- Email: [email protected]
The effect of cinacalcet on intraoperative findings in tertiary hyperparathyroidism patients undergoing parathyroidectomy
The effect of cinacalcet on intraoperative findings in tertiary hyperparathyroidism patients undergoing parathyroidectomy Yash R. Somnay, BS, Eric Weinlander, BA, David F. Schneider, MD, MS, Rebecca S. Sippel, MD, and Herbert Chen, MD, Madison, WI
Introduction. Tertiary hyperparathyroidism (3HPTH) patients who undergo parathyroidectomy (PTX) are often managed with calcium lowering medications such as cinacalcet (Sensipar) before surgery. Here, we assess how cinacalcet treatment influences intraoperative parathyroid hormone (IOPTH) kinetics and surgical findings in 3HPTH patients undergoing PTX. Methods. We reviewed retrospectively 113 patients 3HPTH who underwent PTX, 14 of whom were taking cinacalcet and 112 who were not taking the drug. IOPTH levels fitted to linear curves versus time were used to evaluate the role of cinacalcet. Results. Cinacalcet did not correlate with rates of cure (P = .41) or recurrence (P = .54). Patients taking cinacalcet experienced a steeper decrease in IOPTH compared with those not taking the medication (P = .005). Cinacalcet treatment was associated with an increase in rate of hungry bones (P = .04). Weights of the heaviest glands resected (P = .02) and preoperative PTH levels (P = .0004) were greater among patients taking cinacalcet. Conclusion. Perioperative cinacalcet treatment in patients with 3HPTH alters IOPTH kinetics by causing a steeper decrease in IOPTH, but does not require modification of the standard IOPTH protocol. Although cinacalcet use does not adversely affect cure rates, it is associated with greater preoperative PTH and an increased incidence of hungry bones, hence serving as an indicator of more severe disease. Cinacalcet does not need to be held before operation. (Surgery 2014;156:1308-14.) From the Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Wisconsin, Madison, WI
TERTIARY HYPERPARATHYROIDISM (3HPTH) is an endocrine disorder characterized by the persistent hypersecretion of parathyroid hormone (PTH) in patients with longstanding secondary HPTH (2HPTH) who have undergone successful kidney transplantation to correct their chronic kidney disease.1,2 Although most transplant recipients experience a return to normal PTH secretion after restoration of renal function, #8% of patients retain abnormally functioning parathyroid tissue that fails to resolve.3,4 Consequently, serum levels of PTH remain increased, thereby increasing Presented at the American Association of Endocrine Surgeons meeting in Boston, Massachusetts, April, 2014. Accepted for publication August 8, 2014. Reprint requests: Herbert Chen, MD, K3/705 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.08.003
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serum calcium levels leading to a constellation of debilitating symptoms, including atherosclerosis, nephrolithiasis, osteopenia, osteoporosis, and neuropsychiatric changes.3-7 The mainstay curative approach for patients with 3HPTH is subtotal or total parathyroidectomy (PTX) with forearm implantation of the remnant parathyroid.3-5,8-10 Notably, medical management before operative intervention often employs the use of calcimimetic agents to decrease serum calcium.11 These agents exert their effect by allosterically, activating the calcium-sensing receptors of the parathyroid glands, thus directly suppressing PTH secretion.12 Prior interventions, such as the use of sterols and vitamin D supplementation, proved to be effective in controlling PTH levels, but resulted frequently in hypercalcemia and hyperphosphatemia.13 The advent of the calcimemetic agent cinacalcet (Sensipar, Amgen Inc, Thousand Oaks, CA) introduced a viable therapeutic option for effectively decreasing plasma levels of PTH in patients with 2HPTH on dialysis, while
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simultaneously decreasing calcium and phosphorous levels and avoiding associated symptoms.12-14 In addition to its registered indication for 2HPTH in patients with end-stage renal disease on maintenance dialysis, cinacalcet is also approved to decrease hypercalcemia in patients with parathyroid carcinoma and primary HPTH patients in whom PTX is contraindicated.15,16 Given its mechanism of action and favorable pharmacokinetics, however, cinacalcet has been prescribed increasingly for patients with 3HPTH as described in a number of reports.17-22 Since its introduction, many 3HPTH patients now opt for medical management with cinacalcet in place of PTX.18,23 Accordingly, PTX is often performed in conjunction with calcimimetics such as cinacalcet when managing symptomatic 3HPT patients.23 The purpose of this study was to investigate the influence of cinacalcet treatment on preoperative and postoperative findings, intraoperative PTH (IOPTH) kinetics, and the etiology of disease in patients with 3HPTH. METHODS We reviewed retrospectively 116 patients with 3HPTH undergoing PTX at our institution between March 2001 to March 2013. We defined 3HPTH patients as those who previously had 2HPTH and underwent successful renal transplantation. Patients who were undergoing reoperative PTX from persistent or recurrent HPTH were excluded. These patients were divided into 2 groups composed of those taking cinacalcet and those not taking cinacalcet at the time of PTX. Patients taking cinacalcet before PTX but for whom it was discontinued were categorized in the nontreated group. Patients previously taking cinacalcet who were considered to be in the nontreated group had an average duration of discontinuation before PTX of 428 days. Approval from the University of Wisconsin Institutional Review Board was granted for data collection and analysis. Patients underwent bilateral neck exploration with identification of all parathyroid glands. The number of glands excised depended on the disease etiology. Patients with hyperplasia underwent subtotal PTX. IOPTH monitoring was performed according to our previous report.24 PTH laboratory values were drawn after anesthesia, and at 5, 10, and 15 minutes after excision of all hyperfunctioning glands. A decrease in IOPTH of 50% was used as the criteria to end the operation. Trends in IOPTH monitoring within each group were assessed by calculating the average linear
Somnay et al 1309
slope of IOPTH change based on the initial and final levels drawn during the operation. Slopes between the 2 groups were then compared. Furthermore, we assessed the correlation between cinacalcet treatment and the number of glands discovered. We defined operative cure as serum calcium <10.2 mg/dL at 6 months after PTX. Persistence was defined as a return to calcium levels >10.2 mg/dL within 6 months after PTX, and disease recurrence was defined as a resurgence of serum calcium levels >10.2 mg/dL after a period of normal calcium for $6 months after PTX. Hypocalcemia as a complication of PTX was specified in the setting of hypoparathyroidism with normal renal functioning retained. Such cases were defined as having a calcium level of <8.5 mg/ dL, a PTH of <8 pg/mL, and a normal glomerular filtration rate and creatinine level within 1 week after PTX. If these levels did not resolve within 6 months, these patients were classified as having permanent hypoparathyroidism. We diagnosed hungry bone syndrome in patients who had calcium levels <10.2 mg/dL after PTX beyond postoperative day 4, and these determinations were made initially based on clinical manifestations of prolonged hypocalcemia. Statistical analysis was performed using SPSS software (version 10.0, SPSS Inc, Chicago, IL) using Pearson’s Chisquare test, Fisher’s exact test, and a 2-sided Student t test for continuous variables. Continuous variable are expressed as mean values ± standard error of the mean. RESULTS Patients and demographics. Among the 116 patients with 3HPTH undergoing PTX, 14 (12%) were taking cinacalcet at the time of operation, and 102 (88%) were on no calcimemetics. The median treatment time of cinacalcet was 26 months (range, 1.9–56). The percentage of male patients was 64% among cinacalcet-treated patients and 49% among patients not taking the drug, which was statistically similar (Table I). Vitamin D levels among both groups were also similar, but were on the lower end of normal (Table I). Furthermore, creatinine levels were significantly greater among those taking cinacalcet compared with those not taking the drug (Table I). Although preoperative calcium levels did not differ statistically between the 2 groups, those taking cinacalcet had greater preoperative PTH levels (681 pg/ mL) versus those not taking the drug (271 pg/ mL; P = .0004; Table I). Interestingly, although etiology was not affected by cinacalcet treatment,
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Table I. Patient demographics and laboratory data
Demographics Age (y) Male patientsy (%) Vitamin D (ng/mL) Creatinine (mg/dL) Preoperative Ca (mg/dL) Preoperative PTH (pg/mL) Postoperative Ca (mg/dL) Postoperative PTH (pg/mL) Etiologyy (%) Single adenoma Double adenoma Hyperplasia
Cinacalcet (n = 14; 12%)
No drug (n = 102; 88%) ±1 (49) ± 0.89 ± 0.7 ± 0.12
P value
47 ± 3 9 (64) 29.1 ± 4.4 1.9 ± 0.22 10.5 ± 0.48
52 50 29.9 1.5 10.6
.19 .39 .89 .03* .86
681 ± 274
270 ± 20
.0004*
8.5 ± 0.32
8.9 ± 0.1
.22
118 ± 40
86 ± 11
.37
0 0 14
12 9 81
.17
*P < .05. yFisher’s exact test. Continuous variables are represented as the mean values ± standard error of the mean unless otherwise indicated. Ca, Calcium; PTH, parathyroid hormone.
all patients taking cinacalcet had hyperplasia, whereas 21% of those not on drug did not have hyperplasia (Table I). Cure, complications, and intraoperative findings. PTX in both patient groups resulted in high cure rates (an overall rate of 97%), with a combined recurrence rate of 3%, indicating that surgical intervention is a successful curative approach regardless of cinacalcet treatment (Table II). Cure rates within each group were 93% and 97% among those taking cinacalcet and those not taking a calcimimetic, respectively. Recurrence rates were also low in both groups and did not differ. We noted postoperative complications among cinacalcet-treated patients and those not taking the drug. The overall rates of biochemical postoperative hypocalcemia from permanent hypoparathyroidism did not differ significantly between the 2 groups (Table II). We also observed a significantly greater rate of certain postoperative complications among patients taking cinacalcet. Hungry bone syndrome occurred in 21% of patients taking cinacalcet but only 4% of patients not taking the drug (P = .04; Table II). Other complications, such as voice hoarseness and mild parasthesias, did not differ between the 2 groups. Finally, we compared the average weights of the heaviest resected parathyroid gland between those taking cinacalcet and those not taking the drug. The average weight of the heaviest gland among
Table II. Incidence of cure, recurrence, and hypocalcemia Cinacalcet No drug P (n = 14) (n = 102) value
Variable Cure, n (%) Recurrence, n (%) Complications, n (%) Permanent hypoparathyroidism Transient hoarseness Hungry bone syndrome Parasthesias
13 (93) 1 (7)
99 (97) 5 (5)
.41 .54
0 (0)
1 (1)
.99
1 (7) 3 (21) 2 (14)
2 (2) 4 (4) 4 (4)
.32 .04* .15
*P < .05. All P values calculated based on Fisher’s exact test.
Table III. IOPTH monitoring Variable
Cinacalcet No calcimimetic P (n = 14) (n = 102) value
Pre-excision PTH 711 ± 277 (pg/mL) Percent decrease (%) 77 ± 4 Slope 59 ± 34 *P < .05. IOPTH, Intraoperative hormone.
parathyroid
328 ± 50
.03*
73 ± 3 17 ± 3
.59 .005*
hormone;
PTH,
parathyroid
patients taking cinacalcet (1,309 ± 330 g) was significantly greater than that of those not taking the drug (853.4 ± 58.5; P = .02). IOPTH monitoring. To analyze the influence of cinacalcet on IOPTH kinetics, we plotted IOPTH levels over time, beginning with the pre-excision recording and followed by every reading thereafter. Notably, we found that pre-excision IOPTH values (0 minutes) were greater among cinacalcettreated patients (711 ± 277 vs 328 ± 50 pg/mL; P = .03; Table III). This is aligned with the significant findings from Table I showing a marked increase in preoperative PTH levels taken before the day of PTX among cinacalcet-treated patients. When comparing the patterns of the IOPTH between treatment and nontreatment groups, we found that cinacalcet altered IOPTH kinetics, correlating with a significantly steeper decrease in IOPTH (Figure). The rate of IOPTH change indicated by the average slope of linear fitted curves drawn between pre-excision IOPTH values from each patient and its paired final IOPTH recording were compared between the 2 groups. The rate of decline in IOPTH among patients taking cinacalcet was represented by an average slope of 59 ± 34, whereas for those not taking cinacalcet the average downward slope of IOPTH levels was 17 ± 3 (P = .005; Table III). Notably, there
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Figure. Intraoperative parathyroid hormone (PTH) value plot for patients with tertiary hypoparathyroidism taking cinacalcet and not taking cinacalcet undergoing PTX. The graph below shows a connected line of IOPTH values for those taking cinacalcet (dotted line) and those not taking the drug (solid line), beginning with preexcision (t = 0) IOPTH levels and followed by every value recorded thereafter. Pre-excision IOPTH was greater among those taking cinacalcet* (P = .03). The slope and percent decrease in IOPTH were determined using the pre-excision IOPTH (t = 0 minutes) and the final IOPTH (t = 15 minutes) as an endpoint. IOPTH levels decreased at a significantly steeper slope among patients taking cinacalcetx (P = .005). Standard error of the mean for each IOPTH reading is illustrated with error bars.
was no difference between the 2 groups in their average decreases in IOPTH percentage between the first and last IOPTH recordings (Table III). Finally, we found that there was no difference in the number of patients achieving a 50% drop at any given interval of IOPTH recording between those taking and not taking cinacalcet. The distribution among those achieving surgical cure at 5, 10, and 15 minutes was statistically similar (Table IV). The number of PTH samples required to achieve a 50% decrease also did not differ significantly between the 2 groups (Table IV). Discussion. PTX has been well established as a curative approach for patients with HPTH.4,7 Nevertheless, medical management of 3HPTH has become more widespread since the advent of safe and readily available calcimimetic agents.12,23 Accordingly, medical therapy often precedes or accompanies operative intervention. The calcimimetic cinacalcet was incorporated into management of 3HPTH around 2005 and has since offered patients with severe disease the option of medical therapy in lieu of, and often preceding, PTX.11,23 Although cinacalcet has been shown to resolve hypercalcemia and hyperphosphatemia in 3HPTH patients, most
Somnay et al 1311
patients experience persistence of their hypercalcemic symptoms,23 necessitating PTX. The impact of cinacalcet on IOTPH kinetics and intraoperative protocol has not been described in 3HPTH patients undergoing PTX. In this study of 116 patients with 3HPTH who underwent PTX, 12% were taking cinacalcet at the time of PTX. Overall, cinacalcet treatment was associated with a dramatically steeper decrease in IOPTH during PTX and did not alter the probability of surgical success. The percentage decrease in IOPTH and number of IOPTH recordings required to achieve a 50% decrease were not different among the 2 groups. Collectively, these findings indicate that standardized IOPTH monitoring can be used to confirm successful excavation of hyperfunctioning parathyroid tissue, regardless of perioperative cinacalcet therapy. Moreover, it demonstrates that operative intervention is a highly curative approach with or without cinacalcet. A previous study by Schneider et al25 concluded that calcimimetic treatment at the time of PTX among patients with primary HPTH also affected IOPTH kinetics by causing a steeper decrease in the series of IOPTH readings with a lesser degree of recovery in IOPTH values. Our study found that pre-excision IOPTH values were significantly greater among cinacalcet-treated patients, accounting for the sharper decrease in IOPTH levels that we observed. These greater preoperative PTH levels may reflect salient distinctions in the biochemical severity of HPTH in this group, because these patients warranted PTX after previously requiring and failing a medical approach with cinacalcet. Schneider et al25 went on to attribute a greater degree of postoperative hypocalcemia to multidrug calcimimetic therapy (1 + calcimimetics), but did not report a correlation with the use of only 1 calcimimetic. Similarly, our study did not show a correlation with cinacalcet monotherapy and the rate of overall biochemical postoperative hypocalcemia. Therefore, although cinacalcet alone may not drive postoperative hypocalcemia from hypoparathyroidism among 3HPTH patients, its use may be an indicator of disease severity given these patients’ greater pre-excision IOPTH and its subsequent effect on IOPTH kinetics.25 It is thought that patients requiring calciumlowering medications like cinacalcet may exhibit a more extreme biochemical form of their disease.25 Studies have shown that greater rates of hypercalcemic complications, such as fatigue, depression, and altered mental status, occur among 3HPTH
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Table IV. IOPTH monitoring Cinacalcet (n = 14) 50% decrease achieved by*, n (%) 5 min 1 (7) 10 min 4 (28) 15 min 14 (100) No. of PTH draws to 2.6 ± 0.2 achieve 50% decrease
No drug (n = 102) 4 20 93 2.9
(4) (20) (92) ± 0.1
P value .48 .48 .60 .23
*Fisher’s exact test. Continuous variables are represented as the mean values ± standard error of the mean unless otherwise indicated. IOPTH, Intraoperative parathyroid hormone; PTH, parathyroid hormone.
patients who are referred for cinacalcet treatment versus those requiring no treatment.23 Likewise, previous reports have shown increased rates of postoperative hypocalcemia as well as associated complications among patients on calciumlowering medications such as cinacalcet. Consistent with this report, we found that 3HPTH patients taking cinacalcet experienced greater rates of postoperative complications such as hungry bone syndrome. Furthermore, all of these patients needed to be managed medically with calcitriol and calcium phosphate supplementation to manage their symptomatology until resolution. The correlation between cinacalcet treatment and hypocalcemic complications such as hungry bone syndrome may be an indication of prolonged disease duration and severity from postponing PTX in this patient group.25 Although cinacalcet may indeed serve as an index of disease severity, its direct effects on renal physiology and disease etiology may also contribute to the differences in preoperative and postoperative findings between the 2 groups. In addition to their greater initial IOPTH levels, steeper decrease in IOPTH, and increased incidence of hungry bone syndrome, patients taking cinacalcet had poorer renal function and heavier parathyroid glands. Whether these additional findings are a result of cinacalcet itself or are indicative of a more severe disease state that necessitated medicinal intervention is unclear. Calcimimetics have been suspected to increase the risk of kidney allograft failure or rejection independent of the deleterious effects of prolonged HPTH that may be associated with requiring cinacalcet.23 In this study, cinacalcettreated 3HPTH patients did indeed have lesser creatinine clearance than those not taking the drug (Table I). Additionally, calcimimetics may
impair renal function, thus exacerbating the symptoms associated with abnormal parathyroid function18; the use of calcimimetics may, therefore, lead to direct and visible changes in 3HPT disease progression before PTX. Notably, we found a significant difference in the size of the largest resected gland among patients taking cinacalcet versus the untreated group. The heaviest gland weights among the cinacalcet-treated patients were significantly heavier than that of those not taking cinacalcet. Furthermore, all patients taking cinacalcet experienced 4-gland hyperplasia, although this group only comprised 20% of those not taking cinacalcet, further suggesting that cinacalcet is in indicator of a more severe disease state. Importantly, although cinacalcet was associated with an increase in parathyroid gland burden, it did not affect the etiology of disease, the number of glands excised, or the success of PTX. We recognize that our conclusions are drawn from a study with limitations, largely owing to the our limited sample size, especially among patients taking cinacalcet. We were only able to include 14 patients who were treated with cinacalcet perioperatively. We recognize that patients with whom cinacalcet was discontinued before PTX may still be physiologically affected by the after effects of therapy. In addition, we acknowledge that it was only after 2005 when cinacalcet became accepted as a therapeutic approach for use in 3HPTH. This time period falls midway through our study’s time frame. Presumably, if cinacalcet were available throughout the study period as an alternative to PTX, then a greater number of patients who would be considered as having a more severe disease burden would have at some point been placed taking cinacalcet and would have been included in the treated category. Within our modest interpretation of this study’s findings, our approach of classifying such patients given these limitations did not diminish from identifying significant differences in IOPTH kinetics, preoperative creatinine levels, gland burden, and complications. We recognize that, because our patient sample size is small and restricted to surveying a patient load at single institution, even drawing correlations between cinacalcettreated patients and their disease picture cannot be done with certitude. We conclude that, although cinacalcet treatment may be a determinant of a steeper decrease in IOPTH levels, cinacalcet does not alter operative protocol, does not impact operative success, and does not diminish the effectiveness of PTX. We maintain that those taking cinacalcet are
Somnay et al 1313
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patients with more long-standing HPTH whose surgical treatment has been delayed in an attempt to medically manage their symptomatology. Although cinacalcet alone is effective and safe for managing 3HPTH, patients’ hypercalcemic symptoms often persist. Therefore, regardless of medication status, patients experiencing symptomatic disease should opt for PTX to achieve a more immediate and permanent resolution of hypercalcemia and associated symptoms.
14.
15. 16. 17.
18.
The authors thank Harpreet Gill and Jon Blake Matsamura for their technical assistance. 19.
REFERENCES 1. Pitt SC, Sippel RS, Chen H. Secondary and tertiary hyperparathyroidism, state of the art surgical management. Surg Clin North Am 2009;89:1227-39. 2. Nichol PF, Mack E, Bianco J, Hayman A, Starling JR, Chen H. Radioguided parathyroidectomy in patients with secondary and tertiary hyperparathyroidism. Surgery 2003;134: 713-7. 3. Kerby JD, Rue LW, Blair H, Hudson S, Sellers MT, Diethelm AG. Operative treatment of tertiary hyperparathyroidism: a single-center experience. Ann Surg 1998;227:878-86. 4. Kilgo MS, Pirsch JD, Warner TF, Starling JR. Tertiary hyperparathyroidism after renal transplantation: surgical strategy. Surgery 1998;124:677-83. 5. Nichol PF, Starling JR, Mack E, Klovning JJ, Becker BN, Chen H. Long-term follow-up of patients with tertiary hyperparathyroidism treated by resection of a single or double adenoma. Ann Surg 2002;235:673-8. 6. D’Alessandro AM, Melzer JS, Pirsch JD, Sollinger HW, Kalayoglu M, Vernon WB, et al. Tertiary hyperparathyroidism after renal transplantation: operative indications. Surgery 1989;106:1049-55. 7. Nieto J, Ruiz-Cuevas P, Escuder A, Regas J, Callis L. Tertiary hyperparathyroidism after renal transplantation. Pediatr Nephrol 1997;11:65-8. 8. Kebebew E, Duh QY, Clark OH. Tertiary hyperparathyroidism: histologic patterns of disease and results of parathyroidectomy. Arch Surg 2004;139:974-7. 9. Triponez F, Kebebew E, Dosseh D, Duh QY, Hazzan M, Noel C, et al. Less-than-subtotal parathyroidectomy increases the risk of persistent/recurrent hyperparathyroidism after parathyroidectomy in tertiary hyperparathyroidism after renal transplantation. Surgery 2006;140:990-7. 10. Triponez F, Dosseh D, Hazzan M, Noel C, Vanhille P, Proye CA. Subtotal parathyroidectomy with thymectomy for autonomous hyperparathyroidism after renal transplantation. Br J Surg 2005;92:1282-7. 11. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: a randomized trial. World J Surg 1991;15:745-50. 12. Goodman WG. Calcimimetics: a remedy for all problems of excess parathyroid hormone activity in chronic kidney disease? Curr Opin Nephrol Hypertens 2005;14:355-60. 13. Goodman WG, Hladik GA, Turner SA, Blaisdell PW, Goodkin DA, Liu W, et al. The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis
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patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002;13:1017-24. Goodman WG. Calcimimetic agents and secondary hyperparathyroidism: rationale for use and results from clinical trials. Pediatr Nephrol 2003;18:1206-10. Barman Balfour JA, Scott LJ. Cinacalcet hydrochloride. Drugs 2005;65:271-81. de Francisco AL. Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. Expert Opin Pharmacother 2005;6:441-52. W€ uthrich RP, Martin D, Bilezikian JP. The role of calcimimetics in the treatment of hyperparathyroidism. Eur J Clin Invest 2007;37:915-22. Kruse AE, Eisenberger U, Frey FJ, Mohaupt MG. The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005;20:1311-4. Leca N, Laftavi M, Gundroo A, Kohli R, Min I, Karam J, et al. Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet. Am J Transplant 2006;6:2391-5. Jean G, Vanel T, Terrat JC, Hurot JM, Lorriaux C, Mayor B, et al. [Treatment of secondary hyperparathyroidism resistant to conventional therapy and tertiary hyperparathyroidism with Cinacalcet: an efficiency strategy]. Nephrol Ther 2010;6:105-10. Serra AL, Schwarz AA, Wick FH, Marti HP, W€ uthrich RP. Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005;20:1315-9. Serra AL, Savoca R, Huber AR, Hepp U, Delsignore A, Hersberger M, et al. Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients. Nephrol Dial Transplant 2007;22:577-83. Yang RL, Freeman K, Reinke CE, Fraker DL, Karakousis GC, Kelz RR, et al. Tertiary hyperparathyroidism in kidney transplant recipients: characteristics of patients selected for different treatment strategies. Transplantation 2012; 94:70-6. Haustein SV, Mack E, Starling JR, Chen H. The role of intraoperative parathyroid hormone testing in patients with tertiary hyperparathyroidism after renal transplantation. Surgery 2005;138:1066-71. Schneider DF, Day GM, De Jong SA. Calcium-lowering medications in patients with primary hyperparathyroidism: intraoperative findings and postoperative hypocalcemia. Am J Surg 2012;203:357-60.
DISCUSSION Dr Sally E. Carty (Pittsburgh, PA): It is not entirely clear to me how your study design supports the conclusion because you did not stop Sensipar preoperatively. You just compared 2 groups: One that happened to be on it and one happened to not be on it. So please comment on that. Dr Yash R. Somnay (Madison, WI): We did in fact compare 2 groups of patients: One on the drug and one off. We did not see any difference in rates of transient hypocalcemia between the 2 groups. We do observe the hungry bone syndrome incidence is definitely higher in the cinacalcet group and this should definitely alert the surgeon that they may need to address this postoperatively.
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Cinacalcet itself is probably an indicator of more severe disease and that these patients really are not being helped by it. So they need to be operated on as soon as possible. Dr James Norman (Tampa, FL): These patients can be difficult to treat. Your abstract in the book is different a little bit from what you have presented here. In the book, you talk about single adenomas, double adenomas, and those sorts of things in the abstract. But, of course, you cannot have an adenoma and have a kidney transplant in the same patient. So if you could clarify that a little bit. In your method section, did everybody get a total or subtotal operation? My second question is, unlike patients with primary hyperparathyroidism, the pathophysiology here is more related toward high parathyroid hormone (PTH) levels rather than high calcium levels. So it’s easy to mobilize calcium levels in a patient with tertiary hyperparathyroidism. It is not
Surgery December 2014
easy to normalize their PTH levels, which may be more important. So maybe you could explain a little bit about those 2 factors. Did you look at everybody’s, all 4 parathyroid glands? And second, what is their PTH levels postoperatively? Defining cure by normalization of calcium, in my opinion, in tertiary, is not appropriate. Dr Yash R. Somnay: For your first question, we do bilateral exploration on all patients. Those with hyperplasia underwent subtotal, and those who were diagnosed with single or double had only those number of glands removed. So not everybody received subtotal. About 10-15% of patients in our experience had single or double adenomas. This has also been described by other groups. As for your second question, I do agree that PTH levels are definitely important in assessing whether or not the operation has been successful. These levels are reported in the paper.
Introduction. Tertiary hyperparathyroidism (3HPTH) patients who undergo parathyroidectomy (PTX) are often managed with calcium lowering medications such as cinacalcet (Sensipar) before surgery. Here, we assess how cinacalcet treatment influences intraoperative parathyroid hormone (IOPTH) kinetics and surgical findings in 3HPTH patients undergoing PTX. Methods. We reviewed retrospectively 113 patients 3HPTH who underwent PTX, 14 of whom were taking cinacalcet and 112 who were not taking the drug. IOPTH levels fitted to linear curves versus time were used to evaluate the role of cinacalcet. Results. Cinacalcet did not correlate with rates of cure (P = .41) or recurrence (P = .54). Patients taking cinacalcet experienced a steeper decrease in IOPTH compared with those not taking the medication (P = .005). Cinacalcet treatment was associated with an increase in rate of hungry bones (P = .04). Weights of the heaviest glands resected (P = .02) and preoperative PTH levels (P = .0004) were greater among patients taking cinacalcet. Conclusion. Perioperative cinacalcet treatment in patients with 3HPTH alters IOPTH kinetics by causing a steeper decrease in IOPTH, but does not require modification of the standard IOPTH protocol. Although cinacalcet use does not adversely affect cure rates, it is associated with greater preoperative PTH and an increased incidence of hungry bones, hence serving as an indicator of more severe disease. Cinacalcet does not need to be held before operation. (Surgery 2014;156:1308-14.) From the Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Wisconsin, Madison, WI
TERTIARY HYPERPARATHYROIDISM (3HPTH) is an endocrine disorder characterized by the persistent hypersecretion of parathyroid hormone (PTH) in patients with longstanding secondary HPTH (2HPTH) who have undergone successful kidney transplantation to correct their chronic kidney disease.1,2 Although most transplant recipients experience a return to normal PTH secretion after restoration of renal function, #8% of patients retain abnormally functioning parathyroid tissue that fails to resolve.3,4 Consequently, serum levels of PTH remain increased, thereby increasing Presented at the American Association of Endocrine Surgeons meeting in Boston, Massachusetts, April, 2014. Accepted for publication August 8, 2014. Reprint requests: Herbert Chen, MD, K3/705 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.08.003
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serum calcium levels leading to a constellation of debilitating symptoms, including atherosclerosis, nephrolithiasis, osteopenia, osteoporosis, and neuropsychiatric changes.3-7 The mainstay curative approach for patients with 3HPTH is subtotal or total parathyroidectomy (PTX) with forearm implantation of the remnant parathyroid.3-5,8-10 Notably, medical management before operative intervention often employs the use of calcimimetic agents to decrease serum calcium.11 These agents exert their effect by allosterically, activating the calcium-sensing receptors of the parathyroid glands, thus directly suppressing PTH secretion.12 Prior interventions, such as the use of sterols and vitamin D supplementation, proved to be effective in controlling PTH levels, but resulted frequently in hypercalcemia and hyperphosphatemia.13 The advent of the calcimemetic agent cinacalcet (Sensipar, Amgen Inc, Thousand Oaks, CA) introduced a viable therapeutic option for effectively decreasing plasma levels of PTH in patients with 2HPTH on dialysis, while
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simultaneously decreasing calcium and phosphorous levels and avoiding associated symptoms.12-14 In addition to its registered indication for 2HPTH in patients with end-stage renal disease on maintenance dialysis, cinacalcet is also approved to decrease hypercalcemia in patients with parathyroid carcinoma and primary HPTH patients in whom PTX is contraindicated.15,16 Given its mechanism of action and favorable pharmacokinetics, however, cinacalcet has been prescribed increasingly for patients with 3HPTH as described in a number of reports.17-22 Since its introduction, many 3HPTH patients now opt for medical management with cinacalcet in place of PTX.18,23 Accordingly, PTX is often performed in conjunction with calcimimetics such as cinacalcet when managing symptomatic 3HPT patients.23 The purpose of this study was to investigate the influence of cinacalcet treatment on preoperative and postoperative findings, intraoperative PTH (IOPTH) kinetics, and the etiology of disease in patients with 3HPTH. METHODS We reviewed retrospectively 116 patients with 3HPTH undergoing PTX at our institution between March 2001 to March 2013. We defined 3HPTH patients as those who previously had 2HPTH and underwent successful renal transplantation. Patients who were undergoing reoperative PTX from persistent or recurrent HPTH were excluded. These patients were divided into 2 groups composed of those taking cinacalcet and those not taking cinacalcet at the time of PTX. Patients taking cinacalcet before PTX but for whom it was discontinued were categorized in the nontreated group. Patients previously taking cinacalcet who were considered to be in the nontreated group had an average duration of discontinuation before PTX of 428 days. Approval from the University of Wisconsin Institutional Review Board was granted for data collection and analysis. Patients underwent bilateral neck exploration with identification of all parathyroid glands. The number of glands excised depended on the disease etiology. Patients with hyperplasia underwent subtotal PTX. IOPTH monitoring was performed according to our previous report.24 PTH laboratory values were drawn after anesthesia, and at 5, 10, and 15 minutes after excision of all hyperfunctioning glands. A decrease in IOPTH of 50% was used as the criteria to end the operation. Trends in IOPTH monitoring within each group were assessed by calculating the average linear
Somnay et al 1309
slope of IOPTH change based on the initial and final levels drawn during the operation. Slopes between the 2 groups were then compared. Furthermore, we assessed the correlation between cinacalcet treatment and the number of glands discovered. We defined operative cure as serum calcium <10.2 mg/dL at 6 months after PTX. Persistence was defined as a return to calcium levels >10.2 mg/dL within 6 months after PTX, and disease recurrence was defined as a resurgence of serum calcium levels >10.2 mg/dL after a period of normal calcium for $6 months after PTX. Hypocalcemia as a complication of PTX was specified in the setting of hypoparathyroidism with normal renal functioning retained. Such cases were defined as having a calcium level of <8.5 mg/ dL, a PTH of <8 pg/mL, and a normal glomerular filtration rate and creatinine level within 1 week after PTX. If these levels did not resolve within 6 months, these patients were classified as having permanent hypoparathyroidism. We diagnosed hungry bone syndrome in patients who had calcium levels <10.2 mg/dL after PTX beyond postoperative day 4, and these determinations were made initially based on clinical manifestations of prolonged hypocalcemia. Statistical analysis was performed using SPSS software (version 10.0, SPSS Inc, Chicago, IL) using Pearson’s Chisquare test, Fisher’s exact test, and a 2-sided Student t test for continuous variables. Continuous variable are expressed as mean values ± standard error of the mean. RESULTS Patients and demographics. Among the 116 patients with 3HPTH undergoing PTX, 14 (12%) were taking cinacalcet at the time of operation, and 102 (88%) were on no calcimemetics. The median treatment time of cinacalcet was 26 months (range, 1.9–56). The percentage of male patients was 64% among cinacalcet-treated patients and 49% among patients not taking the drug, which was statistically similar (Table I). Vitamin D levels among both groups were also similar, but were on the lower end of normal (Table I). Furthermore, creatinine levels were significantly greater among those taking cinacalcet compared with those not taking the drug (Table I). Although preoperative calcium levels did not differ statistically between the 2 groups, those taking cinacalcet had greater preoperative PTH levels (681 pg/ mL) versus those not taking the drug (271 pg/ mL; P = .0004; Table I). Interestingly, although etiology was not affected by cinacalcet treatment,
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Table I. Patient demographics and laboratory data
Demographics Age (y) Male patientsy (%) Vitamin D (ng/mL) Creatinine (mg/dL) Preoperative Ca (mg/dL) Preoperative PTH (pg/mL) Postoperative Ca (mg/dL) Postoperative PTH (pg/mL) Etiologyy (%) Single adenoma Double adenoma Hyperplasia
Cinacalcet (n = 14; 12%)
No drug (n = 102; 88%) ±1 (49) ± 0.89 ± 0.7 ± 0.12
P value
47 ± 3 9 (64) 29.1 ± 4.4 1.9 ± 0.22 10.5 ± 0.48
52 50 29.9 1.5 10.6
.19 .39 .89 .03* .86
681 ± 274
270 ± 20
.0004*
8.5 ± 0.32
8.9 ± 0.1
.22
118 ± 40
86 ± 11
.37
0 0 14
12 9 81
.17
*P < .05. yFisher’s exact test. Continuous variables are represented as the mean values ± standard error of the mean unless otherwise indicated. Ca, Calcium; PTH, parathyroid hormone.
all patients taking cinacalcet had hyperplasia, whereas 21% of those not on drug did not have hyperplasia (Table I). Cure, complications, and intraoperative findings. PTX in both patient groups resulted in high cure rates (an overall rate of 97%), with a combined recurrence rate of 3%, indicating that surgical intervention is a successful curative approach regardless of cinacalcet treatment (Table II). Cure rates within each group were 93% and 97% among those taking cinacalcet and those not taking a calcimimetic, respectively. Recurrence rates were also low in both groups and did not differ. We noted postoperative complications among cinacalcet-treated patients and those not taking the drug. The overall rates of biochemical postoperative hypocalcemia from permanent hypoparathyroidism did not differ significantly between the 2 groups (Table II). We also observed a significantly greater rate of certain postoperative complications among patients taking cinacalcet. Hungry bone syndrome occurred in 21% of patients taking cinacalcet but only 4% of patients not taking the drug (P = .04; Table II). Other complications, such as voice hoarseness and mild parasthesias, did not differ between the 2 groups. Finally, we compared the average weights of the heaviest resected parathyroid gland between those taking cinacalcet and those not taking the drug. The average weight of the heaviest gland among
Table II. Incidence of cure, recurrence, and hypocalcemia Cinacalcet No drug P (n = 14) (n = 102) value
Variable Cure, n (%) Recurrence, n (%) Complications, n (%) Permanent hypoparathyroidism Transient hoarseness Hungry bone syndrome Parasthesias
13 (93) 1 (7)
99 (97) 5 (5)
.41 .54
0 (0)
1 (1)
.99
1 (7) 3 (21) 2 (14)
2 (2) 4 (4) 4 (4)
.32 .04* .15
*P < .05. All P values calculated based on Fisher’s exact test.
Table III. IOPTH monitoring Variable
Cinacalcet No calcimimetic P (n = 14) (n = 102) value
Pre-excision PTH 711 ± 277 (pg/mL) Percent decrease (%) 77 ± 4 Slope 59 ± 34 *P < .05. IOPTH, Intraoperative hormone.
parathyroid
328 ± 50
.03*
73 ± 3 17 ± 3
.59 .005*
hormone;
PTH,
parathyroid
patients taking cinacalcet (1,309 ± 330 g) was significantly greater than that of those not taking the drug (853.4 ± 58.5; P = .02). IOPTH monitoring. To analyze the influence of cinacalcet on IOPTH kinetics, we plotted IOPTH levels over time, beginning with the pre-excision recording and followed by every reading thereafter. Notably, we found that pre-excision IOPTH values (0 minutes) were greater among cinacalcettreated patients (711 ± 277 vs 328 ± 50 pg/mL; P = .03; Table III). This is aligned with the significant findings from Table I showing a marked increase in preoperative PTH levels taken before the day of PTX among cinacalcet-treated patients. When comparing the patterns of the IOPTH between treatment and nontreatment groups, we found that cinacalcet altered IOPTH kinetics, correlating with a significantly steeper decrease in IOPTH (Figure). The rate of IOPTH change indicated by the average slope of linear fitted curves drawn between pre-excision IOPTH values from each patient and its paired final IOPTH recording were compared between the 2 groups. The rate of decline in IOPTH among patients taking cinacalcet was represented by an average slope of 59 ± 34, whereas for those not taking cinacalcet the average downward slope of IOPTH levels was 17 ± 3 (P = .005; Table III). Notably, there
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Figure. Intraoperative parathyroid hormone (PTH) value plot for patients with tertiary hypoparathyroidism taking cinacalcet and not taking cinacalcet undergoing PTX. The graph below shows a connected line of IOPTH values for those taking cinacalcet (dotted line) and those not taking the drug (solid line), beginning with preexcision (t = 0) IOPTH levels and followed by every value recorded thereafter. Pre-excision IOPTH was greater among those taking cinacalcet* (P = .03). The slope and percent decrease in IOPTH were determined using the pre-excision IOPTH (t = 0 minutes) and the final IOPTH (t = 15 minutes) as an endpoint. IOPTH levels decreased at a significantly steeper slope among patients taking cinacalcetx (P = .005). Standard error of the mean for each IOPTH reading is illustrated with error bars.
was no difference between the 2 groups in their average decreases in IOPTH percentage between the first and last IOPTH recordings (Table III). Finally, we found that there was no difference in the number of patients achieving a 50% drop at any given interval of IOPTH recording between those taking and not taking cinacalcet. The distribution among those achieving surgical cure at 5, 10, and 15 minutes was statistically similar (Table IV). The number of PTH samples required to achieve a 50% decrease also did not differ significantly between the 2 groups (Table IV). Discussion. PTX has been well established as a curative approach for patients with HPTH.4,7 Nevertheless, medical management of 3HPTH has become more widespread since the advent of safe and readily available calcimimetic agents.12,23 Accordingly, medical therapy often precedes or accompanies operative intervention. The calcimimetic cinacalcet was incorporated into management of 3HPTH around 2005 and has since offered patients with severe disease the option of medical therapy in lieu of, and often preceding, PTX.11,23 Although cinacalcet has been shown to resolve hypercalcemia and hyperphosphatemia in 3HPTH patients, most
Somnay et al 1311
patients experience persistence of their hypercalcemic symptoms,23 necessitating PTX. The impact of cinacalcet on IOTPH kinetics and intraoperative protocol has not been described in 3HPTH patients undergoing PTX. In this study of 116 patients with 3HPTH who underwent PTX, 12% were taking cinacalcet at the time of PTX. Overall, cinacalcet treatment was associated with a dramatically steeper decrease in IOPTH during PTX and did not alter the probability of surgical success. The percentage decrease in IOPTH and number of IOPTH recordings required to achieve a 50% decrease were not different among the 2 groups. Collectively, these findings indicate that standardized IOPTH monitoring can be used to confirm successful excavation of hyperfunctioning parathyroid tissue, regardless of perioperative cinacalcet therapy. Moreover, it demonstrates that operative intervention is a highly curative approach with or without cinacalcet. A previous study by Schneider et al25 concluded that calcimimetic treatment at the time of PTX among patients with primary HPTH also affected IOPTH kinetics by causing a steeper decrease in the series of IOPTH readings with a lesser degree of recovery in IOPTH values. Our study found that pre-excision IOPTH values were significantly greater among cinacalcet-treated patients, accounting for the sharper decrease in IOPTH levels that we observed. These greater preoperative PTH levels may reflect salient distinctions in the biochemical severity of HPTH in this group, because these patients warranted PTX after previously requiring and failing a medical approach with cinacalcet. Schneider et al25 went on to attribute a greater degree of postoperative hypocalcemia to multidrug calcimimetic therapy (1 + calcimimetics), but did not report a correlation with the use of only 1 calcimimetic. Similarly, our study did not show a correlation with cinacalcet monotherapy and the rate of overall biochemical postoperative hypocalcemia. Therefore, although cinacalcet alone may not drive postoperative hypocalcemia from hypoparathyroidism among 3HPTH patients, its use may be an indicator of disease severity given these patients’ greater pre-excision IOPTH and its subsequent effect on IOPTH kinetics.25 It is thought that patients requiring calciumlowering medications like cinacalcet may exhibit a more extreme biochemical form of their disease.25 Studies have shown that greater rates of hypercalcemic complications, such as fatigue, depression, and altered mental status, occur among 3HPTH
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Table IV. IOPTH monitoring Cinacalcet (n = 14) 50% decrease achieved by*, n (%) 5 min 1 (7) 10 min 4 (28) 15 min 14 (100) No. of PTH draws to 2.6 ± 0.2 achieve 50% decrease
No drug (n = 102) 4 20 93 2.9
(4) (20) (92) ± 0.1
P value .48 .48 .60 .23
*Fisher’s exact test. Continuous variables are represented as the mean values ± standard error of the mean unless otherwise indicated. IOPTH, Intraoperative parathyroid hormone; PTH, parathyroid hormone.
patients who are referred for cinacalcet treatment versus those requiring no treatment.23 Likewise, previous reports have shown increased rates of postoperative hypocalcemia as well as associated complications among patients on calciumlowering medications such as cinacalcet. Consistent with this report, we found that 3HPTH patients taking cinacalcet experienced greater rates of postoperative complications such as hungry bone syndrome. Furthermore, all of these patients needed to be managed medically with calcitriol and calcium phosphate supplementation to manage their symptomatology until resolution. The correlation between cinacalcet treatment and hypocalcemic complications such as hungry bone syndrome may be an indication of prolonged disease duration and severity from postponing PTX in this patient group.25 Although cinacalcet may indeed serve as an index of disease severity, its direct effects on renal physiology and disease etiology may also contribute to the differences in preoperative and postoperative findings between the 2 groups. In addition to their greater initial IOPTH levels, steeper decrease in IOPTH, and increased incidence of hungry bone syndrome, patients taking cinacalcet had poorer renal function and heavier parathyroid glands. Whether these additional findings are a result of cinacalcet itself or are indicative of a more severe disease state that necessitated medicinal intervention is unclear. Calcimimetics have been suspected to increase the risk of kidney allograft failure or rejection independent of the deleterious effects of prolonged HPTH that may be associated with requiring cinacalcet.23 In this study, cinacalcettreated 3HPTH patients did indeed have lesser creatinine clearance than those not taking the drug (Table I). Additionally, calcimimetics may
impair renal function, thus exacerbating the symptoms associated with abnormal parathyroid function18; the use of calcimimetics may, therefore, lead to direct and visible changes in 3HPT disease progression before PTX. Notably, we found a significant difference in the size of the largest resected gland among patients taking cinacalcet versus the untreated group. The heaviest gland weights among the cinacalcet-treated patients were significantly heavier than that of those not taking cinacalcet. Furthermore, all patients taking cinacalcet experienced 4-gland hyperplasia, although this group only comprised 20% of those not taking cinacalcet, further suggesting that cinacalcet is in indicator of a more severe disease state. Importantly, although cinacalcet was associated with an increase in parathyroid gland burden, it did not affect the etiology of disease, the number of glands excised, or the success of PTX. We recognize that our conclusions are drawn from a study with limitations, largely owing to the our limited sample size, especially among patients taking cinacalcet. We were only able to include 14 patients who were treated with cinacalcet perioperatively. We recognize that patients with whom cinacalcet was discontinued before PTX may still be physiologically affected by the after effects of therapy. In addition, we acknowledge that it was only after 2005 when cinacalcet became accepted as a therapeutic approach for use in 3HPTH. This time period falls midway through our study’s time frame. Presumably, if cinacalcet were available throughout the study period as an alternative to PTX, then a greater number of patients who would be considered as having a more severe disease burden would have at some point been placed taking cinacalcet and would have been included in the treated category. Within our modest interpretation of this study’s findings, our approach of classifying such patients given these limitations did not diminish from identifying significant differences in IOPTH kinetics, preoperative creatinine levels, gland burden, and complications. We recognize that, because our patient sample size is small and restricted to surveying a patient load at single institution, even drawing correlations between cinacalcettreated patients and their disease picture cannot be done with certitude. We conclude that, although cinacalcet treatment may be a determinant of a steeper decrease in IOPTH levels, cinacalcet does not alter operative protocol, does not impact operative success, and does not diminish the effectiveness of PTX. We maintain that those taking cinacalcet are
Somnay et al 1313
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patients with more long-standing HPTH whose surgical treatment has been delayed in an attempt to medically manage their symptomatology. Although cinacalcet alone is effective and safe for managing 3HPTH, patients’ hypercalcemic symptoms often persist. Therefore, regardless of medication status, patients experiencing symptomatic disease should opt for PTX to achieve a more immediate and permanent resolution of hypercalcemia and associated symptoms.
14.
15. 16. 17.
18.
The authors thank Harpreet Gill and Jon Blake Matsamura for their technical assistance. 19.
REFERENCES 1. Pitt SC, Sippel RS, Chen H. Secondary and tertiary hyperparathyroidism, state of the art surgical management. Surg Clin North Am 2009;89:1227-39. 2. Nichol PF, Mack E, Bianco J, Hayman A, Starling JR, Chen H. Radioguided parathyroidectomy in patients with secondary and tertiary hyperparathyroidism. Surgery 2003;134: 713-7. 3. Kerby JD, Rue LW, Blair H, Hudson S, Sellers MT, Diethelm AG. Operative treatment of tertiary hyperparathyroidism: a single-center experience. Ann Surg 1998;227:878-86. 4. Kilgo MS, Pirsch JD, Warner TF, Starling JR. Tertiary hyperparathyroidism after renal transplantation: surgical strategy. Surgery 1998;124:677-83. 5. Nichol PF, Starling JR, Mack E, Klovning JJ, Becker BN, Chen H. Long-term follow-up of patients with tertiary hyperparathyroidism treated by resection of a single or double adenoma. Ann Surg 2002;235:673-8. 6. D’Alessandro AM, Melzer JS, Pirsch JD, Sollinger HW, Kalayoglu M, Vernon WB, et al. Tertiary hyperparathyroidism after renal transplantation: operative indications. Surgery 1989;106:1049-55. 7. Nieto J, Ruiz-Cuevas P, Escuder A, Regas J, Callis L. Tertiary hyperparathyroidism after renal transplantation. Pediatr Nephrol 1997;11:65-8. 8. Kebebew E, Duh QY, Clark OH. Tertiary hyperparathyroidism: histologic patterns of disease and results of parathyroidectomy. Arch Surg 2004;139:974-7. 9. Triponez F, Kebebew E, Dosseh D, Duh QY, Hazzan M, Noel C, et al. Less-than-subtotal parathyroidectomy increases the risk of persistent/recurrent hyperparathyroidism after parathyroidectomy in tertiary hyperparathyroidism after renal transplantation. Surgery 2006;140:990-7. 10. Triponez F, Dosseh D, Hazzan M, Noel C, Vanhille P, Proye CA. Subtotal parathyroidectomy with thymectomy for autonomous hyperparathyroidism after renal transplantation. Br J Surg 2005;92:1282-7. 11. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: a randomized trial. World J Surg 1991;15:745-50. 12. Goodman WG. Calcimimetics: a remedy for all problems of excess parathyroid hormone activity in chronic kidney disease? Curr Opin Nephrol Hypertens 2005;14:355-60. 13. Goodman WG, Hladik GA, Turner SA, Blaisdell PW, Goodkin DA, Liu W, et al. The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis
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patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002;13:1017-24. Goodman WG. Calcimimetic agents and secondary hyperparathyroidism: rationale for use and results from clinical trials. Pediatr Nephrol 2003;18:1206-10. Barman Balfour JA, Scott LJ. Cinacalcet hydrochloride. Drugs 2005;65:271-81. de Francisco AL. Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. Expert Opin Pharmacother 2005;6:441-52. W€ uthrich RP, Martin D, Bilezikian JP. The role of calcimimetics in the treatment of hyperparathyroidism. Eur J Clin Invest 2007;37:915-22. Kruse AE, Eisenberger U, Frey FJ, Mohaupt MG. The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005;20:1311-4. Leca N, Laftavi M, Gundroo A, Kohli R, Min I, Karam J, et al. Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet. Am J Transplant 2006;6:2391-5. Jean G, Vanel T, Terrat JC, Hurot JM, Lorriaux C, Mayor B, et al. [Treatment of secondary hyperparathyroidism resistant to conventional therapy and tertiary hyperparathyroidism with Cinacalcet: an efficiency strategy]. Nephrol Ther 2010;6:105-10. Serra AL, Schwarz AA, Wick FH, Marti HP, W€ uthrich RP. Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005;20:1315-9. Serra AL, Savoca R, Huber AR, Hepp U, Delsignore A, Hersberger M, et al. Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients. Nephrol Dial Transplant 2007;22:577-83. Yang RL, Freeman K, Reinke CE, Fraker DL, Karakousis GC, Kelz RR, et al. Tertiary hyperparathyroidism in kidney transplant recipients: characteristics of patients selected for different treatment strategies. Transplantation 2012; 94:70-6. Haustein SV, Mack E, Starling JR, Chen H. The role of intraoperative parathyroid hormone testing in patients with tertiary hyperparathyroidism after renal transplantation. Surgery 2005;138:1066-71. Schneider DF, Day GM, De Jong SA. Calcium-lowering medications in patients with primary hyperparathyroidism: intraoperative findings and postoperative hypocalcemia. Am J Surg 2012;203:357-60.
DISCUSSION Dr Sally E. Carty (Pittsburgh, PA): It is not entirely clear to me how your study design supports the conclusion because you did not stop Sensipar preoperatively. You just compared 2 groups: One that happened to be on it and one happened to not be on it. So please comment on that. Dr Yash R. Somnay (Madison, WI): We did in fact compare 2 groups of patients: One on the drug and one off. We did not see any difference in rates of transient hypocalcemia between the 2 groups. We do observe the hungry bone syndrome incidence is definitely higher in the cinacalcet group and this should definitely alert the surgeon that they may need to address this postoperatively.
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Cinacalcet itself is probably an indicator of more severe disease and that these patients really are not being helped by it. So they need to be operated on as soon as possible. Dr James Norman (Tampa, FL): These patients can be difficult to treat. Your abstract in the book is different a little bit from what you have presented here. In the book, you talk about single adenomas, double adenomas, and those sorts of things in the abstract. But, of course, you cannot have an adenoma and have a kidney transplant in the same patient. So if you could clarify that a little bit. In your method section, did everybody get a total or subtotal operation? My second question is, unlike patients with primary hyperparathyroidism, the pathophysiology here is more related toward high parathyroid hormone (PTH) levels rather than high calcium levels. So it’s easy to mobilize calcium levels in a patient with tertiary hyperparathyroidism. It is not
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easy to normalize their PTH levels, which may be more important. So maybe you could explain a little bit about those 2 factors. Did you look at everybody’s, all 4 parathyroid glands? And second, what is their PTH levels postoperatively? Defining cure by normalization of calcium, in my opinion, in tertiary, is not appropriate. Dr Yash R. Somnay: For your first question, we do bilateral exploration on all patients. Those with hyperplasia underwent subtotal, and those who were diagnosed with single or double had only those number of glands removed. So not everybody received subtotal. About 10-15% of patients in our experience had single or double adenomas. This has also been described by other groups. As for your second question, I do agree that PTH levels are definitely important in assessing whether or not the operation has been successful. These levels are reported in the paper.