Therapeutic failure of cinacalcet in a renal transplant patient presenting hyperparathyroidism with severe hypercalcaemia

Sir, In our experience, 10% of renal allograft recipients develop sustained hyperparathyroidism and hypercalcaemia during the first year following renal transplantation. Persistent hypercalcaemia usually requires parathyroidectomy, which represents the only definitive treatment currently available. Cinacalcet, a calcimimetic drug, represents from now on an alternative therapy to avoid surgery. Recent studies have reported successful control of hypercalcaemia by this drug in this situation [1–3]. We report the case of a 25-year-old man, on peritoneal dialysis since 2003, who received a renal graft in November 2004 and developed after transplantation sustained hypercalcaemia at 3.35mmol/l (normal range, 2.2–2.6) with a high level of ionized calcium at 1.88mmol/l (normal range, 1.14–1.31) and an inappropriate plasmatic secretion of parathyroid hormone (PTH) at 607 pg/ml (normal range, 10–55). The glomerular filtration rate, assessed by creatinine clearance, was 73ml/min/1.73m. Treatment with cinacalcet was initiated, at 4 months post transplantation, in an attempt to avoid parathyroidectomy. Despite 2 months of treatment with increasing doses of oral cinacalcet (up to 120mg once daily), hypercalcaemia at 3.09mmol/l (ionized calcium, 1.61mmol/l) persisted with seric PTH concentration of 314 pg/ml. Interestingly hypercalciuria, which was not present in the early post transplantation period (urinary calcium, 4.6mmol/24 h), appeared upon cinacalcet treatment with value at 16mmol/24 h. Because of the persistent threatening high level of serum calcium (value at 3.36mmol/l) associated with hypercalciuria, a sub total parathyroidectomy was finally performed. The reasons for the resistance to cinacalcet need to be elucidated. Non observance of treatment can be excluded. A possible explanation could be a defect of sensitivity to extra cellular calcium or to the calcimimetic drug by the parathyroid cells. This observation also suggests, though not previously observed in studies, that cinacalcet could be responsible for a urinary calcium excretion increase by a direct effect on the calcium sensor located in the thick ascending limb of Henle [4,5]. Indeed, activating mutation of calcium sensor receptor could provide mechanism for the developments of Bartter’s syndrome, which is characterized by an increase in urinary calcium [6,7]. In conclusion, this case demonstrates a therapeutic failure of cinacalcet in a renal transplant patient presenting hypercalcaemia with inappropriate secretion of PTH. Furthermore increase of urinary calcium during cinacalcet treatment must be emphasized and needs to be clarified because it has not been observed in renal transplant recipients who respond successfully to cinacalcet [2,4]. Therefore, further studies, with larger numbers of patients, are required to better define which kind of patient could have resistance and to unravel the real effect of cinacalcet on urinary calcium tubular excretion.