Evaluating the Safety and Rationale for Cinacalcet Posttransplant Hyperparathyroidism and Hypercalcemia

Abstract

Patients with stage 5 chronic kidney disease usually develop secondary hyperparathyroidism with concomitant parathyroid gland hyperplasia. Following renal transplantation, parathyroid glands usually undergo slow involution, resulting in lower parathyroid hormone (PTH) levels and abatement of hypercalcemia and hypophosphatemia. A subset of patients has more severe hyperparathyroidism posttransplant, and develops persistent and significant hypercalcemia.In this issue of the American Journal of Transplantation, Evenepoel et al report the results of a placebo-controlled trial of cinacalcet for management of posttransplant hypercalcemia due to persistent hyperparathyroidism (1). They demonstrate that cinacalcet normalizes serum calcium and lowers PTH. The study randomized 114 patients with severe hyperparathyroidism (mean PTH 318 pg/mL) and hypercalcemia (mean calcium 11.3 mg/dL) an average of 7 months posttransplant. Consistent with prior smaller studies, cinacalcet lowered PTH, normalized serum calcium and increased phosphorus, while placebo treatment led to no significant changes in these parameters. Gastrointestinal side effects from cinacalcet were expected and observed, but the discontinuation rate was quite low.After 1 year of treatment, the cinacalcet group had several other outcomes similar to placebo treatment: no improvement in bone mineral density (BMD) at the distal one-third radius, femoral neck or lumbar spine, and no improvement in biomarkers of high bone turnover (1). Both groups had comparable and stable estimated GFR, allaying concerns raised previously. Following withdrawal of cinacalcet, serum calcium and PTH levels were similar in the cinacalcet and placebo groups, suggesting cinacalcet did not hasten parathyroid gland involution (1).This trial illustrates a biochemical response to cinacalcet, with improvement in hypercalcemia and PTH. However, the duration of follow-up was too short, and the study population too small to examine fracture incidence. Unlike other patients with primary hyperparathyroidism, most renal transplant recipients do not routinely have high bone turnover (2). Bone biopsies in 17 patients (not treated with cinacalcet) with hypercalcemia and hyperparathyroidism 0.6-12 years posttransplant showed eight had osteitis fibrosa (high bone turnover), seven had adynamic bone disease (low bone turnover) and one each had mixed uremic osteodystrophy and osteomalacia (2).Given the high prevalence of low bone turnover in transplant patients with hypercalcemia and hyperparathyroidism, use of cinacalcet (or parathyroidectomy) may exacerbate bone disease, despite normalizing serum calcium. A prospective study performing bone biopsies in 10 patients with hypercalcemia and hyperparathyroidism for an average of 2 years postrenal transplant found low bone turnover present in 4 of 10 prior to cinacalcet (3). After 18-24 months of cinacalcet therapy, 8 of 10 had low bone turnover, including five with undetectable bone formation rates. As in the Evenepoel et al trial, these investigators found cin...

Retrospective Study Looking at Cinacalcet in the Management of Hyperparathyroidism after Kidney Transplantation

“…However, it is important to reiterate that cinacalcet is not yet approved for use in renal transplant recipients. Moreover it is not clear whether either of these treatments is appropriate even if safety and biochemical efficacy are assumed [11]. Bone disease following kidney transplantation is a complex problem with multiple etiologies related to dialysis, corticosteroid therapy, calcineurin inhibitors, and persistent hyperparathyroidism [13].…”

“…There were no new safety signals although follow-up was rather short. These findings are very encouraging but further studies are needed particularly in regard to long-term clinical outcomes [11]. Moreover, there is an unresolved issue as to whether cinacalcet should be discontinued or pursued at the time of kidney transplantation.…”

A Randomized Study Comparing Parathyroidectomy with Cinacalcet for Treating Hypercalcemia in Kidney Allograft Recipients with Hyperparathyroidism

“…20 Alternatively, given the high prevalence of low bone turnover in transplant recipients with hypercalcemia and hyperparathyroidism, it has been suggested that cinacalcet or even parathyroidectomy may exacerbate adynamic bone disease. 22 Adynamic bone disease can be indirectly assessed by bone turnover biomarkers. 23 Among them, alkaline phosphatase is the best.…”

“…There is a paucity of data regarding the optimal management of tertiary hyperparathyroidism. 22 A cost-utility analysis has been reported comparing subtotal parathyroidectomy with cinacalcet in patients on dialysis with severe hyperparathyroidism. 33 This study concluded that surgery was more cost effective if cinacalcet treatment duration reached 16 months.…”

Management of Post-transplant Hyperparathyroidism and Bone Disease

“…Consequently, we prefer to measure the PTH in transplant candidates 2–4 weeks after stopping the calcimimetic as part of the evaluation for transplant. If the PTH is < 800 pg/mL, the patient’s risk of hypercalcemia post-transplant appears to be low [ 16 ]. If the PTH is > 1000 pg/mL, this is indicative of severe HPT-related bone disease.…”