Background. Treatment of persistent hyperparathyroidism in renal transplant patients resistant to calcium and vitamin D sterols is limited and often requires parathyroidectomy. Given the potential hazards linked to surgery, an alternative approach to manage excess parathyroid hormone (PTH) secretion is needed. Calcimimetics inhibit PTH secretion by modulating the calcium-sensing receptor in the parathyroid. Lowering of the serum calcium concentration with the calcimimetic cinacalcet has previously been demonstrated in patients with primary hyperparathyroidism or with secondary hyperparathyroidism on dialysis. Here we present the first clinical observations of a calcimimetic in patients with persistent hyperparathyroidism. Methods. A 30 mg dose of cinacalcet was prescribed once daily for 3 months to seven female and seven male stable renal transplant patients, aged 23-65 years, 7 months to 14 years after transplantation, with a serum creatinine ranging from 89 to 229 µmol/l and persistent hyperparathyroidism. Concomitant medication included cyclosporin and low-dose prednisone in all patients. Results. On cinacalcet, serum calcium decreased and normalized in all but two patients (baseline 2.72±0.03 mmol/l; 1 month 2.42±0.04 mmol/l, P<0.001), whereas serum PTH and phosphate levels did not change significantly. A slight reduction in renal function, as assessed by serum creatinine concentration, was observed at months 2 and 3 (P<0.05). An immunoglobulin-deficient patient developed colitis after 1 week of treatment and cinacalcet was withdrawn. No patient stopped cinacalcet because of other presumed side effects. Conclusion. Calcimimetics are a promising therapy in renal transplant patients with persistent hyperparathyroidism. Prospective controlled studies must now be designed focusing on functionally relevant musculo-skeletal end-points and allowing the exclusion of negative effects on long-term renal and general outcome of such patient

Eisenberger, Ute

Frey, Felix J.

Kruse, Anja E.

Mohaupt, Markus G.

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Nephrol Dial Transplant (2005) 20: 1311–1314doi:10.1093/ndt/gfh924Advance Access publication 7 June 2005Rapid CommunicationThe calcimimetic cinacalcet normalizes serum calcium inrenal transplant patients with persistent hyperparathyroidismAnja E. Kruse, Ute Eisenberger, Felix J. Frey and Markus G. MohauptDepartment of Nephrology and Hypertension, University of Berne, 3010 Berne, SwitzerlandAbstractBackground. Treatment of persistent hyperparathy-roidism in renal transplant patients resistant to calciumand vitamin D sterols is limited and often requiresparathyroidectomy. Given the potential hazardslinked to surgery, an alternative approach to manageexcess parathyroid hormone (PTH) secretion is needed.Calcimimetics inhibit PTH secretion by modulating thecalcium-sensing receptor in the parathyroid. Loweringof the serum calcium concentration with the calcimi-metic cinacalcet has previously been demonstrated inpatients with primary hyperparathyroidism or withsecondary hyperparathyroidism on dialysis. Here wepresent the ﬁrst clinical observations of a calcimimeticin patients with persistent hyperparathyroidism.Methods. A 30mg dose of cinacalcet was prescribedonce daily for 3 months to seven female and seven malestable renal transplant patients, aged 23–65 years,7 months to 14 years after transplantation, with aserum creatinine ranging from 89 to 229 mmol/l andpersistent hyperparathyroidism. Concomitant medica-tion included cyclosporin and low-dose prednisone inall patients.Results. On cinacalcet, serum calcium decreased andnormalized in all but two patients (baseline 2.72±0.03mmol/l; 1 month 2.42±0.04mmol/l, P<0.001),whereas serum PTH and phosphate levels did notchange signiﬁcantly. A slight reduction in renalfunction, as assessed by serum creatinine concentra-tion, was observed at months 2 and 3 (P<0.05). Animmunoglobulin-deﬁcient patient developed colitisafter 1 week of treatment and cinacalcet was with-drawn. No patient stopped cinacalcet because of otherpresumed side effects.Conclusion. Calcimimetics are a promising therapy inrenal transplant patients with persistent hyperpara-thyroidism. Prospective controlled studies must nowbe designed focusing on functionally relevant musculo-skeletal end-points and allowing the exclusion ofnegative effects on long-term renal and general out-come of such patients.Keywords: calcimimetic; cinacalcet; hypercalcaemia;parathormone; persistent hyperparathyroidism;renal transplantIntroductionSecondary hyperparathyroidism is a common compli-cation of renal failure and end-stage renal disease.Despite normalization of renal function and normalconcentrations of 1,25-dihydroxyvitamin D3 afterrenal transplantation, elevated parathyroid hormone(PTH) concentrations often persist, leading to mark-edly increased serum calcium levels, an enhancedfractional excretion of phosphate in the urine anddecreased bone mass [1,2]. This condition is due toglandular hyperplasia and autonomous PTH produc-tion, in part attributable to monoclonality [3]. In aboutone-third of the patients, hyperparathyroidism doesnot completely resolve even after several years ofsuccessful renal transplantation [4–6]. In these patients,surgical treatment is often mandatory. In some ofthese patients, a surgical intervention might be hazard-ous and therefore a medical treatment would be ofinterest.A novel class of compounds called calcimimeticsincreases the sensitivity of the calcium-sensing receptorof the parathyroid cells to extracellular calcium[7–9]. Recently the oral calcimimetic, cinacalcet HCl,was introduced successfully into clinical practice.Cinacalcet rapidly normalized serum calcium andreduced PTH in patients with primary hyperpara-thyroidism, an effect persistant through a follow-up1 year [10,11]. In chronic haemodialysis patientswith secondary hyperparathyroidism, this compoundreduced plasma PTH concentrations together with aCorrespondence and offprint requests to: Markus G. Mohaupt, MD,Department of Nephrology and Hypertension, University HospitalBerne, Inselspital, Freiburgstrasse, CH-3010 Bern, Switzerland.Email: markus.mohaupt@insel.ch The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please email: journals.permissions@oupjournals.orgsubsequent decline in plasma calcium and phosphate[12–15]. So far, calcimimetics have not been prescribedto patients after successful renal transplantation.Therefore, we investigated the effect of cinacalcet instable renal transplant patients with persistent hyper-parathyroidism.Subjects and MethodsFourteen stable renal transplant patients (seven male, sevenfemale, aged 23–65 years) with persistent hyperparathyroi-dism, followed for 7 months to 14 years (median 3.5 years)after renal transplantation, were treated with cinacalcet. Allpatients were followed in our unit. Persistent hyperparathy-roidism was deﬁned by increased serum calcium concentra-tions in the presence of increased PTH levels on dialysis,not normalized 6 months after successful renal transplan-tation despite normal or increased 1,25-dihydroxyvitaminD3 levels.All patients were treated with cyclosporin and doses ofprednisone <10mg/day. In addition, three patients were onazathioprine, ﬁve on mycophenolate mofetil and one onsirolimus. Before cinacalcet treatment, PTH levels rangedfrom 80 to 1295 pg/ml (Figure 1). One patient with a highnormal value of 47 pg/ml was also treated because ofpersistent hypercalcaemia between 2.6 and 2.7mmol/l in thepresence of 1,25-dihydroxyvitamin D3 levels ranging from74 to 126 pmol/l.Patients were given 30mg of oral cinacalcet once daily.Out-patient visits were scheduled before and 1, 2 and 3monthsafter therapy was initiated. The following parameters wereassessed: creatinine, urea, potassium, calcium, phosphate andPTH (intact) in serum, and cyclosporin trough levels in wholeblood; blood pressure; clinical events; and concomitantmedication. Repeated measurements of PTH before and 1,2, 3 and 4 h after intake of cinacalcet were performed in twopatients.Statistical analyses were executed using SYSTAT Version12.0 (SYSTAT Software, Inc.). Paired Student’s t-test andthe Wilcoxon test for longitudinal non-parametric data wereused where applicable. All data given are means±SEM if nototherwise indicated.ResultsEffect of cinacalcet on serum PTH, calciumand phosphateSerum PTH did not change in response to cinacalcetadministration. Although the data shown in Figure 1suggest a decline for the entire population, due to thelarge inter- and intra-individual variability in responseto the calcimimetic, this decline was not statisticallysigniﬁcant. In order to better understand this varia-bility, we measured the serum concentrations of PTHbefore and 1, 2, 3 and 4 h following the intake ofcinacalcet in two patients on long-term therapy andobserved an acute decline (Figure 2). The trough levelsof PTH (concentrations in the morning before theintake of cinacalcet) ranged between 55 and 130 pg/mlin these two patients.Serum total calcium concentrations declined in allsubjects after cinacalcet was given and remained stableover the entire period of observation (P<0.001)(Figure 1). In all patients except two, a normalizationof serum calcium below 2.55mmol/l was observed. Inone of these two patients, the serum calcium declinedfrom 2.71 to 2.63mmol/l and in the other from 2.71 to2.60mmol/l. Mean serum phosphate concentrationsremained unchanged throughout the study period.Before cinacalcet, one patient had hypophosphataemia(0.54mmol/l), which disappeared with treatment. Twopatients experienced a slight hyperphosphataemiabetween 1.65 and 1.77mmol/l while on the calcimi-metic. The CaP product was not affected by cina-calcet and the highest value observed was 4.27mmol/l2.No consistent changes were detected with respect to thefractional calcium and phosphate excretion and serumalkaline phosphatase levels (results not shown).Clinical observationsDuring the treatment period, the immunosuppressiveregimen remained unchanged. The whole blood troughMonth of treatment0 1 2 3Phosphate concentration, mmol/l0.00.70.80.91.01.11.21.31.4Calcium concentration, mmol/l0.02.32.42.52.62.72.82.9PTH concentration, pg/ml01002003004005002.10 – lower limit1.55 – upper limitFig. 1. Serum concentrations of PTH, calcium and phosphatebefore (month 0) and during treatment (months 1–3) withcinacalcet (mean, SEM). Upper and lower limits of normal rangesare depicted by dotted lines.1312 A. E. Kruse et al.concentrations of cyclosporin were not affected bycinacalcet. At baseline, cyclosporin levels rangedfrom 64 to 177 ng/ml, after 1 month of treatmentfrom 73 to 172 ng/ml, at 2 months from 51 to 131 ng/mland after 3 months from 80 to 181 ng/ml. With respectto diuretic and antihypertensive therapy, only minorchanges occurred. In one patient, 20mg of furosemideand in another 5mg of torasemide were withdrawn2 months after therapy with cinacalcet was initiated.None of the patients was on a calcium supplement.Two patients received 0.5 and 1.75 mg/week of 1,25-dihydroxyvitamin D3 for 2 months. Five patientswere additionally prescribed 1,25-dihydroxyvitaminD3 (0.75–1.75 mg/week) at month 2.Blood pressure remained unchanged during therapywith cinacalcet (results not shown). The glomerularﬁltration rate, as assessed by serum creatinine concen-trations, decreased during the observation period.Serum creatinine concentrations were 140±15 mmol/lat baseline, 139±16 mmol/l after 1 month, 153±17 mmol/l after 2 months and 148±16 mmol/l after3 months of treatment (P<0.05 at months 2 and 3).One patient with a known immunoglobulin deﬁ-ciency and recurrent intestinal disease developed severediarrhoea and colitis 1 week after cinacalcet had beenprescribed. Cinacalcet was withdrawn and the resultsfrom the electrolyte and PTH measurements are notconsidered for the present analysis. Another patientexperienced a myocardial infarction without arrhyth-mia or complications after 2 months of treatment. Thepatient received a percutaneous transluminal angio-plast with stent implantation. She continued to takecinacalcet thereafter and the results were included inthe present analysis. No patient stopped cinacalcetbecause of other presumed side effects.DiscussionHere we present the ﬁrst clinical observations in stablerenal transplant patients with persistent hyperpara-thyroidism treated with a calcimimetic. These resultsdemonstrate that a low dose of cinacalcet given oncedaily signiﬁcantly reduces the serum calcium concen-tration. The decline in the PTH concentrations wasnot signiﬁcant (Figure 1). This might be attributedﬁrst to the small number of subjects investigated,and/or second to the peculiar pharmacokinetics/pharmacodynamics of cinacalcet. Peacock andco-workers recently analysed the pharmacodynamicsof cinacalcet in patients with primary hyperparathy-roidism at week 24 of chronic prescription of cinacalcet[10]. At 2 h after the morning dose of cinacalcet, theyobserved a decline of PTH from 80 to 50 pg/ml. At8 h, the PTH concentrations again reached the pre-dose values. Peacock and co-workers estimated thatthe area under the plasma concentration–time curve ofPTH over each 24 h cycle was reduced by 20% [10].A similar rapid and transient response of PTH to theadministration of cinacalcet was reported for dialysispatients with secondary hyperparathyroidism [16,17],suggesting an immediate but transient effect of thexenobiotic on PTH release. Thus, if the purpose ofcinacalcet prescription was to normalize not only theserum calcium concentration, but also the area underthe concentration–time curve of PTH, the drug has tobe dosed at least twice a day in renal transplantpatients. Given the known beneﬁcial effects of PTHfor normal bone formation, it is unknown whethernormalization of PTH is a valid potential objective.In addition to its effect on bone, PTH enhancesthe urinary excretion of phosphate by regulating thetype IIa (Na2þ)/Pi co-transporter in the proximaltubule [18]. In line with this effect, we observed anormalization of the phosphate level in the onlyhypophosphataemic patient and a slight hyperphos-phataemia in two patients previously normophospha-taemic. With cinacalcet treatment, the serum phosphateconcentrations increased by 10% in patients withprimary hyperparathyroidism [10,11], whereas in dia-lysis patients these concentrations declined by 8%[13]. The mechanism for the decrease of serumphosphate concentrations in dialysis patients isunknown. Thus, the effect of cinacalcet on serumphosphate levels appears to be complex in patientswith kidney diseases and has to be taken into con-sideration when this drug is prescribed. While hypo-phosphataemia is a practically relevant issue after renaltransplantation and a reduced urinary excretion ofphosphate by the calcimimetic might be beneﬁcial,hyperphosphataemia is more relevant in subjects witha reduced glomerular ﬁltration rate. Therefore, specialattention has to be paid in the future to the changes ofthe serum phosphate levels induced by calcimimeticsin renal transplant patients with a steadily changingrenal function.In order to protect the bone from the unwarrantedeffects of high PTH, parathyroidectomy is oftenconsidered as a therapeutic option in patients withpersistent hyperthyroidism after renal transplantation.Retrospective analyses revealed that such surgicalinterventions might be associated with a decline inthe glomerular ﬁltration rate as assessed by serumHours after dosing of cinacalcet0 1 2 3 4PTH concentration, pg/ml020406080100120140Fig. 2. Serum PTH concentrations before (hour 0) and after dosingof cinacalcet (hours 1–4) in two renal transplant patients on chroniccinacalcet therapy.Cinacalcet in persistent hyperparathyroidism 1313creatinine concentrations. For instance, Rostaingand co-workers observed a signiﬁcant and persistentincrease in serum creatinine levels in eight out of34 patients after parathyroidectomy, an effect par-ticularly present in those patients presenting withhypertension before surgery [19]. Lee and co-workersfollowed 22 patients for 1 year after parathyroidectomyand reported a steeper rise in serum creatinine aftersurgery when compared with the 2 years before theintervention. The effect of parathyroidectomy on theserum calcium concentration was signiﬁcantly moreaccentuated in patients exhibiting a worsening of graftfunction after parathyroidectomy [20]. To the best ofour knowledge, it is unknown whether the declinein renal function after surgery was attributable to theintervention itself and/or to the changes of the mineralmetabolism induced by the removal of the parathyroidglands. To answer this question, future prospectivestudies comparing the impact on the serum creatinineconcentrations of a calcimimetic with that of para-thyroidectomy might be useful. In our group ofpatients, a slight increase in serum creatinine concen-trations could be identiﬁed. However, the studyduration of 3 months does not allow characterizationof the long-term effects of cinacalcet treatment on renaltransplant function.In conclusion, the calcimimetic cinacalcet is apromising alternative to parathyroidectomy in patientswith persistent hyperparathyroidism after renal trans-plantation. To exclude a negative impact of cinacalceton long-term renal or general outcome of kidneytransplant recipients, future studies should focus onthe glomerular ﬁltration rate of the allograft andconsider functionally relevant musculo-skeletal andtherapeutic endpoints.Conﬂict of interest statement. None declared.References1. Lewin E. Involution of the parathyroid glands afterrenal transplantation. Curr Opin Nephrol Hypertens 2003; 12:363–3712. Torres A, Lorenzo V, Salido E. Calcium metabolism andskeletal problems after transplantation. J Am Soc Nephrol 2002;13: 551–5583. Arnold A, Brown MF, Urena P, Gaz RD, Sarfati E, Drueke TB.Monoclonality of parathyroid tumors in chronic renal failureand in primary parathyroid hyperplasia. J Clin Invest 1995; 95:2047–20534. Cundy T, Kanis JA, Heynen G, Morris PJ, Oliver DO. Calciummetabolism and hyperparathyroidism after renal transplantation.Q J Med 1983; 52: 67–785. Koch Nogueira PC, David L, Cochat P. Evolution ofsecondary hyperparathyroidism after renal transplantation.Pediatr Nephrol 2000; 14: 342–3466. Torres A, Rodriguez AP, Concepcion MT et al. Parathyroidfunction in long-term renal transplant patients: importance ofpre-transplant PTH concentrations. Nephrol Dial Transplant1998; 13 [Suppl 3]: 94–977. Drueke TB. Modulation and action of the calcium-sensing receptor. Nephrol Dial Transplant 2004; 19 [Suppl 5]:V20–V268. Hammerland LG, Garrett JE, Hung BC, Levinthal C,Nemeth EF. Allosteric activation of the Ca2þ receptorexpressed in Xenopus laevis oocytes by NPS 467 or NPS 568.Mol Pharmacol 1998; 53: 1083–10889. Nemeth EF, Steffey ME, Hammerland LG et al. Calcimimeticswith potent and selective activity on the parathyroid calciumreceptor. Proc Natl Acad Sci USA 1998; 95: 4040–404510. Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA,Shoback D. Cinacalcet hydrochloride maintains long-termnormocalcemia in patients with primary hyperparathyroidism.J Clin Endocrinol Metab 2005; 90: 135–14111. Shoback DM, Bilezikian JP, Turner SA, McCary LC,Guo MD, Peacock M. The calcimimetic cinacalcet normalizesserum calcium in subjects with primary hyperparathyroidism.J Clin Endocrinol Metab 2003; 88: 5644–564912. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agentacutely suppresses parathyroid hormone levels in patients withchronic renal failure. Rapid communication. Kidney Int 1998;53: 223–22713. Block GA, Martin KJ, de Francisco AL et al. Cinacalcet forsecondary hyperparathyroidism in patients receiving hemodial-ysis. N Engl J Med 2004; 350: 1516–152514. Drueke TB. Treatment of secondary hyperparathyroidism ofdialysis patients with calcimimetics as a valuable addition toestablished therapeutic means. Pediatr Nephrol 2005; 20:399–40315. Lindberg JS, Culleton B, Wong G et al. Cinacalcet HCl,an oral calcimimetic agent for the treatment of secondaryhyperparathyroidism in hemodialysis and peritoneal dialysis:a randomized, double-blind, multicenter study. J Am SocNephrol 2005; 16: 800–80716. Goodman WG, Hladik GA, Turner SA et al. The calcimimeticagent AMG 073 lowers plasma parathyroid hormone levelsin hemodialysis patients with secondary hyperparathyroidism.J Am Soc Nephrol 2002; 13: 1017–102417. Quarles LD, Sherrard DJ, Adler S et al. The calcimimeticAMG 073 as a potential treatment for secondary hyperpara-thyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14: 575–58318. Murer H, Hernando N, Forster L, Biber J. Molecularmechanisms in proximal tubular and small intestinal phos-phate reabsorption (plenary lecture). Mol Membr Biol 2001;18: 3–1119. Rostaing L, Moreau-Gaudry X, Baron E, Cisterne JM,Monrozies-Bernadet P, Durand D. Changes in blood pressureand renal function following subtotal parathyroidectomy inrenal transplant patients presenting with persistent hypercalce-mic hyperparathyroidism. Clin Nephrol 1997; 47: 248–25520. Lee PP, Schiffmann L, Offermann G, Beige J. Effects ofparathyroidectomy on renal allograft survival. Kidney BloodPress Res 2004; 27: 191–196Received for publication: 17.3.05Accepted in revised form: 3.5.051314 A. E. Kruse et al.

The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism

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