A case report of severe calciphylaxis – suggested approach for diagnosis and treatment

We present a patient with a complex history of calciphylaxis. The underlying bone disease was certainly the result of long term end stage renal failure and of two poorly functioning kidney allografts. Hyperparathyroidism had been present for more than 10 years and despite cinacalcet therapy and achieving calcium, phosphate, and iPTH serum levels within the recommended ranges [21], the patient continuously had flares of calciphylaxis.

Our patient had several predisposing factors for calciphylaxis [2], such as hyperparathyroidism, obesity, and diabetes that had been present for a long time. Nevertheless, the immediate trigger for the acute worsening of calciphylaxis is unknown: There was no sudden drop in renal allograft function as GFR was consistently below 20 mL/min after an anti-rejection therapy 3 months prior to the crisis. Moreover, coumadin therapy had been stopped several months before and dosage of vitamin D and calcium-based phosphate binders had not been changed recently.

Initial therapeutic interventions were in accordance with the general recommendations [2, 8, 11], including normalization of serum calcium and phosphate levels by dialysis, cessation of calcium-containing phosphate binders, vitamin D, and thiazide diuretics, substitution of vitamin K, and sodium thiosulfate treatment dose-adjusted to the renal function. The patient also received a trial of plasmapheresis, without clinical improvement.

According to the current guidelines [21] a bone biopsy should be considered in conditions with unclear mineral and bone disturbances, e.g. fractures or unexplained hypercalcemia. We decided to take a bone biopsy shortly after admission for several reasons: (i) calciphylaxis may occur in both, high and low turnover bone disease [9], (ii) our patient had a prolonged therapy with cinacalcet which can suppress bone turnover [15], and (iii) we were uncertain whether laboratory parameters such as BAP and iPTH are sufficiently informative in this situation.

The initial histomorphometric analysis revealed low turnover osteopathy, an unexpected result in view of the moderately high iPTH and a BAP in the upper normal range. Consequently, daily dialysis with low calcium and citrate anticoagulation was initiated to induce hypocalcemia and hypophosphatemia, with the aim to minimize extraosseous calcium crystal deposition and to stimulate bone turnover by hypocalcemia-triggered PTH synthesis. After 7 weeks of this intensified treatment an increased iPTH and BAP was observed.

Our subsequent trial with teriparide was well tolerated, resulted in a reduction of pain, and was not associated with increases in serum calcium despite reduced dialysis intensity. At the end, bone turnover was significantly activated as illustrated by a sustained increase of BAP and the histologic findings in the post-mortem bone biopsy. It is certainly difficult to conclude which of the treatments (intensified dialysis or teriparatide) was the major contributor to the improved bone metabolism. Increases in iPTH and BAP were already observed with intensified dialysis alone. It remains speculative whether bone activation by teriparatide helped to maintain stable calcium levels. Because of the short observation time after initiation of teriparatide we were unable to evaluate the long-term evolution of BAP under this treatment. Also, we could not determine whether alternative treatment schedules (i.e. once per week; [22]) would have been more beneficial. It should be noted that occurrence of calciphylaxis has been reported during teriparatide treatment [23]; yet it is unknown if reduced or increased bone turnover was present in these patients. Of course, high turnover bone disease would be a contraindication for teriparatide. Also, reliable control of serum calcium and awareness of potential deterioration of calciphylaxis is mandatory in any patient receiving this treatment.

Similar to observations from Sugimto et al., iPTH levels dropped shortly after teriparatide administration [24]. This probably reflects a negative feedback of endogenous PTH generation in response to teriparatide administration. Teriparatide (rhPTH 1–34) in turn, is not detected by the iPTH laboratory test. We can only speculate why an endogenous PTH level of greater than 300 pg/mL at admission was associated with adynamic bone metabolism and in turn, why application of teriparatide should be efficient in this situation. First, endogenous PTH can be oxidized in uremia which is associated with decreased biological activity [25]. Further, administration of teriparatide leads to a considerable increase in 1–34 PTH levels up to 10fold above the upper normal physiologic PTH concentrations [26].

Our case demonstrates that identification of the underlying bone metabolism is of crucial importance for an appropriate and specific treatment of calciphylaxis. Laboratory results cannot sufficiently reflect the status of bone turnover which has been reported before [27]. In our case, initial iPTH and BAP analyses were suggestive of normal or high turnover but the bone biopsy clearly showed adynamic bone disease. Therefore, we believe that in most cases with calciphylaxis a bone biopsy should be considered to avoid erroneous and potentially harmful treatments. For example, in our patient parathyroidectomy, treatment with bisphosphonates or cinacalcet would have aggravated adynamic bone disease and thus, probably impaired the calciphylaxis.

Our suggestion therefore is a gradual approach that should be evaluated in further studies (Fig. 4). Initially, general actions should include stopping of medication that can precipitate hypercalcemia, normalization of high serum calcium and phosphate levels, administration of sodium thiosulfate [2, 8, 11, 13]. Plasma exchange might be considered but procedural risks including infections should be balanced against potential benefits. As early as possible, a bone biopsy should be considered to determine the type of bone disorder. Ideally, assessment of bone metabolism includes tetracycline labelling. However, the labelling procedure delays early diagnosis and directed treatment and thus, should be decided individually. Once the bone disorder is characterized bone metabolism can be corrected – either by reducing or increasing bone turnover – to prevent further deterioration of calciphylaxis.