Overview of the safety, efficiency, and potential mechanisms of finerenone for diabetic kidney diseases

Diabetic kidney disease (DKD) is a common disorder with numerous severe clinical implications. Due to a high level of fibrosis and inflammation that contributes to renal and cardiovascular disease (CVD), existing treatments have not effectively mitigated residual risk for patients with DKD. Excess activation of mineralocorticoid receptors (MRs) plays a significant role in the progression of renal and CVD, mostly by stimulating fibrosis and inflammation. However, the application of traditional steroidal MR antagonists (MRAs) to DKD has been limited by adverse events. Finerenone (FIN), a third-generation non-steroidal selective MRA, has revealed anti-fibrotic and anti-inflammatory effects in pre-clinical studies. Current clinical trials, such as FIDELIO-DKD and FIGARO-DKD and their combined analysis FIDELITY, have elucidated that FIN reduces the kidney and CV composite outcomes and risk of hyperkalemia compared to traditional steroidal MRAs in patients with DKD. As a result, FIN should be regarded as one of the mainstays of treatment for patients with DKD. In this review, the safety, efficiency, and potential mechanisms of FIN treatment on the renal system in patients with DKD is reviewed.


Introduction
Chronic kidney disease (CKD) is a significant global public health challenge characterized by persistent abnormalities in kidney structure or function such as albuminuria, abnormal urinary sediment and decreased estimated glomerular filtration rate (eGFR) for at least three months, with associated symptomology (1,2).It is a major contributor to morbidity and mortality on a world scale, with a reported prevalence of 9.1% in 2017 (3).CKD is anticipated to rank as the fifth-leading cause of death around the world by 2040 and the second-cause of death before the end of the century in countries with extended life expectancies (4).Over 850 million individuals worldwide have CKD, acute kidney injury (AKI), and are receiving renal replacement therapy (5).The prevalence has been increasing with serious and significant implications for public health and society attributed to disease burden, complications leading to cardiovascular (CV) morbidity, excess mortality, and costs associated with managing kidney failure (3).
Among a broad range of etiologies, diabetes has emerged as the primary cause of CKD globally, with an grown risk of disease progression, CV events, and mortality (6,7).About 40% of individuals diagnosed with type 2 diabetes (T2D) are susceptible to the development of diabetic kidney disease (DKD), a condition that may progress to end-stage kidney disease (ESKD) and subsequently contribute to the burden of CV disease (CVD) (8)(9)(10)(11)(12)(13).The mortality rate of DKD exceeds that of diabetes alone or CKD without diabetes by more than two-fold (14,15).The coexistence of diabetes and CKD has been demonstrated to shorten the average life expectancy by about 16 years, representing a major challenge for society and public health systems all over the world (14).Therefore, new strategies that not only protect the kidney but also reduce the risk of CV events development should be imperatively taken into account in patients with DKD.
While renin-angiotensin system (RAS) blockers (e.g., angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB)) and sodium-glucose co-transporters-2 inhibitors (SGLT2i) have shown beneficial renal and CV effects in DKD patients by targeting hemodynamic and metabolic drivers of CKD progression (35)(36)(37)(38)(39)(40), they inadequately address the inflammation and fibrosis driven by MR overactivation, leading to a persistent high residual risk of CKD progression and CV events development, even in response to combined treatment by these two therapies (9,13,37,38,41).Therefore, a comprehensive approach is imperative to address the broader pathogenesis of DKD patients, including increased fibrosis and inflammation (25,32,(42)(43)(44).Given this context, it is evident that MR antagonists (MRAs) play a pivotal role in the prevention of fibrosis and inflammation in both the renal and CV systems.
At the renal level, MR blockage significantly reduces albuminuria and promotes the preservation of renal function (32,(45)(46)(47).In the past years, classical steroidal MRAs like firstgeneration spironolactone and second-generation eplerenone, while potentially beneficial for nephroprotection and cardioprotection, are hindered by the risk of hyperkalemia and other progestogenic and antiandrogenic adverse effects (AEs) such as breast tenderness, gynecomastia, erectile dysfunction in men, and menstrual irregularities in premenopausal women, particularly in patients with DKD (48)(49)(50)(51)(52)(53)(54)(55).The risk of hyperkalemia can escalate up to 8-fold in patients with moderate-to-severe CKD using steroidal MRAs (53,56).While these AEs are not typically lifethreatening, they can undermine treatment adherence and persistence, with roughly half of the patients discontinuing MRAs and 10% of patients continuing at reduced dose due to hyperkalemia (54).The conundrum of possessing effective therapies but not employing them due to safety concerns has prompted substantial efforts over the past two decades to develop novel MRAs with improved safety profiles.Now, the emergence of the nonsteroidal MRAs (NS-MRAs) with an improved benefit-risk profile, exemplified by finerenone (FIN), offers a new opportunity for MRAs in DKD (57).To overcome the inherent limitations of steroidal MRAs by achieving high MR specificity and a balanced distribution between cardiac and renal tissues, FIN, a novel, nonsteroidal, selective, and potent third-generation MRA with enhanced antifibrotic and antiinflammatory properties and a reduced incidence of hyperkalemia compared to traditional MRAs, is currently the most studied and has received approved for the treatment of DKD (58-61).An array of preclinical and clinical studies has substantiated the efficacy and safety of FIN in conferring renal and CV benefits.
On these grounds, this review aims to elucidate the molecular mechanisms of FIN and provide insights into its efficacy and safety across the spectrum of DKD patients, including those with and without a history of CVD.

Physiological and pathophysiological roles of MR in the kidney
The primary physiological role of the MR, found in the epithelial cells of the kidney and colon, is to regulate water and electrolyte balance (62).However, MR is also present in non-epithelial cells within the kidney and various extrarenal tissues, including the heart and vasculature (63).Upregulation of MR in these non-epithelial cells in the heart and kidney leads to increased transcription of profibrotic genes such as transforming growth factor-b-1 (TGF-b1), connective tissue growth factor, plasminogen activator inhibitor-1 (PAI-1), and various extracellular matrix proteins including fibronectin and collagens, all of which are associated with renal and cardiac fibrosis (33).Additionally, there is a positive correlation between elevated levels of serum aldosterone and an increased susceptibility to renal failure in both diabetic and non-diabetic individuals (64).Accumulating evidence indicates that the activation of MR is linked to injury in podocytes through various mechanisms.These mechanisms include the involvement of Ras-related C3 botulinum toxin substrate 1 (Rac1), the reduction of autophagy which is crucial for podocyte maintenance, and an increase in NADPH oxidases (NOX) activity resulting in oxidative stress and further leads to the upregulation of a cascade of proinflammatory cytokines and profibrotic proteins (65).Subsequently, development of albuminuria, reduced renal blood flow, and AKI lead to the progression of chronic renal interstitial inflammation and fibrosis (65, 66).Thus, MRAs may potentially delay the progression of CKD irrespective of its underlying cause (64).Accordingly, although blocking MR in non-epithelial cells has a positive impact, blockade of MR in epithelial cells increases the risk of hyperkalemia.The contrasting roles of MR in physiological and pathobiological processes need careful consideration of their interplay when implementing medication.
3 Effect of FIN on renal reactive oxygen species, inflammation and fibrosis

Renal ROS
In the renal context, the overactivation of MR leads to an increased presence of ROS through the upregulation of NOX (67-69).These superoxide radicals have the potential to disrupt the normal functioning of both the renal vasculature and tubules.Additionally, hydrogen peroxide, another byproduct of this process, contributes to dysfunction, particularly in the preglomerular region (67-69).Nitric oxide (NO) bioavailability and increased oxidant damage are linked to ischemia in renal IR injury-inducing AKI (70).The generation of oxidative stress is decreased by the pharmacologic use of FIN or the genetic removal of MR in smooth muscle cells (SMCs) (71).In both mice (71) and rats (72), FIN has been demonstrated to suppress the expression of markers of tubular injury in the kidney, such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) (Table 1).It has also been shown that after renal IR damage, FIN normalizes pathophysiologic elevations in the oxidative stress markers like malondialdehyde and 8hydroxyguanosine (Figure 1) (72).

Renal inflammation
In a murine knockout model of glomerulonephritis, it was observed that signaling of the MR in myeloid cells contributes to the progression of renal injury (29).One possible protective effect of MR knockout on myeloid cells against renal damage is a reduction in the recruitment of neutrophils and macrophages (29).The decrease in leukocytes was associated with the downregulation of pro-inflammatory markers' gene expression, such as tumor necrosis factor-a (TNF-a), matrix metalloproteinase (MMP)-12, inducible NO synthase, and C-C motif chemokine ligand 2 (CCL-2) (29).
Recruitment of macrophages is crucial during both the injury and repair phases after a kidney ischemia event (74).Activation of MR in monocytes tends to polarize macrophages toward an "inflammatory M1" phenotype (75).The rationale for utilizing MRAs to impede the progression from AKI to CKD is supported by the fact that MR inhibition via FIN promotes increased expression of interleukin (IL)-4 receptor in murine kidney IR models, subsequently facilitating the polarization of macrophage toward an M2 phenotype (27).This shift is accompanied by decreased macrophage mRNA expression of the proinflammatory cytokine TNF-a and the M1 macrophage marker IL-1b (27).Additionally, there is a reduction in the inflammatory population of CD11b + , F4/80 + , and Ly6C high macrophages (27).In uninephrectomized (UNX) DOCA-treated mice, the downregulation of kidney retinoid-related orphan receptor (ROR) gamma t-positive T-cells, along with a significant reduction in UACR, demonstrates significant renal protection in response to FIN treatment (76).Notably, MR antagonism by FIN can modulate inflammation as indicated by its ability to reduce proinflammatory cytokines like IL-6 and IL-1ß following renal ischemic damage (27).Furthermore, FIN has been shown to lower the expression of renal NGAL (71, 72), which is released during systemic inflammation by neutrophils and in response to tubular injury by renal tubular cells ( 7 1 , 7 2 ).The p ro-in fl am ma to ry c yt ok in e mo noc y t e chemoattractant protein-1 (MCP-1) is also reduced by FIN in the DOCA-salt model of cardiorenal end-organ damage (77).Both NGAL and MCP-1 play significant roles in the progression of human CKD (78,79).Renal osteopontin (OPN) expression was also decreased in a DOCA-salt rat CKD model following FIN treatment (77).OPN is believed to regulate various aspects of renal fibrogenesis, including fibroblast proliferation, macrophage activation and infiltration, cytokine secretion, and extracellular matrix production.It is associated with CKD progression, with elevated plasma levels detected in the early stages of CKD (80).FIN also offers protection against podocyte damage in a murine model of CKD progression in T2D (UNX mice with T2D fed a HS diet), as indicated by reduced production of fibronectin and inflammatory markers such as MCP-1 and PAI-1 in glomeruli (Figure 1) (81).

Renal fibrosis
The development of kidney fibrosis is a critical factor in the progression of CKD and eventual renal failure, as it disrupts the structural integrity of renal tubules and adjacent blood vessels.Studies conducted on individuals with kidney diseases have identified pro-fibrotic cytokines like TGF-b, MCP-1, and MMP-2 as potential biomarkers for fibrosis development, which have been correlated with worsening renal function (WRF) (82).Additionally, plasma levels of PAI-1 have showed moderate correlations with fibrosis observed in biopsies (82).To investigate the role of MR in fibrosis development and CKD progression, as well as the effectiveness of FIN in mitigating renal fibrosis, various preclinical models have been employed.In the DOCAsalt rat model of CKD, FIN treatment led to a reduction in renal mRNA expression of the pro-fibrotic marker PAI-1 and a decrease in renal fibrosis as evaluated through histopathology (77).The study revealed that the administration of FIN had a dose-dependent effect in diminishing the upregulation of mRNA expression of MMP-2, which serves as a significant indicator of tissue remodeling (77).In a rat model of hypertensive cardiorenal disease, FIN also attenuated renal fibrosis and reduced the production of pro-fibrotic collagen type I a 1 chain (COL1A1) in the kidney (83).Moreover, FIN dose-dependently suppressed pathologic myofibroblast accumulation and collagen deposition in a mouse model of renal fibrosis, irrespective of changes in systemic blood pressure or inflammatory markers (84).The levels of the fibrotic biomarkers PAI-1 and naked cuticle homolog 2 (NKD2) were concomitantly decreased in the kidneys (84), with recent reports identifying NKD2 as a specific marker for myofibroblasts in human renal fibrosis (85).In a chronic CKD rat model characterized by renal dysfunction, elevated proteinuria, and extensive tubule-interstitial fibrosis, treatment with FIN effectively limited collagen deposition and fibrosis in the kidney, as confirmed through histopathological assessments (72).FIN also inhibited the upregulation of the pro-fibrotic cytokine TGF-b and collagen-I expression in the kidneys (72).Likewise, in a mouse CKD model featuring unilateral, IR-induced tubulo-interstitial fibrosis, FIN administration resulted in a significant reduction in the severity of renal fibrosis (27) (Figure 1 and Table 1).

Renal protection of FIN in animal models
The efficacy of FIN for renal protection in animal experiments has been evaluated in recent years (Table 1).Kolkhof et al. (77) found that FIN consistently protects from functional as well as structural end-organ damage in kidneys with a reduced risk of electrolyte disturbances in the 10-week rat deoxycorticosterone acetate (DOCA)/salt model in a dose-dependent manner, with the most significant effect at 10 mg/kg•d.Histological analyses indicated that when compared at equinatriuretic doses, FIN outperformed eplerenone in reducing proteinuria and alleviating glomerular, tubular, and vascular damage (77).Similarly, Luettges et al. (76) conducted experiments highlighting FIN's protective effects against functional and morphological renal damage and its ability to exert antihypertensive actions in mice subjected to the DOCA-Salt model.In a rodent model transitioning from AKI to CKD, FIN demonstrated efficacy in preventing AKI induced by ischemiareperfusion (IR) and the subsequent chronic and progressive deterioration of kidney function and structure (27, 71, 72).These long-term protective effects of FIN were also observed in a preclinical model involving large white pigs (71).Furthermore, prophylactic FIN administration efficiently prevented increased plasma creatinine, urea, and proteinuria (27, 71, 72).Current investigations have unveiled the favorable impact of FIN on both arterial distensibility and albuminuria in the munich Wistar frömter (MWF) CKD model (45, 46).In uninephretomized db/db mice fed a HS diet, Hirohama et al. (81) reported that FIN ameliorated albuminuria, associated with reduced BP and glomerular injury.Nevertheless, in ZSF1 rats with diabetes, the administration of FIN did not significantly affect kidney function but did reduce renal hypertrophy (86).

Renal protection of FIN in clinic
The efficacy and safety profiles of FIN were evaluated in 4 phase II trials in patients with CVD and kidney disease within the ARTS program and 2 phase III trials in patients with DKD (Table 2) (Figure 2) (87-92).

Clinical efficacy of FIN treatment for patients with CKD and T2D
The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN), a pioneering multicenter, phase II clinical trial investigating the use of FIN in combination with a RAS inhibitor in individuals with DKD exhibited significant reductions in albuminuria and enhancements in the urine albumin-creatinine ratio (UACR) after 90 days of treatment with FIN (7.5-20 mg/day) in comparison to a placebo (91).The results of the ARTS-DN Japan trial, which included 96 Japanese patients with DKD receiving a RAS inhibitor, support those of ARTS-DN (92).Detailed dose-exposure-response modeling and simulation, encompassing an analysis of both ARTS-DN and ARTS-DN Japan, suggested that the effects of FIN were predominantly saturated at a dosage of 20 mg, with both 10 mg and 20 mg administered once daily proving to be safe and effective in reducing albuminuria (93).Furthermore, there were no discernible differences in the incidence of a 30% decrease in eGFR between the treatment groups (91).
Certainly, the most comprehensive insights into the advantages of FIN in individuals with DKD have been garnered through pivotal phase III clinical trials: FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) (88); FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) (87); and the predefined combined analysis known as FIDELITY (Combined FIDELIO-DKD and FIGARO-DKD Trial program analysis) (94).
FIDELIO-DKD, a multicenter, double-blind randomized controlled trial (RCT), has furnished the initial clinical evidence affirming that MR blockade yields improvements in kidney outcomes for patients with DKD (88).This study included 5734 adults with DKD who were already receiving the maximum tolerated doses of an ACEI or ARB and maintained a serum potassium concentration of 4.8 mmol/ L (88).Eligible patients had a UACR 30-<300 mg/g, an eGFR of 25-<60 ml/min/1.73m 2 , and diabetic retinopathy, or they had a UACR of 300-5000 mg/g and an eGFR of 25-<75 ml/min/1.73m 2 (88).Following a median follow-up of 2.6 years, the results of the FIDELIO-DKD study exhibited a significantly lower incidence of the primary composite outcome, encompassing kidney failure, a sustained eGFR decline of ≥40% from baseline, or death from renal causes in the FIN group compared to the placebo group (17.8% vs. 21.1%)(88).At the 4-month post-treatment mark, UACR demonstrated a 31% reduction compared to the placebo group, with this difference persisting throughout the trial (88).A secondary model-based analysis of FIDELIO-DKD showed that the early UACR effect of FIN was predictive of its long-term impact on eGFR decline, and these effects were found to be independent of the concurrent use of SGLT2i (95).Furthermore, FIN achieved a placebo-subtracted reduction of 14% in the crucial secondary composite outcome, encompassing CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for heart failure (HF) (88).In a secondary analysis of the FIDELIO-DKD trial, FIN was shown to reduce the risk of newly diagnosed atrial fibrillation/flutter compared to placebo, irrespective of a history of atrial arrhythmias at baseline (3.2% vs. 4.5%) (96).
Similarly, in the next major phase III FIGARO-DKD clinical trial (87), which enrolled 7437 adults with DKD across a wider range of CKD stages (a UACR of 30-<300 mg/g and an eGFR of 25-90 mL/ min/1.73m 2 or a UACR of 300-5000 mg/g and an eGFR of≥60 ml/ min/1.73m 2 ) already treated with maximum tolerated doses of an ACEI or ARB and maintaining a serum potassium concentration less than 4.8 mmol/L, a notable 13% reduction in the composite primary outcome, comprising CV death, nonfatal stroke, nonfatal MI, or hospitalization for HF, was observed after a mean follow-up of 3.4 years (87).While a lower incidence rate for the eGFR ≥40% kidney composite endpoint was noted with FIN compared to placebo, it did not reach statistical significance (P = 0.069).Nevertheless, a greater treatment effect was noted on the eGFR ≥57% kidney composite endpoint, with a 36% relative risk reduction for ESKD (P = 0.041) (87).FIN achieved a 32% greater reduction in UACR from baseline to 4 months compared to placebo (87), and its impact on kidney outcomes was particularly pronounced in patients with significantly elevated albuminuria as opposed to those with moderately increased albuminuria (97).An analysis derived from the FIGARO-DKD study emphasizes the importance of albuminuria screening in T2D patients, as early initiation of treatment effectively mitigated the risk of CV events and albuminuria progression in individuals with moderately elevated albuminuria (98).
The outcomes of the FIDELITY study, which pooled data from FIDELIO-DKD and FIGARO-DKD involving over 13,000 patients, revealed significant reductions associated with FIN, including a 23% reduction in the risk of kidney composite events (renal failure, >57% eGFR reduction, and renal disease-related death), a 20% reduction in dialysis initiation, a 32% reduction in UACR from baseline to 4 months, a 14% reduction in the primary composite CV outcome, and a 22% reduction in HF hospitalizations compared to placebo (94).Moreover, it's worth emphasizing that FIN induced a modest reduction in mean systolic BP at 4 months (3.2mmHg vs. 0.5 mmHg increase with placebo) in the FIDELITY pooled analysis (94).While it did not exhibit significant differences between groups in the whole population from both FIDELIO-DKD and FIGARO-DKD, a FIDELITY post hoc analysis of a subgroup of patients with treatment-resistant hypertension showed a significant differences of the least squares mean change in office systolic BP between FIN and placebo groups during the first 4 months (−7.1 mmHg vs. −1.3mmHg, respectively) (P <.0001) (99).Meanwhile, the cardiorenal effects of FIN do not seem to be primarily mediated by its antihypertensive properties, as the impact on BP was minimal compared to spironolactone (94,99).There is no evidence suggesting a correlation between the antialbuminuric effects of FIN and changes in BP.
Further analyses demonstrate that FIN provides robust renal and CV efficacy and safety benefits across the spectrum of DKD (100,101).FIN consistently showed improvements in indicators of kidney injury, as evidenced by a reduction in UACR and function, with better preservation of eGFR in the chronic phase, compared to placebo in patients with stage 4 CKD (101).However, the effect of FIN on the composite kidney outcome in patients with stage 4 CKD exhibited inconsistencies between early and late years of follow-up, with a notable loss of precision over time (101).A recent study included nine patients with advanced DKD with an eGFR below 25 mL/min/1.73m 2 revealed that FIN caused a significantly slower decline in eGFR in patients with advanced DKD, thus providing initial evidence that FIN is effective across a wide range of renal functions (102).As such, further large-scale investigation will be necessary to confirm the efficacy and safety of FIN in DKD patients with an eGFR below 25 mL/min/1.73m 2 .Furthermore, some FIDELITY analyses emphasize the benefits of early treatment initiation and co-administration of potassiumbinding agents to maximize the protective effects of FIN in individuals with DKD (100,103).FIN improved cardiorenal outcome in patients with DKD, regardless of baseline HbA1c (94,104,105), HbA1c variability ( 104), diabetes duration ( 104), baseline insulin use (104,105), baseline HF history (106, 107), prevalent atherosclerotic CVD (108), and history of atrial fibrillation/flutter at baseline (96).Additionally, it is worth noting that the antihypertensive effect of adding FIN to a maximally tolerated dose of ACEI or ARB was relatively modest (87,88).
In conclusion, these results suggest that in patients with DKD, FIN may be an effective treatment for kidney and CV protection.In fact, FIN has been approved by the U.S. Food and Drug Administration (FDA) in 2021 to reduce the risk of sustained eGFR decline, ESKD, nonfatal MI, hospitalization for HF, and CV death in adults with DKD (109).In addition, the European Medicines Agency (EMA) authorized the marketing of FIN for routine clinical use in patients with DKD on 16 February 2022 (110).Recently published guidelines from the American Diabetes Association (ADA) (111)(112)(113), the American Association of Clinical Endocrinology (AACE) (114) and the updated Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group (112, 115) recommend the addition of the oral NS-MRAs FIN to standard treatment in patients with DKD (Figure 2).

Clinical efficacy of FIN treatment for patients with CVD and kidney disease
The phase IIa study known as Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) (89) represents the inaugural RCT of FIN.It encompassed both a double-blind placebo group and an open-label spironolactone comparison group and targeted individuals with heart failure with reduced ejection fraction (HFrEF) along with mild or moderate CKD.This study established safe dosing of FIN and demonstrated that FIN exhibited equivalent or greater reductions in albuminuria and Nterminal pro-B-type natri (89) uretic peptide (pro-BNP) levels compared to spironolactone.The study results indicated that individuals receiving FIN (10 mg q.d.) showed a significant smaller decrease in eGFR than those receiving spironolactone at visit 7 (day 29 + 2) (-2.69 vs. -6.70ml/min/1.73m 2 ) (P ¼ 0.0002-0.0133)(89).
In the phase IIb ARTS-Heart Failure (ARTS-HF) study ( 90), which included 1066 patients diagnosed with HFrEF and T2D and/ or CKD, there was a notable indication of benefit associated with FIN.Specifically, there was a significant reduction in the composite clinical outcome, which included events such as all-cause mortality, CV hospitalization, or emergency admissions due to worsening HF, among patients treated with FIN in comparison to those receiving eplerenone.A recent prespecified analysis of FIGARO-DKD indicated that FIN reduced the risk of developing HF independent of a history of HF (107).These findings suggest that FIN may offer valuable prospects as a treatment option for patients with heart failure with preserved ejection fraction (HFpEF), particularly those who also have T2D and/or CKD.

The safety of FIN treatment
Even though FIN has beneficial effects on renal outcomes, the safety of FIN therapy is important and is an essential precondition for clinical application.AEs associated with using FIN include the risk of hyperkalemia, renal insufficiency and sex hormoneassociated AEs.
The safety profile of FIN underwent thorough investigation within an extensive phase II clinical trial program, encompassing over 2000 patients who had HFrEF, CKD, and/or T2D or with DKD (Table 2) (89)(90)(91).In the ARTS study, it was evident that the mean rise in serum potassium levels over a 28-day period was significantly lower in all four dosage groups of FIN when compared to the spironolactone group (0.04 to 0.30 vs. 0.45 mmol/L, respectively) and there was lower incidence of hyperkalemia with FIN vs spironolactone (5.3% vs 12.7%, p = 0.048) (89).In the ARTS-HF study, the mean increase in serum potassium from baseline to Day 90 was greater in the eplerenone group than in the FIN groups (90).Hyperkalemia, defined as a serum potassium elevation exceeding 5.6 mmol/L, was observed in 4.3% of patients, with the incidence of hyperkalemic events and treatment-emergent AEs (TEAEs) being similar in both the FIN and eplerenone groups (90).Within the ARTS-DN trial, permanent discontinuation of the medication due to hyperkalemia was not reported in the placebo group or the FIN 10 mg/day group.However, it occurred in 2.1%, 3.2%, and 1.7% of patients randomized to the FIN 7.5 mg/day, 15 mg/day, and 20 mg/ day groups, respectively (91).Secondary safety outcomes, including a decline in eGFR of ≥30% and the incidence of other serious AEs, did not exhibit significant differences between the various treatment groups (91).In summary, these phase II trials collectively demonstrate that hyperkalemia does not serve as a substantial impediment to the utilization of FIN for renal protection (89)(90)(91).
With respect to the safety profile in the FIDELIO-DKD phase III trial (88), it is noteworthy that FIN treatment was generally welltolerated, and the distribution of AEs was comparable between the FIN and placebo groups.It is worth mentioning that the incidence of serum potassium levels exceeding 5.5 mmol/L was higher in the FIN group compared to the placebo group (21.7% vs. 9.8%), and hyperkalemia-related AEs occurred at a double rate in FIN-treated patients compared to those receiving placebo (18.3% vs. 9.0%).However, it's important to highlight that severe hyperkalemiarelated AEs necessitating hospitalization were infrequent (1.4% vs. 0.3%), and there were no reported fatalities directly attributed to hyperkalemia.Permanent discontinuation of the medication was observed in 2.3% of patients in the FIN group and 0.9% in the placebo group.A secondary model-based analysis of FIDELIO-DKD revealed that higher FIN doses were linked to lower serum potassium levels and reduced incidences of hyperkalemia, guided by serum potassium-based dose adjustments (116).Additionally, FIN exhibited a lower risk of AEs related to sex hormones (117).In the FIGARO-DKD trial (87), the incidence of overall AEs and the risk of serious AEs leading to discontinuation were similar between the FIN and placebo groups.Although the occurrence of severe hyperkalemia was slightly higher with FIN than placebo (0.7% vs. 0.1%), it is noteworthy that no fatal hyperkalemia events were reported.The discontinuation rate due to hyperkalemia was also higher with FIN compared to placebo (1.2% vs. 0.4%, respectively).However, none of the hyperkalemia-related AEs resulted in fatalities.In the FIDELITY pooled analysis (94), 18.5% of patients who got FIN experienced treatment-related AEs, compared to 13.3% of patients who received a placebo, with AEs leading to treatment discontinuation occurring in 6.4% vs. 5.4% of patients, respectively.Hyperkalemia was more common with FIN than with placebo (14% vs. 6.9%).Hospitalizations due to hyperkalemia (0.9% and 0.2%, respectively) were minimal, and the incidence of hyperkalemia leading to permanent treatment discontinuation was low across study arms but occurred more frequently with FIN (1.7%) than with placebo (0.6%).However, no hyperkalemiarelated AEs were fatal.The incidence of TEAEs was comparable between the FIN and placebo groups, and there were no notable increases in AEs related to sex hormones or AKI compared to the placebo group.Regarding patients with CKD stage 4, the safety profile of FIN in individuals with T2D remained consistent with that of CKD stages 1 to 3. A FIDELITY post hoc analysis showed that FIN was related to a lower risk of hyperkalemia compared with spironolactone with/without a potassium-binding agent (99).
In conclusion, FIN appeared safe and effective in most clinical studies (Table 2).Nevertheless, baseline eGFR and serum potassium levels should be evaluated before initiation of FIN, and periodic measurement of serum potassium should still be performed during treatment with FIN, and the dose adjusted as needed.Additionally, implementing dietary interventions, avoiding agents that have the potential to induce hyperkalemia (118), correcting metabolic acidosis, and using potassium-lowering drugs (119) are effective strategies for preventing hyperkalemia.
7 Combination treatment with ACEI/ ARB and SGLT2i/glucagon-like peptide-1 receptor agonists A subgroup analysis, based on various MRAs, indicates that the relative risk of hyperkalemia when combining ACEI/ARB with FIN is lower compared to eplerenone or spironolactone (120).
Additionally, the combination of FIN with a SGLT2i like empagliflozin at low dose provides renal protection effect and effectively reduces proteinuria, plasma creatinine, uric acid, BP, cardiac and renal lesions, and mortality in a nondiabetic hypertensive cardiorenal disease model (50).However, multiple clinical studies, including FIDELIGO-DKD, have illustrated that FIN alone reduces UACR independently of SGLT2i (121).In the FIDELITY analyses, FIN outperformed placebo in terms of cardiorenal outcomes in individuals with DKD, regardless of SGLT2i usage (73,94).In other words, SGLT2i did not alter the effects of FIN on the primary endpoint.However, as for the safety, MRAs increase serum potassium concentration and the risk of hyperkalemia while SGLT2is reduce the risk of hyperkalemia (122,123), which makes the combination of SGLT2i with MRAs an attractive treatment option from a safety perspective.Analysis from the FIDELIO-DKD trial reveals that when combined with FIN, treatment with an SGLT2i may offer protection from hyperkalemia events despite low number of hyperkalemia events was observed (73,117).Moreover, it should be pointed out that in several trials, the SGLT2i dapagliflozin and MRA eplerenone reduce albuminuria and the incidence of hyperkalemia was significantly less during treatment with dapagliflozin-eplerenone compared with eplerenone alone (124, 125).These findings offer a convincing reason for evaluating the long-term efficacy and safety of combined SGLT2i and MRA treatment and may make eplerenone, a secondgeneration MRA, combined with SGLT2i, a second option for patients who can't tolerate FIN or can't afford such an expensive drug price of FIN.
Regarding GLP-1RAs, a post hoc exploratory analysis of the FIDELIO-DKD and FIGARO-DKD trials found that FIN reduces UACR in patients, irrespective of whether they were using GLP-1RAs use at the beginning of the study.The effects on kidney and CV outcomes remain consistent regardless of GLP-1RA usage, with no obvious safety signals associated with the combination treatment (126,127).
In summary, the results from clinical studies comparing combination therapy to monotherapy vary.Understanding the molecular mechanisms and potential interactions between FIN, ACEI/ARB, and SGLT2i/GLP-1RA agents remains unclear.Consequently, further clinical trials and in-depth mechanistic research are essential to provide conclusive evidence.

Ongoing trials
So far, clinical investigation into the kidney and CV disease outcomes associated with FIN have primarily focused on individuals with DKD.However, it's essential to emphasize that the FIDELIO-DKD and FIGARO-DKD trials specifically enrolled participants with DKD, characterized by an eGFR of ≥25 mL/min/ 1.73 m 2 , normal serum potassium levels, and albuminuria.Consequently, the current approval of FIN cannot be generalized to the entire population of individuals with DKD.Hence, further research is needed to clarify this aspect.Ongoing studies are exploring the role of triple therapy, consisting of RAS blockade, SGLT2i, and FIN, in individuals with DKD (CONFIDENCE study, NCT05254002) (128).Additionally, there are investigations into the efficacy and safety of FIN in subjects with CKD who do not have diabetes (FIND-CKD study, NCT05047263) (129), as well as an examination of treatment in patients with DKD treated with FIN in routine clinical practice, including safety assessments (FINE-REAL study, NCT05348733) (130).
The CONFIDENCE trial is an ongoing phase II randomized controlled trial designed to investigate the combination of FIN and empagliflozin compared with each drug alone in 807 participants with T2D, stage 2-3 CKD and UACR ranging from ≥300 to <5000 mg/g (128).This trial is estimated to be completed by 2024 and will comprehensively evaluate the cumulative efficacy, safety, and tolerability of dual therapy (128).The study will primarily focus on endpoints related to UACR, change in eGFR, and the incidence of hyperkalemia (128).However, as of this writing, no prospective clinical trials were planned to judge the combination of FIN and GLP-1RAs in patients with DKD.
Initiated in September 2021, the FIND-CKD trial includes nondiabetic CKD patients with an eGFR ranging from 25-90 mL/min/ 1.73 m 2 and a UACR between ≥200 to ≤3500 mg/gCr (129).The primary objective of this study is to assess the change in eGFR from baseline to 32 months in both the placebo and FIN groups.
The ongoing FINE-REAL study (130) aims to demonstrate treatment patterns in patients with DKD receiving FIN in routine clinical practice and assess the safety of FIN.FINE-REAL will provide meaningful insights into DKD patients treated with FIN, capturing AEs, specifically hyperkalemia, and identifying how they are handled in routine clinical care.The FINE-REAL study will aid to inform decision-making about initiating FIN in individuals with DKD and also shed light on the dynamics of adoption of new therapies in different regions and health systems, providing conducive perspectives for international guidance and implementation.

Conclusion and future advancement
FIN is a third-generation, selective and potent NS-MRA that has been illustrated in clinical trials to slow CKD progression, reduce the risk of CV events development and hyperkalemia compared to traditional steroidal MRAs in patients with DKD through specific impacts on inflammatory and fibrotic pathways.As such, FIN is a valuable addition to the treatment landscape for managing DKD.However, more clinical trials and deep mechanism research are needed to provide conclusive evidence for the combination treatment of FIN with ACEI/ARB and SGLT2i/GLP-1RAs.Additionally, further large-scale investigations are supposed to confirm the efficacy and safety of FIN in DKD with an eGFR below 25 mL/min/1.73m 2 and assess the clinical usage of FIN in patients with CKD but without diabetes.Besides, few studies have assessed whether this novel NS-MRA retain their beneficial effects across various kidney diseases as those observed with extant steroidal MRA, and there is no evidence for use in other settings like resistant hypertension, ascites due to cirrhosis, or primary hyperaldosteronism as compared to the firstand secondgeneration MRAs spironolactone or eplerenone.In addition, whether MR blockade alleviates IR injury in kidney transplantation is an intriguing topic.To justify these usages, comparative studies will need to be conducted for these specific conditions.

FIGURE 1 FIN
FIGURE 1 FIN displays beneficial effects against DKD and renal IR damage by different mechanisms of action in kidney.Diabetic and ischemic environment induce hyperactivation of MR and trigger three pathways, which can start a great variety of molecular, cellular, tissue and subsequently organ responses.On contrast, MRA FIN blocks the binding of aldosterone and MR, then blocks and attenuates those pathophysiological progressions.First, FIN alleviate oxidative stress by attenuating oxidative DNA damage and reducing the production of ROSs.The second major mechanism, FIN reduce the upregulation of pro-inflammatory mediators, leading to reduced inflammation.FIN also leads to reduced fibrosis by downregulating fibrotic biomarkers.In these ways, FIN shows renal-cardiovascular protective effect.Created by BioRender.com.

FIGURE 2
FIGURE 2Summary of the milestones and main trials of finerenone.Created by BioRender.com.

TABLE 1
Efficacy of FIN for renal protection in animal experiments.proteinuria, glomerular tubular and vascular damage, risk of electrolyte disturbances, cardiac hypertrophy, BNP, renal expression of pro-inflammatory and pro-fibrotic markers (PAI-1, MCP-1, OPN, and MMP-2); FIN ↑: end-organ protection, systolic and diastolic left ventricular function FIN ↓: albuminuria, plasma MMP-2 and MMP-9 activities, superoxide anion levels, intrinsic (mesenteric) arterial stiffness; FIN ↑: plasma pro-MMP-2 activity, NO bioavailability FIN has direct anti-fibrotic properties resulting in reduced myofibroblast and collagen deposition accompanied by a reduction in renal PAI-1 and NKD2 expression in mouse models of progressive kidney fibrosis at BP-independent dosages FIN ↓: Salt-induced activation of Rac1-MR pathway associated with Sgk1 upregulation and subsequent increased expressions of cleaved a-ENaC and phosphorylated NCC in distal tubules and glomeruli.FIN ↓: fibronectin; inflammatory markers (MCP-1 and PAI-1)

TABLE 2
Efficacy of FIN for renal protection in clinic.