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Published ahead of print on January 25, 2006
Clin J Am Soc Nephrol 1: 323-326, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.00500705
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Renal Transplantation

Improvement in Hypercalcemia with Cinacalcet after Kidney Transplantation

Titte R. Srinivas*, Jesse D. Schold*, Karl L. Womer{dagger},{ddagger}, Bruce Kaplan*, Richard J. Howard§, Charles M. Bucci*, and Herwig-Ulf Meier-Kriesche*

* Divisions of Nephrology, Hypertension and Transplantation; {dagger} Nephrology; § Department of Surgery, University of Florida, Gainesville, Florida; and {ddagger} Division of Nephrology, Gainesville Veterans Affairs Medical Center and University of Florida, Gainesville, Florida

Address correspondence to: Dr. Titte R. Srinivas, Kidney and Pancreas Transplant Program, University of Florida, Box 100224, 1600 SW Archer Road, Gainesville, FL 32610-0224. Phone: 352-846-2692; Fax: 352-392-5465; srinitr{at}medicine.ufl.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Cinacalcet, a calcimimetic, was evaluated in persistent hyperparathyroidism after kidney transplantation (Tx). Ten kidney transplant recipients and one kidney-pancreas recipient with persistent post-Tx hypercalcemia (serum calcium [SCa] > 10.2 mg/dl), stable graft function, and intact parathyroid hormone (iPTH) ≥2 times normal received 30 mg/d cinacalcet between 2 mo and 5 yr after Tx. SCa, serum phosphorus (SP), and iPTH were measured before and after cinacalcet. Mean pre-cinacalcet SCa was 10.9 mg/dl (8.6 to 11.9 mg/dl). Average pre-cinacalcet SP was 2.9 mg/dl (1.8 to 4.0 mg/dl). Mean pre-cinacalcet iPTH was 267.0 pg/ml (99 to 723 pg/ml). After cinacalcet, SCa decreased on average by 1.6 mg/dl (95% confidence interval 1.2 to 2.1; P < 0.0001). Post-cinacalcet SP increased on average 0.45 mg/dl (P = 0.046). Post-cinacalcet iPTH averaged 156.9 mg/dl (P = 0.10). Graft function remained stable. Cinacalcet lowers SCa and raises SP in the short term in patients with persistent post-Tx hyperparathyroidism; long-term bone effects and persistent hyperparathyroidism merit further study.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Hypercalcemia is a frequent complication that ensues after successful kidney transplantation (KTx) (1). Persistent hyperparathyroidism (HPT) is the most frequent cause of post-KTx hypercalcemia (1). The usual management of hypercalcemia after KTx involves a period of conservative management followed by parathyroidectomy in cases with unremitting hypercalcemia >6 to 12 mo after KTx (1). In recent years, intravenous vitamin D3 and other vitamin D analogs have been used in dialysis patients to suppress parathyroid hormone (PTH) levels (2). After successful KTx, these agents are discontinued abruptly, followed by an increase in PTH levels, a change in the known natural history of HPT attendant to renal failure. Recently, the calcimimetic agent cinacalcet was approved to treat the HPT that accompanies renal failure (3,4). We hypothesized that cinacalcet may be effective in lowering serum calcium (SCa) and PTH levels in some patients with persistent post-KTx hypercalcemia. We report herein our experience with cinacalcet in the management of persistent HPT and hypercalcemia after KTx. We also compare and contrast our experience with the recently published experience of two other groups that have used cinacalcet in a similar manner (5,6).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
This study is a retrospective review of the clinical experience with cinacalcet at the University of Florida Kidney Transplant Program. Ten KTx patients (nine deceased donor, two living donor; six male, five female) and one simultaneous kidney-pancreas Tx patient with stable renal allograft function and persistent hypercalcemia after KTx (SCa >10.2 mg/dl), intact PTH (iPTH) greater than twice the upper limit of normal and stable graft function were started on a single daily oral dose of 30 mg cinacalcet. Cinacalcet was started between 2 mo and 5 yr (median 3 yr) after KTx. We measured SCa, phosphorus (P), and iPTH before and after cinacalcet. After cinacalcet, SCa and P were obtained monthly. We did not allow concomitant treatment with bisphosphonates or vitamin D. Only one patient received a small dose of neutral potassium phosphate at a dose of 250 mg twice daily. All of these measurements were made at the clinical laboratory of our institution in the context of usual clinical care. All patients had their blood drawn for measurement of biochemical parameters early in the morning before taking any of their medications, in accordance with usual instructions provided by our transplant clinic. All patients were instructed to take cinacalcet with their morning dose of medications after breakfast. Immunosuppression consisted of cyclosporine or tacrolimus and mycophenolate mofetil or azathioprine with corticosteroids. Only one of the patients had received antithymocyte globulin induction. Cyclosporine (Neoral; Novartis Pharmaceuticals, Hanover, NJ) was dosed to achieve trough levels of 275 to 35 ng/ml in the first month after Tx, 225 to 250 ng/ml to month 3, and 125 to 175 ng/ml thereafter. Tacrolimus (Prograf; Astellas Pharmaceuticals, Chicago, IL) dose was titrated to trough levels of 10 to 12 ng/ml in the first month after Tx, 8 to 10 ng/ml thereafter to day 90 after Tx, and 5 to 7 ng/ml thereafter. Prednisone was tapered to a maintenance dose of 10 mg/d by 90 d after Tx. This retrospective review of the use of cinacalcet in persistent hypercalcemia after KTx was approved by the Institutional Review Board at the University of Florida.

General linear models were used to assess the change in parameters over time. Repeated measures at a given interval were treated as a blocking variable. Analyses were conducted using SPSS software Version 13.0 (SPSS, Chicago, IL) and SAS version 9.1 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
The demographic characteristics of the study patients are summarized in Table 1. The mean pre-cinacalcet SCa was 10.9 mg/dl (8.6 to 11.9 mg/dl), and the average pre-cinacalcet serum P)SP) was 2.9 mg/dl (1.8 to 4.0 mg/dl). Mean pre-cinacalcet iPTH was 267.0 pg/ml (99 to 723 pg/ml).


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  		Table 1. Patient demographics and baseline characteristics

 
After treatment with cinacalcet, the mean SCa was 9.3 mg/dl (7.5 to 10.7 mg/dl). With cinacalcet treatment, SCa decreased on average by 1.6 mg/dl, a statistically significant reduction (95% confidence interval [CI] 1.2 to 2.1; one-tailed P < 0.0001). This change in SCa was evident within 1 wk to 4 mo of starting cinacalcet (data shown in Table 2) and was sustained during the follow-up period ranging between 3 and 18 mo. The post-cinacalcet SP was 3.3 mg/dl, and SP increased on average 0.45 mg/dl (one-tailed P = 0.046). The raw values of pre- and post-cinacalcet iPTH, SCa, SP, and serum creatinine measurements are shown in Table 2. Five of eight patients with paired measurements of iPTH exhibited reductions in iPTH. The average post-cinacalcet iPTH was 156.9 mg/dl, a 41.5% reduction (one-tailed P = 0.10). These results are summarized in Table 3 and depicted in Figure 1. Pre-cinacalcet serum creatinine averaged 1.52 mg/dl, and the mean serum creatinine after cinacalcet was 1.44 mg/dl (P = 0.23; Table 3).


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  		Table 2. Biochemical parameters before and after treatment with cinacalceta

 

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  		Table 3. Change in SCa, SP, and PTH levels with CIN treatment

 

Figure 1
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  		Figure 1. Change in serum calcium and phosphorus with cinacalcet. SCA, serum calcium; SP, serum phosphorus; CIN, cinacalcet.

 
One patient was frankly noncompliant and was not taking her cinacalcet as directed, leading to stoppage of the cinacalcet. No significant changes in the renal function, BP, or hematocrit were noted in the follow-up period (data not shown). In one other patient, who had a simultaneous kidney-pancreas Tx, cinacalcet was stopped during a hospitalization for urosepsis and never restarted. No episodes of acute rejection or other side effects that were ascribable to cinacalcet have been noted to date. We also did not observe any unexpected need for dose modification of calcineurin inhibitors as a result of possible interactions with cinacalcet during the study (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Persistence of HPT after renal Tx may reflect secondary HPT in the face of suboptimal renal allograft function or autonomous secretion of PTH by functioning adenomas (1,7,8). The effects of such unregulated PTH hypersecretion are bone resorption principally manifest as progressive osteopenia or osteoporosis of the femoral neck, vascular calcification, and frank hypercalcemia with attendant complications (1). Traditional management in these circumstances dictates parathyroidectomy in an effort to prevent ongoing bone resorption or symptomatic hypercalcemia (1). Calcimimetics, phenylalkylamine agonists of the calcium sensing receptor, mimic the effect of extracellular calcium on this receptor and suppress the secretion of PTH by the parathyroid gland (9–11). In effect, these agents trick the parathyroid gland into a response that is appropriate for hypercalcemia despite a relatively normal ambient serum calcium concentration (12,13). Cinacalcet, the prototype of this class of compounds, has been used effectively in treating the secondary HPT of renal failure (3,4,14,15) and in primary HPT (16,17). More recently, cinacalcet has been used in KTx recipients (5,6). Kruse et al. (5) reported successful reduction in SCa levels in 14 KTx recipients with persistent HPT after TX. They did not see, however, a statistically significant decrease in PTH levels (5). These findings are very similar to ours. In our case series, five of eight patients with paired PTH measurements exhibited reduction in PTH levels with cinacalcet. This reduction of PTH levels averaged approximately 40%, a clinically significant suppression of PTH, albeit just approaching statistical significance. Increases in SP concentrations were noted and were statistically significant, corroborating the findings of both Kruse et al. (5,13) and Serra et al. (6,13). These findings are in contrast to the findings with cinacalcet in dialysis patients who have a reduction in SP with cinacalcet, most likely a reflection of preserved renal function in the transplant recipient (5,6,14). Kruse et al. (5) additionally noted a trend toward increasing serum creatinine concentrations in their study. We have not noted any such increases in serum creatinine in our patients to date. The study reported by Serra et al. (6) evaluated 11 renal transplant recipients who received cinacalcet for persistent HPT and did note statistically significant decreases in iPTH in addition to the decrease in serum calcium as observed in our series and the study of Kruse et al. (5). It should be noted that in our study and also in the study reported by Kruse et al. (5), cinacalcet was used in a single daily oral dose of 30 mg. The rebound increase in serum PTH after initial suppression that occurs with single daily doses of cinacalcet could account in part for this finding and account for the discordance between suppression of PTH levels and decline in SCa (5). In contrast, in the study reported by Serra et al. (6), some patients did receive higher doses of cinacalcet.

There are many obvious limitations to our study. We used cinacalcet in the relatively uncontrolled setting of clinical practice and did not take into account pre-Tx levels of PTH and pre-Tx therapy with vitamin D or its analogs. Furthermore, spontaneous resolution of HPT after successful Tx is expected in the majority of cases. However, as alluded to earlier, abrupt discontinuation of pre-Tx calcitriol or vitamin D analog treatment after Tx may manifest as HPT after Tx. That resolution of this increase in PTH levels after vitamin D (or analog) withdrawal may represent in entirety the falling levels of PTH seen in our patient cohort seems unlikely as most patients had persistence of HPT beyond 1 yr after Tx, at the time when cinacalcet was started (7,18,19). The lack of a control group in a pilot study such as ours is another obvious limitation.

Past efforts to prevent post-Tx bone disease with calcitriol has been limited by hypercalcemia, and enthusiasm for bisphosphonates is often dampened by concerns of adynamic bone disease (20–22). In this regard, calcimimetics offer a direct means of suppressing PTH secretion and possibly mitigating the systemic and skeletal complications of HPT (5,12,13,16).

Our study and the published studies of Kruse et al. (5) and Serra et al. (6) thus far have not assessed the effects of calcimimetics on markers of bone formation or resorption, bone mineral density, and bone histology in the renal transplant population. These will need to be necessary parameters to evaluate in future studies that assess the effects of cinacalcet in the kidney transplant population. In our study and the studies reported by Kruse et al. (5) and Serra et al. (6), the effects of cinacalcet on SCa, SP, and PTH were observed in the context of excellent graft function at >1 yr after Tx. These findings thus support a possible role for cinacalcet in the management of tertiary HPT (7,8). In our study, no significant interactions observed between cinacalcet and the calcineurin inhibitors or other drugs were noted. These findings mirror those reported both by Kruse et al. (5) and Serra et al. (6).


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Cinacalcet seems to offer an alternative to parathyroidectomy in the management of persistent post-KTx HPT. Cinacalcet’s long-term efficacy, safety, long-term effects on bone biology, and resolution of the systemic burden of HPT after KTx merit further study.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received July 20, 2005. Accepted December 13, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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  2. Wu-Wong JR, Tian J, Goltzman D: Vitamin D analogs as therapeutic agents: A clinical study update. Curr Opin Investig Drugs 5: 320–326, 2004[Medline]
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  6. Serra AL, Schwarz AA, Wick FH, Marti HP, Wuthrich RP: Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 20: 1315–1319, 2005[Abstract/Free Full Text]
  7. Lewin E: Involution of the parathyroid glands after renal transplantation. Curr Opin Nephrol Hypertens 12: 363–371, 2003[CrossRef][Medline]
  8. Arnold A, Brown MF, Urena P, Gaz RD, Sarfati E, Drueke TB: Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 95: 2047–2053, 1995[Medline]
  9. Drueke TB: Modulation and action of the calcium-sensing receptor. Nephrol Dial Transplant 19[Suppl 5]: V20–V26, 2004
  10. Hammerland LG, Garrett JE, Hung BC, Levinthal C, Nemeth EF: Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568. Mol Pharmacol 53: 1083–1088, 1998[Abstract/Free Full Text]
  11. Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC, DelMar EG, Balandrin MF: Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci USA 95: 4040–4045, 1998[Abstract/Free Full Text]
  12. Olgaard K, Lewin E: Prevention of uremic bone disease using calcimimetic compounds. Annu Rev Med 52: 203–220, 2001[CrossRef][Medline]
  13. Nemeth EF, Bennett SA: Tricking the parathyroid gland with novel calcimimetic agents. Nephrol Dial Transplant 13: 1923–1925, 1998[Free Full Text]
  14. Goodman WG, Hladik GA, Turner SA, Blaisdell PW, Goodkin DA, Liu W, Barri YM, Cohen RM, Coburn JW: The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 13: 1017–1024, 2002[Abstract/Free Full Text]
  15. Quarles LD, Sherrard DJ, Adler S, Rosansky SJ, McCary LC, Liu W, Turner SA, Bushinsky DA: The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 14: 575–583, 2003[Abstract/Free Full Text]
  16. Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90: 135–141, 2005[Abstract/Free Full Text]
  17. Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M: The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 88: 5644–5649, 2003[Abstract/Free Full Text]
  18. Cundy T, Kanis JA, Heynen G, Morris PJ, Oliver DO: Calcium metabolism and hyperparathyroidism after renal transplantation. QJ Med 52: 67–78, 1983[Abstract/Free Full Text]
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