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ESPN has described this region’s matchups as “intoxicating” with a “lethal overdose” of talent and depth. Each team in their own right is capable of going all the way! This bracket consists of 4 international teams that represent the most lethal of all the nephrologic insults counterbalanced by 4 teams that define the best defensive strategies against renal injury. Led by Aristolochic Acid, Toxic Metals, and the much vilified and maligned DSHEA 1994 (Dietary Supplement Health and Education Act of 1994), fans will have to choose between political, oxidative, and pro-malignant offensive powerhouses versus defensive specialists utilizing adsorption, chelation, and enzyme inhibition game plans.  Is the best offense a good defense or is the best defense a good offense?

Selection committee member for the Poisons & Toxins Bracket:

Warren L. Kupin, MD
Professor of Medicine
University of Miami

Dr. Kupin is a graduate of Medical College of Wisconsin, and completed his residency and nephrology fellowship at Henry Ford Hospital. He is a Associate Director of Transplant Nephrology at the University of Miami Miller School of Medicine and Course Director for the Nephrology Module for Sophomore Students in the regular MD track and the MD/MPH track.

Meet the competitors for the Poisons & Toxins Bracket!

(1) Aristolochic Acid  versus (8) Hemoperfusion

Cinderella stories do happen but this first round match could be a blowout. Size, speed, and worldwide distribution all favor Aristolochic Acid but analysts report that the adsorbing performance of Hemoperfusion during the regular season shows that anything is “bound” to happen in the playoffs. Is this the year of an upset?

Aristolochic Acid

A perennial powerhouse, Aristolochic Acid is a derivative of numerous flowering species, many of whom can come off the bench and take over for starters without missing a mutated DNA link. Aristolochic acid has been wreaking havoc in the urogenital tract for centuries primarily as part of Chinese herbal supplements. This carcinogen came to attention after a major outbreak of CKD and transitional cell cancer in Belgium in 1993. The cuplret was ultimately determined to be a Chinese weight-loss formula adulterated with Aristolochia . Since then Aristolochic acid has been linked as a significant cause of CKD in China and Taiwan and most recently as the etiology of Balkan Nephropathy. Aristolochia Clematis, which grows along the banks of the Danube, has been implicated as the cause of the unique transitional cell cancer risk and CKD in the Danube basin. In recognition of the success and popularity of Aristolochic Acid in causing kidney disease, the Nephrology community has honored this team with its own disease designation  – Aristolochic Acid Nephropathy (AAN).

The International Agency for Research on Cancer and the World Health Organization (WHO)  have labeled Aristolochic acid as a type I human carcinogen but it continues to be an undeclared ingredient in up to 20% of Chinese herbal products. Aristolochic acid is absorbed by the proximal tubule and leads to lifelong irreparable DNA damage resulting in a markedly increased risk of multifocal, asynchronous transitional cell cancers of the bladder, ureter, and renal pelvis. The true impact of Aristolochic acid on the worldwide incidence of CKD in both developed and developing countries is unknown but everyone must respect this team and its ability to mutate its way to the Final Four. This team is on a worldwide mission for domination.

Hemoperfusion

They squeaked into the tournament mainly based on their early hype. But this team may have life for one more run at the finals.

This extracorporeal treatment for intoxications was first developed in the 1940s and used clinically in the 1970s. The theory was based on the success of oral activated charcoal (carbon) for acute drug overdoses. The microporosity of both carbon and synthetic resins increases the surface area from approximately 1.7 m² for a standard dialyzer to over 300 m² for a hemoperfusion device. This markedly improves the clearance of certain drugs by adsorption. The combination of hemodialysis with activated charcoal resins within the dialyzer was felt to be a major scientific breakthrough. In addition to poisoning this technique was also applied to elevated ammonia levels in hepatic encephalopathy.

Hemoperfusion devices (cartridges) come in two different flavors: a charcoal cartridge for water soluble drugs and a synthetic resin cartridge to for more lipid-soluble drugs. Both of these filters targeted drugs with molecular weights up to 40,000 and are particularly useful for protein-bound drugs, which are typically poorly dialyzable.

In clinical practice these perfusion devices have been limited by thrombocytopenia (major risk), hypocalcemia, hypoglycemia, and hypothermia. Additionally, the cartridges are chemically saturable so they can only be used once and require anticoagulation with heparin.

The introduction of high-flux dialysis and hemofiltration devices has superseded the routine use of these devices. Currently there are only limited applications for hemoperfusion treatments in patients with multiorgan system failure and drug or poison intoxication.

(3) Toxic Metals versus (6) Fomepizole

This matchup highlights a marked contrast in style. The Toxic Metals have consistent success on requiting from all over the periodic table and utilize a variety of diverse mechanistic pathways. In contrast, Fomepizole has always been focused and maintained expertise in restricting itself to one specific task with deadly accuracy. This could be a toss-up !

Toxic Metals

This team was originally called heavy metals but decided that this was too confusing to rock and roll fans and a name change was required to strike fear into the kidneys of its opponents. Moreover since all the metals in this group have a diversity of molecular weights and charges,  the term “heavy metals” was scientifically inaccurate and has been replaced by the more appropriate and intimidating term “toxic metals”. The systemic and nephrotoxic potential of this group and often the lack of effective prevention, detection, and treatment gives them a high ranking.

The starting five of the team are lead, cadmium, mercury, arsenic, and aluminum. However coming off the bench are the equally nephrotoxic platinum, uranium, and gold. The majority of toxic metal accumulation is a result of occupational exposure particularly in the manufacturing sector. In the U.S., the Occupational Safety and Health Administration (OSHA) protects workers from toxic metals in the workplace but in many countries of the world there is no similar legislation. Epidemics of CKD in certain parts of Sri Lanka, Thailand, Japan, and India have been linked to Lead and other toxic metal pollution from industrial waste leaching into the agricultural fields, resulting in widespread population exposure over many years.

Currently the adulteration of herbal therapy especially Aryuvedic products from India with toxic metals has led to warnings by the NKF to avoid these agents. Herbal therapy worldwide is felt to be a very significant source of inadvertent toxic metal exposure.

Most toxic metals result in proximal tubule injury and progressive tubulointerstitial fibrosis. Mercury and gold both cause secondary membranous nephropathy and nephrotic range proteinuria.

Due to an under-appreciation of their contribution to kidney disease and the lack of obvious clinical manifestations along with inaccurate or difficult to perform diagnostic tests, toxic metals have been below the radar of most nephrologists. This could be the dark horse of the tournament.

Fomepizole

Also known as 4-methypyrozole, Fomepizole is the only FDA-approved competitive inhibitor of alcohol dehydrogenase. Fomepizole is the primary pharmaceutical treatment of ethylene or diethylene glycol, methanol, or propylene glycol intoxication. The primary goal of therapy is to prevent the parent compound from being metabolized into its more toxic metabolites. There are two treatments:

1. The first is an alcohol drip that must be carefully titrated and monitored for excessive respiratory and CNS depression. Ethanol used for the alcohol infusion in the ER must be kept in a locked highly regulated often secretive part of the ER to avoid recreational use of this therapy by the staff. The effort to maintain control over the ethanol supply is demanding and time consuming.
2. The second option is Fomepizole, which requires no special invoice control. Once administered there is an immediate cessation of conversion of the alcohols to their often more toxic byproducts. This therapy can be a game changer in ethylene and methanol overdoses.

Fomepizole has a higher paid roster than the toxic metals, with an average cost being a minimum of $4000 for a treatment course.  The ease of administration is balanced by the cost of this agent. Recently the use of Fomepizole may be expanded to individuals with the “Asian Flush” syndrome due to an aldehyde dehydrogenase deficiency leading to an increase in acetaldehyde and a long term higher risk of esophageal cancer.

If cost were not a factor, Fomepizole would be the exclusive treatment of these alcohol overdoses: unique, effective, and safe. A formidable opponent.

(4) Glycyrrhizic acid vs (5) Chelation Therapy

This matchup features two equally matched contenders in a battle of consonants vs vowels. Glycyrrhizic acid holds the prestige among all the competitors in the year’s field for having been the only team name used in the Scripp’s National Spelling Bee contest and the one with the fewest true vowels. Chelation therapy for years has been an under-achiever, never quite reaching its true potential. Will this be the year Chelation therapy binds its way to the title or will it be another easy first round inhibition victory by Glycyrrhizic acid?

Glycyrrhizic Acid

This derivative of the root of the plant Glycyrrhiza Glabra (commonly referred to as Licorice) has shown itself to be a metabolic masterpiece of selective inhibition and syndromic potential. Licorice is used worldwide for its sweet flavor and potential medicinal benefits particularly in peptic ulcer disease. It is highly prevalent as an additive to herbal candies, gums, tobacco products, traditional Chinese and Indian herbal supplements, and cooking spices.

Glycyrrhizic Acid is an inhibitor of  the enzyme 11-b hydroxy steroid dehydrogenase. This leads to the condition called apparent mineralocorticoid excess (Pseudohyperaldosteronism) with hypokalemia, hypertension and metabolic alkalosis. In the U.S., all licorice that is sold has undergone a process of de-glycyrrhizination (DGL) so that none of the metabolic side effects will occur. In Europe however licorice is available as the pure form without undergoing DGL.

It is not clear how many cases of hypertension or hypokalemia worldwide could be related to ingestion of glycyrrhizic acid but it remains a very important concern and its mechanism of action is a commonly asked question on nephrology board examinations.

Chelation Therapy

This professional team should not be confused with the amateurs often seen advertising in the newspaper willing to chelate all forms of disease from cancer to autism to heart disease. Chelation therapy in this tournament represents a group of well-defined agents used for the treatment of toxic metal accumulation.

Although most of the press has focused on EDTA (ethylenediaminetetraacetic acid) which is FDA approved for the treatment of lead intoxication there is a more senior member of the team – BAL (British anti-Lewisite). This agent was the first true chelation therapy developed in WWI for the treatment of arsenic-based poison gas called Lewisite. It has subsequently been approved for lead, arsenic, and mercury poisoning. Derivatives of BAL have now joined the team and include DMSA (2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropanesulfonic acid), both used for lead , arsenic, and mercury removal. In addition, not to be overlooked is deferoxamine, used for iron overload conditions, and D-penicillamine, which may be used for copper and other heavy metal overdoses.

In a clinical nephrology practice, meta-analysis demonstrates that the early use of EDTA in patients with presumptive lead nephropathy has resulted in improved renal function and can retard progression even in patients with diabetic nephropathy who have high lead burdens.

Using modern dialysis techniques, which include intensive water purification methods and the introduction of non- aluminum-based phosphate binders, the syndrome of aluminum overload in ESRD patients has become almost nonexistent. However the use of chelation therapy with deferoxamine is still considered to be the treatment of choice for this disorder should it ever be diagnosed.

Chelation therapy should only be initiated once the diagnosis of toxic metal accumulation is made. This mandates a high index of suspicion to test for Toxic Metal exposure. The Chelation therapy team motto is “It’s not over, until it’s bound!”

(2) Dietary Supplement Health and Education Act of 1994 (DSHEA) vs (7) Osmolar Gap

This is a dream matchup of offense vs defense. Can the legally binding and federally mandated defense of the DSHEA Act of 1994 hold off the aggressive diagnostic skills of the Osmolar gap? This is the first meeting of these two opponents in a match that could come down to the final possession.

Dietary Supplement Health and Education Act of 1994 (DSHEA)

This team represents the FDA’s major defensive strategy in the management of the marketing and distribution of vitamin and herbal supplements in the U.S. Moving away from a more standard “zone’ defense, DSHEA utilizes a more nontraditional, one-on-one approach.  In spite of numerous Congressional efforts, DSHEA has employed the same strategy for 20 years. Only selected supplements reported by the public to the FDA due to adverse reactions are reviewed in a lengthy process to see if further actions (public warnings, removal from the market) are needed.

DSHEA is a landmark federal legislation that guides the government’s role in the regulation of herbal and vitamin supplements. It guards the rights of individuals to choose what they wish to take for health benefits. The history of this act is important to truly evaluate the impact it has had on pharmaceutical safety and financial success of the supplement industry.

Prior to 1962, the FDA was not required to evaluate the efficacy and claims of any drug or supplement marketed in the U.S. The 1938 Food, Drug and Cosmetic Act only mandated that the drug companies demonstrate to the FDA that their drug was safe. However there was no regulation of advertising claims or any requirement of efficacy. The tragic thalidomide birth defects in Europe, however, forced an overhaul on the operations of the FDA. The Kefauver Harris Amendment or “Drug Efficacy Amendment” of 1962 required all manufacturers to provide proof of effectiveness of all drugs sold.

However, due to intense lobbying by the supplement industry and their persuasion of many U.S. Senators, an exemption to the Kefauver Harris Amendment was passed in 1994 called the Dietary Supplement Health and Education Act (DSHEA). This change in the law allowed all vitamin and herbal supplement manufacturers to be exempt from FDA review. No longer was the FDA required to evaluate the marketing and efficacy claims of any herbal and vitamin supplement. The manufacturers were asked to place the following disclaimer on all products that make health claims: “This statement has not been evaluated by the Food and Drug Administration . This product is not intended to diagnose, treat, cure, or prevent any disease”. This is the only warning consumers are provided regarding the lack of FDA review of the supplement industry. Recent polls show that less than half of  Americans know that the FDA does not review or monitor the efficacy herbal and vitamin supplements.

The market for supplements in the U.S. now exceeds 5 billion dollars a year. Numerous reports of morbidity and mortality from intentional and unintentional adulteration, improper manufacturing, unreported ingredients and microbiologic contaminants have occurred as a result of DSHEA.  Multiple professional organizations including the FDA, the NKF, the AMA have all voiced concerns that the safety of the American public cannot be guaranteed from dietary supplements due to a lack of governmental control directly related to the sweeping changes brought about by DSHEA.

Osmolar Gap

This is a quick and under-recognized team that always gets off to a fast start but has a habit of losing accuracy as the game advances into the 3^rd and 4^th quarter. Osmolar gap employs the same offensive strategy in the management of alcohol derivatives intoxication as the serum and the urine anion gap do for classifying acidotic states. The Osmolar Gap uses a simple, no-frills, attack meant to immediately catch their opponents off guard so treatment can be initiated before end organ damage.

The Osmolar gap measures the difference between the measured and the calculated osmolalities for the purpose of diagnosing an alcohol based intoxication. Typically used for ethylene glycol and methanol overdoses, the osmolar gap will also detect the presence of regular alcohol, diethylene glycol, propylene glycol and isopropyl alcohol. An osmolar gap of  more than 10 mOsm/L is a positive result suggesting that one of these alcohols is present.

The Osmolar Gap has a limited repertoire and cannot identify the exact intoxicating agent. In addition, the metabolism of the toxic alcohols by alcohol dehydrogenase limits this formula to the first 12-24 hours of the overdose. The presence of CKD or ketoacidosis, the infusion of maltose (IVIG infusions) or mannitol and the absorption of sorbitol or glycine (TURP irrigation solutions)  can hinder the sensitivity of the Osmolar Gap and create a false positive elevation.

In spite of its limitations, the Osmolar Gap has earned its seeding in the tournament as it has remained an important tool for ER physicians and housestaff in the diagnosis of a toxic alcohol ingestion.

-Written and Edited by Dr. Warren Kupin

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