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Mineralocorticoid receptor antagonists in diabetic kidney disease — mechanistic and therapeutic effects

Abstract

Chronic kidney disease (CKD) is the leading complication in type 2 diabetes (T2D) and current therapies that limit CKD progression and the development of cardiovascular disease (CVD) include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and sodium–glucose co-transporter 2 (SGLT2) inhibitors. Despite the introduction of these therapeutics, an important residual risk of CKD progression and cardiovascular death remains in patients with T2D. Mineralocorticoid receptor antagonists (MRAs) are a promising therapeutic option in diabetic kidney disease (DKD) owing to the reported effects of mineralocorticoid receptor activation in inflammatory cells, podocytes, fibroblasts, mesangial cells and vascular cells. In preclinical studies, MRAs consistently reduce albuminuria, CKD progression, and activation of fibrotic and inflammatory pathways. DKD clinical studies have similarly demonstrated that steroidal MRAs lead to albuminuria reduction compared with placebo, although hyperkalaemia is a major secondary effect. Non-steroidal MRAs carry a lower risk of hyperkalaemia than steroidal MRAs, and the large FIDELIO-DKD clinical trial showed that the non-steroidal MRA finerenone also slowed CKD progression and reduced the risk of adverse cardiovascular outcomes compared with placebo in patients with T2D. Encouragingly, other non-steroidal MRAs have anti-albuminuric properties in DKD. Whether or not combining MRAs with other renoprotective drugs such as SGLT2 inhibitors might provide additive protective effects warrants further investigation.

Key points

  • Current therapeutic options to slow the progression of chronic kidney disease (CKD) in type 2 diabetes (T2D) and reduce its cardiovascular consequences mainly include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and sodium–glucose co-transporter 2 inhibitors. However, the residual risk of CKD progression and cardiovascular death remains high.

  • Mineralocorticoid receptor activation in non-epithelial cells leads to the activation of inflammatory and fibrotic pathways in the kidney, and has deleterious effects in podocytes and mesangial cells.

  • Pharmacological inhibition of the mineralocorticoid receptor reduces albuminuria, kidney fibrosis, glomerular lesions and inflammation in preclinical models of CKD in T2D; beneficial cardiovascular effects have also been observed.

  • Clinical studies show that steroidal mineralocorticoid receptor antagonists (MRAs) have an anti-albuminuric effect in diabetic kidney disease, but the risk of hyperkalaemia associated with the use of these drugs has limited their use and evaluation for hard kidney and cardiovascular outcomes.

  • Promising novel non-steroidal MRAs with a better therapeutic index than steroidal MRAs have been developed — in the FIDELIO-DKD trial, finerenone reduced CKD progression and improved cardiovascular outcomes compared with placebo when added to an optimized regimen of renin–angiotensin–aldosterone system inhibitors and the incidence of hyperkalaemia was very low. Other non-steroidal MRAs reduced albuminuria in phase II and phase III clinical trials.

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Fig. 1: Aldosterone-mediated pro-inflammatory effects in macrophages and T cells.
Fig. 2: The beneficial effects of MRAs in the kidney, heart and vasculature in preclinical studies of DKD.
Fig. 3: Differential expression of the mineralocorticoid receptor and SGLT2 in kidney cells.

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Acknowledgements

This work was supported by the Fight-HF Avenir Investment Program (ANR-15-RHUS-0004), the Fondation de Recherche sur l’Hypertension Artérielle (REIN/NgalPA - 2017/2018) and the ANR NGAL-HT (ANR-19-CE14-0032-02).

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All authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

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Correspondence to Frederic Jaisser.

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G.L.B. is the principal investigator of FIDELIO (Bayer), serves on the steering committee of the FLOW trial (Novo Nordisk) and the CALM-2 trial (Vascular Dynamics), and is a consultant for Merck, Relypsa, Alnylam and KBP Biosciences. F.J. received research grants from AstraZeneca and Bayer SAS and honoraria from AstraZeneca, Bayer SAS and KBP Biosciences. The other authors declare no competing interests.

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Barrera-Chimal, J., Lima-Posada, I., Bakris, G.L. et al. Mineralocorticoid receptor antagonists in diabetic kidney disease — mechanistic and therapeutic effects. Nat Rev Nephrol 18, 56–70 (2022). https://doi.org/10.1038/s41581-021-00490-8

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