Mineralocorticoid receptor antagonists

in diabetic kidney disease

Fellow 江哲甫

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 Outline
• Diabetic kidney disease
• Mechanism of mineralocorticoid receptor
activation
• Mineralocorticoid receptor antagonists
• Potential for combination therapies in DKD

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Diabetic kidney disease
Diabetic kidney disease
Mineralocorticoid receptor activation

仁心仁術 優質服務 團隊榮譽 追求卓越

Barrera-Chimal, J., Girerd, S. & Jaisser,
仁心仁術 優質服務F. Mineralocorticoid
團隊榮譽 追求卓越
receptor antagonists and kidney diseases: pathophysiological
basis. Kidney Int. 96, 302–319 (2019).
仁心仁術 優質服務 團隊榮譽 追求卓越
Profibrotic and pro-inflammatory roles
仁心仁術 優質服務 團隊榮譽 追求卓越
仁心仁術 優質服務 團隊榮譽 追求卓越
Barrera-Chimal, J., Girerd, S. & Jaisser,
仁心仁術 優質服務F. Mineralocorticoid
團隊榮譽 追求卓越
receptor antagonists and kidney diseases: pathophysiological
basis. Kidney Int. 96, 302–319 (2019).
 Use of MRAs to treat DKD
• Spirolactone in preclinical data

Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM,

Brown L. Reversal of cardiac and renal fibrosis by
仁心仁術 優質服務 團隊榮譽 追求卓越
pirfenidone and spironolactone in streptozotocin-diabetic
rats. Br J Pharmacol. 2001;133(5):687-694.
• Eplerenone

Guo, C. et al. Mineralocorticoid receptor antagonist reduces renal

仁心仁術 優質服務 團隊榮譽 追求卓越
injury in rodent models of types 1 and 2 diabetes mellitus.
Endocrinology 147, 5363–5373 (2006).
• AZD9977

Bamberg, K. et al. Preclinical pharmacology of AZD9977: a novel

仁心仁術 優質服務 團隊榮譽 追求卓越
mineralocorticoid receptor modulator separating organ protection
from effects on electrolyte excretion. PLoS ONE 13, e0193380 (2018).
• Finerenone

Lachaux, M. et al. Short- and long-term administration of the non-steroidal

mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-
related cardio-renal dysfunction. Diabetes Obes. Metab. 20, 2399–2407 (2018).
Epstein M, Kovesdy CP, Clase CM, Sood MM, Pecoits-Filho R.
Aldosterone, Mineralocorticoid Receptor Activation, and CKD: A
Review of Evolving Treatment Paradigms. Am J Kidney Dis.
2022;80(5):658-666.
仁心仁術 優質服務 團隊榮譽 追求卓越
(MIRAD)
(FIDELIO-DKD)
Cardiovascular outcome
 Risk of hyperkalaemia with MRAs
• Pre-dialysis (CKD 3-4)
• eGFR < 45 ml/min/1.73m2
• baseline serum K >4.5 mEq/l

Yang, C. T., Kor, C. T. & Hsieh, Y. P. Long-term effects of spironolactone

仁心仁術 優質服務 團隊榮譽 追求卓越
on kidney function and hyperkalemia- associated hospitalization in
patients with chronic kidney disease. J. Clin. Med. 7, 459 (2018).
 Risk of hyperkalaemia with MRAs
• Dialysis patients
• 25 mg/d spironolactone regime was safe and well
tolerated (Spin-D, MiREnDa)
• Ongoing trials:
• Aldosterone bloCkade for Health Improvement
EValuation in End-stage renal disease (ACHIEVE;
NCT03020303)
• The Aldosterone Antagonist Chronic Hemodialysis
Interventional Survival Trial (ALCHEMIST;
NCT01848639)
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 Prevention strategies
• Potassium monitoring
• Patient education
• Dietary counselling
• Avoidance of polypharmacy
• Use of potassium binders

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 Combination therapies in DKD
• MRAs + ACEI/ARBs
• MRAs + SGLT2i

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Modes of action of SGLT2i and MRAs
Modes of action of SGLT2i and MRAs
Kolkhof, P. et al. Effects of finerenone combined with empagliflozin
仁心仁術 優質服務 團隊榮譽 追求卓越
in a model of hypertension-induced end-organ damage. Am. J.
Nephrol. 52, 642–652 (2021).
 Take home message
• Renal hemodynamics changes, oxidative stress, inflammation,
hypoxia and overactive renin-angiotensin-aldosterone system
(RAAS) are involved in the pathogenesis of DKD.
• 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.
• Promising novel non-steroidal MRAs have been developed. Such
as finerenone reduced CKD progression and improved CV
outcomes in FIDELIO-DKD trial.
• Potential additive renoprotective effect of MRAs and SGLT2i
requires more clinical data.
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 Reference
• The Kidney: Brenner and Rector’s, 11 Edition 2020
• Lin YC, Chang YH, Yang SY, Wu KD, Chu TS. Update of pathophysiology and management of diabetic
kidney disease. J Formos Med Assoc. 2018;117(8):662-675.
• Barrera-Chimal J, Lima-Posada I, Bakris GL, Jaisser F. Mineralocorticoid receptor antagonists in diabetic
kidney disease - mechanistic and therapeutic effects. Nat Rev Nephrol. 2022;18(1):56-70.
• Rossier, B. C., Baker, M. E. & Studer, R. A. Epithelial sodium transport and its control by aldosterone:
the story of our internal environment revisited. Physiol. Rev. 95, 297–340 (2015).
• Barrera-Chimal, J., Girerd, S. & Jaisser, F. Mineralocorticoid receptor antagonists and kidney diseases:
pathophysiological basis. Kidney Int. 96, 302–319 (2019).
• Epstein M, Kovesdy CP, Clase CM, Sood MM, Pecoits-Filho R. Aldosterone, Mineralocorticoid Receptor
Activation, and CKD: A Review of Evolving Treatment Paradigms. Am J Kidney Dis. 2022;80(5):658-666.
• Ferreira NS, Tostes RC, Paradis P, Schiffrin EL. Aldosterone, Inflammation, Immune System, and
Hypertension. Am J Hypertens. 2021;34(1):15-27.
• Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM, Brown L. Reversal of cardiac and renal fibrosis
by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol. 2001;133(5):687-
694.
• Guo, C. et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1
and 2 diabetes mellitus. Endocrinology 147, 5363–5373 (2006).

仁心仁術 優質服務 團隊榮譽 追求卓越

 Reference
• Bamberg, K. et al. Preclinical pharmacology of AZD9977: a novel mineralocorticoid receptor modulator
separating organ protection from effects on electrolyte excretion. PLoS ONE 13, e0193380 (2018).
• Lachaux, M. et al. Short- and long-term administration of the non-steroidal mineralocorticoid receptor
antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction. Diabetes Obes.
Metab. 20, 2399–2407 (2018).
• Lachaux, M. et al. Short- and long-term administration of the non-steroidal mineralocorticoid receptor
antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction. Diabetes Obes.
Metab. 20, 2399–2407 (2018).
• Yang, C. T., Kor, C. T. & Hsieh, Y. P. Long-term effects of spironolactone on kidney function and
hyperkalemia- associated hospitalization in patients with chronic kidney disease. J. Clin. Med. 7, 459
(2018).
• Kolkhof, P. et al. Effects of finerenone combined with empagliflozin in a model of hypertension-
induced end-organ damage. Am. J. Nephrol. 52, 642–652 (2021).
• Shen, L. et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an
analysis of DAPA-HF. JACC Heart Fail. 9, 254–264 (2021).
• Ferreira, J. P. et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart
failure: EMPEROR-Reduced. J. Am. Coll. Cardiol. 77, 1397–1407 (2021).

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