivity, happiness, and relaxation when I go to bed at night.
- Consume high prana foods (green, organic, whole and unprocessed food) that are energy giving, and necessary to function with the highest levels of productivity.
- Practice mediation for 10 minutes on a daily basis.
- Avoid naps during the daytime.
- Accomplish harder tasks during the daytime only, and keep easier or funnier tasks to the evening time.
- Caring for the people I love which is a powerful pathway to my personal growth, long lasting happiness, and stress relief.
- Self-care, maintain work-life balance, and make time for friends and people I care about.
Pre-bedtime routine:
- Go to sleep and wake up at the same time all days of the week (including weekends). It’s okay to deviate a little occasionally, but there should be a defined target for your sleep and wake up times.
- Refrain from caffeine intake (coffee or tea) 6-8 hours before bedtime.
- No eating after 8:00 PM.
- Lower all lights by a certain time at night.
- Set phone and PC on night-mode, and reduce the brightness on my devices’ screens.
- Stop the use of electronic devices at least 30 minutes before going to sleep.
- Turn off the TV in my bedroom as well as all electronics that might illuminate the room.
- Maintain self-care, healthy diet, and proper hydration.
Bedtime setting:
- Adjust LST (no light, no sound, low temperature).
- Wear light and comfortable sleepwear; sleep on breathable fresh bedding .
- Make my bed my haven; avoid reading or working in bed to associate the bed only with sleep.
- Charge phone away from bed
Wake up routine to stay energized:
- Start the morning with proper hydration and stretching exercises.
- After a warm shower, shower with cold water for up to 5 minutes.
- Journaling and setting the daily highlights.
The Bottom Line
One of the key pillars for building a healthy foundation for good sleep is implementing daytime habits that support a solid nighttime routine. By controlling stress and following the tips above, I have managed to improve my sleep from an average of 3 interrupted hours of sleep into continuous 6 hours of sleep. I’m waking up happier, more put together, more productive, and, most importantly, healthier. I continue to strive for 8 hours of quality sleep. I would like to end with a quote from Dr. Mathew Walker in his book Why We Sleep: “the best bridge between despair and hope is a good night’s sleep”.
Read the bio of Rania M. AlQenneh here.
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As mentioned in a previous blog, the integrative approach to many kidney diseases should be personalized, yet comprehensive. It starts with understanding an individual’s genetic predisposition, current and previous lifestyle choices and exposures, triggers of the current disease process, and unique nutritional status. In addition, it’s important to identify an individual’s spiritual, mental and emotional state. This type of approach can help the provider develop a personalized plan that includes attainable lifestyle modifications for the patient.
The ability of the patient to make these changes is the cornerstone of this tailored management plan. Although implementing and adhering to lifestyle modifications can be challenging, it’s not a reason to quit. In order to understand how to overcome these challenges, we talked about the brain and implementing changes in this blog. Understanding synaptic pruning and neuroplasticity can help us in this process.
Implementing Lifestyle Modifications
Now let’s utilize what we discussed above to help patients implement the lifestyle modifications we recommend for those with kidney disease. Of course, willpower varies from person to person. So, what we are suggesting here might not be for everyone, but we think the information is helpful.
Think about it
Now that we know that the brain is hardwired to follow habits, we can approach lifestyle habits without judging or beating ourselves up. The first step in implementing lifestyle modifications is to think about these changes. It will help to write down or talk to someone about the thoughts associated with these changes. Think about lifestyle habits that are currently working and any that are not in order to help identify patterns. Identifying these patterns can be a good starting point to help the brain perceive the need for change. Remember, the brain wants to be efficient and it will always default to the “pre-wired” unhealthy habits if we let it. So, spending extra energy and utilizing that pre-frontal cortex to teach the brain new things is required in the beginning.
Pick one thing
Once patterns have been identified, it’s best to implement one change at a time to avoid overwhelming the brain. It can be helpful to work with a provider or coach to devise a plan of action. Oftentimes, it is beneficial to start with easier changes, as successful implementation of the new habits can help build momentum. For example, an individual may decide an easy change would be to not snack or drink sugary beverages/alcohol after dinner. It is important to note that what is easy for one person may not be as easy for another, so personalization of an action plan is critical.
Plan it
Having a plan can make or break a person’s ability to stick with the new habits. It’s easy for the brain to default to old habits when there isn’t a plan in place. For example, using the weekend to plan out and/or prepare meals for the upcoming week can help ensure healthy eating habits during the week for someone who orders take-out when they get home tired after work. Taking the guess work out of things can set someone up for success.
Learn from mistakes
Let’s face it, mistakes can happen. They don’t indicate failure or give reason to quit. There may have been some variables that were not accounted for. It’s important to learn from mistakes and improve the planning process for the future.
Repeat, repeat, repeat
The most important step in making these modifications permanent is repetition. Repetition creates new patterns and neural pathways via synaptic pruning so that the brain will default to them instead of the previous unhealthy habits. The amount of time this takes depends on the individual’s willpower and commitment. This is not going to be easy but, as they say practice makes perfect.
The Bottom Line
Implementing lifestyle modifications is crucial in the fight against the chronic kidney disease epidemic and foundational to the integrative approach to kidney health. It can be a challenging process but understanding the brain’s efficacy and patterns can help individuals make the changes needed to lead a healthier lifestyle.
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