By Majd Isreb, MD, FACP, FASN, IFMCP
Exposure to Arsenic has been associated with increased risk for cancer and it is also linked to kidney disease. In this blog we discuss the sources of arsenic exposure, how our body handle arsenic, its effects on the kidneys, and the genetic and epigenetics of arsenic.
Sources of exposure
Drinking water appears to be the greatest source of arsenic exposure worldwide. In addition, exposure from ingested foods comes from food crops grown in arsenic-contaminated soil or irrigated with arsenic-contaminated water. Even if the water you drink is filtered and does not have arsenic, it is possible that the food that you eat is contaminated with arsenic, particularly rice. Arsenic is also found in high concentrations in cigarettes.
Even if the water you drink is filtered and does not have arsenic, it is possible that the food that you eat is contaminated with arsenic, particularly rice
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Found naturally in the environment, arsenic is mobile and cannot be destroyed. When arsenic compounds interact with oxygen or other molecules or bacteria it changes into different forms that can dissolve in water. Cosmetics and personal care products are another often overlooked major source of exposure.
How our body detoxifies arsenic
After ingestion or exposure, arsenic is metabolized and detoxified by a process called methylation. An enzyme called arsenic methyltransferase (AS3MT) adds a methyl groups to arsenic compounds to help neutralize it and eliminate it. This enzyme has been detected in human liver, kidney, bladder, heart, lung, testes and adrenal glands. Glutathione, known as the master antioxidant also plays a key role in arsenic detoxification.
The various arsenic forms bind to glutathione. The compound arsenic-glutathione can easily exit the cells and circulate in the blood. The glutathione-bound arsenic compound can be excreted by the kidneys or in the bile. The kidneys are the major site of elimination of arsenic and they are, therefore, highly exposed to it. Arsenic can also accumulate in the kidneys. Many transporters have been implicated in arsenic excretion in the tubules portion of the filtering units of the kidneys (the nephron). Inhibition or genetic changes in these transporters can lead to enhanced arsenic toxicity.
The kidneys are the major site of elimination of arsenic and they are, therefore, highly exposed to it. Arsenic can also accumulate in the kidneys.
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Interestingly, the water channel, aquaporin 3, has been found to increase the uptake of arsenic in the kidneys. These channels play a crucial role in water handling by the kidneys. They help our body preserve water. Increasing water intake decrease the incorporation of these channels to the cells of the tubules in the kidneys. Therefore, increasing filtered water intake can help decreasing the kidney exposure to arsenic.
Finally, a transporter called multidrug resistance transport protein 2 (MRP2) transport arsenic-glutathione complexes and excrete them out of kidney cells into the urine. Studies show that the increase in the production of glutathione and MRP-2 increase the body’s ability to detoxify arsenic. Selenium is important for this process and selenium deficiency can enhance arsenic toxicity.
Selenium and zinc deficiencies can enhance arsenic toxicity.
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Arsenic effects on the kidneys
Acute exposure of the kidneys to toxic levels of arsenic leads to inflammation in the tubules of the kidneys. This can lead to protein loss in the urine. It can also lead to elevated calcium levels in the blood. Arsenic exposure activates cell growth can lead to cancer. Arsenic can also lead to oxidative stress and cellular injury. Arjunolic acid (an anti-oxidant which is present in fruit specially guava) was found to decrease the toxicity of the arsenic on the kidneys. Zinc is also protective. Chronic exposure can lead to high blood pressure, protein loss in the urine, and chronic kidney disease.
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Genetics and Genomics Impact on Arsenic Toxicity
You can now see that various processes are involved in the handling of arsenic by the body from detoxification to transport to elimination. Genetic variants of any of these steps can either be protective or can increase arsenic toxicity. For example, a single nucleotide polymorphism (SNP), or genetic mutation, that increases glutathione production can be protective since glutathione helps to eliminate arsenic safely. However, a SNP in the gene that codes for MRP2 may potentially decrease arsenic excretion leading to increased toxicity.
Arsenic accumulation and toxicity can lead to oxidative DNA damage. It also inhibits DNA repair. This explains the increased risk for cancer after exposure to arsenic. Chronic exposure to even small concentrations of arsenic can have synergistic effect on other factors that can cause cancer such as UV light and smoking.
Arsenic exposure can cause indirect DNA damage through processes of DNA methylation and histone acetylation. These altered epigenetic expressions have been linked to kidney inflammation and damage. More recently, it was noted that long term exposure to low level of arsenic (below what is considered safe by the EPA guidelines) were associated with epigenetic changes that caused kidney scarring.
it was noted that long term exposure to low level of arsenic (below what is considered safe by the EPA guidelines) were associated with epigenetic changes that caused kidney scarring.
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The Bottom Line
Most arsenic exposure is due to drinking and showering with unfiltered water. Arsenic exposure leads to extensive cellular damage which increases the risk for cancer and kidney disease. Nutritional deficiencies can enhance its toxicity, but you can take steps to reduce your risks.
- Choose a home filtration device that effectively removes heavy metals, including arsenic. Not all consumer filters will remove arsenic, consider upgrading to Clearly filtered, Multipure and Aquasauna water filter systems.
- Always choose organic produce whenever possible, However, when it comes to rice and teas – organic isn’t enough. Look for products that screen for arsenic levels.
- Antioxidants are protective against arsenic damage, so a diet high in antioxidants like citrus fruit, green tea, blueberries, and dark chocolate will be naturally protective. Enhance detoxification by eating dark leafy greens, cruciferous veggies (like broccoli, kale, and cabbage), and sulforaphane-rich foods like garlic and onion contain high concentrations of nutrients that increase our detoxification capacity.
- Load up on fiber and mineral-rich root veggies, which help trap and eliminate toxins through your digestive system.
- There are several lifestyle modifications that can support improved detoxification, including Epsom-salt baths, sauna, lymphatic massage, sweat-inducing workouts, and dry brushing.
- If like many Americans you’re not having consistent daily bowel movements, you’re not adequately detoxifying and should consider working with a healthcare provider to address your digestion and motility.
Foot Note:
There are different forms of arsenic compounds. There are organic and inorganic forms with different oxidation states. The inorganic forms are easier to absorb by the gut and, therefore, are more hazardous. The most commonly ingested inorganic compounds are the trivalent and the pentavalent forms (depending on the level of oxidation). The trivalent forms appear to be the most toxic.
The post Arsenic and Kidney Health appeared first on Integrative Kidney.]]>2.2 million adverse drug reactions occur in the United States annually, and medication efficacy rates vary considerably. Pharmacogenomics offers the solution for safe and highly personalized drug therapy
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By Lara Zakaria, PharmD, CNS, CDN, IFMCP
Variability in response to pharmaceutical therapy is due to multiple, complex individual variations in basic physiological differences like age, sex, and weight, as well as metabolism, absorption, organ function, and disease state. These variables mean patients require monitoring, dose adjustments, and sometimes alternative therapy (drug switch).
This is why medications come in various doses, formulations, and options exist within a drug class. Prescribers follow “best practice guidelines” that allow them to choose an alternative when one drug therapy fails or is not tolerated due to side effects or ADR. But even with these well-researched guidelines, the choice and dosage of a medication can still be a guess.
Wouldn’t it be a relief to be able to predict in advance how someone might respond to medication, avoiding guessing, saving time, and improving patient outcomes?
Thanks to advances in the field of genetics called pharmacogenomics (PGx), clinicians are starting to use genetic information to personalize drug therapy. Though this has a broad range of benefits, our focus here will be on how this impacts those who have kidney disease (CKD) or kidney transplants.
Prescribers follow “best practice guidelines” … But even with these well-researched guidelines, the choice and dosage of a medication can still be a guess. Wouldn’t it be a relief to be able to predict in advance how someone might respond…
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Defining Pharmacogenomics
DNA is made up of a sequence of four nucleotides, (adenine, cytosine, guanine, and thymine). The genetic sequence serves as a template that our cells use to make thousands of proteins which are essential for carrying out all biological functions that maintain life. This includes the enzymes, receptors, and channels that are involved in the absorption, transport, and metabolism of drugs.
Alterations in the sequence, like single nucleotide polymorphisms (SNPs), or errors in the original code, may affect the efficiency of protein production. In turn, this may alter the efficacy or toxicity of a medication for an individual with that SNP.
When scientists began exploring pharmacogenetics in the 1950s, clinical research focused on connecting single genetic variations with a predictable outcome in drug therapy. In the last decade and a half, it has led to an evolution of pharmacogenomics, exploring the complex interplay of genetic and environmental influences on individual genetic expression.
Pharmacogenomics explores complex interplay of genetic and environmental influences on individual genetic expression
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Aside from being a relatively new area of focus, this nuanced difference is what makes “omics” research more challenging to translate into clinical application. Even though we’re only at the tip of the proverbial iceberg of this revolutionary approach to individualized medicine, useful clinical implications are already emerging, in particular when it comes to medications often used in kidney patients.
Last 20 years yielded a rapid influx of genomic data, with over 20,000 new #pharmacogenomics citations in PubMed, 3500+ gene-drug variant associations reported, and ~200 medications with FDA approved Pgx labeling
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Pharmacogenomics of kidney disease management
To date, there are approximately 300+ medications with FDA-approved PGx labeling recommendations. Of these, a handful is common in kidney disease patients. These categories include*:
- Cardiovascular Disease (CVD) – including clopidogrel (CYP2C19), simvastatin (SLOCO1B1) among other HMG-COA inhibitors, also known as “statins,” and warfarin (multiple, including CYP2C9, CYP4F2, VOKORC1, and potentially APOE, ABCB1, and UGT1A1)
- Transplant medications – including azathioprine (TPMT), tacrolimus (CYP3A4/3A5), and the antifungal agent voriconazole (CYP2C19)
- Hyperuricemia (elevated circulating uric acid) – allopurinol (HLA-B)
- Diabetes, with metformin being the most well-known (SNP rs11212617).
| Therapeutic Category | Drug | Genetic SNP |
| Cardiovascular Disease (CVD) | Clopidogrel | CYP2C19 |
| HMG-CoA inhibitors (statins) | SLOCO1B1 | |
| Warfarin | CYP2C9, CYP4F2, VOKORC1, and potentially APOE, ABCB1, and UGT1A1 | |
| Transplant medications | Azathioprine | TPMT |
| Tacrolimus | CYP3A4/3A5 | |
| voriconazole (antifungal agent) | CYP2C19 | |
| Hyperuricemia (elevated circulating urea) | Allopurinol | HLA-B*58:01 |
| Diabetes | Metformin | SNP rs11212617 |
* This is a list narrowed down limited to the strength of available evidence and relevance to KD by Adams et al.
The need for individualized therapy in kidney patients
Even when dosing is in line with best practice guidelines, they may still be sub-optimal or nephrotoxic (toxic to the kidney). Either situation for a transplant or KD patient may be life-threatening. Knowing in advance how a patient will respond to therapy means avoiding the cycle of “guess, assess and adjust,” saving valuable time.
Let’s use the medication tacrolimus, as an example. Tacrolimus is a very widely used and preferred immunosuppressant medication used in patients after a kidney transplant. Monitoring is very important because there’s a small margin of error for dosing. Due to this narrow therapeutic window, a little too much of the drug can quickly result in toxicity, while slightly under-dosing will be ineffective and potentially cause transplant rejection. Either situation can be life-threatening for a transplant patient.
Tacrolimus is metabolized by enzymes (part of the cytochrome P450 class) referred to as CYP3A4 and CYP3A5. It’s understood that individuals considered “hyper-metabolizers” – enzymes work faster than average to metabolize (break down) the drug – require higher dosing to achieve therapeutic efficacy. Meanwhile, slow metabolizers, require smaller doses to maintain safe and effective therapeutic levels. Because of the narrow therapeutic window, there is a small margin for accuracy, making these variations in metabolic functions particularly relevant to safety and outcome.
It’s interesting to note that there are various factors that influence CYP3A4/3A5 rate of metabolism. Use of other common medications like acetaminophen, clarithromycin, SSRI antidepressants (like fluoxetine and sertraline), and even caffeine, cannabis, and phytonutrient compounds naturally found in foods and herbs can also serve to up or downregulate the function of CYP3A4/3A5– further confounding or contributing to successfully achieving the narrow therapeutic window.
Another interesting example is the case of the transporter gene SLCO1B1 and its effect on statin therapy. This anti-cholesterol medication class (which includes simvastatin, rosuvastatin, pravastatin, etc) is well known for an ADR which causes muscle breakdown: rhabdomyolysis. Risk increases with increased blood concentration or dosage. Furthermore, muscle breakdown can add stress to the kidney.
SLOCO1B1 is responsible for transporting the drug out of the blood and into the liver for detoxification. In individuals with genetic variations that reduce the function of the transporter, accumulations are more likely to occur, and rhabdomyolysis is more likely even at lower drug dosage than typically expected. Combine this with environmental factors or combination drug therapy that may further slow detoxification, liver function, or drug clearance, and you can start to see how multiple factors may contribute to presentations of this ADR.
Should you get genetic testing?
There is a multitude of consumer tests offering direct-to-consumer genomic and health data like 23andMe, among others. The health reports are limited, and may omit some crucial lifestyle and epigenetic factors, but can be a good starting point. Raw SNP data can be obtained, but interpretation requires a strong understanding of clinical significance so working directly with a healthcare professional with appropriate training is strongly recommended.
There are also professional tests and reports available through your health care provider like IntellexxDNA and MyDNA. Your PGx-literate provider can help you choose the appropriate test, and most importantly guide you in recommendations once you have your results in hand.
It’s essential to remember that the field of PGx is relatively young and complex. When we talk about genetics, we cannot ignore the significance of epigenetics. In a previous blog, we discussed how dietary and lifestyle modifications can affect expressions of these genetic traits.
Another related emerging field is nutrigenomics– a cousin to PGx – focusing on the effect of nutrients on genetic expression. When interpreting emerging findings in omics, clinicians must take into consideration the effect of factors like nutrition, herbal use, as well as environmental toxins, and medication on epigenetics expression. The individualized and integrative approach to managing kidney disease will rely on the nephrologists, pharmacists, and clinical nutritionists of the not-so-distant future working together to layer those factors to maximize therapeutic benefit and reduce harm to patients.
The post Pharmacogenomics: Advances in Individualized Treatment in Kidney Disease appeared first on Integrative Kidney.]]>