Lithium and the Kidney: Old Observations & New Insights

Lithium is indispensable as an effective treatment for bipolar affective disorder. However, it has a narrow therapeutic index with desired therapeutic levels between 0.6 and 1.2 mEq/L. Lithium is handled by the kidney (responsible for almost all its excretion) in a manner very similar to sodium. It has a molecular weight of 7 daltons, has a moderate volume of distribution, is <10% protein bound and is therefore readily dialyzable. Lithium may cause of myriad of renal related toxicities, some of which are classic descriptions and some which are less well known. Much of this has been discussed on RFN before (here, here) but I felt a refresher with some additions was due.

Nephrogenic Diabetes Insipidus (NDI)

This is perhaps the best know and most common complication of lithium therapy, with an estimated prevalence of 20-70%. Patients present with polyuria and polydipsia due to a urinary concentrating defect that can lead to volume depletion, especially if access to free water is restricted. Lithium downregulates aquaporin-2, vasopressin-activated water channels expressed on the collecting duct principal cells. It is worth noting that ongoing volume depletion from NDI may aggravate the risk of supra-therapeutic levels and therefore chronic nephrotoxicity. Amiloride may help as it inhibits lithium reabsorption via ENaC in the collecting duct.    

Renal tubular Acidosis (RTA)

Lithium may induce a hyperchloremic non-anion gap metabolic acidosis, analogous to a distal RTA. It is likely due to decreased distal proton secretion. Unlike acidosis associated with amiloride, it is not associated with hyperkalemia probably because of their different effects on distal H⁺/K⁺-ATPase function.

Acute Lithium Nephrotoxicity

This may occur as an overdose in newly treated patients or those on long-term lithium therapy. Acute lithium intoxication may cause altered mental status and acute kidney injury. Drugs which decrease GFR (NSAIDs/RAAS inhibitors) may exacerbate intoxication as can thiazides, which cause a natriuresis and a subsequent reabsorption of Na (and lithium). With preserved renal function and mild intoxication, increasing urine output/forced diuresis may be all that is needed. Care should be taken using 0.9%NaCl if hypernatremia from NDI is present. As mentioned above, lithium is readily dialyzable and hemodialysis (ideally using a high flux membrane to aid clearance) is the primary management for severe cases. A lithium level >4mEq/L is considered an absolute indication for dialysis in most cases. A level >2.5mEq/L with severe symptoms, or renal impairment which will slow native clearance, is also an indication. If in doubt, most nephrologists would have a low threshold for dialysis, although it is usually not needed with a level <2.5mEq/L. Drug levels drop rapidly during dialysis but they do rebound so extended and repeated sessions are usually necessary. Continuous therapies are less efficient so are not desirable if severe intoxication is present but may be used if conventional dialysis is not immediately available.

Chronic Tubulointerstitial Nephritis (TIN)

A chronic TIN with interstitial fibrosis and tubular dropout is the commonest pathology seen when patients with lithium and renal impairment are biopsied. Consistent with this is a bland urine sediment with little/no proteinuria being common (although not exclusive-see next section). As nephrologists, our view of the prevalence of lithium induced CKD is skewed. The exact prevalence is difficult to determine but many patients have preserved renal function. The tricky decision is whether (and if so when) to stop therapy? This is rarely a decision the nephrologist can make alone and should be balanced with efficacy of treatment/alternatives available and usually led by the psychiatrist in my opinion.

Nephrotic Syndrome

It is less well known that lithium may be associated with a glomerulopathy. Minimal change disease is most often described but membranous nephropathy and FSGS has also been reported. Cases were considered lithium induced as proteinuria disappeared upon cessation of the drug, and when re-challenged (for psychiatric reasons), the nephrotic syndrome recurred. A series of 24 patients with lithium-induced nephrotoxicity from New York included one quarter with nephrotic-range proteinuria. My initial thoughts were that the FSGS lesions were likely secondary to nephron loss and resulting hyperfiltration injury. However, arguing against this is that presence of FSGS lesions did not correlate with severity of tubulointerstitial lesions. Moreover, there was a high incidence of extensive podocyte foot process effacement, to a degree uncommon in secondary FSGS. The mechanism of glomerular toxicity is unclear.

Renal Cell Tumors

It has recently been reported in Kidney International that chronic lithium use is associated with an increased risk of kidney tumours.  After a mean duration of lithium exposure of >21 years, patients had a significantly higher risk of solid renal tumours compared with gender, age and eGFR matched controls [Standardized Incidence Ratio i.e. ratio of observed-to-expected numbers of renal cancers was 7.51 and 13.69 in men and women respectively]. The tumours were a mixed bag of benign (oncocytomas, angiomyolipomas etc.) and malignant (clear cell, stromal, papillary) lesions. While these results are thought provoking, this was a retrospective study and the design seems open to detection bias in my opinion (were patients on lithium screened more than regular individuals?).

Hyperparathyroidism

As previously posted, lithium may cause hypercalcemia and stimulate PTH via a variety of postulated mechanisms (see previous post).

NephMadness 2014 Part 2 - Poisons and Toxins Bracket

In the poisons and toxins bracket I learnt some interesting facts. The Dietary Supplement Health and Education Act of 1994 (DSHEA 94) is an example of the power of big business in Washington. Subsequent to acts such as the Nutrition Advertising Coordination Act of 1991 that would have tightened the regulations regarding supplement labeling there was a campaign to exempt supplements and vitamins from the rigorous standards of the FDA. One advertisement featured Mel Gibson being arrested by the FDA for buying vitamin C! On October 25 1994, president Bill Clinton signed the Act into law, saying that "After several years of intense efforts, manufacturers, experts in nutrition, and legislators, acting in a conscientious alliance with consumers at the grassroots level, have moved successfully to bring common sense to the treatment of dietary supplements under regulation and law.” This shocking discovery (for me) made DHSEA go all the way to the sweet sixteen to be knocked out by fomepizole. 

Another very interesting fact was that Glycyrrhizic acid is removed from licorice sold in the US by a process called de-glycyrrhizination (DGL). This eliminates to risk of apparent mineralocorticoid excess (AME). Us Europeans should take a leaf out of the FDAs book!

Please feel free to post a comment on your picks for the poisons bracket!

Mercury rising

A patient who had been working in a recycling company that handled thermometers presented with fever, dry cough, fatigue and rash. Based on imaging (CXR showed massive radio-opaque material in the lungs, right atrium and right ventricle; skeletal survey showed radio-opaque deposits in the kidneys, bowel wall, and bladder wall), symptoms, and a positive history of exposure, a diagnosis of mercury intoxication was made. The patient developed multi-organ failure including anuric acute renal failure, and nephrology was consulted. Further background details on the case can be found here. What is the treatment and the role of dialysis in mercury intoxication? 


Metallic mercury has a widespread use both within industry and in many everyday objects such as thermometers, dental amalgams, batteries, fluorescent light bulbs, and many others. Mercury intoxication can result from vapor inhalation, resulting in severe respiratory symptoms, or from injection, usually in cases of attempted suicide. 


The chelating agents 2,3- dimercaptopropanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are central to the management of mercury toxicity. DMSA is given orally, and can cause leucopenia and elevated liver enzymes. DMPS is an intravenous medication and its use is associated with hypotension. In our patient, DMSA 500 mg po q 8hrs was given for 4 days, before it was discontinued because of elevated LFTs and leucopenia. We then started DMPS with CRRT but unfortunately, after two weeks of supportive treatment, the patient died. 


Chelators such as DMPS and DMSA work by mobilizing mercury and facilitating its excretion through the kidneys. This creates a management conundrum in the anuric patient, as this route of excretion is not available. Consistent with this, our patient’s blood mercury levels rose dramatically during chelator treatment, despite CRRT. We hypothesize that the administration of DMPS mobilized mercury from extracellular deposits and redistributed it to the blood and organs, but it failed to be adequately eliminated from the body because of anuria. For this reason, intensive CRRT with a high-flux dialyzer is a critical adjunct to chelator therapy. If this is not available, continuous renal replacement therapy with chelators have showed better mercury clearance than conventional dialysis, whereas peritoneal dialysis has been shown to be ineffective at clearing mercury. These principles should be borne in mind in other heavy metal poisonings also. Other management pearls I took from this unusual case were to initiate dialysis early and to give DMSA at a lower and more frequent dose to avoid serious side effects. 


Tarek Alhamad M.D.

Peak or Trough?

We were recently consulted on a patient with a history of repeated admissions with pneumonia who had developed AKI following treatment with Tobramycin. It got me thinking about the mechanisms of aminoglycoside toxicity. The traditional teaching is that aminoglycosides are best administered in once daily doses in order to reduce toxicity but given the fact that this should lead to higher peak levels, it seems counterintuitive that this might prevent nephrotoxicity. However, this makes sense when you understand how aminoglycosides damage the kidneys.

Aminoglycosides are freely filtered at the glomerulus. 90% of the drug is excreted unchanged in the urine while the rest is reabsorbed in the proximal tubule. As Nate mentioned in a previous post, they bind to phospholipids in the cell membranes in the S1 and S2 segments of the proximal tubule. During ischemic episodes, there is some uptake in the S3 segment also. They are subsequently endocytosed via the transmembrane protein, megalin, and accumulate in the cytosol where they mediate their toxicity. The degree of renal damage associated with the various aminoglycosides is related to the ability of the drug to bind to these phospholipids. The more binding that occurs, the more nephrotoxicity. Gentamicin is the most toxic, followed by tobramycin, amikacin and streptomycin. The reason why once daily dosing is better is that this transport mechanism is saturatable and beyond a certain concentration, no more drug is taken up. Thus, peak levels correlate with bactericidal ability while trough levels correlate with renal (and oto-) toxicity.

Interestingly, this is similar to the mechanism of renal toxicity associated with imipenem. There have been efforts to develop a drug that could be co-administered with aminoglycosides that would inhibit their transport in the proximal tubule and thus prevent their nephrotoxic effects, but unfortunately none have been successful.

Gentamicin is made up of four components and when these are administered separately, it turns out that one of them, C2, does not appear to be absorbed as readily into the proximal tubular cells while still retaining the bactericidal ability of the whole drug. This may have potential for reducing nephrotocity in patients who are particularly at risk – i.e. pre-existing AKI or ischemia.

Acetaminophen & the kidney

As a new renal fellow I’ve felt fairly comfortable with the list of NSAID associated renal conditions. But after taking care of a patient this past month with fulminant hepatic failure due to a Tylenol overdose it’s been interesting to find that acetaminophen has a bit of a list of it’s own…

1) Acetaminophen induced ATN – Our patient presented after intentionally taking 40 grams of Tylenol in a suicide attempt. On presentation he had sediment and urine chemistries supportive of ATN and subsequently developed fulminant hepatic failure.

Acute tubular necrosis has been reported to occur both in the presence and absence of hepatotoxicity. The mechanism of renal injury has not been well defined. Mouse models suggest a possible role of acetaminophen induced endoplasmic reticulum stress with subsequent renal epithelial cell apoptosis.

Unlike liver injury, there is no evidence that N-Acetylcysteine attenuates renal injury.

2) Analgesic nephropathy – One of the many causes of chronic interstitial nephritis.

Analgesic nephropathy appears to result from chronic exposure to at least two anti-pyretic analgesics (one of which is sometimes acetaminophen) along with caffeine or codeine. On CT the kidneys often have a characteristic shrunken bumpy appearance with accompanying papillary calcifications.

3) Metabolic gap acidosis secondary to 5-Oxoproline accumulation – 5-Oxoproline is an intermediate metabolite in the gamma-glutamyl cycle shown below in a figure from a nice review in CJASN.

The gamma-glutamyl cycle produces glutathione, which is important in the conjugation and urinary excretion of the acetaminophen metabolite NAPQI.

5-Oxoproline accumulation is hypothesized to occur through a variety of mechanisms. Chronic acetaminophen ingestion may lead to a depletion of intracellular glutathione stores. This leads to lack of feedback inhibition of gamma-glutamylcysteine synthetase, which in turn leads to a rise in gamma-glutamylcysteine which is partially converted to 5-Oxoproline.

Malnourishment may play a role by leading to decreases in hepatic glutothione stores. There is possibly some difference between male and female enzyme activity in the gamma-glutamyl cycle that accounts for the female predominance of reported cases and renal dysfunction may lead to a decrease in 5-Oxoproline excretion.

Recognition of this rare entity is key as stopping of acetaminophen often leads to resolution of acidosis. N-acetycysteine has been used in a couple of cases successfully. It theoretically assists by increasing intracellular glutothione stores.

Graham Abra, MD

Hemoperfusion

The first order of business for today's Renal Fellow Network is to welcome another regular contributor to the mix: nephrology fellow Albert Lam, of Brigham & Women's Hospital. Fresh off the Nephrology boards, Albert will be periodically posting his renal pearls of wisdom for the benefit of renal fellows everywhere.

Today's post is on hemoperfusion. If you've never had experience with hemoperfusion, you're not alone: according to this 2008 Kidney International paper by Tyagi et al, use of hemoperfusion has sharply declined over the past several years, and the indications for its use are infrequent.

What is it, exactly? The hemoperfusion procedure is employed in the treatment of specific intoxications and consists of running a patient's blood through a column containing adsorbent particles to which the toxin binds and are removed from the circulation. These adsorbent particles can either be charcoal (which binds water-soluble drugs) or various polystyrene resins (which bind lipid-soluble molecules). Since dialysis is generally successful at removing most low molecular weight, water-soluble molecules which are not protein-bound, it makes sense that hemoperfusion would be considered only when dialysis is not effective (e.g., high molecular weight, highly-protein bound, large VOD drugs). Some of the drugs traditionally removed via hemoperfusion are theophylline and barbiturates, both of which have fallen out of favor (and thus may account some for the decline in the use of hemoperfusion). Valproic acid compounds can also be effectively removed via hemoperfusion, though dialysis is marginally effective as well. Other factors which have contributed to lower hemoperfusion usage include improvements in dialysis technology (e.g., use of continuous therapies and high-flux membranes) as well as the high expense associated with hemoperfusion cartridges, which cannot be reused. Complications of hemoperfusion include thrombocytopenia, leukopenia, and hypocalcemia.

Anabolic Steroids as a Cause of Secondary FSGS?

A very interesting article in this month's JASN by Herlitz et al describes a cohort of 10 bodybuilders with chronic kidney disease, making a compelling case that anabolic steroid use is an underrecognized cause of secondary FSGS. The paper is strengthened by the fact that nine of the patients underwent renal biopsy documenting surprisingly aggressive forms of FSGS in many of these patients, including some with the "collapsing" variant of FSGS and others with surprisingly high degrees of interstitial fibrosis and tubular atrophy which are not characteristially seen with secondary FSGS. Perhaps even more convincingly for providing a link between bodybuilding and secondary FSGS, the authors describe a patient whose serum creatinine and proteinuria IMPROVE once the patient's intensive steroid/exercise regimen stops, then gets worse when he returns to this regimen against the advice of his physicians.

There are other health problems already associated with anabolic steroid use--these include gynecomastia, dyslipidemia, testicular atrophy, decreased fertility rates, some forms of hepatotoxicity, neuropsychiatric disorders, and developing a massively enlarged head a la disgraced baseball player Barry Bonds. It seems as if kidney disease can now be added to the list.

As a caveat, however, the authors also point out that there are potential other explanations for how bodybuilding might be linked to FSGS. These individuals were typically on regimens consisting of complicated cocktails of steroids, growth hormone, insulin, protein shakes, diuretics, and other supplements whose content is not carefully regulated. Therefore it remains possible that a substance other than anabolic steroids is the common nephrotoxin amongst these individuals. Furthermore, it's already known that elevated BMI in obese patients can result in secondary FSGS; perhaps their increased lean body mass itself drives the process. High protein diets may expose podocytes to unusually high serum protein levels; could this contribute to toxicity?

One final tidbit I learned from this article: individuals who take creatine supplements (another baseball reference: this is one of the few substances that home run guru Mark McGwire has admitted to taking) may have a falsely-elevated serum creatinine based on the fact that creatine is coverted to creatinine. This limitation can be overcome by measuring a full creatinine clearance in which a 24-hour urine creatinine and simultaneous serum creatinine are used.

Death by Soy Sauce?

Bizarre case of hypernatremia:  a suicide attempt by a 73 year-old Japanese man in which the individual drank massive amounts of soy sauce.  According to this 2006 Neurology paper by Machino et al, the patient presented with vomiting, tremor, and altered mental status, along with a serum Na of 188 mEq/L, a serum chloride of 142 mEq/L, and a serum osmolarity of 314 mOsm/kg.  MRI imaging demonstrated symmetric brain shrinkage consistent with severe, acute hyperosmolarity.  Fortunately, rapid correction of the patient's sodium (the soy sauce ingestion had apparently been within 12 hours of his initial presentation) led to rapid clinical improvement.  A similar 2004 case report by Sakai et al suggests that acute hemodialysis is another way to rapidly reverse hypernatremia as caused by acute soy sauce ingestion (over 1 Liter in this paper!). 

An unusual case of hyperkalemia and renal failure: matchsticks

Okay, you're probably not going to see this in your lifetime, but imagine how cool you'll seem when you whip out "matchstick ingestion" as part of the differential diagnosis for hyperkalemia and AKI.

Matchstick heads are comprised of over 50% potassium chlorate (KClO3); it is an oxidizing agent which makes matches flammable and can also be found in many explosives and fireworks. Unfortunately, it also happens to be nephrotoxic. In this interesting case report by Mutlu et al, the authors describe a 21-year-old man who attempted to commit suicide by ingesting 120 matchsticks. When he first presented to the ED, he had a serum potassium of 7.4 with peaked T-waves. The potassium chlorate results in a rapid oxidative destruction of RBCs while also causing methemoglobinemia, and acute renal failure is common. A toxic dose is listed as being 5 grams; the patient in this case report only ingested 2 grams was fortunately treated successfully using acute potassium-lowering therapy and hyperbaric oxygen therapy (for the methemoglobinemia).

Wood's Lamp Trick for Diagnosing Ethylene Glycol Toxicity

One of the more common (and potentially successful) suicide attempts is to drink a bunch of antifreeze, which contains ethylene glycol. As we all know, this is typically diagnosed by characteristic lab abnormalities: patients present initially with an osmolar gap, and as the ethylene glycol is gradually metabolized to the organic acid oxalate, it evolves into an anion gap metabolic acidosis.

Another trick for diagnosing ethylene glycol is to use a Wood's lamp--which emits ultraviolet light. Most commercial antifreeze contains a compound which fluoresces under ultraviolet light; this is included so that car mechanics can detect potential antifreeze leaks. Thus, it is theoretically possible to detect a recent ingestion of antifreeze by seeing whether or not a patient suspected of an overdose is fluorescent under uv light. I use the word "theoretical" because there is some literature out there such as this which cast the sensitivity and specificity of uv-fluorescent urine into doubt.

Renal effects of licorice

Licorice--particularly European licorice which contains higher doses of the natural sweetener glycyrrhizic acid (GZA)--needs to be considered in the differential diagnosis of hyperaldosteronism. Here's how it works:

The mineralocorticoid receptor, expressed in cortical collecting duct cells, is the means through which aldosterone mediates potassium and proton secretion while enhancing sodium reabsorption via the ENac. It turns out that cortisol can also interact with (and activate) the mineralocorticoid receptor--however it does not usually do so based on the presence of the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, which chemically modifies cortisol such that it is unable to interact with the mineralocorticoid receptor. The GZA compound in European licorice inhibits 11-beta-hydroxysteroid dehydrogenase, thereby allowing endogenous cortisol levels to constantly signal via the mineralocorticoid receptor.

The end-result is the production of

1. Hypokalemia
2. Metabolic alkalosis
3. Increased extracellular volume as a result of enhanced sodium reabsorption.
   

These effects are reversible upon withdrawal of licorice. The condition is sometimes called "pseudoprimary aldosteronism" since it presents clinically like primary hyperaldosteronism, but differs in that serum and urine aldosterone levels are low and serum renin activity is low (in contrast to primary hyperaldosteronism, where serum & urine aldo levels are high).

Not only is GZA present in licorice, but it also used sometimes used in chewing tobacco. The European Union suggests that people should not consume any more than 100mg of GZA a day, equivalent to about 50 grams of licorice sweets.

Links from Other Nephrology Blogs

A few links for today, borrowing heavily from other Nephrology Blogs:

There is an interesting interchange on Kidney Notes responding to some highly negative comments made about the field of Nephrology by a practicing nephrologist "Nephrogirl."

The Precious Bodily Fluids Blog (with lots of great handouts/power point presentations of nephrology topics posted online if you haven't seen them already) has done a thorough job of covering the Chinese melamine milk contamination story, here and here. Did you know that the business owners of the offending milk-producing companies in China were sentenced to DEATH? Can you imagine that happening to CEO's in the U.S.?

The Nephrology Blog (also lots of interesting and useful posts in the past few months) points out the recent passing of Dr. Willem Kolff, credited with being the inventor of the dialysis machine. Did you know that the first person to survive using the artificial kidney machine was allegedly a Nazi collaborator? Interesting stuff.

'Shrooms and Renal Failure

While toxic mushroom ingestions are generally known for their ability to cause acute liver failure, certain varieties of mushrooms can also result in acute renal failure.

One such type of mushroom is Amanita smithiana, (shown at left) which is responsible for causing relatively rapid (e.g. within a few days of ingestion) renal failure. The mechanism is felt to be ATN and there have been several case reports of this type of mushroom ingestion in the Pacific Northwest region of the United States.

Another distinct type of mushroom-induced acute renal failure is those produced by Cortinarius species (shown at bottom). These are found mostly in Europe, and the mechanism of renal injury here is a tubulointerstitial nephritis. As such, onset can be delayed (3 days - 3 weeks) and often less severe than Amanita-induced renal toxicity.

Also, as liver failure is still the most common disease associated with toxic mushroom ingestion, hepatorenal syndrome (as a secondary event) must also need to be strongly considered in an individual with renal failure following mushroom ingestion.

Toad Skin-Induced Hyperkalemia

Why is there a picture of a toad on the Renal Fellow Network?

In reading the most recent edition of ESRD/Dialysis "NephSAP" (the ASN's periodic review of relevant nephrology-themed literature), I learned about an unusual cause of hyperkalemia: toad skin. In Southeast Asia, toads may be used as food, and in some Chinese traditional medications toad venom extract may be an ingredient. Toad skin in particular is particularly rich in bufadienolides, molecules which are similar in structure to digitalis, and thereby induce toxicity due to inhibition of the Na-K ATPase. Individuals with toad-skin toxicity may present with arrhythmias and hyperkalemia and CKD/ESRD patients would be especially susceptible to these effects. In addition to standard treatments for hyperkalemia, this can be managed with high-dosage administration of digoxin-specific Fab fragments, much like digoxin toxicity.

Cadmium Toxicity

Heavy metals & the kidney are an interesting topic all-around. Aberrant metabolism of heavy metals such as iron, copper, lead all contribute to significant renal pathology. And you can add the heavy metal cadmium to that list as well.

Cadmium toxicity is most notably manifest as renal tubular impairment, specifically in the proximal convoluted tubule, though it may also result in hepatotoxicity and osteoporosis.

Normal cadmium handling begins in the liver, where it binds to the small molecular weight protein metallotheionein. The metallotheionein-cadmium complexes are freely filtered at the glomerulus, then gets taken up at the proximal tubule by pinocytosis. The metallotheionein-cadmium complexes are degraded in lysosomes and excess cadmium is excreted into the tubular lumen via a specific transporter. Large amounts of cadmium can overwhelm this system and lead to proximal tubular damage. Not surprisingly, this results in a Fanconi's Syndrome which can include a proximal (type II) RTA, glucosuria, phosphaturia, and amino aciduria. One of the ways in which subtle proximal tubular damage via cadmium can be monitored is to look for urine b-2 microglobulin levels, which are handled in the PCT via a similar mechanism as metallotheionein.

Toluene & The Kidney

Toluene--a hydrocarbon which is present in gasoline, paint thinners, and many industrial solvents--can have a variety of effects on acid-base metabolism by the kidney:  it can cause both a non-anion gap OR an anion gap metabolic acidosis, depending on whether or not the exposure is acute or chronic.

The most well-described with chronic or repeated exposure--as might be seen in a patient who has the unhealthy habit of glue sniffing, or "huffing"--is a renal tubular acidosis, resulting in a non-anion gap metabolic acidosis and hypokalemia.  Multiple case reports support the existence of both distal and proximal RTAs with toluene exposure.

However, acute toluene exposure can also lead to an anion gap.  This is because the major byproduct of  toluene breakdown by the liver's cytochrome p-450 system is hippuric acid, which is an (unmeasured) organic acid.   

This is why your 1st-grade teacher told you to stop sniffing the glue.

Isopropyl Alcohol

Isopropyl alcohol is unique amongst the toxic alcohols (e.g., ethylene glycol, methanol, etc) in that it causes an osmolar gap WITHOUT causing an anion gap.  In addition, unlike the toxic alcohols listed above, it is the isopropanol itself which is toxic, rather than its metabolites.  Therefore treatment of isopropyl alcohol ingestion with fomepizole (an alcohol dehydrogenase inhibitor) is not advised.  Ketones will be positive as isopropyl alcohol is metabolized to acetone.  At blood levels >400 mg/dL, isopropyl alcohol can cause hypotension and CNS depression, and since it is easily dialyzable, dialysis may be employed to hasten the elimination of isopropanol.

  

Kitty Dukakis, wife of former presidential candidate Michael Dukakis, was once hospitalized after drinking a small amount of isopropyl alcohol.  

Lead Nephropathy

The first report that lead can cause nephrotoxicity was by Lancereaux in 1863, who observed chronic kidney disease in an artist who habitually would hold paintbrushes in his mouth; there are some who believe that the collapse of the Roman empire was partially due to lead contamination of wine.

There are three ways in which lead may cause renal toxicity:

1. acute lead poisoning--a massive, acute lead exposure (which may occur in children who eat lead-based paint chips) can lead to Fanconi Syndrome and acute kidney injury, along with other symptoms such as colic, encephalopathy, and anemia.

2. chronic lead poisoning--chronic exposure to lead--as might occur with an occupational exposure for instance--is characterized by a chronic interstitial nephritis, and is often associated with hypertension and gout. Gout is actually quite rare in other forms of CKD, so the appearance of gout and CKD together should prompt screening for serum lead levels.

3. lead-induced hypertension--lead can lead to renal disease indirectly by causing hypertension--a finding which has been confirmed in numerous epidemiologic studies.

Lithium as a dialyzable toxin

Lithium is one of the classic dialyzable toxins, as it is very small (atomic # of 3) and elevated Li levels (>2.5 meq/L) may result in tremor, ataxia, vomiting, seizures, or even coma.

However it is somewhat unique amongst toxins in that chronic users tend to have a greater susceptibility to Li toxicity than an individual taking an acute Li overdose for the first time. This is based on the fact that Li has a very high volume of distribution (VOD), and it takes a large exposure (usually over a prolonged period of time) in order to saturate these stores.

Also, as a result of its large VOD, dialysis in instances of Li toxicity may require prolonged periods of time and/or multiple sequential days of dialysis due to a significant "rebound effect."

Starfruit Toxicity

Starfruit (Averrhoa carambola) is a popular tropical fruit in numerous countries of Asia and South America, and is increasing found in Western countries as well. Why am I writing about this on the Renal Fellow Network?

It turns out that the starfruit contains an as-yet unidentified substance which is renally cleared which may act as a neurotoxin in individuals with severely reduced renal clearance. There are numerous case series (Neto et al, Nephrol Dial Transplant 2003, 18(1):120-125) which describe ESRD or advanced CKD patients which, after ingesting as little as one starfruit, went on to develop neurologic symptoms ranging from hiccups to seizures to coma to even death. Injection of purified starfruit toxin into uremic rat brain can also induce neurologic problems. Interestingly, the toxin appears to be dialyzable, as altered mental status can be rapidly improved with dialysis.

In addition to this unidentified neurotoxin which can cause major neurologic problems, starfruit contains another renally-relevant substance: it is rich in oxalate. In patients with CKD, oxalate crystal deposition may accelerate renal deterioration.