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