T h e ne w engl a nd jour na l o f medicine

E di t or i a l

Finerenone — Halting Relative Hyperaldosteronism in Chronic Kidney Disease

Julie R. Ingelfinger, M.D., and Clifford J. Rosen, M.D.

Type 2 diabetes is the most common cause of the mineralocorticoid receptor also functions as chronic kidney disease (CKD) and end-stage re- a transcription factor that can increase the levels nal disease. Cardiovascular risk and the risk of of inflammatory cytokines as well as genes tar- progression of kidney disease are very high geting water resorption.4 The mineralocorticoid among patients with diabetes mellitus, particu- receptor is present in the distal tubule of the larly among those with CKD. Clinical strategies kidney and also within glomeruli on podocytes to prevent cardiovascular disease and the devel- and mesangial cells. Mild hyperaldosteronism, opment of new diabetic kidney disease or to which occurs in patients with CKD, can also slow the progression of CKD that is already mediate inflammation through the mineralocor- present have been incorporated into clinical ticoid receptor, increasing local levels of reactive practice for the past three decades and include oxygen species and profibrotic factors. Thus, angiotensin-converting–enzyme inhibitors, angio- high levels of aldosterone and its receptor may tensin-receptor blockers and, more recently, affect multiple kidney compartments. sodium–glucose cotransporter 2 (SGLT2) inhibi- Strategies to decrease aldosterone activation tors (gliflozins), such as dapagliflozin and em- make sense, and drugs that interfere with the pagliflozin. However, few of the other drug binding of aldosterone to its receptor have been classes studied have ultimately proved renopro- used in a number of clinical conditions, particu- tective — witness, for example, the ultimately larly cardiovascular disease, for several decades. disappointing clinical trial experience with bar- Spironolactone, first synthesized in 1957, is a doxolone,1 aliskiren,2 and the erythrocyte stimu- steroidal, nonselective inhibitor of the mineralo- latory agent darbepoetin.3 corticoid receptor that is still widely used. The Aldosterone, a mineralocorticoid hormone, is steroidal, selective inhibitor eplerenone has been a downstream target of activation of the renin– available since the 1980s. Both of these steroidal angiotensin system (RAS) (reviewed in Barrera- mineralocorticoid receptor antagonists may lead Chimal et al.4 with respect to CKD). Angiotensin to hyperkalemia in a high proportion of patients II, corticotropin, and potassium are considered and have other unwelcome side effects, such as the main drivers of aldosterone release from the gynecomastia, erectile dysfunction, and dysmen- adrenal zona glomerulosa. However, other fac- orrhea. Furthermore, steroidal mineralocorticoid tors such as nitric oxide, endothelin, and a vari- receptor antagonists may decrease the glomeru- ety of pituitary and adipose-tissue factors can lar filtration rate (GFR). In contrast, the dihy- stimulate aldosterone synthesis. Once released, dropyridine finerenone is a selective inhibitor, as aldosterone binds to the mineralocorticoid re- are apararenone and esaxerenone, and less often ceptor, leading to sodium retention and potas- cause hyperkalemia. sium loss, thereby controlling fluid and electro- The use of mineralocorticoid receptor antago- lyte status as well as blood pressure. Furthermore, nists to affect CKD is a relatively recent concept.4

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In CKD, aldosterone levels are inversely propor- probably by reducing the activity of the mineralo- tional to the GFR and are also associated with corticoid receptor.10 Although the present trial inflammation. Although the evidence that antago- does not add mechanistic data, the concept nizing the mineralocorticoid receptor is benefi- seems apt, and the authors speculate that tissue cial in patients with cardiovascular disease has remodeling may explain the results. Phase 3 been known, evidence that such therapy helps in trials of the other dihydropyridine mineralo- patients with CKD is less robust. In a 2008 me- corticoid receptor antagonists are awaited. In ta-analysis, Bomback et al. observed that the use addition, trials that are longer term than the of mineralocorticoid blockers decreased protein- FIDELIO-DKD trial will be important. That being uria without resulting in hyperkalemia or de- said, a way to decrease the relative hyperaldoste- creasing the GFR.5 A recent small, randomized, ronism in patients with CKD seems a promising controlled trial by Minakuchi et al. compared strategy. eplerenone with placebo in patients with CKD Disclosure forms provided by the authors are available with and observed a benefit in terms of progression.6 the full text of this editorial at NEJM.org. The phase 2b Mineralocorticoid Receptor An- From Tufts University School of Medicine, Boston, and the tagonist Tolerability Study–Diabetic Nephropa- Center for Clinical and Translational Research, Maine Medical thy, which compared finerenone with placebo in Center Research Institute, Scarborough (C.J.R.). patients with type 2 diabetes and CKD, showed This editorial was published on October 23, 2020, at NEJM.org. an improved urinary albumin-to-creatinine ratio 7 1. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl (primary outcome). Phase 3 trials have been in type 2 diabetes and stage 4 chronic kidney disease. N Engl J widely anticipated. Med 2013; 369: 2492-503. Bakris et al. now report in the Journal the re- 2. Tang SCW, Chan KW, Ip DKM, et al. Direct Renin Inhibition in Non-diabetic chronic Kidney disease (DRINK): a prospective sults of the phase 3 Finerenone in Reducing randomized trial. Nephrol Dial Transplant 2020 July 2 (Epub Kidney Failure and Disease Progression in Dia- ahead of print). betic Kidney Disease (FIDELIO-DKD) trial.8 They 3. Haller H, Bertram A, Stahl K, Menne J. Finerenone: a new mineralocorticoid receptor antagonist without hyperkalemia: found a benefit of finerenone as compared with an opportunity in patients with CKD? Curr Hypertens Rep 2016; placebo with respect to CKD progression among 18: 41. patients with relatively advanced CKD and type 4. Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid re- ceptor antagonists and kidney diseases: pathophysiological basis. 2 diabetes and thus for persons at high risk for Kidney Int 2019; 96: 302-19. kidney-related (and heart-related) events. A car- 5. Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. diovascular benefit was evident early (as soon as Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic a month) and continued; the kidney-related ben- review. Am J Kidney Dis 2008; 51: 199-211. efit was seen after 1 year. However, the apparent 6. Minakuchi H, Wakino S, Urai H, et al. The effect of aldoste- benefit with respect to CKD progression was rone and aldosterone blockade on the progression of chronic kidney disease: a randomized placebo-controlled clinical trial. less than that reported with canagliflozin in the Sci Rep 2020; 10: 16626. recent Canagliflozin and Renal Events in Diabe- 7. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on tes with Established Nephropathy Clinical Evalu- albuminuria in patients with diabetic nephropathy: a random- 9 ized clinical trial. JAMA 2015; 314: 884-94. ation (CREDENCE) trial. One explanation for 8. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone the different findings in the two trials, as noted on chronic kidney disease outcomes in type 2 diabetes. N Engl J by Bakris et al., is the fact that SGLT2 inhibitors Med. DOI: 10.1056/NEJMoa2025845. 9. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal were allowed in the present trial, whereas pa- outcomes in type 2 diabetes and nephropathy. N Engl J Med tients treated with mineralocorticoid receptor 2019; 380: 2295-306. antagonists were excluded from the CREDENCE 10. Capelli I, Gasperoni L, Ruggeri M, et al. New mineralocorti- coid receptor antagonists: update on their use in chronic kidney trial. disease and heart failure. J Nephrol 2020; 33: 37-48. Data from laboratory models indicate that DOI: 10.1056/NEJMe2031382 finerenone decreases inflammation and fibrosis, Copyright © 2020 Massachusetts Medical Society.

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