The effect of mineralocorticoid receptor antagonists (MRAs) on kidney outcomes may vary according to heart failure status, whereby patients with heart failure seem to experience no improvement of kidney outcomes with MRAs (both steroidal and nonsteroidal), which contrasts with patients with type 2 diabetes and albuminuric CKD who experienced improvement of kidney outcomes with the nonsteroidal MRA (nsMRA) finerenone.1 As hypothesized by ourselves and others,2 this difference in response to MRA therapy according to heart failure status may be related to (1) patients' characteristics, as heart failure trials included patients with and without type 2 diabetes, whereas CKD trials included only patients with type 2 diabetes and albuminuria; (2) the risk of kidney events, which is lower in heart failure when compared with albuminuric CKD; (3) the relatively short follow-up time of heart failure trials may not provide enough time for the drug to improve kidney outcomes; (4) the presence of more non–kidney-related competing risks in heart failure than in CKD; and (5) reduction of renal perfusion and increased venous pressures more characteristic of heart failure. Specifically, patients with heart failure seem to be prone to more pronounced hemodynamic changes with MRAs, which, in the context of nephrosclerosis, aging, and polypharmacy, impair kidney autoregulatory mechanisms and may lead to kidney hypoperfusion.3
However, a more uniform comparison between heart failure and CKD would be possible if circumscribed to patients with type 2 diabetes. In this regard, a recent report from the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; NCT04435626) trial focused on the effects of finerenone among patients with type 2 diabetes.4
Heterogeneity of Kidney Effects of Finerenone in Type 2 Diabetes by Heart Failure and CKD Status: Is Albuminuria the Key?
Finerenone has been tested in patients with type 2 diabetes and various degrees of kidney disease. In FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease; NCT02540993), 5764 patients with type 2 diabetes and CKD were included. The mean eGFR was 44±13 ml/min per 1.73 m2, and the median urinary albumin-to-creatinine ratio (UACR) was 852 (446–1634) mg/g. In FIGARO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease; NCT02545049), 7352 patients with type 2 diabetes and CKD were included. The mean eGFR was 68±22 ml/min per 1.73 m2, and the median UACR was 308 (108–740) mg/g. In FINEARTS-HF, 2764 patients had type 2 diabetes (46% of the total population). The mean eGFR was 60±20 ml/min per 1.73 m2, and the median UACR was 29.5 (10.0–131.0) mg/g.4 Therefore, on average, the FINEARTS-HF type 2 diabetes population exhibited a lower eGFR than that of FIGARO-DKD and higher eGFR than that of FIDELIO-DKD. However, FINEARTS-HF type 2 diabetes patients exhibited a much lower (10–30 times) average UACR than that of FIGARO-DKD and, particularly, FIDELIO-DKD. These striking differences in albuminuria levels raise the question of whether the observed differences in the effect of finerenone on kidney outcomes of patients with type 2 diabetes is related predominantly to the degree of albuminuria and not to heart failure.
Across all of these trials, a prespecified composite kidney end point was assessed, defined as the time to first occurrence of: a sustained 57% decline in eGFR from baseline, eGFR to <15 ml/min per 1.73 m2, initiation of maintenance dialysis, kidney transplantation, or death attributable to kidney causes,4–6 allowing the comparison of the same kidney end point among patients with type 2 diabetes with and without heart failure and across different levels of albuminuria.
In FIDELIO-DKD, over a median follow-up of 2.6 years, the composite kidney outcome was significantly lower in patients receiving finerenone (n=167; 5.9%) than in those receiving placebo (n=245; 8.6%), corresponding to event rates of 2.41 and 3.54 per 100 patient-year with a hazard ratio (HR) of 0.68 (95% confidence interval [CI], 0.55 to 0.82).5 In FIGARO-DKD, over a median follow-up of 3.4 years, the composite kidney outcome was significantly lower in patients receiving finerenone (n=108; 2.9%) than in those receiving placebo (n=139; 3.8%), corresponding to event rates of 0.95 and 1.23 per 100 patient-year with a HR of 0.76 (95% CI, 0.60 to 0.99).6 In FINEARTS-HF, over a median follow-up of 2.6 years, patients with type 2 diabetes in the finerenone group exhibited a higher number of adverse kidney events (n=28; 2.0%) compared with those receiving placebo (n=18; 1.3%), corresponding to event rates of 1.0 and 0.6 per 100 patient-year and a HR of 1.59 (95% CI, 0.88 to 2.89).4
In Figure 1A, we show a grading attenuation of treatment effect with finerenone (versus placebo) with lower albuminuria, with a pronounced point estimate 32% relative reduction in kidney events among patients with the highest albuminuria enrolled in FIDELIO-DKD, a less pronounced 24% relative reduction in kidney events among patients with intermediate levels of albuminuria enrolled in FIGARO-DKD, and a tendency toward a higher risk of kidney events among patients with the lowest levels of albuminuria enrolled in FINEARTS-HF. The treatment effect was well-correlated with UACR level, as shown in Figure 1B.
Figure 1.
Effect of finerenone versus placebo on kidney outcome across trials with graded albuminuria levels in type 2 diabetes. (A) FIDELIO-DKD, high albuminuria; FIGARO-DKD, intermediate albuminuria; FINEARS-HF, low albuminuria. (B) Bubble plot showing a linear correlation between albuminuria levels and treatment effect on kidney end point. The most pronounced benefit is present among patients with the highest albuminuria levels, and a tendency to worse kidney outcomes is present among patients with the lowest albuminuria levels. UACR, urinary albumin-to-creatinine ratio; kidney outcome, prespecified composite kidney end point defined as the time to first occurrence of any of the following: a sustained 57% decline in eGFR from baseline, eGFR to <15 ml/min per 1.73 m2, initiation of maintenance dialysis, kidney transplantation, or death attributable to kidney causes. CI, confidence interval; FIDELIO-DKD, Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease; FIGARO-DKD, Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease; FINEARTS-HF, Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; T2D, type 2 diabetes.
It should be noted that in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist; NCT00094302), with a median eGFR of 65 ml/min per 1.73 m2 and UACR of 27 mg/g, despite not reporting the above referred standardized kidney end point, the steroidal MRA spironolactone did not improve kidney outcomes in patients with insulin-treated type 2 diabetes and showed a tendency for a higher risk of episodes of serum creatinine ≥3.0 mg/dl.7
As stated above, previous reports suggested that the risk of kidney events and follow-up time could influence the (lack of) kidney outcome improvement in heart failure trials. However, as we may observe, despite a lower risk of kidney events in the placebo group of FINEARTS-HF, the risk of kidney events was similar with finerenone in FINEARTS-HF and FIGARO-DKD with annualized incidence rates of ≈1 event per 100 patient-year, throughout a comparable median follow-up time of ±2.6 years in both trials.
Importantly, patients using loop diuretics (a treatment that helps identify heart failure status in patients without a formal heart failure diagnosis) in FIDELIO-DKD and FIGARO-DKD experienced a similar kidney benefit with finerenone as those not using loop diuretics at baseline.8 Findings support the hypothesis that heart failure status is not the major driver in influencing the kidney effects of MRAs.
Hence, the explanation for different MRA effects on kidney outcomes cannot be fully explained by differences in patients' characteristics (here all have type 2 diabetes), follow-up time, or heart failure status. We therefore hypothesize that the main determinant of kidney benefit with MRAs (at least with the nsMRA finerenone) is the degree of albuminuria.
Why Is Albuminuria the Main Determinant of Kidney Benefit with MRAs?
In patients with type 2 diabetes and albuminuria, glomerular hyperfiltration is a well-established central mechanism in the progression of kidney disease, primarily driven by damage to the endothelial layer of the glomerular filtration apparatus. Moreover, proteinuria (including albuminuria) is a driver of CKD progression by direct toxicity to the proximal tubules, causing atrophy, inflammation, and fibrosis.9
Mineralocorticoid receptors (MR) are present in the kidneys, particularly in vascular endothelial cells. In this context, aldosterone acts through MR causing damage of the endothelial glycocalyx and, consequently, increasing albuminuria.10 The nsMRA finerenone slows the progression of kidney disease by antagonizing the deleterious effects of aldosterone in the kidneys, reducing endothelial damage, albuminuria, and kidney disease progression. Albuminuria is a marker of aldosterone excess and enhanced MR activity in the vascular endothelium indicating damage of the glomerular filtration barrier; therefore, nsMRAs slow the progression of kidney disease in patients with increased albuminuria because albuminuria is a marker of MR overactivation in capillary endothelial cells leading to podocyte injury and glycocalyx disruption in the kidneys.11 On the other hand, in patients without albuminuria, MRAs (both steroidal and nonsteroidal) may not slow the progression of kidney disease, as these patients may predominantly experience the hemodynamic changes in the kidneys without the benefits of endothelial barrier protection.
In conclusion, albuminuria is a marker of endothelial damage and MR overactivation by aldosterone in the kidneys. Therefore, nsMRAs improve kidney outcomes among patients with albuminuria, likely because MR overactivation plays a central role in the progression of kidney disease in this group, unlike in patients without albuminuria.
Acknowledgments
The content of this article reflects the personal experience and views of the author and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or JASN. Responsibility for the information and views expressed herein lies entirely with the authors.
Footnotes
J.P.F. and L.M. are co-first authors.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F420.
Author Contributions
Conceptualization: Joao Pedro Ferreira.
Formal analysis: Joao Pedro Ferreira.
Investigation: Luís Mendonça, Milton Packer.
Supervision: Milton Packer.
Writing – original draft: Joao Pedro Ferreira, Luís Mendonça.
Writing – review & editing: Joao Pedro Ferreira, Pedro Marques, Luís Mendonça, João Sérgio Neves, Milton Packer, Faiez Zannad.
Funding
None.
References
- 1.Vaduganathan M Filippatos G Claggett BL, et al. Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes. Nat Med. 2024;30(12):3758–3764. doi: 10.1038/s41591-024-03264-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Vaduganathan M Neuen BL McCausland F, et al. Why has it been challenging to modify kidney disease progression in patients with heart failure? J Am Coll Cardiol. 2024;84(22):2241–2245. doi: 10.1016/j.jacc.2024.08.034 [DOI] [PubMed] [Google Scholar]
- 3.Mendonça L, Neves JS, Testani J, Zannad F, Ferreira JP. MRAs, SGLT2 inhibitors and kidney outcomes in CKD and HF: differences in diseases, drugs, or both? JACC Heart Fail. 2025;13(8):102514. doi: 10.1016/j.jchf.2025.102514 [DOI] [PubMed] [Google Scholar]
- 4.Butt JH Jhund PS Henderson AD, et al. Finerenone, glycaemic status, and heart failure with mildly reduced or preserved ejection fraction: a prespecified analysis of the FINEARTS-HF trial. Eur J Heart Fail. 2025;27(7):1326–1341. doi: 10.1002/ejhf.3649 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bakris GL Agarwal R Anker SD, et al.; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. New Engl J Med. 2020;383(23):2219–2229. doi: 10.1056/NEJMoa2025845 [DOI] [PubMed] [Google Scholar]
- 6.Pitt B Filippatos G Agarwal R, et al.; FIGARO-DKD Investigators. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. New Engl J Med. 2021;385(24):2252–2263. doi: 10.1056/NEJMoa2110956 [DOI] [PubMed] [Google Scholar]
- 7.Huynh T Harty BJ Claggett B, et al. Comparison of outcomes in patients with diabetes mellitus treated with versus without insulin + heart failure with preserved left ventricular ejection fraction (from the TOPCAT study). Am J Cardiol. 2019;123(4):611–617. doi: 10.1016/j.amjcard.2018.11.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Mentz RJ Anker SD Pitt B, et al.; on behalf of the FIDELIO-DKD and FIGARO-DKD Investigators. Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by diuretic use: a FIDELITY analysis. Eur J Heart Fail. 2025;27(5):764–774. doi: 10.1002/ejhf.3569 [DOI] [PubMed] [Google Scholar]
- 9.Makhammajanov Z, Gaipov A, Myngbay A, Bukasov R, Aljofan M, Kanbay M. Tubular toxicity of proteinuria and the progression of chronic kidney disease. Nephrol Dial Transplant. 2024;39(4):589–599. doi: 10.1093/ndt/gfad215 [DOI] [PubMed] [Google Scholar]
- 10.Butler MJ Ramnath R Kadoya H, et al. Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx. Kidney Int. 2019;95(1):94–107. doi: 10.1016/j.kint.2018.08.024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Crompton M Ferguson JK Ramnath RD, et al. Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx. JCI Insight. 2023;8(5):e154164. doi: 10.1172/jci.insight.154164 [DOI] [PMC free article] [PubMed] [Google Scholar]