Calciphylaxis

An ESRD patient on CAPD was recently admitted to our hospital with possible pneumonia. It was noticed that he had painful plaque-like necrosis, with areas of ulceration. Even in the absence of a skin biopsy, the consensus was that he had calciphylaxis based on gross appearance alone and as a result, he was started on intravenous Sodium Thiosulfate 5g three times weekly.

Calciphylaxis (or calcific uremic arteriolopathy) is an uncommon but dreaded complication of renal failure characterized by painful nodular or plaque-like subcutaneous calcification often leading to ischemia, necrosis, ulceration and secondary infection. Calciphylaxis mostly occurs in patients with ESRD receiving hemo- or peritoneal dialysis although it is known to occur also in patients with CKD. Well described risk factors include female sex, hyperphosphatemia, hypercalcemia, hyperparathyroidism, the use of Ca-containing phosphate binders, vitamin D, and hypercoagulable states.

The diagnosis usually is made easily by characteristic clinical, bone scan and x-ray findings of well-defined tumor-like masses of Ca. (see previous posts)

Treatment recommendations have included reduction of serum Ca and P (and the CaxP product) by the use of low Ca dialysis baths, cessation of Ca-containing phosphate binders and vitamin D supplements, use of sevelamer, and possibly parathyroidectomy in refractory cases. Several case reports have reported the successful treatment of calciphylaxis with Sodium Thiosulfate. Sodium thiosulfate pentahydrate (Na2S2O3) has a molecular weight of 248. It distributes throughout extracellular fluids and is normally is excreted unchanged in the urine. It has been used as antidote for acute cyanide poisoning and as a topical treatment for acne and pityriasis versicolor. The theory is that sodium thiosulfate inhibits the precipitation of Ca salts and also leads to dissolution of Ca deposits into a more soluble form (Ca thiosulfate salts). The treatment is required for up to 4-12 months although a reduction of pain is usually seen within a couple of weeks. The main side effect is an anion gap metabolic acidosis that is related to the retention of sulfate salts. It has been suggested that patients who develop this complication can be treated with a high bicarbonate dialysis.

Back to our patient, we increased the dose of sodium thiosulfate to 25g. After 2 weeks treatment, the patient was tolerating the medication well and reported a significant improvement both in the pain, and in the necrotic lesions.

Posted by Tarek Alhamad

To Treat of Not

A 46 year old man with a recent diagnosis of acute leukemia and white count of 90,000 was transferred to our facility with non-oliguric AKI secondary to tumor lysis syndrome. The patient was hypocalcemic (Ca 5.2mg/dl) and hyperphosphatemic (PO4 11 mg/dl). His K was 5.8 mmol/L and his creatinine was 3.5 mg/dl. He was making around 200mls/hr of urine and he was asymptomatic. The Hem/Onc resident called nephrology looking for advice about whether or not the hypercalcemia should be treated and if he would be better off getting D5W with bicarbonate instead of normal saline.

TLS is a result of rapid and massive breakdown of tumor cells, either spontaneously or after the initiation of cytoreductive therapy. Because potassium is stored primarily in the intracellular compartment, its rapid release into the extracellular compartment during TLS can lead to hyperkalemia. Similarly, hyperphosphatemia results from a massive release of intracellularly stored phosphate, that can lead to secondary hypocalcemia. Uric acid is the end product of the catabolism of purines, which are released from the breakdown of nucleic acids. That lead us to the laboratory definition of TLS, that was developed by Cairo and Bishop.

Renal injury can result from two components; the deposition of uric acid and calcium phosphate crystals, and non-crystal mechanisms including renal vasoconstriction, alteration in renal autoregulation through inhibition of nitric oxide synthesis and a resulting decrease in endothelial cell nitric oxide, and stimulation of the renin-angiotensin system.

It is best to avoid IV calcium administration unless hypocalcemia is symptomatic because it might increase the risk of calcium phosphate precipitation and the potential for additional kidney injury. It is also best to monitor serum ionized calcium levels, especially in patients with hypoalbuminemia.

When rasburicase is available, hyperuricemia is seldom an indication for dialysis. Rasburicase is a recombinant urate oxidase that converts uric acid to the more water-soluble product allantoin (which is not dependent on urinary pH for its solubility).

Uric acid solubility is low and increases as urinary pH becomes more alkaline. However, calcium phosphate is more soluble at an acidic pH; therefore, urinary alkalinization may lead to increased calcium-phosphate crystallization and precipitation.

Therefore, especially when rasburicase is available to manage the hyperuricemia, urinary alkalinization should be avoided.

Going back to the patient, neither Ca nor bicarbonate was given. Uric acid was not measurable the next day following the use of rasburicase. PO4 decreased gradually over the next few days, and no dialysis was required during the hospitalization.
Update: As a commenter pointed out below, rasburicase continues to work in vitro unless the sample is immediately placed on ice and the "undetectable" uric acid level may have been artefactual.

Posted by Tarek Alhamad

Gassy

When putting a patient on CRRT, the choice of buffer these days is largely dependent on whether or not you want to use citrate for anticoagulation. Most of our patients get either citrate or bicarbonate. However, not so long ago, the main buffer was lactate. When bicarbonate was first being used as a buffer for CRRT, it had to be added separately to each bag and, in our institution at least, it came in a glass bottle next to the CVVH fluid.

More recently, the bicarbonate comes in a separate compartment of the same replacement fluid bag and just prior to use, a valve is broken and the bicarbonate-rich fluid is mixed with the rest. I had previously assumed that this was because you do not want to mix bicarbonate with calcium because of the risk of precipitation. However, in our institution, we currently use calcium-free replacement fluid and so there is no risk of precipitation (the calcium is given intravenously to the patient based on a sliding scale).

It turns out that the reason for the separate bicarbonate bags is much more interesting. Most i.v. fluid bags are gas permeable. Therefore, if you leave bicarbonate in the bag for a prolonged period of time, CO2 will leach out of the bags. By a passive process, the bicarbonate in the fluid will then be converted to CO2 which will come out of solution and will in turn leach. You will, in the end be left with very little bicarbonate in the bags. To get around this, the manufacturers of dialysate fluids used put the bicarbonate in a separate glass bottle, This is expensive and cumbersome and is prone to errors if somebody forgets to add it to the solution. Instead, now the bicarbonate-containing dialysate fluids are double-bagged. The inner bag contains the solution and is gas-permeable as before. The outer bag is constructed of a thicker, non-permeable plastic that keeps the CO2 inside. Also, to reduce diffusion further, the air between the two bags has a relatively high CO2 concentration. 

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.