Chelation therapy is gaining recognition. During such treatment, metals are removed from the system by converting them to a chemically inert form that can be excreted. The chemical agents used to accomplish this are administered orally or intravenously; and to practice safely, specific laboratory diagnostics must be considered.

Parenteral Chelation: Which Renal Function Test?

The parenteral administration of chelating agents requires a healthy renal system. While experienced physicians have noted that a slightly compromised renal function does not necessarily need to exclude chelation therapy as an option, it is advised not to use IV chelation when renal function is impaired. Before the first treatment involving any type of parenteral chelation, it is essential to evaluate renal function. When renal function is impaired, parenteral chelation with chemical chelating agents such as EDTA or DMPS may not be the treatment of choice, especially by an inexperienced therapist. The following are some of the basic renal function tests.

Purpose of the Tests

• To evaluate kidney function and aid in the diagnosis of kidney disease.
• To monitor the progression of renal insufficiency.
• The BUN-to-creatinine ratio may aid in the evaluation of a person’s state of hydration.

Special Concerns

• A diet rich in meats can cause transient elevations of serum creatinine and creatinine clearance.
• A high-protein diet or dehydration elevates BUN levels.
• Exercise may increase creatinine clearance.
• Some medications may affect BUN levels, serum creatinine, and creatinine clearance.

If a renal function test, such as Serum Creatinine is borderline high or high, a more in-depth evaluation is needed.

Below is a list of renal function tests aiming to create an understanding of function and necessity. Bevor laboratory diagnostics are implemented, evaluate the patient’s medication and renal history.

Creatinine, General Information: Creatinine is a waste product of muscle metabolism and of creatine phosphate, the chemical that is produced by the body to supply energy, mainly to muscles. Age, ethnicity, gender, height and weight are used to calculate the creatinine level.

Creatinine is excreted exclusively by the kidneys, and its level in the blood is proportional to the glomerular filtration rate (GFR). When kidney function is impaired, less creatinine is excreted, thus its concentration increases in blood. Variations from normal creatinine levels could indicate kidney dysfunction and muscle problems (like rhabdomyolysis).

Serum Creatinine: The serum creatinine concentration is dependent on muscle mass, the patient’s sex and age, race, and the amount of dietary protein consumed. In general, a serum creatinine test can give a good estimate of the actual glomerular filtration rate (GFR). It is the screening test most recommended for evaluating renal function. If results are doubtful, Cystatin C should be used to ascertain renal function.

Cystatin C: This is a low-molecular weight protein produced by all cells of the body with a nucleus. Unlike creatinine, cystatin C is not significantly affected by muscle mass, race, or diet.

When released into the blood, cystatin C is freely filtered in the kidneys. After glomerular filtration, cystatin C is reabsorbed and broken down at a constant rate. When kidney function is impaired, less cystatin C is excreted, and its concentration increases in the blood.

Cystatin C (in serum) could replace Serum Creatinine. It is recommended when renal function is not clearly established.

Urine Creatinine: This test reflects on fluid intake and renal function. A urine creatinine level of 0.8 to 1.2 g/L is considered normal for an unchallenged urine sample. A level below 0.8 indicates that the sample is diluted. The higher the fluid intake (through infusion fluid or drinking), the lower the urine creatinine level.

This test is commonly part of a urine metal analysis evaluation. It is used to calculate milligram or microgram per liter measurements to milligram or microgram per gram creatinine. This conversion reduces the potentially great margin of error that otherwise can result from a faulty sample collection and an incorrect sample volume.

A urine creatinine value of < 0.3 g/L is internationally used as the low borderline level for the conversion of test values to mg/g and mcg/g creatinine. When lower creatinine levels are measured (usually due to a high fluid intake during urine collection time), the borderline value of 0.3 g/l is used for the conversion.

If a challenged urine sample shows creatinine levels higher than those seen in the unchallenged baseline urine, dehydration and/or kidney stress is indicated.

Creatinine Clearance: Usually a 24-hour urine collection is collected for this test. Note: The twenty-four-hour creatinine clearance overestimates GFR in patients with poor renal function.

Glomerular Filtration Rate (GFR): The GFR measures how much creatinine is in the blood and how much of it reappears in the urine. It is an overall indicator of kidney function. Age, ethnicity, gender, height and weight are used to calculate the GFR.

• Blood sample: Blood collection should be done simultaneous with urine collection and can be drawn at the beginning or end of the urine sample collection. A blood sample that has been collected in previous days is not suitable for the creatinine clearance test.
• Calculate creatinine clearance (glomerular filtration rate – GFR) from a timed urine collection (time, volume, and creatinine concentration), and plasma creatinine. In pediatrics, it is generally corrected to a body surface area of 1.73 m² (standard body surface area of an adult). Most laboratories provide the calculated rate.
• The National Kidney Foundation website allows you to simply calculate the GFR https://www.kidney.org/professionals/KDOQI/gfr_calculator
• Also see https://www.calculatorpro.com/calculator/gfr-glomerular-filtration-rate-calculator/

The exact value of GFR is difficult to determine. eGFR is estimated using equations based on serum creatinine or cystatin C levels.

Blood urea nitrogen (BUN): This test provides a rough measurement of the glomerular filtration rate, the rate at which blood is filtered in the kidneys. Urea is formed in the liver as an end-product of protein metabolism. Urea is carried to the kidneys for excretion and nearly all kidney diseases show an inadequate urea excretion, resulting in elevated BUN levels in the blood. Other causes of high BUN levels include gastrointestinal bleeding and steroid treatment.

What Tests Prior to Oral Chelation Treatment?

Oral chelators such as DMPS, DMSA and d-Penicillamine have a history of use. These chelating agents are swallowed, generally on an empty stomach. Oral chelators first pass through the gastrointestinal (GI) tract, the first binding site. Metals found in the GI tract are bound, forming metal-chelates, which are easily excreted via feces and also via urine.

It thus makes sense to start any type of oral chelation treatment with a GI cleanse, including liver and colon support. It should be noted that metal-chelate bonds are strongest in a slightly alkaline environment. Lactobacillus acidophilus and other probiotics are microorganisms that are able to improve pH and/or restore the gut flora. Probiotics are considered generally safe to consume but may cause bacteria-host interactions and unwanted side effects in rare cases.

Constipation or diarrhea must be treated prior to oral chelation, or else the patient may experience side effects such as intestinal cramping.

Liver function test might be recommended prior to chelation.

Sensitive patients should be started with a dose lower than the recommended one. For example, for DMSA the recommended oral dose is 10 mg/kg BW. A sensitive patient may have to be started with a starting dose of 50 or 100 mg. If no negative reaction is noted, the dosage can be increased according to body weight, age, condition, medical and pharmaceutical recommendation.

The absorption rate and binding ability of oral chelators is lower than that of those applied parenterally. For example: the binding ability of 250 mg DMPS applied orally is approximately 50% of the equal dose administered parenterally.

A body suffering from chronic metal exposure problems developes symptoms over time and often adjusts to its toxic environment. To slowly reduce a system’s toxic burden will take time, but the body appreciates a gentle reversal of its chronic condition to health.

The efficiency of the metal detoxifying process can be determined through urine and fecal testing.

Fecal Metal Test: Testing maybe performed before and/or after oral chelation treatment. A comparison of pre- and post-results will indicate how effectively metals are bound in the GI tract. Patients suffering from digestive disorders (liver, colon etc.) must be carefully evaluated before oral chelator are given.

Pre-Sampling Suggestions

• Take probiotics, one to three times daily for one to two weeks prior to oral chelation.
• Four days prior to chelation, stop consuming fish and algae products such as chlorella.
• Two days prior to chelation, stop taking nutritional supplements or metal-containing medications (such as antacids), unless medically needed.
• Make sure the patient had a good bowel movement prior to chelation.
• On the day of chelation, give the oral chelator with one glass of water (200 ml room temperature) on an empty stomach unless otherwise indicated.
• For most oral chelators, DMSA included, the main metal binding will occur during the first three to six hours. after intake. Provide one more glass of water during that time. No tea or coffee should be consumed.
• Two hours after the intake of the chelator, bread, fruit, or a boiled egg may be eaten.
• After sample taking is completed, the patient should drink enough water. He may eat normally.
• Pre-Chelation Sample:

1. Before the fecal sample is taken, write patient name on the test tube provided by the laboratory.
2. Place clean toilet paper or a paper towel in the toilet to collect some feces.
3. Use spatula to fill one or two scoops of fecal matter into the test tube provided by the laboratory. Leave spatula with fecal sample in test tube. Do not fill up test tube.
4. Make sure the test tube containing the stool sample is tightly closed. Place it in the protective cover and send with patient information to the laboratory. Overnight shipping is not needed.

Chelation Sample: After the oral chelator intake, collect some of the first stool sample. This should not be sooner than three to four hours after the oral chelator intake. Follow Step 1 to 4 as outlined under Pre-Chelation Sample.

After sample taking is completed, the patient can resume his normal food and fluid intake. Please note that a sufficient water consumption helps to flush the renal system.

A comparison of test values will demonstrate how the oral chelator affected metal binding in the GI tract. For instance, if the arsenic concentration is higher before chelation, this indicates that some form of arsenic was ingested before chelation. If the arsenic concentration is higher in the post-chelation test, we can assume that the arsenic-excretion increased due to oral chelation process.

Urine Tests to Evaluate Metal Chelation

Urine is a liquid waste product. This fluid produced by the kidneys consists of excess water and the toxic waste products from food and drink. It normally is a clear, transparent fluid of amber color. The urine of an inadequately hydrated person is more concentrated and darker in color, while the urine of a well hydrated person is light. The more hydrated a person is, the more watery the urine. When taking riboflavin-containing B-vitamins, urine turns dark-yellowish. After the consumption of red beets, urine turns purplish red, because the beet color is not metabolized by the body, and thus excreted as is.

The average amount of urine excreted in 24 hours is from 40 to 60 ounces (about 1200 cubic centimeters or 1.2 liters). Chemically, the urine is mainly an aqueous (watery) solution of salts (sodium chloride and other metals), urea and uric acid. Normally, urine contains about 960 parts of water to 40 parts of solid matter. Abnormally, it may contain sugar (in diabetes), albumen (as in some forms of kidney disease), bile pigments, or abnormal quantities of one or another of its normal components.

Urine contains minerals, trace elements, including toxic ones and is, in most cases, an easy-to-obtain material. When we compare a nonchallenged versus a challenged urine sample, we assess the chelating agent’s effectiveness and the detoxification process.

Following is an excerpt from Margret E. Sears’ “Chelation: Harnessing and Enhancing Heavy Metal Deotxification – A Review,” published online at Scientific World Journal (April 18, 2013). This review clearly states the importance of comparing levels of metals in urine before and after the administration of chelating agents.

One of the most effective methods to evaluate net retention, or at least the biologically readily available metal load, is to compare the levels of metals in urine before and after the administration of a pharmaceutical chelating agent such as CaNa₂EDTA, DMSA, or DMPS (Hoet 2006) Variously known as “mobilization,” “chelation challenge,” or a “provocation” test, this procedure is not universally accepted as standard of care. Criticisms have included risks of the chelating drugs, and inappropriate comparisons of the provocation results with population norms rather than with patient baseline concentrations [85]. Indeed, some go so far as to say that any testing for metals when the exposure has not been identified; that is, when there is no reason for suspicion based upon known environmental history that toxins may be elevated, is inappropriate because of the possibility that false positives may lead to inappropriate, ineffective therapies and their attendant risks (Hoffman 2007). The use of chelation for diagnostic purposes, following dental amalgam removal or in asymptomatic patients with baseline urine or blood levels approximating population norms was deemed inappropriate in 2005 by staff of the Agency for Toxic Substances and Disease Registry (Risher 2005). Another criticism of use of a provocation test to judge net retention is the lack of a standard protocol, and laboratory reference ranges or guidance for interpretation of results (Brodkin 2007). Nevertheless, these shortcomings do not fundamentally invalidate the concept; work in this regard has started. Hansen et al. established such norms for protocol involving an oral DMPS test with four-hour urine collection, among 2223 citizens in Luxembourg (Hansen et al).

Pre- and post-challenge testing may allow the clinician to identify which chelating agent is the most effective for the patient, and if oral agents are employed, possible absorption or tolerance problems may be identified. An open research question has to do with changes in metals excreted over an extended course of chelation treatments; whether in a person with high levels of multiple metals, one will be preferentially chelated initially, with a second then third being excreted over time with repeated treatments. This research would aid interpretation of chelation challenge tests, as well as enhance knowledge of chelation therapy itself.

Comparison of baseline and provoked urine levels is entering standard practice and was used to determine inclusion in a trial of chelation therapy for children with autism. In this trial, however, a few children experienced worsening symptoms. Such worsening is ascribed to redistribution of toxic metals, with insufficient excretory mechanisms in place, leading some practitioners to prefer unprovoked analyses up front, in sensitive, fragile patients. Therapy may be guided by parental, caregiver, and patient observations.

Baseline Urine Collection Protocol

Before the chelator is administered, patient must void bladder. Of that a small sample of 5-7 ml is collected and serves as the baseline urine.

If a 24-hour collection is needed, follow this procedure unless told otherwise.

• You will be given 1 or more containers for collecting and storing your urine. A brown plastic container is typically used. You will need to transfer the urine from the collecting container to the storage container. You will need to keep it cold.
• The 24-hour collection may start at any time during the day after you urinate. But your healthcare provider may tell you when to start. It is common to start the collection the first thing in the morning. It is important to collect all urine in the following 24-hour period.
• Don’t save the first urine. Flush this first specimen and make a note of the time. This is the start time of the 24-hour collection.
• All urine, after the first flushed specimen, must be saved, stored, and kept cold for the next 24 hours.
• After 24 hours (of the start time) try to urinate to finish the collection process. No problem if you can’t urinate at this time.
• Once the urine collection has been completed, a small (5-7ml) sample of the urine needs to be taken into a test tube provided by the lab. To do this, gently shake/invert the container before you use the syringe to draw the needed 5-7 ml of urine into the tube. This is the sample needed for the metal test.

Note: A 24-hour urine collection is a safe, easy test. People can collect urine on their own, but certain factors may affect the accuracy of a 24-hour urine collection. These include the following:

• Forgetting to collect some of your urine
• Going beyond the 24-hour collection period and collecting too much urine
• Losing urine from the specimen container through spilling
• Not keeping urine cold while collecting it
• Acute stress
• Vigorous exercise
• Certain foods, such as coffee, tea, cocoa, fish, algae and supplements may be high in minerals or trace elements.

The Urine Challenge (Provocation) Test

• Before the chelation agent is administered, the patient should empty his/her bladder.
• Thereafter, it is best not to urinate for the duration of the chelation treatment i.e. allow urine to collect in the bladder. If this is not possible, urine should be collected in a clean container.
• The Urine Collection time for most chelators is the chelator’s half-life plus the time it takes to administer it. Specifics are listed under each chelator.
• For specifics about the consumption of food or drink during the chelation treatment, see information as provided for the individual chelating agent.
• After the infusion time is finished and if patient collected urine in the bladder, he/she can urinate directly into a small urine cup. Of that 5-7 ml is needed for the post urine metal test. Specifics are listed under each chelator.
• For the remainder of the day, the patient should drink plenty of water and eat normally.

A comparison of metal excretion values before and after chelation indicates the effectiveness of the chelation treatment

References

Brodkin E, et al. Lead and mercury exposures: interpretation and action. Canadian Medical Association Journal. 2007;176(1):59–63.

Hansen G, et al. Evaluation of the mercury exposure of dental amalgam patients by the Mercury Triple Test. Occupational and Environmental Medicine. 2004;61(6):535–540.

Hoet P, et al. Clinical evaluation of a lead mobilization test using the chelating agent dimercaptosuccinic acid. Clinical Chemistry. 2006;52(1):88–96.

Hoffman HE, Buka I, Phillips S. Medical laboratory investigation of children’s environmental health. Pediatric Clinics of North America. 2007;54(2):399–415.

Lorscheider F, Syed N. How Mercury Causes Brain Neuron Degeneration. University of Calgary Faculty of Medicine Dept. of Physiology and Biophysics 2008. https://www.youtube.com/watch?v=BtFsy0rQsak

Risher JF, Amler SN. Mercury exposure: evaluation and intervention. The inappropriate use of chelating agents in the diagnosis and treatment of putative mercury poisoning. NeuroToxicology. 2005;26(4):691–699