Patients on maintenance dialysis with severe secondary hyperparathyroidism (SHPT) present a complex clinical challenge. Despite decades of study, the role of parathyroidectomy (PTX) in the management of SHPT remains uncertain. In theory, PTX occupies a well defined space: to paraphrase Kidney Disease Improving Global Outcomes (KDIGO) guideline 4.2.5, individuals with high levels of parathyroid hormone (PTH) refractory to medical treatment should be referred for consideration of surgery (1,2). In reality, the nephrology community continues to grapple with how to best use PTX to treat severe PTH elevations.
The intriguing origins of PTX are recounted in several accounts that are well worth reading (3,4). There is some controversy about when the procedure was first performed, but PTX for the indication of osteitis fibrosa cystica seems to have first been undertaken in Vienna in 1925 by Felix Mandl (5). PTX for SHPT may have been first reported in 1960, when two patients with “renal failure” underwent subtotal PTX (6). PTX seems to have entered the mainstream for patients on dialysis by the 1990s accompanied by the admonition that “…the most important factor in the outcome of surgery is to have a highly skilled surgeon experienced in parathyroid surgery” (7)—sound advice regarding this complex procedure.
In this issue of the Clinical Journal of the American Society of Nephrology, Kim et al. (8) report changes in PTX rates in patients on maintenance dialysis from 2002 to 2011. Kim et al. (8) find that rates declined sharply in 2004 and 2005 before increasing again and stabilizing from 2006 to 2011. To fully appreciate their findings, however, we must first consider them within the broad historical trends in PTX and contextualize them within the framework of seminal events that have shaped SHPT management, such as the introduction of new medications, the formulation of new clinical practice guidelines, and the publication of key studies.
Several essential epidemiologic studies provide an important backdrop to the investigation by Kim et al. (8). Kestenbaum et al. (9), in an early study, reviewed PTX rates from 1990 to 1999. Kestenbaum et al. (9) found that adjusted PTX rates were relatively stable at approximately 9–10/1000 patient-years from 1990 to 1995 and then, decreased fairly sharply, reaching a nadir of about 6/1000 patient-years in 1998. Kestenbaum et al. (9) speculated that this decline might have been because of widespread adoption of intravenous calcitriol and an “increased awareness of SHPT as a multi-system disease,” although they did not have access to patient-level or aggregate data on PTH levels or calcitriol prescription rates (9). Foley et al. (10) then extended follow-up to 2002, confirming the finding of a nadir in 1998, but also reporting a new peak of nearly 12/1000 patient-years in 2002. Foley et al. (10) were uncertain as to why this increase occurred, especially because new formulations of intravenous vitamin D sterols were being introduced (11). A follow-up study (12), examining trends out to 2007, showed an abrupt decrease in 2004–2006 and a nadir at <6/1000 patient-years in 2005, during which time approximately 90% of patients were receiving intravenous vitamin D sterols. Somewhat presciently, Li et al. (12) speculated that the decrease in 2004–2006 might have been because of the introduction of cinacalcet.
The most recent trends reported by Kim et al. (8) further clarify this picture. Using the National Inpatient Sample (NIS), Kim et al. (8) confirm that PTX rates declined sharply in 2004 and 2005, reaching a nadir of about 3.3 procedures per 1000 patients, and that the rates increased again before becoming relatively constant at approximately 5/1000 patients from 2006 to 2011. It is important to note that differences in study designs mean that the rates are not directly comparable across all published reports, although this should not affect contextualization of broad trends. A major benefit of the NIS is that the study sample is unconstrained by insurance status, allowing observation of patients without Medicare who tend to be younger and more likely to undergo PTX than older patients. A possible weakness, however, is that the indication for PTX was uncertain; about 15% of patients underwent PTX on hospital day 2 or later, suggesting that PTX may not have been an uncomplicated elective primary procedure in their study sample (8).
Kim et al. (8) attribute the decrease in PTX rates in 2004 and 2005, quite reasonably, to the 2004 introduction of cinacalcet (13). During those years, speculation abounded that cinacalcet might constitute what was colloquially termed a medical PTX, perhaps rendering PTX obsolete in all but the most refractory patients. Although it is true that, many years later, cinacalcet can likely be credited with decreasing PTX rates as shown in a randomized clinical trial (14) and a recent meta-analysis (15), its introduction has not, as Kim et al. (8) show, resulted in a sustained rate decrease. This may be because randomized clinical trials, conducted in idealized environments, test efficacy and therefore, likely represent an upper limit of the performance of an intervention. Appreciation of this phenomenon has prompted calls to acknowledge the important role of pragmatic clinical trials, which often generate estimates of real world effectiveness (16,17). The issue of efficacy versus effectiveness seems particularly acute in the case of cinacalcet: for reasons that remain elusive, cinacalcet has not been used as many thought it would be, with many patients experiencing only intermittent exposure and rebounding when exposure ceases (18). This practice likely reduces cinacalcet’s long-term effectiveness.
One somewhat unexpected finding is that PTX rates have not decreased substantially after the publication of the 2009 KDIGO clinical practice guidelines on CKD-mineral and bone disorder, which greatly liberalized the acceptable PTH target range (1). Large dialysis providers in the United States now commonly use protocols in which the target PTH levels are between 150 and about 500–600 pg/ml. Because PTX generally seems to be reserved for patients with PTH levels >1000 pg/ml, it is likely that relatively few patients with PTH levels of 300–600 pg/ml were previously being referred for PTX; as such, the guideline change may not have had the effect of averting many PTXs.
Whether the equilibrium that has developed concerning PTX represents the optimal treatment approach is unclear. A well designed observational study could conceivably provide insights into this issue, but it would have to overcome the powerful source of confounding known as nonrandom treatment allocation. This refers to the scenario in which two patients who seem similar are actually characterized by important differences about which only the bedside physician has intimate knowledge, making comparison of like to like patients in an observational study extremely challenging. Such analyses have been attempted, sometimes from a cost-effectiveness perspective (19); future observational work should use the most advanced design and analytic approaches, such as marginal structural models, and/or techniques such as inverse probabilities of treatment and censoring weighting, to compare outcomes between patients treated with PTX and those treated medically.
Clinical practice guidelines for CKD-mineral and bone disorder are currently being revisited. In any future recommendation involving the role of PTX, several factors should be considered. First, recent work has shown that the risk-to-benefit ratio of PTX may be more unfavorable than traditionally appreciated. A nontrivial 2% mortality rate in the month after PTX was reported using data from a large national dialysis provider (20). Second, PTX, which undoubtedly reduces PTH levels enormously in most patients, seems to fail in a surprisingly large subset, and hypocalcemia remains a substantial problem in many patients even 6–12 months after surgery (21). These findings likely diminish enthusiasm for PTX. However, another finding might cast PTX in a more favorable light: a recent study examining complications of PTX for primary hyperparathyroidism (n>17,000) in California showed a halving of complication rates over time (22). A modest consolidation of procedures performed in high-volume centers may be partially responsible. Although patients on dialysis were excluded from that study, experience at the level of the operative center and the individual physician would presumably have a spillover effect, conferring benefits to patients on dialysis undergoing PTX for SHPT. Third, another consideration is that patients on dialysis are living longer than ever before (23). The largest gains, as expected, are among the youngest patients, precisely those at highest risk of developing unremitting hyperparathyroidism. Fourth, the introduction of a potent calcimimetic, etalcalcitide, is imminent (24,25) and will likely provide a new treatment option for patients with SHPT.
The nephrology community should engage in a robust discussion about the appropriate role of PTX in patients on maintenance dialysis with SHPT. More work is needed examining which types of patients might benefit from PTX, such as those likely to live longest, and which types might incur undue risk, such as those who are nonadherent with therapy and who may be at elevated risk of life–threatening adverse events after surgery. Tailored therapy could conceivably involve the use of noninvasive markers of bone turnover, such as alkaline phosphatase fractions, or other assessments of bone health to help determine which patients would benefit from one approach over another approach. With the substantial growth in the maintenance dialysis population in the United States and across the world, optimal treatment of severe SHPT is likely to be a major clinical issue faced by the nephrology community for the foreseeable future.
J.B.W. has participated in projects undertaken by the Chronic Disease Research Group that were funded by Amgen, Inc. (Thousand Oaks, CA).
The author thanks Allan J. Collins, Areef Ishani, and Geoffrey A. Block for helpful insights, but this acknowledgment does not necessarily constitute their endorsement of the author’s views contained herein. J.B.W. also thanks Chronic Disease Research Group colleagues Anne Shaw (for manuscript preparation) and Nan Booth (for manuscript editing).
This work was supported by the Minneapolis Medical Research Foundation, Chronic Disease Research Group.
1. KDIGO: KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int 76(Suppl 113): S1–S130, 2009
2. Uhlig K, Berns JS, Kestenbaum B, Kumar R, Leonard MB, Martin KJ, Sprague SM, Goldfarb S: KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis 55: 773–799, 2010
3. Organ CH Jr.: The history of parathyroid surgery, 1850-1996: The Excelsior Surgical Society 1998 Edward D Churchill Lecture. J Am Coll Surg 191: 284–299, 2000
4. Dubose J, Ragsdale T, Morvant J: “Bodies so tiny”: The history of parathyroid surgery. Curr Surg 62: 91–95, 2005
5. Delbridge LW, Palazzo FF: First parathyroid surgeon: Sir John Bland-Sutton and the parathyroids. ANZ J Surg 77: 1058–1061, 2007
6. Stanbury SW, Lumb GA, Nicholson WF: Elective subtotal parathyroidectomy
for renal hyperparathyroidism. Lancet 1: 793–799, 1960
7. Llach F, Nikakhtar B: Parathyroidectomy
in dialysis patients: Indications, surgical approach, complications and clinical management after surgery. Semin Dial 9: 332–338, 1996
8. Kim SM, Long J, Montez-Rath ME, Leonard MB, Norton JA, Chertow GM: Rates and outcomes of parathyroidectomy
for secondary hyperparathyroidism
in the United States. Clin J Am Soc Nephrol 11: 1260–1267, 2016
9. Kestenbaum B, Seliger SL, Gillen DL, Wasse H, Young B, Sherrard DJ, Weiss NS, Stehman-Breen CO: Parathyroidectomy
rates among United States dialysis patients: 1990-1999. Kidney Int 65: 282–288, 2004
10. Foley RN, Li S, Liu J, Gilbertson DT, Chen SC, Collins AJ: The fall and rise of parathyroidectomy
in U.S. hemodialysis patients, 1992 to 2002. J Am Soc Nephrol 16: 210–218, 2005
11. Martin KJ, González EA: Vitamin D analogues for the management of secondary hyperparathyroidism
. Am J Kidney Dis 38[Suppl 5]: S34–S40, 2001
12. Li S, Chen YW, Peng Y, Foley RN, St Peter WL: Trends in parathyroidectomy
rates in US hemodialysis patients from 1992 to 2007. Am J Kidney Dis 57: 602–611, 2011
13. Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG, Hercz G, Cunningham J, Abu-Alfa AK, Messa P, Coyne DW, Locatelli F, Cohen RM, Evenepoel P, Moe SM, Fournier A, Braun J, McCary LC, Zani VJ, Olson KA, Drüeke TB, Goodman WG: Cinacalcet for secondary hyperparathyroidism
in patients receiving hemodialysis. N Engl J Med 350: 1516–1525, 2004
14. Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS; EVOLVE Trial Investigators: Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 367: 2482–2494, 2012
15. Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GF: Calcimimetics for secondary hyperparathyroidism
in chronic kidney disease patients. Cochrane Database Syst Rev 12: CD006254, 2014
16. Rothwell PM: External validity of randomised controlled trials: “To whom do the results of this trial apply?”. Lancet 365: 82–93, 2005
17. Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, Oxman AD, Moher D; CONSORT group; Pragmatic Trials in Healthcare (Practihc) group: Improving the reporting of pragmatic trials: An extension of the CONSORT statement. BMJ 337: a2390, 2008
18. Reams BD, Dluzniewski PJ, Do TP, Yue SV, Bradbury BD, Kshirsagar AV, Brookhart MA: Dynamics of cinacalcet use and biochemical control in hemodialysis patients: A retrospective New-user cohort design. BMC Nephrol 16: 175, 2015
19. Narayan R, Perkins RM, Berbano EP, Yuan CM, Neff RT, Sawyers ES, Yeo FE, Vidal-Trecan GM, Abbott KC: Parathyroidectomy
versus cinacalcet hydrochloride-based medical therapy in the management of hyperparathyroidism in ESRD: A cost utility analysis. Am J Kidney Dis 49: 801–813, 2007
20. Ishani A, Liu J, Wetmore JB, Lowe KA, Do T, Bradbury BD, Block GA, Collins AJ: Clinical outcomes after parathyroidectomy
in a nationwide cohort of patients on hemodialysis. Clin J Am Soc Nephrol 10: 90–97, 2015
21. Wetmore JB, Liu J, Do TP, Lowe KA, Ishani A, Bradbury BD, Block GA, Collins AJ: Changes in secondary hyperparathyroidism
-related biochemical parameters and medication use following parathyroidectomy
. Nephrol Dial Transplant 31: 103–111, 2016
22. Abdulla AG, Ituarte PH, Harari A, Wu JX, Yeh MW: Trends in the frequency and quality of parathyroid surgery: Analysis of 17,082 cases over 10 years. Ann Surg 261: 746–750, 2015
23. Weinhandl E, Constantini E, Everson S, Gilbertson D, Li S, Solid C, Anger M, Bhat JG, DeOreo P, Krishnan M, Nissenson A, Johnson D, Ikizler TA, Maddux F, Sadler J, Tyshler L, Parker T 3rd, Schiller B, Smith B, Lindenfeld S, Collins AJ: Peer kidney care initiative 2014 report: Dialysis care and outcomes in the United States. Am J Kidney Dis
65[6 Suppl 1]: Svi–S140, 2015
24. Martin KJ, Pickthorn K, Huang S, Block GA, Vick A, Mount PF, Power DA, Bell G: AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism
in a single-dose study in hemodialysis patients. Kidney Int 85: 191–197, 2014
25. Bell G, Huang S, Martin KJ, Block GA: A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism
in hemodialysis patients. Curr Med Res Opin 31: 943–952, 2015