The farnesoid X receptor: a potential target for expanding the therapeutic arsenal against kidney disease

ABSTRACT

Introduction: Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor widely distributed among tissues, a major sensor of BA levels, primary suppressor of hepatic BA synthesis and secondary regulator of lipid metabolism and inflammation. Chronic kidney disease is a common, multifactorial condition with metabolic and inflammatory causes and implications. An array of natural and synthetic FXR agonists has been developed, but not yet studied clinically in kidney disease.

Areas covered: Following a summary of FXR’s physiological functions in the kidney, we discuss its effects in renal disease with emphasis on chronic and acute kidney disease, chemotherapy-induced nephrotoxicity, and renal neoplasia. Most information is derived from animal models; no relevant clinical study has been conducted to date.

Expert opinion: Most available preclinical data indicates a promising outlook for clinical research in this direction. We believe FXR agonism to be an auspicious approach to treating renal disease, considering that multifactorial diseases call for ideally wide-reaching therapies.

KEYWORDS:

• FXR
• bile acids
• kidney disease
• metabolism
• nephrotoxicity
• renal cancer
• treatment
• acute kidney injury

Article highlights

• The farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor that primarily leads to inhibition of BA biosynthesis as part of a homeostatic mechanism.

• The kidney is a ‘non-conventional’ target of FXR, where the latter participates in BA excretion, but also in fatty acid (FA) metabolism and oxidation-reduction within the renal cells and even in the modulation of urine volume and osmolality.

• In renal disease, FXR mediates direct antilipogenic, anti-inflammatory, antifibrotic and antioxidant effects within the renal parenchyma.

• The renal benefit from FXR’s systemic effects (on blood glucose, FA and BA levels, and the vasculature) is less clear-cut than the benefit from its direct renal effects.

• All in all, FXR impacts favorably on the kidney in the context of chronic kidney disease, acute kidney injury and chemotherapy-induced nephrotoxicity.

• FXR agonists constitute possible nephroprotective drugs with the potential to repair renal tissue damage rather than just stall renal pathogenic processes.

Clinical research is warranted, as all available data to date regarding the kidney are derived from animal models or in vitro experiments.

Declaration of interest

The 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.