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.

iv iron preparations

Because of the generally poor GI absorption of iron in the setting of ESRD, iron supplementation in dialysis patients is now carried out by intravenous formulations of iron complexed to various carbohydrates. The idea is that these carbohydrate moieties can function as "molecular shields", allowing for the safe delivery of iron to its target tisues while simultaneously preventing iron-mediated oxidative damage. Here are some of the main iv iron formulations and their unique attributes:

1. iron gluconate (Ferrlicit). In my limited experience, it appears to me that Ferrlicit and Venofer control the lion's share of iv iron formulations in U.S. dialysis centers. A typical course of Ferrlicit typically given in the ESRD patient is 125mg iv qdialysis session x 8 doses.

2. iron sucrose (Venofer). Also a popular option, the typical dosing for Venofer is 100mg iv qdialysis x 10 doses. Both Venofer and Ferrlicit offer fairly rapid release of iron. Also, Venofer is FDA-approved for iron repletion in non-dialysis-dependent CKD patients whereas Ferrlicit is not.

3. iron dextran (Dexferrum, Imferon): this is not used much anymore because of a significantly higher risk of anaphylactic reactions than the more modern Ferrlicit and Venofer. Iron dextran was typically given as a smaller "test dose" prior to giving the full dose, as a precaution against anaphylaxis.

4. low-molecular weight iron dextran (CosmoFer, InFed): it is important to distinguish low-molecular weight dextran from high molecular weight dextran because its risk of adverse events is so much lower.

5. ferumoxytol (Feraheme): this is a newly-released formulation of "iron oxide nanoparticles." Sounds very space-age, doesn't it? The reported advantage is that it can be given in large bolus doses--thus making it preferable for the treatment of iron deficiency in CKD, where a patient would otherwise be required to make multiple trips to an infusion center to get their Venofer or Ferrlicit. Further assessments of safety and efficacy are still needed.

hemojuvelin

Several months back I posted something on hepcidin--the 25 amino acid peptide secreted by the liver which appears to be the "master regulator" of iron metabolism, and whose levels appear to be perhaps increased in ESRD patients, providing a possible explanation for the anemia of chronic kidney disease.

Hemojuvelin is a protein which has recently been identified as a critical regulator of hepcidin, and thus also likely an important player in anemia of chronic kidney disease.  Clues as to hemojuvelin's function comes from children with mutations in this gene, which result in severe juvenile-onset hemochromatosis (as evidenced from the positive Prussian blue staining of a liver biopsy specimen, shown above left).  

Hemojuvelin turns out to be a co-receptor, acting at the plasma membrane, for the BMP signaling pathway, which is necessary for the secretion of hepcidin from hepatocytes.  As elevated hepcidin levels are associated with anemia of chronic disease and decreased access to reticuloendothelial stores, it stands to reason that inhibitors of the BMP pathway--either small molecule BMP inhibitors such as this, or a soluble form of hemojuvelin such as this--might be successfully used to decrease hepcidin expression and therefore treat anemia of chronic kidney disease.  

ALSO:  Be the coolest kid on the block to know the Top 10 Nephrology Stories of 2008 according to the Precious Bodily Fluids nephrology blog!

DRIVE Study

There are numerous reasons as to why an ESRD patient might be "EPO-resistant", and perhaps the most obvious one to exclude initially is iron deficiency: you can't make more red blood cells if you don't have enough iron (pictures in lump metal form on the left). Generally speaking, iron deficiency is traditionally diagnosed by having a low MCV, a transferrin saturation less than 20%, and a ferritin level <200.>

However, there is some confusion as to what to do with patients who are EPO-resistant despite having apparently "adequate" iron stores based on the values above. Using ferritin as a marker for iron stores has some caveats associated with it, as ferritin is upregulated during inflammation and thus may underestimate the degree of functional iron deficiency in a dialysis patient.

With this mind, the makers of Ferrlicit designed the DRIVE study, in which dialysis patients with a low Hgb (<11.0g/dL), high ferritin (500-1200 mg/dL), and low transferrin saturation (<25%) were randomized to receive (or not) 1 gram of iv iron administered over dialysis sessions. Both this trial as well as the follow-up DRIVE-II study reported that the iron-treated
group developed higher Tf-sat's and a reduced EPO requirement, suggesting that in some patients an elevated ferritin is not a good marker for iron deficiency. Although the authors report no significant safety issues in the iron-treated group compared with the control group, there is still some concern about the use of continuous iv iron in patients with chronic
inflammation.

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.

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.