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Cinacalcet Treatment for Stable Kidney Transplantation Patients With Hypercalcemia due to Persistent Secondary Hyperparathyroidism: A Long-term Follow-up
Cinacalcet Treatment for Stable Kidney Transplantation Patients With Hypercalcemia due to Persistent Secondary Hyperparathyroidism: A Long-term Follow-up R.P. Paschoalin, J.-V. Torregrosa, A. Sánchez-Escuredo, X. Barros, C.E. Durán, and J.M. Campistol ABSTRACT Background. Cinacalcet is an effective treatment for hypercalcemia due to persistent hyperparathyroidism (HPT) in patients who have undergone kidney transplantation (KT). Few data are available about their long-term follow-up. Objective. We aimed to evaluate the long-term efficacy of cinacalcet in functioning stable KT subjects with hypercalcemia secondary to persistent HPT. Material and Methods. Twenty-three patients (6 men) with a stable KT showed persistent hypercalcemia (⬎12 months) secondary to HPT (parathyroid hormone by radioimmunoassay [iPTH] ⬎ 150 pg/mL). The mean age was 54 ⫾ 13 years. Time after KT to beginning cinacalcet treatment was 36.5 ⫾ 37.9 (range 12 to 172) months. Initial cinacalcet doses were 30 mg/d. Median follow-up was 53 ⫾ 7.4 months (range 42 to 60 months). We determined serum calcium, phosphorus, alkaline phosphatase, iPTH, creatinine, and immunosuppressant concentrations at baseline as well as 3, 6, and 12 months and after every 6 months thereafter. Results. Initial serum calcium was 11 ⫾ 0.65 mg/dL and mean calcium during treatment, 10.25 ⫾ 0.81 mg/dL (P ⬍ .001). Initial serum phosphorus was 2.8 ⫾ 0.58 mg/dL and mean value serum phosphorus during the treatment period, 3.13 ⫾ 0.6 mg/dL (P ⫽ 0.015). Initial iPTH was 260 ⫾ 132 pg/mL and during the treatment period; 237 ⫾ 131 pg/mL (P ⫽ ns). There was no change in renal function nor in immunosuppressant blood levels. Doses of cinacalcet at the end of the follow-up were 40.4 ⫾ 18.9 mg/d. Conclusion. Cinacalcet was effective for long-term control of hypercalcemia related to persistent HPT for patients with stable KT. ERSISTENT secondary hyperparathyroidism (HPT) with hypocalcemia and hypophosphatemia are common issues among 17% to 50% of patients beyond the first year after kidney transplantation (KT).1 It may adversely affect the outcomes of renal transplant recipients. Therefore, effective control of persistent HPT is an important therapeutic goal after KT. Cinacalcet is being used to treat hypercalcemia in these patients. It has shown efficacy to lower PTH and serum calcium concentrations and to increase phosphorus content.2,3 Some studies have shown the safety and efficacy of cinacalcet during short-term treatment after KT.4,5 Other studies have suggested that long-term treatment with cinacalcet may increase urinary calcium excretion and renal calcium deposits, consequently altering graft function.6 But
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no long-term studies support this hypothesis. The aim of the present study was to review the efficacy of cinacalcet as a long-term treatment for hypercalcemia secondary to persistent HPT after KT. MATERIALS AND METHODS This retrospective observational study included 23 kidney transplant patients (6 men) who underwent treatment with cinacalcet due to persistent HPT with hypercalcemia. The concentrations calcium adjusted From the Nephrology and Kidney Transplantation Unit, Hospital Clinic, Barcelona, Spain. Address reprint requests to Jose-Vicente Torregrosa, Institut Clinic de Nefrología i Urología, Kidney Transplant Unit, Hospital Clinic de Barcelona, Villarroel, 170. CP 08036, Barcelona, Spain E-mail: [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.09.049
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2588
Transplantation Proceedings, 44, 2588 –2589 (2012)
CINALCET TREATMENT for albumin at time of enrollment in the study were greater than 10.5 mg/dL. The patients had never received cinacalcet before transplantation and were at least 1 year post-KT before introduction of cinacalcet. Patients began treatment with cinacalcet at 30 mg per day, which was subsequently adjusted seeking a target of decreasing serum calcium to the normal range (⬍ 10.5 mg/dL). They received cinacalcet at a median of 53 ⫾ 7.4 months (range, 42 to 60 months). The mean patient age at transplantation was 54 ⫾ 13 years and time on hemodialysis before KT was 9.5 ⫾ 7.3 years. The immunosuppressive treatment consisted of a calcineurin inhibitor (n ⫽ 17) and a mammalian target of rapamycin antagonist (n ⫽ 6), in addition to mycophenolate mofetil and/or steroids. Serum creatinine, calcium, phosphorus, alkaline phosphatase, and parathyroid hormone by radioimmunoassay (iPTH) concentrations were evaluated at baseline as well as 3, 6, and 12 month during the first year and every 6 months for the rest of the follow-up period.
RESULTS
The initial 30-mg cinacalcet dose was adjusted to a mean of 40.4 ⫾ 18.9 mg/d. Time from the beginning of cinacalcet treatment until after KT was 36.5 ⫾ 37.9 months (range 12 to 172). The mean dose during the study is shown in Fig 1. Three months after cinacalcet introduction, we observed a significant reduction in calcium and increase in phosphorus toward normal values that were maintained during the follow-up. Basal serum calcium was 11 ⫾ 0.65 mg/dL and mean calcium during the treatment period; 10.25 ⫾ 0.81 mg/dL (P ⫽ .001). Basal serum phosphorus was 2.8 ⫾ 0.58 mg/dL and mean serum phosphorus during treatment, 3.13 ⫾ 0.6 mg/dL (P ⫽ 0.015). iPTH decreased albeit not significantly: Basal iPTH was 260 ⫾ 132 pg/mL and mean value during treatment, 237 ⫾ 131 pg/mL (P ⫽ .55). There were no changes in renal function. Basal creatinine was 1.24 ⫾ 0.34 mg/dL and during treatment, 1.26 ⫾ 0.55 mg/dL (P ⫽ .88). These results are summarized in Fig 2. No patient reported an adverse event due to the drug. DISCUSSION
As shown in other studies, cinacalcet normalizes serum calcium in hypercalcemic transplantation patients with HPT.4 In our study, the blood levels of calcium decreased significantly at 3 months after cinacalcet introduction, and remained controlled during the follow-up. Secondary to the
Fig 1.
Mean dose during study.
2589
Fig 2.
Evolution of serum biochemical parameters.
decrease in iPTH, the phosphorus increased persisting in the normal range. All of our patients showed persistent hypercalcemia over more than 12 months after KT before starting treatment with cinacalcet. However, they responded well to cinacalcet. Persistent HPT after KT is responsible for allograft calcifications, probably through phosphaturia7 as well as loss of bone mineral density and increased fracture.8 A reduction of i-PTH blood levels might improve these problems.9 Although treatment with cinacalcet is not clearly established for KT patients, we believe that stable KT patients with hyperparathyroidism and hypercalcemia or hypophosphatemia should receive the drug to avoid allograft calcifications and maintain bone health. In summary, cinacalcet was effective for long-term control of hypercalcemia related to persistent secondary hyperparathyroidism in patients with stable KT. REFERENCES 1. Evenepoel P, Claes K, Kuypers D, et al: Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study. Nephrol Dial Transplant 19:1281, 2004 2. Serra AL, Schwarz AA, Wick FH, et al: Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 20:1315, 2005 3. Bergua C, Torregrosa JV, Cofán F, et al: Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism. Transplant Proc 39:2254, 2007 4. Schwarz A, Merkel S, Leitolf H, et al: The effect of cinacalcet on bone remodeling and renal function in transplant patients with persistent hyperparathyroidism. Transplantation 15; 91:560, 2011 5. El-Amm JM, Doshi MD, Singh A, et al: Preliminary experience with cinacalcet use in persistent secondary hyperparathyroidism after kidney transplantation. Transplantation 83:546, 2007 6. Courbebaisse M, Diet C, Timsit MO, et al: Effects of cinacalcet in renal transplant patients with hyperparathyroidism. Am J Nephrol 35:341, 2012 7. Evenepoel P, Lerut E, Naesens M, et al: Localization, etiology and impact of calcium phosphate deposits in renal allografts. Am J Transplant 9:2470, 2009 8. Bergua C, Torregrosa JV, Fuster D, et al: Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism. Transplantation 86:413, 2008 9. Torregrosa JV, Campistol JM, Montesinos M, et al: Evolution of bone mineral density after renal transplantation: related factors. Nephrol Dial Transplant 10(suppl 6):111, 1995
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no long-term studies support this hypothesis. The aim of the present study was to review the efficacy of cinacalcet as a long-term treatment for hypercalcemia secondary to persistent HPT after KT. MATERIALS AND METHODS This retrospective observational study included 23 kidney transplant patients (6 men) who underwent treatment with cinacalcet due to persistent HPT with hypercalcemia. The concentrations calcium adjusted From the Nephrology and Kidney Transplantation Unit, Hospital Clinic, Barcelona, Spain. Address reprint requests to Jose-Vicente Torregrosa, Institut Clinic de Nefrología i Urología, Kidney Transplant Unit, Hospital Clinic de Barcelona, Villarroel, 170. CP 08036, Barcelona, Spain E-mail: [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.09.049
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2588
Transplantation Proceedings, 44, 2588 –2589 (2012)
CINALCET TREATMENT for albumin at time of enrollment in the study were greater than 10.5 mg/dL. The patients had never received cinacalcet before transplantation and were at least 1 year post-KT before introduction of cinacalcet. Patients began treatment with cinacalcet at 30 mg per day, which was subsequently adjusted seeking a target of decreasing serum calcium to the normal range (⬍ 10.5 mg/dL). They received cinacalcet at a median of 53 ⫾ 7.4 months (range, 42 to 60 months). The mean patient age at transplantation was 54 ⫾ 13 years and time on hemodialysis before KT was 9.5 ⫾ 7.3 years. The immunosuppressive treatment consisted of a calcineurin inhibitor (n ⫽ 17) and a mammalian target of rapamycin antagonist (n ⫽ 6), in addition to mycophenolate mofetil and/or steroids. Serum creatinine, calcium, phosphorus, alkaline phosphatase, and parathyroid hormone by radioimmunoassay (iPTH) concentrations were evaluated at baseline as well as 3, 6, and 12 month during the first year and every 6 months for the rest of the follow-up period.
RESULTS
The initial 30-mg cinacalcet dose was adjusted to a mean of 40.4 ⫾ 18.9 mg/d. Time from the beginning of cinacalcet treatment until after KT was 36.5 ⫾ 37.9 months (range 12 to 172). The mean dose during the study is shown in Fig 1. Three months after cinacalcet introduction, we observed a significant reduction in calcium and increase in phosphorus toward normal values that were maintained during the follow-up. Basal serum calcium was 11 ⫾ 0.65 mg/dL and mean calcium during the treatment period; 10.25 ⫾ 0.81 mg/dL (P ⫽ .001). Basal serum phosphorus was 2.8 ⫾ 0.58 mg/dL and mean serum phosphorus during treatment, 3.13 ⫾ 0.6 mg/dL (P ⫽ 0.015). iPTH decreased albeit not significantly: Basal iPTH was 260 ⫾ 132 pg/mL and mean value during treatment, 237 ⫾ 131 pg/mL (P ⫽ .55). There were no changes in renal function. Basal creatinine was 1.24 ⫾ 0.34 mg/dL and during treatment, 1.26 ⫾ 0.55 mg/dL (P ⫽ .88). These results are summarized in Fig 2. No patient reported an adverse event due to the drug. DISCUSSION
As shown in other studies, cinacalcet normalizes serum calcium in hypercalcemic transplantation patients with HPT.4 In our study, the blood levels of calcium decreased significantly at 3 months after cinacalcet introduction, and remained controlled during the follow-up. Secondary to the
Fig 1.
Mean dose during study.
2589
Fig 2.
Evolution of serum biochemical parameters.
decrease in iPTH, the phosphorus increased persisting in the normal range. All of our patients showed persistent hypercalcemia over more than 12 months after KT before starting treatment with cinacalcet. However, they responded well to cinacalcet. Persistent HPT after KT is responsible for allograft calcifications, probably through phosphaturia7 as well as loss of bone mineral density and increased fracture.8 A reduction of i-PTH blood levels might improve these problems.9 Although treatment with cinacalcet is not clearly established for KT patients, we believe that stable KT patients with hyperparathyroidism and hypercalcemia or hypophosphatemia should receive the drug to avoid allograft calcifications and maintain bone health. In summary, cinacalcet was effective for long-term control of hypercalcemia related to persistent secondary hyperparathyroidism in patients with stable KT. REFERENCES 1. Evenepoel P, Claes K, Kuypers D, et al: Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study. Nephrol Dial Transplant 19:1281, 2004 2. Serra AL, Schwarz AA, Wick FH, et al: Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 20:1315, 2005 3. Bergua C, Torregrosa JV, Cofán F, et al: Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism. Transplant Proc 39:2254, 2007 4. Schwarz A, Merkel S, Leitolf H, et al: The effect of cinacalcet on bone remodeling and renal function in transplant patients with persistent hyperparathyroidism. Transplantation 15; 91:560, 2011 5. El-Amm JM, Doshi MD, Singh A, et al: Preliminary experience with cinacalcet use in persistent secondary hyperparathyroidism after kidney transplantation. Transplantation 83:546, 2007 6. Courbebaisse M, Diet C, Timsit MO, et al: Effects of cinacalcet in renal transplant patients with hyperparathyroidism. Am J Nephrol 35:341, 2012 7. Evenepoel P, Lerut E, Naesens M, et al: Localization, etiology and impact of calcium phosphate deposits in renal allografts. Am J Transplant 9:2470, 2009 8. Bergua C, Torregrosa JV, Fuster D, et al: Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism. Transplantation 86:413, 2008 9. Torregrosa JV, Campistol JM, Montesinos M, et al: Evolution of bone mineral density after renal transplantation: related factors. Nephrol Dial Transplant 10(suppl 6):111, 1995