Secondary hyperparathyroidism in chronic kidney disease: pathophysiology, current treatments and investigational drugs

ABSTRACT

Introduction

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD). It begins as an adaptive increase in parathyroid hormone levels to prevent calcium and phosphate derangements. Over time, this condition becomes maladaptive and is associated with increased morbidity and mortality. Current therapies encompass phosphate-lowering strategies, vitamin D analogues, calcimimetics and parathyroidectomy. These approaches harbor inherent limitations, stimulating interest in the development of new drugs for SHPT to overcome these limitations and improve survival and quality of life among CKD patients.

Areas covered

This review delves into the main pathophysiological mechanisms involved in SHPT, alongside the treatment options that are currently available and under active investigation. Data presented herein stem from a comprehensive search conducted across PubMed, Web of Science, ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) spanning from 2000 onwards.

Expert Opinion

The advancements in investigational drugs for SHPT hold significant promise for enhancing treatment efficacy while minimizing side effects associated with conventional therapies. Although several challenges still hinder their adoption in clinical practice, ongoing research will likely continue to expand the available therapeutic options, refine treatment strategies, and tailor them to individual patient profiles.

KEYWORDS:

• Calcimimetics
• CaSR
• chronic kidney disease
• phosphate
• PTH
• secondary hyperparathyroidism
• vitamin D
• VDRA

Article highlights

• Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), characterized by an increase in serum levels of parathyroid hormone (PTH), a key regulator of calcium and phosphate homeostasis.

• SHPT is associated with severe bone and cardiovascular (CV) disease, exacerbating morbidity and mortality rates in CKD patients.

• Potential targets for SHPT treatment include phosphate, calcium sensing receptor (CaSR), vitamin D receptor (VDR), FGF23/αKlotho/FGFR axis, post-transcriptional factors (Pin1 and miRNAs), and molecules involved in PTG cell proliferation.

• Current therapeutic options encompass phosphate binders (PBs), vitamin D analogues, calcimimetics and parathyroidectomy (PTX), each accompanied by specific adverse effects and limitations.

• Novel iron-based PBs (PT20 and AP301), along with the new pan-inhibitor of phosphate transporters (AP306), are promising alternatives capable of reducing pill burden and gastrointestinal side effects associated with currently available PBs.

• DP001, a novel form of active vitamin D, exhibits high selectivity for the parathyroid tissue and has shown efficacy in reducing PTH levels with minimized calcemic actions.

• Despite the effectiveness of available calcimimetics in lowering PTH levels, there is interest in discovering new calcimimetic compounds (e.g. AC265347) to mitigate hypocalcemia, gastrointestinal side effects, and drug-drug interactions.

• The potential to modulate PTH gene expression and FGF23/αKlotho/FGFR signaling at the molecular level offers exciting prospects with future drugs targeting specific miRNAs.

• Photodynamic therapy (PDT), currently used in oncologic diseases, has shown promising preliminary results as alternative option to PTX in cases of drug-resistant SHPT or non-adherent patient populations.

Declaration of interest

M Cozzolino has received honoraria from Amgen, Vifor CLS, AbbVie to participate in Advisory Boards. The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.”

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.