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Consider a step therapy approach for the treatment of hyperparathyroidism and mineral and bone disorder in patients on dialysis

Issue: July 2019

ByGeorge R. Aronoff, MD, MS, FACP, FASN

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Managing the cascade of illness triggered by the imbalance of calcium and phosphorus challenges physicians who care for patients with CKD.

Delineated in this article is a methodical approach that organizes, in a stepwise fashion, the management of secondary hyperparathyroidism (SHPT) and the resulting mineral and bone disorder (CKD-MBD). The underlying concept of CKD-MBD step therapy is to begin first with interventions with the least likelihood for adverse events, progressing to additional therapies as necessary with the recognition of increased risks and challenges associated with those interventions.

While we await further clinical evidence to better inform our practices, as newer medications are introduced and more extensively studied, this step therapy strategy starts with and relies heavily on the most proven drug and non-drug therapies. The approach, informed by the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) practice guidelines¹ and the 2003 Kidney Disease Outcomes Quality Initiative practice guidelines,² progresses to additional options while maintaining patient safety as the first priority.

As CKD-MBD is a multifactorial manifestation of CKD, successful treatment requires a holistic approach to managing calcium, phosphorus, vitamin D, parathyroid hormone (PTH) and fibroblast growth factor (FGF23). As noted by KDIGO, the processes contributing to CKD-MBD are closely interrelated and contribute to morbidity and mortality in these patients.³

Step therapy management

• Hyperphosphatemia, hypocalcemia and hypercalcemia

Hyperphosphatemia is an inevitable clinical consequence of CKD in its advanced stages, as well as an important risk factor for SHPT and cardiovascular disease.⁴ Epidemiological data suggest that elevated serum phosphorus levels are associated with higher rates of morbidity and mortality.⁵ Due to the interdependence of calcium, phosphorus, vitamin D, PTH and FGF23, hyperphosphatemia serves as a catalyst in the progression of CKD-MBD in patients on dialysis and may be the earliest biochemical manifestation of CKD-MBD. Therefore, phosphorus management is the initial focus of MBD step therapy in patients with CKD.

Source: Brandon Frawley

To control serum phosphorus within normal ranges, phosphate intake should be moderately restricted by means of dietary modifications, with care taken to ensure dietary protein needs are not compromised. If dietary management proves insufficient to control serum phosphorus levels, phosphate-binding agents can be added to reduce intestinal absorption of phosphate.

The use of dietary restriction together with oral phosphate binders is a well-established practice in the management of patients with advanced stages of CKD.⁶ A systematic review of medications used as phosphate binders, including calcium salts, aluminum salts, magnesium salts, sevelamer-HCl and lanthanum carbonate, demonstrated that all are effective in lowering serum phosphorus levels.⁷ An observational, prospective study of patients prescribed phosphate binders demonstrated a 29% lower risk of all-cause mortality and a 22% lower risk of cardiovascular mortality in the nearly 7,000 patients studied.⁸

In its 2017 updated guidelines, KDIGO suggests treatment for lowering high serum phosphorus should be based on serial assessments of serum phosphorus, calcium and PTH levels, considered together. KDIGO recommends serum calcium be lowered toward the normal range; hypercalcemia be avoided; calcium-based phosphate binders be restricted for certain patients receiving phosphate-lowering treatment; and the long-term use of aluminum-containing phosphate binders be avoided. KDIGO further recommends increasing dialytic phosphorus removal, if necessary, for persistent hyperphosphatemia.⁹

Enhancing dialysis clearance of phosphorus also helps address patient non-adherence. However, adherence should be emphasized with patients early in the process to preclude the need for this escalation of treatment. For example, even such simple steps as considering patient preference in the choice of phosphate binders can help promote medication adherence.

In ESRD, hyperphosphatemia is associated with increased mortality. The treatment goal is the management of hyperphosphatemia while avoiding hypercalcemia.¹⁰ For that reason, 2009 KDIGO guidelines recommended diminished use of the calcium-based phosphate binders. Calcium-based binders may be useful for patients with hypocalcemia, but when appropriate should be replaced with non-calcium containing binders once calcium levels are returned to normal.¹¹

Hypercalcemia is publicly reported to CMS and is one of the National Quality Forum-endorsed performance metrics.¹² As hypercalcemia results with the development of hyperparathyroidism, it must be closely monitored and controlled.

Hypercalcemia can contribute to a higher risk of vascular disease.¹³ In fact, both hyperphosphatemia and hypercalcemia associated with SHPT have been tied to vascular calcification,¹⁴ which is predictive of adverse clinical outcomes and mortality.¹⁵ KDIGO based its recommendations on vascular calcification on the understanding that the presence and severity of cardiovascular calcification strongly predicts cardiovascular morbidity and mortality in patients with CKD.¹⁶ Its updated recommendations state that it is reasonable to consider patients with advanced-stage CKD at highest cardiovascular risk if known vascular or valvular calcification is present, and to use that knowledge to guide management of their CKD-MBD.¹⁷

Hypocalcemia must be managed as well. Hypocalcemia drives the release of PTH, escalates the progression of hyperparathyroidism and CKD-MBD, and can result from the use of calcimimetics drugs intended to control PTH levels. A recent retrospective observational analysis involving a large dialysis cohort confirmed the increased risk of mortality associated with hypocalcemia.¹⁸ Clearly, the management of serum calcium levels is critical in preventing the advancement of CKD-MBD and controlling the risk of bone abnormalities and cardiovascular calcification.

• Vitamin D and analogues

Following an initial focus of therapy to manage hyperphosphatemia with diet and phosphate binders, subsequent treatment should be considered, if necessary, to address dietary vitamin D deficiency.

Vitamin D is essential in proper mineral homeostasis and musculoskeletal function, serving as a transport molecule for calcium. Most patients with CKD have reduced circulating levels of calcitriol and insufficient or deficient 25(OH)D, which facilitates a rise in PTH production.¹⁹

Given a preference within the step therapy approach for treatments with minimal adverse side effects, beginning first with nutritional vitamin D supplementation and progressing as necessary to vitamin D analogs seems rational. KDIGO updated recommendations state it is reasonable to reserve calcitriol and vitamin D analogs for patients with advanced-stage CKD with severe and progressive hyperparathyroidism. Calcitriol and synthetic vitamin D analogs raise serum calcium and phosphate levels, necessitating caution among patients with increased phosphorus and calcium levels.²⁰

Vitamin D supplementation administered to patients on hemodialysis normalizes vitamin D levels in some patients deficient in vitamin D without causing hypercalcemia or increasing phosphorus or PTH levels.^21,22 However, when nutritional vitamin D is not sufficient, vitamin D analogs can be used to help restore mineral homeostasis and curtail the progression of SHPT and CKD-MBD. Studies indicate calcitriol or synthetic vitamin D analogs, when used to treat new patients on hemodialysis, are associated with a survival advantage, including a decline in all-cause mortality and cardiovascular deaths.^23-25

It is important to note that if overcorrected, excessive suppression of the parathyroid gland with current therapies, particularly calcium-containing phosphate binders and vitamin D analogs, can lead to adynamic bone disease, which also increases the risk for fractures as well as for metastatic calcification.²⁶ However, inappropriately addressed PTH levels also can lead to low bone turnover or adynamic bone disease.²⁷

• Calcimimetics

In cases of more severe SHPT, where target levels cannot be attained by attempts to control phosphorus levels or through the use of vitamin D and vitamin D analogs, it is reasonable to add calcimimetics, beginning first with cinacalcet as an adjunct therapy. Etelcalcetide, for which clinical evidence is more limited, should be reserved for patients whose hyperparathyroidism remains unresponsive or for patients with uncontrolled SHPT who cannot tolerate cinacalcet without intolerable side effects.

Cinacalcet acts to lower PTH levels by binding to the calcium sensing receptor, imitating calcium’s effect on the parathyroid gland. Adding cinacalcet increases the likelihood patients will attain target PTH levels, particularly if adequate doses of vitamin D are not possible due to elevated serum calcium or phosphorus levels.^28-31 However, cinacalcet has not been proven to provide a benefit on mortality and cardiovascular outcomes.^32-33 Updated KDIGO guidelines suggest the use of calcimimetics, calcitriol, or vitamin D analogs, or a combination of those therapies, in patients with advanced-stage CKD undergoing therapy to control elevated PTH levels.³⁴

Typically, patients are directed to take cinacalcet daily at home. However, adherence is a concern due to gastrointestinal discomfort that includes nausea and vomiting, both adverse events that also can impact nutrition and adherence to other medications. Administering cinacalcet three times a week at a dialysis center greatly improves adherence and may be equally as effective for some patients. In addition to gastrointestinal symptoms, cinacalcet decreases serum calcium concentrations and can result in hypocalcemia.³⁵

Etelcalcetide is a relatively new calcimimetic drug characterized by a different molecular structure. Etelcalcetide binds to the calcium sensing receptor at a different site than cinacalcet. Etelcalcetide is administered intravenously. Due to its ability to affect favorable laboratory results for PTH serum levels, etelcalcetide therapy is promising in terms of potentially improved patient outcomes. Administered on a limited basis in practice settings, etelcalcetide’s risk profile is not as well established as that for cinacalcet. In addition, requiring special handling to avoid exposure to light in the dialysis unit and needing to be given intravenously during the rinse back procedure at the conclusion of a dialysis treatment present operational challenges to its use.

Adverse events

In two parallel, randomized trials, etelcalcetide was more effective than placebo in reducing PTH by 27 weeks as compared with placebo among 1,023 patients on hemodialysis with hyperparathyroidism.³⁶ However, adverse events experienced by the patients who received etelcalcetide included hypocalcemia, muscle spasms, nausea, vomiting and prolongation of the QTc interval on ECG. Trials also have demonstrated a higher occurrence of hypocalcemia among patients, requiring additional interventions to bring calcium levels back in line with target values.³⁷ In a prospective, randomized, controlled clinical trial, etelcalcetide was found to cause symptomatic hypocalcemia and prolongation of the QTc interval more frequently than cinacalcet.³⁸

Etelcalcetide use met the non-inferiority criteria compared to cinacalcet in a randomized trial comparing IV etelcalcetide with oral placebo and oral cinacalcet with IV placebo among patients on hemodialysis with hyperparathyroidism. In the trial, PTH levels among participants were reduced by more than 30% in 68.2% of patients.³⁹ Administration of etelcalcetide intravenously to patients is conducted three times weekly while on in-center dialysis. The IV administration of etelcalcetide also could provide potential benefits due to improved patient adherence to the medication.

Oral cinacalcet is recommended as the first choice when a calcimimetic is needed to control SHPT. Given the relative lack of extensive clinical experience related to the use of etelcalcetide compared to that of well-established cinacalcet, the step therapy approach to the management of SHPT, based on patient safety, would suggest reserving the use of etelcalcetide for those patients unresponsive or intolerant to other measures. Due to an increased risk of hypocalcemia, cinacalcet and etelcalcetide should never be administered together, and an appropriate wash-out period is required when switching patients from one to the other.

Balance risks and benefits

Clinicians continually balance the risk of adverse events with the benefit of pharmacological therapy. The step approach to managing SHPT and CKD-MBD in patients on hemodialysis with elevated PTH levels prioritizes patient safety as we work to avoid the consequences that would result from allowing biochemical and hormonal imbalances to go unchecked. We intervene to help prevent progressive CKD-MBD by starting with those therapies that are effective but have the lowest probability or potential for serious adverse events. This approach requires achieving a balance of phosphate binders, calcitriol or synthetic vitamin D analogs and calcimimetics, all administered within their respective therapeutic windows. As the effects of SHPT and CKD-MBD manifest gradually in patients, changes in management steps occur gradually for several months, guided by serial changes in relevant biochemical measurements.

As patients move through the spectrum of CKD-MBD and SHPT, the extent of intervention increases over time with additional therapies added as they become necessary, each with its own set of risks and challenges:

• dietary phosphorus counseling and administration of phosphate binders;
• vitamin D supplementation or replacement;
• addition of oral cinacalcet as an adjunct therapy; and
• transition if needed from oral cinacalcet to IV etelcaletide.

For patients who fail to respond to these dietary, medical and pharmacological interventions, the long-standing KDIGO recommendation is to address severe HPT in patients with advanced-stage CKD with parathyroidectomy.⁴⁰

As practitioners address the abnormal biochemical measurements that accompany CKD and the development of CKD-MBD, they bear in mind whether there is credible evidence that altering these values pharmacologically improves import patient-centered outcomes like mortality, hospitalizations and quality of life. Further research addressing those issues is warranted. In addition, electronic decision support tools that consider the complex relationships of multiple, interdependent laboratory values and interventions will likely be useful in the future.

Conclusion

The step therapy approach outlined here is consistent with current standards and guidelines for the treatment of patients with CKD and can serve as a helpful resource for clinicians as they work toward standard target levels of calcium, phosphorous, vitamin D and PTH in this complex patient population. Before medical treatments became available to address imbalances of these important biochemical and hormonal components, SHPT in patients with CKD resulted in considerable morbidity and mortality.⁴¹ Effective use of the step therapy approach to SHPT and MBD can help to protect patients from the effects of poor bone health and cardiovascular disease that lie at the end of the CKD-MBD spectrum.

• References:

1. KDIGO Work Group. Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.189.
2. Natl Kidney Foundation. Am J Kidney Dis. 2003;doi:10.1053/S0272-6386(03)00905-3.
3. KDIGO Work Group. Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.189.
4. KDIGO Work Group, Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.192.
5. Ibid.
6. Ibid.
7. KDIGO Work Group, Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.192.
8. Cannata-Andia JB, et al. Kidney Int. 2013;doi:10.1038/ki.2013.185.
9. KDIGO Work Group, Ofl J Intl Soc Neph. 2017;doi:10.1016/j.kisu.2017.04.001.
10. Quarles LD, et al. Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients. UpToDate. 2017.
11. KDIGO Work Group. Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.192.
12. Natl Quality Forum. Dept Human Svc. 2015;ISBN:978-1-68248-002-1.
13. Quarles LD, et al. Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients. UpToDate. 2017.
14. Cunningham J, et al. Clin J Am Soc Neph. 2011;doi:10.2215/CJN.06040710.
15. KDIGO Work Group. Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.191.
16. Ibid.
17. KDIGO Work Group. Ofl J Intl Soc Neph. 2017;doi:10.1016/j.kisu.2017.04.001.
18. KDIGO Work Group. Ofl J Intl Soc Neph. 2017;doi:10.1016/j.kisu.2017.04.001.
19. KDIGO Work Group. Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.192.
20. Quarles LD, et al. Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients. UpToDate. 2017.
21. Massart A, et al. Am J Kidney Dis. 2014;doi:10.1053/j.ajkd.2014.04.020.
22. Saab G. Nephron Clin Pract. 2007;doi:10.1159/000098645.
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24. Teng M, et al. N Engl J Med. 2003;doi:10.1056/NEJMoa022536.
25. Wolf M, et al. Kidney Int. 2007;doi:10.1038/sj.ki.5002451.
26. Quarles LD, et al. Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients. UpToDate. 2017.
27. KDIGO Work Group. Ofl J Intl Soc Neph. 2009;doi:10.1038/ki.2009.192.
28. Moe SM, et al. Kidney Int. 2005;doi:10.1111/j.1523-1755.2005.67139.x.
29. Messa P, et al. Clin J Am Soc Nephrol. 2008;doi:10.2215/CJN.03591006.
30. Arenas MD, et al. Nephrol Dial Transplant. 2007;doi:10.1093/ndt/gfl840.
31. Fishbane S, et al. Clin J Am Soc Nephrol. 2008;doi:10.2215/CJN.01040308.
32. Palmer SC, et al. PLoS Med. 2013;doi:10.1371/journal.pmed.1001436.
33. EVOLVE Trial Investigators, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1205624.
34. KDIGO Work Group. Ofl J Intl Soc Neph. 2017;doi:10.1016/j.kisu.2017.04.001.
35. EVOLVE Trial Investigators, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1205624.
36. Amgen Inc. KAI Pharmaceuticals Inc. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208325Orig1s000Lbledt.pdf. Accessed July 23, 2018.
37. Ibid.
38. Amgen Inc. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021688s017lbl.pdf. Accessed July 23, 2017.
39. Ibid.
40. KDIGO Work Group. Ofl J Intl Soc Neph.2017;doi:10.1016/j.kisu.2017.04.001.
41. KDIGO Work Group. Ofl J Intl Soc Neph.2009;doi:10.1038/ki.2009.192.

• For more information:
• George R. Aronoff, MD, MS, FACP, FASN, is vice president of clinical affairs at DaVita Kidney Care in Denver and is an adjunct professor of medicine and pharmacology at the University of Louisville School of Medicine in Louisville, Kentucky.

Disclosure: Aronoff reports no relevant financial disclosures.