Objectives: Persistent secondary hyperparathyroidism is common after successful kidney transplant, with concomitant hypercalcemia and hypophosphatemia potentially leading to reduced graft survival and increased cardiovascular risk. Cinacalcet, a calcimimetic agent that activates the calcium-sensing receptors in parathyroid glands, is a therapeutic option. In this study, we assessed the long-term treatment effects of cinacalcet for a period of up to 5 years in a cohort of kidney transplant recipients.

Materials and Methods: Forty-seven patients with secondary hyperparathyroidism (intact parathyroid hormone level > 70 pg/mL or 7.43 pmol/L) and hypercalcemia (corrected calcium > 10.4 mg/dL or 2.6 mmol/L) were considered eligible for treatment with cinacalcet and were included in the analysis. Data were recorded at initiation of treatment and every 6 months up to a maximum follow-up of 60 months. A control group of patients treated with placebo, conventional treatment, or surgical treatment was not available for this study.

Results: Mean follow-up time was 45 ± 16 months. Treatment with cinacalcet was initiated at a median of 25 months after renal transplant. Serum calcium decreased by 0.21 mmol/L (2.69 vs 2.48 mmol/L; 95% confidence interval, 0.08-0.345; P < .001) during the first 6 months, and this reduction was sustained during follow-up. Intact parathyroid hormone level decreased by 7.68 pmol/L (32.96 ± 36.4 vs 25.28 ± 19.5 pmol/L; 95% confidence interval, -6.42 to 21.75; P = not significant) at 6 months, whereas at the end of follow-up intact parathyroid hormone level decreased further by 20.07 pmol/L (32.96 ± 36.4 vs 12.89 ± 5.73 pmol/L; 95% confidence interval, 2.02-38.1; P < .01). Mean starting dose of cinacalcet was 33.5 ± 10 mg/day. According to the therapeutic response, cinacalcet dose increased steadily and reached 51.1 ± 33 mg/day at the end of the observation period. Mean serum phosp-horus increased significantly, whereas estimated glomerular filtration rate remained virtually stable throughout follow-up. Adverse reactions were observed in 4 patients, comprising mild gastro-intestinal complaints.

Conclusions: Long-term treatment with cinacalcet in kidney transplant recipients with secondary hyperparathyroidism is effective in controlling hypercalcemia and correcting hypophosphatemia, without affecting graft function while being well-tolerated.

Key words : Hypophosphatemia, Kidney function, Renal transplant

Introduction

Secondary hyperparathyroidism is a frequent complication of end-stage renal disease. After successful kidney transplant, secondary hyper-parathyroidism usually remits; however, it persists in 30% to 50% of patients 1 year after transplant.^1-3 Risk factors for the development of persistent secondary hyperparathyroidism after kidney transplant include the duration of renal replacement therapy and the severity of secondary hyper-parathyroidism before transplant.^1,4

In kidney transplant recipients, persistent secondary hyperparathyroidism is characterized by elevated serum parathyroid hormone (PTH) and/or hypercalcemia and hypophosphatemia.^2,5 Parathyroid hormone increases bone resorption, inhibits fractional renal calcium excretion, and promotes calcitriol production by the kidney allograft. Calcitriol, in turn, increases calcium absorption from the intestinal tract. These mechanisms contribute to the development of hypercalcemia. Furthermore, PTH decreases phos-phate reabsorption by the renal tubules, leading to phosphaturia and hypophosphatemia, which are common findings in kidney transplant recipients especially in the first months after transplant.^6,7 Persistent secondary hyperparathyroidism after kidney transplant increases the risk of bone fractures⁸ and has been related to worse graft survival⁹ and increased cardiovascular risk due to increased vascular calcification.¹⁰

Vitamin D analogs have been extensively used for the treatment of posttransplant secondary hyper-parathyroidism; however, their use is hampered by the development of hypercalcemia. In addition, bisphosphonates are commonly prescribed in kidney transplant recipients for the prevention and treatment of osteoporosis.¹¹ Both of these medi-cations may lead to decreased bone turnover and predispose to the development of adynamic bone disease.¹²

Cinacalcet is a calcimimetic drug that allos-terically activates the calcium-sensing receptor expressed on the surface of the chief cells of the parathyroid gland. Calcium-sensing receptor activation inhibits PTH secretion and leads to a decrease in serum calcium.^13,14 Cinacalcet has not been officially approved for use in kidney transplant recipients with persistent secondary hyperparathyroidism, although it has been used off-label in an effort to improve hypercalcemia and avoid parathyroidectomy. However, its efficacy in this group of patients remains under investigation.

In the present study, we prospectively assessed the long-term treatment effects of cinacalcet in kidney transplant recipients with persistent second-ary hyperparathyroidism and hypercalcemia, followed for a period of up to 5 years.

Materials and Methods

Patient selection and study design
This was a prospective single-center study. Adult patients (> 18 years) who received a deceased-donor kidney allograft from January 2008 through December 2014 and who commenced treatment with cinacalcet due to secondary hyperparathyroidism and hypercalcemia were considered eligible for participation in the study. Exclusion criteria were estimated glomerular filtration rate (eGFR) at initiation of treatment of < 20 mL/min/1.73 m² and refusal to provide informed consent. Over the study period, we followed 362 patients in the outpatient transplant clinic. Fifty-two patients met the inclusion criteria and provided informed consent. Of these, 3 patients were excluded from the study: 1 because of diagnosis of pancreatic cancer 2 months after commencement of cinacalcet and 2 because of consent withdrawal at 2 and 4 months after initiation of treatment. Of the 49 patients included in the study, 2 more patients were lost to follow-up before their 12-month scheduled visit and were excluded from the analysis. Finally, 47 patients were included in the analysis. Data were recorded at initiation of treatment with cinacalcet and every 6 months until a maximum follow-up of 60 months. Although recruitment stopped at the end of 2014, data collection continued for another year (until end of 2015). The study protocol was approved by our Local Ethics Committee on human research and was in accordance with the Helsinki Declaration, as revised in 2000.

Definitions and data collection
Hyperparathyroidism was defined as intact PTH (iPTH) of > 7.43 pmol/L (70 pg/mL). Hypercalcemia was defined as serum calcium corrected for serum albumin > 2.6 mmol/L (10.4 mg/dL). Hypercalcemia persisting for more than 3 months despite review of medications was considered as an indication for treatment with cinacalcet. The following data were recorded at initiation of treatment and at each scheduled visit thereafter: serum iPTH, calcium, phosphate, albumin, alkaline phosphatase, creatinine, eGFR (Modification of Diet in Renal Disease), cinacalcet dose, calcineurin inhibitor trough levels, and 24-hour urinary protein excretion.

Statistical analyses
Continuous variables were reported as means, standard deviations (SD), and range of values as appropriate. Changes of examined values from baseline were evaluated using repeated-measures analysis of variance (ANOVA) or one-way ANOVA as appropriate. Comparisons of changes in serum iPTH, calcium, and phosphorus concen-trations between subgroups of patients were performed using t test or Mann-Whitney U test as appropriate. Statistical analyses were performed with GraphPad software 5.03 (GraphPad, La Jolla, CA, USA).

Results

Study population
Clinical and demographic data of study patients are summarized in Table 1. Mean follow-up time was 45 ± 16 months (range, 12-60 mo), with 21 patients having 60 months of follow-up. Cinacalcet treatment was initiated at a median of 25 months after renal transplant, with 12 patients starting cinacalcet during the early posttransplant period (up to 30 days after surgery).

All patients received an immunosuppressive regimen consisting of a calcineurin inhibitor (tacrolimus or cyclosporine in 24 and 23 patients, respectively), plus mycophenolate mofetil, or mycophenolic acid and corticosteroids.

At baseline, none of the patients received active vitamin D or analogs. Nevertheless, 8 patients received alfacalcidol, in addition to cinacalcet, during their follow-up. In these patients, alfacalcidol was started 24 months (range, 6-54 mo) after initiation of treatment with cinacalcet. Median dose of alfacalcidol was 0.25 μg (range, 0.125-0.5 μg), and median duration of treatment was 12 months (range, 6-36 mo). Two patients were receiving alfacalcidol at the end of follow-up (60 months), whereas in the remaining 6 patients, alfacalcidol was stopped because of recurrence of hypercalcemia. No patients received calcium salt-prescribed therapy at any point of follow-up.

Effect of cinacalcet on serum calcium and intact parathyroid hormone levels
Serum calcium decreased by 0.21 mmol/L (2.69 ± 0.14 vs 2.48 ± 0.23 mmol/L; 95% confidence interval [CI], 0.08-0.345; P < .001) during the first 6 months; during the remainder of follow-up, the reduction reached a maximum of 0.41 mmol/L (2.69 ± 0.14 vs 2.28 ± 0.19 mmol/L; 95% CI, 0.255-0.568; P < .001) at 54 months after initiation of treatment (Table 2). The cinacalcet-induced calcium reduction was sustained during the entire follow-up (Figure 1A).

Serum iPTH decreased by 7.68 pmol/L (32.96 ± 36.4 vs 25.28 ± 19.5 pmol/L; 95% CI, -6.42 to 21.75; P = not significant) at 6 months, whereas, at the end of follow-up (60 months), iPTH decreased further, reaching a reduction of 20.07 pmol/L (32.96 ± 36.4 vs 12.89 ± 5.73 pmol/L; 95% CI, 2.02-38.1; P < .01) (Figure 1B).

When patients were grouped by baseline eGFR (of more or less than 60 mL/min/1.73 m²), although iPTH at 6 months after the initiation of cinacalcet decreased in both groups, this decrease reached significance only in patients with eGFR < 60 mL/min/1.73 m² (30.03 vs 22.6 pmol/L; P = .04). In contrast, serum calcium was significantly decreased in both groups, whereas serum phos-phorus was increased (data not shown).

Cinacalcet dosing
Patients received a daily mean starting dose of 33.5 ± 10 mg of cinacalcet (range, 15-60 mg). According to the therapeutic response (serum calcium and iPTH levels), cinacalcet dose increased steadily, reaching a maximum mean dose of 57.7 ± 33 mg (range, 15-150 mg) at 48 months of follow-up (P < .05). At the end of the observation period, mean cinacalcet dose remained at 51.1 ± 33 mg (range, 15-150 mg). Dose adjustments were necessary early after initiation of treatment in a clearly upward manner to achieve calcium reduction toward normal levels (Figure 2). Most importantly, although normal serum calcium concentration (2.38 ± 0.185 mmol/L) had already been achieved 12 months after initiation of cinacalcet, its dose had to be increased further after that time point (Figure 2). The clinical significance of this observation was that, to maintain a normal serum calcium concentration, a constant cinacalcet upward titration was needed.

Effect of cinacalcet on serum phosphorus, alkaline phosphatase, estimated glomerular filtration rate, urinary protein excretion, and calcineurin inhibitors
Mean serum phosphorus concentration showed a gradual, significant increase after the initiation of cinacalcet, which remained until the end of follow-up (ANOVA, P < .01) (Figure 1C). Mean phosphorus concentration peaked at month 54 (0.93 ± 0.26 vs 1.107 ± 0.21 mmol/L; P < .05), which coincided with a nadir in mean calcium concentration (2.28 ± 0.19 mmol/L).

Serum alkaline phosphatase showed a lowering trend from a mean concentration of 1648 ± 146 μkat/L (range, 0.46-10.03 μkat/L) at the initiation of treatment to 1309 ± 0.43 μkat/L (range, 0.66-2.24 μkat/L) at 60 months, which did not reach statistical significance.

Estimated glomerular filtration rate remained virtually stable throughout follow-up. It showed a nonsignificant increase (48.3 ± 21 vs 54.6 ± 17 mL/min/1.72 m²; P = not significant) at 6 months after the initiation of treatment. At the end of the 60-month observation period, it reached 47.2 ± 15 mL/min/1.72 m², indicating the safety profile of the drug in renal transplant recipients at least as far it concerned long-term graft function.

Proteinuria decreased 6 months after the initiation of treatment (222 vs 158 mg/24 h, P = not significant), and remained at lower levels compared with the starting values for 18 months (222 vs 187 mg/24 h; P = not significant). Thereafter, a gradual, nonstatistically significant increase was observed (327 ± 325 mg/24 h at 60 mo). This slight increase in proteinuria could be due to gradual graft dysfunction and chronic allograft nephropathy.

Calcineurin inhibitor trough levels were not significantly affected during the entire follow-up.

Adverse effects
Adverse reactions were observed in 4 patients (8.5%) and included mild gastrointestinal complaints, which were successfully treated with cinacalcet dose reduction.

Discussion

Cinacalcet has been extensively used for the treatment of secondary hyperparathyroidism in dialysis patients. However, its use in kidney transplant recipients remains off-label. Several prospective^15-30 and retrospective^31-41 observational cohort studies have examined the potential effects of cinacalcet in kidney transplant recipients. Most of these studies have included small cohorts with short follow-up periods, whereas only 4 studies have reported follow-up of greater than 3 years.^30,38,39,41 More recently, the first double-blind, randomized controlled trial⁴² with 1-year follow-up compared cinacalcet versus placebo in kidney transplant recipients with persistent secondary hyper-parathyroidism.

The main feature of the present study is its long follow-up, reaching 60 months (mean 45 months) in 21 patients (45%). Presently, only 1 study has reported a similar follow-up, yet the cohort was much smaller.³⁸

In agreement with all previous studies, our data suggest that long-term treatment with cinacalcet is effective in correcting hypercalcemia and main-taining serum calcium within normal levels. This effect was particularly achieved during the first year of treatment. In addition, it was effective in correcting hypophosphatemia. Our results also showed that the effect of cinacalcet on serum iPTH was modest, reaching statistical significance at the end of follow-up. The most relevant studies in the literature have shown that treatment with cinacalcet decreases serum iPTH. However, in the studies with long-term follow-up, this effect was not evident, as only 2 studies showed a significant decrease in serum iPTH.^39,41 In 2 others,^30,38 the decrease in serum iPTH was not significant. Correction of hypophosphatemia has also been shown in most but not all previous studies.^18,19,28,30

The observed effects of cinacalcet, however, come at the cost of an increase in drug dosing, as mean dose almost doubled toward the end of the observation period. Despite early restoration of normocalcemia at 12 months, which was the primary therapeutic target, cinacalcet dose continued to increase during the entire follow-up. This indicates that continuous uptitration of cinacalcet is needed to achieve a sustainable effect on serum calcium, thus substantially increasing the costs of a long-term treatment.

With regard to graft function, stable eGFR and a slight, nonsignificant increase in mean urinary protein excretion throughout the whole follow-up indicated that treatment with cinacalcet did not significantly affect graft function. Available studies have shown contradicting results, as some have reported worsened graft function after treatment with cinacalcet,^20,27,29,36 whereas others have shown improved^22,35,37 or stable graft function.⁴¹ We also did not observe any perturbations in calcineurin inhibitor trough levels, and the immunosuppressive regimen was not changed in any of the patients for reasons related to the use of cinacalcet or after initiation of the drug.

Major adverse events were not observed throughout the follow-up, and the drug was not discontinued in any patient due to adverse events. Mild gastrointestinal symptoms were observed in 8.5% of patients. In 2 patients, gastrointestinal discomfort was more severe but was relieved after dose reduction. These observations point toward a good safety profile of the drug; however, they cannot be generalized as the study cohort was small.

Limitations of this study include the small number of patients and the observational cohort design, which renders it vulnerable to selection bias. The lack of a control group (we had no comparison groups of patients treated with placebo, conventional treatment, or parathyroidectomy) significantly limited the robustness and generalizability of our results. Furthermore, an important limitation of this and all other relevant studies published so far is the use of surrogate endpoints. Thus, it is unknown whether the observed biochemical effects of treatment of cinacalcet can have a positive impact on hard outcomes such as bone fracture risk, vascular calcifications, or cardiovascular mortality in kidney transplant recipients. In contrast, results from the EVOLVE trial⁴³ in dialysis patients have not shown a benefit of treatment with cinacalcet on cardiovascular risk of death or major cardiovascular events.

Finally, treatment with cinacalcet has been con-sidered as an alternative to surgical parathyroidectomy or as an option for delaying parathyroidectomy. However, it remains uncertain whether delaying or avoiding parathyroidectomy confers a clinical benefit to the patient. Recently, a small randomized study has demonstrated parathyroidectomy to be superior to the use of cinacalcet for treating hypercalcemia in kidney transplant recipients with secondary hyper-parathyroidism.⁴⁴ Moreover, the cost-effectiveness of long-term treatment with cinacalcet has to be weighed against that of surgical parathyroidectomy.

In conclusion, the present study has shown that long-term treatment with cinacalcet is effective in controlling hypercalcemia and correcting hypo-phosphatemia in kidney transplant recipients with secondary hyperparathyroidism, without signifi-cantly affecting graft function and while being well-tolerated by most patients. However, in light of recent evidence showing that cinacalcet may not improve hard outcomes and may not be superior to parathyroidectomy in kidney transplant recipients with secondary hyperparathyroidism, there is a need for adequately powered, well-designed randomized controlled trials with long-term follow-up to compare these 2 treatment options.

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