• 1.

    Chertow GM, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:24822494. doi: 10.1056/NEJMoa1205624

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Block GA, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: Two randomized clinical trials. JAMA 2017; 317:146155. doi: 10.1001/jama.2016.19456

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Block GA, et al. Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: A randomized phase 3 trial. J Am Soc Nephrol 2019; 30:641652. doi: 10.1681/ASN.2018080832

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Ardelyx Ardelyx Announces Positive Topline Results from Pivotal Phase 3 PHREEDOM Study Evaluating Tenapanor in CKD Patients on Dialysis. Published December 3, 2019. Accessed December 25, 2020. https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-announces-positive-topline-results-pivotal-phase-3

    • Search Google Scholar
    • Export Citation
  • 5.

    Block GA, et al. A pilot randomized trial of ferric citrate coordination complex for the treatment of advanced CKD. J Am Soc Nephrol 2019; 30:14951504. doi: 10.1681/ASN.2018101016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Edmonston DL, et al. Design and rationale of HiLo: A pragmatic, randomized trial of phosphate management for patients on maintenance hemodialysis. Am J Kidney Dis [published online ahead of print December 3, 2020]. doi: 10.1053/j.ajkd.2020.10.008; https://www.ajkd.org/article/S0272-6386(20)31131-8/fulltext

    • Search Google Scholar
    • Export Citation
  • 7.

    Pragmatic Randomised Trial of High Or Standard PHosphAte Targets in End-stage Kidney Disease (PHOSPHATE). ClinicalTrials.gov: NCT03573089. https://clinicaltrials.gov/ct2/show/NCT03573089

Novel Agents in CKD-MBD A Second Lease on Life or Flogging a Dead Horse?

  • 1 Mayuri Trivedi, DM, is assistant professor, Nephrology Services, Department of Medicine, LTMGH, and consultant nephrologist and transplant physician, Hinduja Healthcare Surgical and S L Raheja Fortis Hospital, Mumbai, India. Sanjeev Nair, DM, is associate professor in the Department of Nephrology, Saveetha Medical College and Hospital, Chennai, India.
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Mineral bone disease (MBD) has proven to be a Pandora’s box for most clinicians treating chronic kidney disease (CKD), including end-stage kidney disease (ESKD). Although the body of literature highlighting the various bone metabolic abnormalities associated with ESKD as definite risk factors for mortality, cardiovascular disease, increased risk of fractures, and other musculoskeletal complications grows stronger, the therapeutic agents to deal with these abnormalities continue to keep us on edge (Table 1).

Table 1.

Reasons for skepticism among nephrologists regarding novel drugs for MBD

Table 1.
MBD = mineral bone disease

In recent years, a few novel agents have been promoted as game changers in the management of this important complication of ESKD. Time will tell whether they will be successful in matching the hype and actually improving patient outcomes.

Currently approved treatments for the mineral bone abnormalities in ESKD include phosphate binders to treat the hyperphosphatemia and calcimimetic drugs and active vitamin D analogs to treat the associated secondary hyperparathyroidism. In 2012, a randomized, placebo-controlled trial, EVOLVE, with cinacalcet, a first-generation calcimimetic agent, did not significantly reduce the risk of death or non-fatal cardiovascular events in ESKD patients with secondary hyperparathyroidism (1). Recently, a second-generation intravenous calcimimetic agent, etelcalcetide, was approved to be used thrice per week post-regular hemodialysis (2). It reportedly reduces the parathyroid hormone (PTH) levels by at least 30% from baseline by 20−27 weeks of use, along with lowering serum phosphate and fibroblast growth factor (FGF)-23 levels. This was achieved without loading the patient with calcium, thus minimizing the risk of soft tissue and arterial calcification similar to cinacalcet albeit with lesser gastrointestinal side effects and a convenient thrice-weekly post-dialysis dosing. However, despite this proposed benefit, the drug does seem to share the hypocalcemia potential of the calcimimetic drug class with an increased incidence of hypocalcemia-related life-threatening complications compared to placebo.

Phosphate binders are commonly used drugs in kidney disease. A new kid on the block, tenapanor, is a minimally absorbed novel drug that inhibits the gastrointestinal sodium/hydrogen exchanger 3 (NHE3) and is used as an anti-constipation agent in irritable bowel syndrome. It acts by reducing paracellular phosphate transport in the intestine and thus acts via a non-phosphorus binding mechanism to reduce serum phosphate levels by as much as 1–1.2 g/dL over an 8-week period of use. Apart from soft stools and increased bowel movements, this drug did not differ significantly from placebo and shows some potential in improving the management of MBD (3). In the absence of good quality data, however, we will have to wait to see whether tenapanor will prove beneficial in the treatment of MBD. We are awaiting publication of the phase 3 clinical trial, called the PHREEDOM study, looking at tenapanor versus placebo in patients with ESKD on dialysis (4).

Ferric citrate is a relatively more researched novel agent, which is an oral, calcium-free, iron-based phosphate binder that not only helps in reducing serum phosphate levels but also helps in treatment of another common complication of CKD, i.e., anemia. So apart from phosphate reduction, the added improvement of iron parameters can potentially cut costs and reduce the pill burden for these patients. Block et al. (5), in their recent study, showed a beneficial effect on the biochemical parameters with an excellent safety profile.

The advent of newer agents for the treatment of MBD in CKD may help in improving the cardiovascular outcomes. However, robust data with randomized controlled trials that measure patient-centric outcomes as well as hard outcomes like mortality benefit are needed to back the claims that inspire the hope of improved outcomes. The results of the recently announced HiLo trial will be important to watch. HiLo is a multi-center, pragmatic, randomized controlled trial that aims to study all-cause mortality and all-cause hospitalizations in ESKD patients with high-phosphate (≥6.5 mg/dL) or low-phosphate (≤5.5 mg/dL) levels (6). Another similar trial, the results of which may have an impact on our approach to MBD management, is the PHOSPHATE trial (7).

Regardless of the final status of these drugs, the management of MBD must move beyond surrogate outcomes like biochemical improvements and be measured by its impact on patient-centric outcomes, as well as hard outcomes, including improved cardiovascular and mortality outcomes in the long run.

The authors report no conflict of interest.

References

  • 1.

    Chertow GM, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:24822494. doi: 10.1056/NEJMoa1205624

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Block GA, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: Two randomized clinical trials. JAMA 2017; 317:146155. doi: 10.1001/jama.2016.19456

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Block GA, et al. Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: A randomized phase 3 trial. J Am Soc Nephrol 2019; 30:641652. doi: 10.1681/ASN.2018080832

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Ardelyx Ardelyx Announces Positive Topline Results from Pivotal Phase 3 PHREEDOM Study Evaluating Tenapanor in CKD Patients on Dialysis. Published December 3, 2019. Accessed December 25, 2020. https://ir.ardelyx.com/news-releases/news-release-details/ardelyx-announces-positive-topline-results-pivotal-phase-3

    • Search Google Scholar
    • Export Citation
  • 5.

    Block GA, et al. A pilot randomized trial of ferric citrate coordination complex for the treatment of advanced CKD. J Am Soc Nephrol 2019; 30:14951504. doi: 10.1681/ASN.2018101016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Edmonston DL, et al. Design and rationale of HiLo: A pragmatic, randomized trial of phosphate management for patients on maintenance hemodialysis. Am J Kidney Dis [published online ahead of print December 3, 2020]. doi: 10.1053/j.ajkd.2020.10.008; https://www.ajkd.org/article/S0272-6386(20)31131-8/fulltext

    • Search Google Scholar
    • Export Citation
  • 7.

    Pragmatic Randomised Trial of High Or Standard PHosphAte Targets in End-stage Kidney Disease (PHOSPHATE). ClinicalTrials.gov: NCT03573089. https://clinicaltrials.gov/ct2/show/NCT03573089

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