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An interesting question came up recently in a Hyponatremia forum regarding why someone with SIADH specific gravity (concentration of urine) would be so varied. If I can still concentrate and dilute my urine why then do I still suffer from Hyponatremia, she asked. While the answer, of course, is far from simple one obvious conclusion is well you probably have type A. There are 4 types of SIADH. 1. Variable and erratic vasopressin release. 2. Low level basal continuous secretion. 3. A reset osmostat type which responds normally just at a lower set point. 4. The so called Nephrogenic SIADH where a gain of function mutation at the V2 receptor leads to a constant ADH like effect. This has low levels of vasopressin.  The 4 types of SIADH The most obvious next question is does this change the management? I would say absolutely yes. The typical erratic SIADH type A and constant type B would require the usual approach. This is fluid restriction, high protein diet, UreaAide, Vaptan and so forth. If you however have the reset osmostat, type C, you may have more difficulty in achieving a normal sodium level, and perhaps not as imperative we do so. Lastly type D, for example will be completely unresponsive to vaptan therapies.
In closing most folks with SIADH likely fall into type A or B SIADH, but reset osmostat maybe more challenging to treat chronically and type D although rare, will not respond to typical therapies. Thus concluding yes type does matter. 1. Hyponatremia secondary to the SIADH: Theraputic decision-making in real-life cases. October 2013 CKJ. 2. UpToDate SIADH diagnosis and treatment. Accessed July 5, 2021. 3. Credit Hyponatremia support group Facebook group for the great question.
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Urea is a medical food, used for the treatment of Hyponatremia (low sodium). Urea works by osmosis. It draws excess water out via the kidneys, resulting in increased sodium levels without the need for salt tablets and/or extreme fluid restrictions. Medical foods, like UreaAide, can be purchased directly by patients without a prescription, but should only be taken under the supervision of a medical provider. Hyponatremia is a common medical condition that is diagnosed by a simple blood test. Your medical provider may also order urine tests. Most often, Hyponatremia is due to the inability of the body to excrete excess water. This excess water accumulates in the blood, dilutes the sodium level, and leads to low serum sodium. The signs and symptoms of Hyponatremia may include: Headaches Drowsiness Falls Disturbances in bone health/Osteoporosis Slow reaction time Seizures Brain swelling And even death2 UreaAide, is a form of urea distributed by Kidneyaide. We currently offer two varieties. Firstly, the individual dose packets that have a natural, refreshing mint flavor. These packets are convenient and easy to use. Secondly, we offer an unflavored urea in a multidose, resealable package with dosing scoop. This option offers patients a lower cost alternative and allows them to add their own flavoring.  The FDA defines a medical food as: "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation."1 The FDA goes on to say "Medical foods are not those simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition."1 A medical food therefore, must be given under the supervision of a medial provider for a specific disease process. Medical foods are not drugs and are not under the same guidelines as a pharmaceutical. They are treated more like a dietary supplement. There are strict label requirements including: Name of product Net contents Complete List of ingredients in descending order of predominance Name and location of business  Label requirements met for a medical food including: Name, Net Contents, Complete list of ingredients, and location of business. ,Medical foods also must comply with all the manufacturing guideline of any foods in the United States. This includes an FDA registered facility, current good manufacturing practices, and proper packaging.
What about a prescription? This is an excellent question that comes up a lot especially for our products UreaAide packets and UreaAide unflavored. As these are medical foods and not drugs, a prescriptions is not necessary to purchase. We sell direct to consumers which actually saves money by cutting out the middle man (pharmacies). Having said that this also means getting medical foods covered by insurance can be difficult. Often, if covered, this would be under the medical benefit and not the pharmaceutical benefit. Are medical foods a qualified Medical expense? Will my HSA/FSA/MSA cover it? Medical foods are a tax deductible qualified medical expense with any tax differed health account. This is discussed in the publication 502 by the IRS.2 Herein they state the following criteria to meet coverage: 1. The food doesn't satisfy normal nutritional needs 2. The food alleviates, or treats an illness 3. The need for a food is substantiated by a physician This is by definition a medical food such as UreaAide for the management of Hyponatremia (low sodium). What about a National Drug Code number (NDC)? This is interesting, the FDA actually states medical foods should NOT have a NDC number as this could be considered misleading to consumers, as they are not drugs.1 They go on to say: "The presence of an NDC number on a food product that is not a drug misbrands the product under section 403(a)(1) of the FD&C Act. In addition, any representation that creates an impression of official FDA approval through the use of an NDC number in labeling constitutes misbranding.1 In closing medical foods are non-prescription supplements that can be purchased directly. They should be taken only under the supervision of a medical provider but must have certain labeling and manufacturing requirements. Medical foods are qualified medical expenses and any health saving account may be used to purchase. Medical foods may be covered by insurance companies but not typically. If they are covered it would usually be under the medical benefit and not the pharmaceutical benefit. References: 1. FAQ about medical foods second edition. FDA. https://www.fda.gov/media/97726/download 2. Publication 502. IRS. Qualified Medical Expenses https://www.irs.gov/pub/irs-pdf/p502.pdf  Reset osmostat is a sub-type of SIADH (type C in the nephrology literature). It is essentially your body having a higher threshold for low sodium. In other words your body will allow the sodium to run lower, to a lower set point than what is typical1. As you drink water, under normal circumstances, the body will suppress ADH and your kidneys will release that water, keeping blood sodium levels in a narrow range. In SIADH this does not occur and high water intake dilutes the sodium. In reset osmostat only as the sodium tracks closer to normal does that secretion of ADH take hold. Due to this those with reset osmostat tend to stay consistently in the 125-135 mEq/L serum sodium range. This is a new normal for that individual patient, and the system is still intact just at a lower set point. This phenomenon is actually a normal occurrence in pregnancy. Some clinical clues to the diagnoses of Reset Osmostat include1,2:
•Sodium in the 125-134 range for several days despite varying water and salt intake •Fractional Excretion of Uric Acid in the normal 4-11% range •Rule out primary polydypsia •Greater than 80% of a water load (20 ml/kg) excreted in a 4 hour period (low urine osm) The idea is this is asymptomatic and no definitive treatment is absolutely indicated. However most clinicians would still try to correct the sodium based on the fact that even mild Hyponatremia is correlated with significant morbidity and mortality. 1. Indian J Nephrol. 2019 Jul-Aug; 29(4): 232–234. 2. Ten common pitfalls in the evaluation of patients with hyponatremia Filippatos, T.D. et al.European Journal of Internal Medicine, Volume 29, 22 - 25 We realized we could really bring the cost down if we sold our same USP grade Urea but just left it unflavored. Before KidneyAide there was only one company making one Urea in the entire US. We loved how well Urea worked to bring sodium levels up, but didn’t love the cost for our patients. This backdrop is the reason for our existence. Could we lower the cost and still provide a high quality product? We were able to accomplish this goal with our UreaAide 15 gram premium natural mint flavored packets. We cut the cost to the consumer by 30%. The hard part, however, is that for many that is still quite a bit of money as insurance often will not cover the cost. Given our simple mission to help lower the cost of Urea, we had to do more. Recently we were testing some new flavors, mixing Urea with berry, chocolate and even coffee. We had some blue Gatorade powder and thought, wonder if we simply mixed Urea powder with Gatorade powder. The same kind you can buy at Walmart or Target. Well we had to admit, this tasted pretty darn good. We were impressed and realized, we could really bring the cost down if we sold our same USP grade Urea and just left it unflavored. When we asked our customers and showed them the over 60% cost savings plus they can chose any flavor they like, people were excited. UreaAide unflavored was born. 30 doses per bag with easy 15 gram dosing scoop. The Urea won’t clump as they are in microspheres not crystal form. The bag is aluminum Mylar, easy-open and resealable, making it durable and long lasting. UreaAide unflavored, just like UreaAide packets are made in an FDA registered, cGMP facility in the United States. So check us out and get out of the low salt brain fog. As we like to say: “Fix your sodium simply, safely, and effectively for less with UreaAide unflavored Urea.”   A study in the journal of Bone and Mineral Research published in 2010, sought to answer this very question. We already know low sodium is linked to falls and imbalance so if it also causes bone weakness it’s a pretty scary proposition. We also know about 1/3 of total body sodium is in the bones so if your blood sodium is low it’s likely leeching out from your bones to compensate.
The investigators initially looked at a rat model of Hyponatremia (low sodium). They discovered that after only 3 months the bone density was decreased by 30% compared to rats with normal sodium levels. Microscopically what they realized is the low sodium seemed to cause more bone break down and less bone building. This was quite concerning and so they next turned to human data. The investigators looked at a large cohort of adults aged 50 plus (called NHANES 3), and did some predictive modeling. They discovered a striking 2-3 fold increased risk of osteoporosis in the low sodium group. Another study published in 2015 in the journal of Clinical Endocrinology and Metabolism found similar results. These investigators looked at a very large cohort of US adults. They used regression models to look at the odds of both recent and chronic low sodium and osteoporosis. They found similarly a 3-4 fold increase risk of osteoporosis and low sodium. They also noted the lower the sodium and the longer the sodium was down the higher the risk for osteoporosis. This data plus the known increased fall and fracture data confirms that even mild Hyponatremia should be treated and monitored closely with special care and attention to overall bone health. To find good affordable treatment option for low sodium check us out KidneyAide.com Here’s links to the articles https://pubmed.ncbi.nlm.nih.gov/19751154/ https://academic.oup.com/jcem/article/100/8/3021/2830001?login=true  Hyponatremia may be associated with Hypothyroidism (low thyroid levels/function), especially with severe hypothyroidism and myxedema. Myxedema is a constellation of symptoms associated with severe hypothyroidism including:
•Confusion •Swelling •Hypothermia (low body temperature) •Bradycardia (slow heart rate) •Hypotension (low blood pressure) •Hypoglycemia (low blood sugar) With this being said thyroid function is often checked, with a simple blood test, to be sure this is not the cause of the low sodium level. In those with myxedema, it’s the decrease in cardiac output which leads to the release of ADH (anti diuretic hormone) via carotid sinus baroreceptors. The ADH release is the signal that tells the kidney to reclaim and hold on to water, which ultimately dilutes the sodium level in the blood. Slower kidney function (GFR) may also be contributing via the kidneys inability to excrete excess water properly. It is interesting however, that often these hypothyroid cases mimic SIADH, with high, rather then low urine sodium, despite the low cardiac function. In closing, we want to be sure that thyroid levels are tested as part of the workup for SIADH/Hyponatremia. Useful links and sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470237/#__sec2title https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450783/ https://www.webmd.com/a-to-z-guides/myxedema-coma#2-3 https://www.aafp.org/afp/2000/1201/p2485.html https://healthjade.net/myxedema-coma/ INTRODUCTION: HYPONATREMIA SIGNS AND SYPMTOMS. Hyponatremia, low blood sodium level, is a relatively common condition. Hyponatremia is the most common electrolyte disturbance to impact patients in clinical settings1. Most often, Hyponatremia is due to the inability of the body to excrete excess water. This excess water accumulates in the blood, dilutes the sodium level, and leads to low blood sodium levels. The effects of Hyponatremia and low blood sodium levels include:
WHAT CAUSES THE BODY TO HOLD WATER TOO TIGHTLY? There are many possible Hyponatremia causes. The way I like to explain it is to consider our evolution. When we were living in the stone ages and a saber tooth tiger was chasing us, or we were under a great deal of stress due to difficulty finding clean water sources, our body was programmed to hold water tightly, to avoid dehydration. Fast forward to 2020, and we find different ‘stressors’ that may signal the body to hold water to tightly. These 'stressors' include:
The hormone that is secreted in these disease states is called Anti-Diuretic Hormone (ADH). ADH does just what its name implies; it is anti-diuresis (urinate). The urine turns dark and concentrated, and water excretion comes to a near halt. HYPONATREMIA TREATMENT For starters, we must be sure there aren't other reasons for the dilution effect. Examples of this include heart failure and liver disease. Both can cause fluid retention due to different mechanisms. These diseases are often treated with a low sodium diet and diuretics (fluid pills). Hyponatremia may also be caused by excessive water intake relative to solid food intake. This is termed primary polydipsia or tea and toast. These diseases are treated with simple fluid restriction and an increase in food intake. Let's think back to the causes of Hyponatremia. Now that we have talked about the other processes, the term SIADH always gets brought up. This is a syndrome of inappropriate antidiuretic hormone release. A bit confusing, but if you follow the name, it is an improper release of the hormone that does not allow the kidney to release water. This is what occurs in those examples, as mentioned earlier, the lung disease, brain disease, pain, or nausea scenarios. SIADH will therefore cause the kidney to hold water inside and not release it, diluting the sodium level in the blood and lead to some of those ominous symptoms. To treat this SIADH process, we must start with a fluid restriction as a part of a Hyponatremia diet. Usually, this would be about 1 liter (32 oz) or less per day. This does include all liquids and not just water. Often that is not enough, and the patient will require further interventions. In previous days we may have used diuretics and salt tablets for Hyponatremia, however more recent studies have shown this to be somewhat ineffective when compared to fluid restriction alone and have significantly more side effects.3 More recently, Tolvaptan has come to market. Tolvaptan is an oral antagonist (blocker) of the ADH receptor in the kidney. This medication works by blocking the signal and thus allowing the body to expel all that excess water.However, this medication's downsides are high cost at over $300 a tablet and low but severe liver injury potential. There are also side effects, including overcorrection of the sodium level (which can be quite dangerous), urinating excessively at night, and extreme thirst with Tolvaptan. Lastly, there is oral Urea for the treatment of SIADH. Urea works by osmosis. It draws water out naturally through the kidney, ridding the body of excess water without the need for salt tablets or extreme fluid restrictions. Urea is a medical food and is thus allowed to be purchased directly by the patient without a prescription. Medical foods like Urea should be taken only under the supervision of a medical practitioner. Urea has minimal if any side effects. It truly is a natural product, medical food, and not a pharmaceutical agent. Urea has a somewhat intense, slightly salty taste and is thus best made palatable by flavorings. Our company, KidneyAide.com, distributer of UreaAide, is an example of this with a natural refreshing mint flavor, dosed in individual packs, and easily purchased online. We have expanded our options further and now have a lower cost multi-dose unflavored UreaAide Urea that can be mixed with any powdered flavor you like. In closing, Hyponatremia or low sodium is a common disorder that may cause multiple vague symptoms which only a blood test can detect. A thorough investigation is necessary to tease out the reason for the disturbance. There are several ways to treat Hyponatremia. With the example of SIADH fluid restriction, urea products such as UreaAide, Tolvaptan, or salt plus water pills may all be options to help rid the body of excess water and get the sodium level back into the normal range. Thus alleviating the symptoms of low sodium and getting back to feeling great again. Citations 1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006 Jul;119(7 Suppl 1):S30-5. doi: 10.1016/j.amjmed.2006.05.005. PMID: 16843082. 2. Goce Spasovski, Raymond Vanholder, Bruno Allolio, Djillali Annane, Steve Ball, Daniel Bichet, Guy Decaux, Wiebke Fenske, Ewout J. Hoorn, Carole Ichai, Michael Joannidis, Alain Soupart, Robert Zietse, Maria Haller, Sabine van der Veer, Wim Van Biesen, Evi Nagler, on behalf of the Hyponatraemia Guideline Development Group, Clinical practice guideline on diagnosis and treatment of hyponatraemia, Nephrology Dialysis Transplantation, Volume 29, Issue suppl_2, 1 April 2014, Pages i1–i39 3. Efficacy of Furosemide, Oral Sodium Chloride, and Fluid Restriction for Treatment of Syndrome of Inappropriate Antidiuresis (SIAD): An Open-label Randomized Controlled Study (The EFFUSE-FLUID Trial) Krisanapan P., Vongsanim S., Pin-on P., Ruengorn C., Noppakun K. (2020) American Journal of Kidney Diseases, 76 (2) , pp. 203-212.   1. Urea’s molecular formula is CO-(NH2)2. Pubchem.
2. Urea is also known as Carbamide, 57-13-6, Carbonyldiamide, IsoUrea. Pubchem 3. Urea is found naturally in our skin and is one of our body’s natural moisturizers. Many skin care products contain Urea at various percentages, Eucerin 10% Urea is an example of one. 4. Urea has a molecular weight of 60.056 g/mol very similar to Sodium Chloride 58.44 g/mol (that’s why 1 packet of 15 g UreaAide is equal to ~7 salt tablets). 5. Urea is formed naturally in the liver. The liver, via the urea cycle, takes 2 toxic Ammonia molecules from protein breakdown plus Carbon Dioxide to form 1 Urea molecule. Urea May then be excreted safely through the urine. 6. An IV formulation of Urea Ureaphil (40 grams/vial) was available, and first used in the 1960’s for increased intracerebral pressure. Ureaphil was later discontinued in 2006, as other products like mannitol came on to market. 7. Urea 13-C is a radiolabelled urea molecule used in the diagnosis of stomach ulcers by the bacterium Helicobacter Pylori. H. Pylori contains the enzyme Urease which will break down Urea to Ammonia and radioactive C02 where the CO2 can be detected in the breath. C-13 Urea breath test 8. Urea is considered extremely safe and there are no reports, to our knowledge, of Osmotic Demyelination with the us of Urea for Hyponatremia. 9. Urea has been used for SIADH since at least 1980 where G Decaux et al. showed it’s effectiveness and published the data in the American Journal of Medicine. 10. Over 90% of oral Urea is absorbed in the upper GI tract. Urea has a half life of only about 2 hours, and an oral dose of Urea is completely excreted by the kidneys by 12 hours. Blood Purif 2020;49:212–218  Pseudohyponatremia, as the name implies, is not what we consider true hyponatremia. In fact, it is a laboratory error (pseudo-greek derivation meaning false; feigned). When serum sodium is measured with the standard indirect ion-selective electrode (ISE) method it is measured in an aqueous solution, diluted, and there is always an assumption that plasma is precisely 93% water. When the samples are analyzed and something in the sample is "displacing" the plasma water, then the actual amount of sodium detected will be lower. What can displace the plasma water? Lipids, as in a very high triglyceride levels for starters. These elevated triglyceride levels, typically >1500 mg/dl, are often seen in conjunction with pancreatitis. Elevated proteins may also lead to Pseudohyponatremia; typically seen with diseases like Multiple Myeloma with total proteins in excess of 10 g/dL. Lastly, in severe biliary obstruction we may see very high levels of cholesterol and lipoproteins (lipoprotein x) usually with cholesterol levels over 1000 mg/dL.
This error can be avoided if a whole blood sample is drawn and analyzed with direct ion-selective electrode like the arterial blood gas method. Because this is not true hyponatremia, the treatment is directed at the underlying process and not on the low sodium. |
AuthorDr. Barry is a board certified Nephrologist, Internal Medicine, and certified Hypertension Specialist. Archives
July 2021
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