Primary Aldosteronism and the Role of Mineralocorticoid Receptor Antagonists for the Heart and Kidney

Abstract

Primary aldosteronism is the most common cause of secondary hypertension but is frequently underrecognized and undertreated. Moreover, patients with primary aldosteronism are at a markedly increased risk for target organ damage to the heart and kidney. While patients with unilateral primary aldosteronism can be treated surgically, many patients with primary aldosteronism are not eligible or willing to undergo surgery. Steroidal mineralocorticoid receptor antagonists are highly effective for treating primary aldosteronism and reducing the risk for target organ damage. However, steroidal mineralocorticoid receptor antagonists are often under-prescribed and can be poorly tolerated by some patients due to side effects. Non-steroidal mineralocorticoid receptor antagonists reduce adverse renal and cardiovascular outcomes among patients with diabetic kidney disease and are better tolerated than steroidal mineralocorticoid receptor antagonists. While their blood pressure-lowering effects remain unclear, these agents may have a potential role in reducing target organ damage in patients with primary aldosteronism.

INTRODUCTION

Almost half of United States (US) adults have hypertension, and rates of blood pressure (BP) control are worsening over time (1; 2). The prevalence of hypertension is growing in many populations worldwide, and is a major driver of disability, morbidity, and mortality (3). Primary aldosteronism (PA) is the most common cause of secondary hypertension. The prevalence of PA increases as severity of hypertension increases, and PA occurs in up to 20% of patients with stage 2 hypertension and resistant hypertension (4).

Current guidelines recommend testing for PA in all patients with treatment resistant hypertension (i.e., uncontrolled hypertension on optimal dosing of at least 3 antihypertensive agents or requiring 4 antihypertensive agents to achieve adequate control); hypertension with hypokalemia (either spontaneous or induced by treatment with a diuretic); hypertension with an adrenal incidentaloma; hypertension with obstructive sleep apnea; hypertension with a first-degree relative with PA; or hypertension with a family history of hypertension or stroke at age <40 years (1; 5). Nonetheless, population-based evidence suggests that PA is grossly underrecognized: less than 2% of individuals with resistant hypertension or hypertension with hypokalemia ever undergo initial testing (i.e., plasma aldosterone concentration and renin activity or direct renin) (6; 7). Important steps in PA diagnosis include confirmatory testing (e.g., sodium-loading, fludrocortisone suppression test, or captopril challenge test) as well as assessment for lateralization to one adrenal gland vs. bilateral disease (5). Many patients with unilateral PA benefit from surgical adrenalectomy. Those with bilateral PA, who are not surgical candidates, or who are uninterested in or unlikely to benefit from surgery are most often treated with the steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone or eplerenone.

MRAs have been used for decades to control BP and serum potassium in patients with PA (8) and other forms of hypertension (9). More importantly, growing evidence supports the extended benefits of MRA use for target tissue protection, by mitigating the insults triggered via inappropriate MR activation. The goal of this report is to review epidemiologic and mechanistic relationships between PA, MRAs, and target organ damage to the heart and kidneys, and to evaluate the potential for novel non-steroidal MRAs to improve hypertension management and mitigate target organ damage in patients with PA and other forms of hypertension (Figure).

Figure.

Current barriers and potential solutions to facilitate adequate attenuation of target organ damage in primary aldosteronism (PA) using mineralocorticoid receptor antagonists (MRAs).

EPIDEMIOLOGY OF TARGET ORGAN EFFECTS OF PA ON THE HEART AND KIDNEYS

Cardiovascular Effects

PA is associated with left ventricular (LV) hypertrophy (10–12), larger cardiac chamber volumes (13), and impaired systolic and diastolic function (10; 14; 15). In addition to exhibiting adverse cardiac remodeling, patients with PA have a substantial burden of clinical cardiovascular disease, with prevalence estimates ranging from 9.4-35% (11; 16–21) and excess incident cardiovascular events (CVEs) compared with non-PA hypertension despite recognition and targeted treatment of PA (11; 20–23).

Several distinct CVEs are more frequently identified in PA and may reflect specific target organ consequences of aldosterone-mineralocorticoid receptor (MR) interaction. These include coronary artery disease (CAD), heart failure (HF), stroke, and atrial fibrillation. Prevalent CAD has been reported in 2.1-20% of patients with PA (11; 16; 18–21), and in a large meta-analysis, PA was associated with a pooled odds ratio (OR) for CAD of 1.77 (95% confidence interval [CI] 1.10-2.83) versus non-PA hypertension (24). Similarly, HF has been reported in up to 4.1% of patients with PA (11; 16; 19; 20) and at approximately two-fold higher rates than non-PA hypertension (OR 2.05, 95% CI 1.11-3.78) (24). Stroke, including both ischemic and hemorrhagic subtypes, is enriched in PA with a reported prevalence of 6.1-12.9% (11; 12; 16; 20; 21; 25) and a pooled OR of 2.58 (95% CI 1.93-3.45) compared to non-PA hypertension (24). Atrial fibrillation is also overrepresented in PA, with prevalence estimates ranging from 2.8-7.3% (11; 12; 16; 17; 19) and OR 3.52 (95% CI 2.06-5.99) compared to hypertensive controls (24).

Given the consistently higher rates of CVEs reported in PA compared to non-PA hypertension, these studies suggest that PA may exert a direct effect on cardiovascular risk that is not mediated by BP. However, differences in duration and severity of hypertension and related comorbidities cannot be fully accounted for in these observational analyses, and thus the degree to which cardiovascular risk in PA is truly independent of BP is unknown.

Renal Effects

PA is associated with glomerular hyperfiltration and a higher risk of microalbuminuria (OR 2.09, 95% CI 1.40-3.12) and overt proteinuria (OR 2.68, 95% CI 1.89-3.79) compared to non-PA hypertensive controls (26). In a retrospective Japanese registry study of 2366 patients with PA, the authors reported a 10.3% prevalence of overt proteinuria (27), comparable to rates reported in smaller European studies (18; 28). Correspondingly, the frequency of microalbuminuria in PA has been estimated at 26.5-42% (11; 18; 28).

There is limited evidence of how renal effects of PA translate to clinical renal endpoints. However, Hundemer et al. evaluated the risk of incident chronic kidney disease (CKD) in 520 patients with PA and 15464 age- and eGFR-matched controls with non-PA hypertension (29). Medically treated PA was associated with 55.6 cases of incident CKD per 1000 person-years compared to 35.6 per 1000 person-years among controls (adjusted hazard ratio [HR] 1.63, 95% CI 1.33-1.99), and patients with PA experienced a more rapid decline in eGFR. In the subset of patients with diabetes, PA was associated with more than 2-fold risk of incident albuminuria versus essential hypertension (adjusted HR 2.52, 95% CI 1.28-4.96) (29).

Key Gaps

Considering the consistently poor rates of PA screening and detection (4; 6; 7; 30–32), accurate estimates of the rates of cardiovascular and renal complications in PA are elusive. With substantial increases in screening, a greater proportion of hypertension could be classified as PA and as such, the burden of cardiovascular and renal disease attributable to PA may be much greater than currently recognized. In several large general population cohort studies of adults without a diagnosis of PA, greater aldosterone concentrations – especially independent of renin, i.e., consistent with PA pathophysiology – were associated with LV hypertrophy (33), coronary atherosclerosis (34), HF (35), stroke (36), and cardiovascular death (36). Whether improvements in screening and detection and treatment of PA at milder or earlier stages can mitigate adverse outcomes remains to be proven.

EPIDEMIOLOGY OF STEROIDAL MRA USE IN PA AND HYPERTENSION

PA

Steroidal MRAs are the primary non-surgical treatment for PA among patients with bilateral PA or who are not candidates for or are unwilling to pursue surgical adrenalectomy (5). While surgical adrenalectomy for unilateral PA may provide greater reduction in BP than MRAs (37; 38), MRAs are effective at lowering BP and improving hypokalemia in patients with PA. Observational studies demonstrate that MRAs are associated with a 25% lower systolic BP, with almost half of individuals achieving adequate blood pressure control after initiation of these agents on a lower number of total antihypertensive medications compared with prior to treatment (8; 39).

Hypertension

High quality evidence supports the treatment of resistant hypertension with MRAs due to high efficacy with regard to BP control (9; 40). Approximately 70% of adults with resistant hypertension are recommended to be treated with MRAs as the agent of choice after first-line antihypertensive therapy has been optimized (i.e., with an angiotensin receptor blocker or angiotensin-converting enzyme inhibitor, calcium channel blocker, and thiazide or thiazide-like diuretic), even in the absence of PA (41). The only patients in whom MRAs are not recommended for this purpose are those with hyperkalemia or at risk for hyperkalemia, such as in advanced chronic kidney disease.

Providers often cite the intention to empirically treat resistant hypertension with MRAs as rationale for not testing for PA. However, data from the National Health and Nutrition Examination Survey demonstrated that 1.7% of individuals with controlled resistant hypertension and 3.1% of those with uncontrolled resistant hypertension in the US were on an MRA between 1988-1994, which only improved to 4.4% and 6.9% in 2005-2008 (42). Similar findings were observed using data from the National Ambulatory Medical Care Survey, which demonstrated that 3.6% of patients with resistant hypertension were on MRAs from 2006-2010 (43). In subsequent years, as mounting high-quality evidence supports the use of these agents for patients with resistant hypertension, prescribing patterns remain disappointingly low. A study of US Marketscan data from 2008-2014 demonstrated that MRA use only increased from 7.4% to 10.2% over the course of follow-up (44). In a more recent population-based cohort study of 269,010 Veterans with incident resistant hypertension who were followed from 2000-2017, only 13% of eligible patients were ever initiated on an MRA (6). Being tested for PA was associated with a 3.75-fold (95% CI 3.34-4.20) higher likelihood of initiation of an MRA, after censoring individuals with biochemical evidence of PA or adrenalectomy.

STEROIDAL VS. NON-STEROIDAL MRAS: MECHANISMS OF ACTION AND ADVERSE EFFECTS

Several key differences are noted between steroidal MRAs (spironolactone and eplerenone) and nonsteroidal MRAs (finerenone) in the mode of action, tissue distribution, pharmacokinetics, effect on cofactor recruitment, and gene expression (45). Development of non-steroidal MRAs was influenced by the high incidence of hyperkalemia and eGFR reduction with the use of steroidal MRAs, thus resulting in the gap in care of patients with advanced CKD. Most of the available evidence on non-steroidal MRAs exists for finerenone. Finerenone is a passive antagonist of the MR, and distinct from steroidal MRAs (46). It has no affinity to androgen or glucocorticoid receptor. Finerenone has a non-steroidal structure and demonstrates a unique MR binding conferring its high potency and selectivity for the MR. Steroidal MRA tissue distribution has been shown to be higher in kidneys versus heart, while for finerenone, an equal kidney-heart distribution was documented which likely explains a lower impact of finerenone on the electrolyte balance in comparison to steroidal MRAs (47). As opposed to spironolactone, finerenone is less lipophilic, with minimal kidney elimination. It has a short half-life and no active metabolites (48; 49). The MR presents distinct domains for specific ligand binding and activation, with multiple cofactors known to lead to MR-mediated transcriptional response (50). In comparison to eplerenone, finerenone is more potent in blocking MR cofactor binding, and may block deleterious gene activation by MR independently of aldosterone (50).

Both spironolactone and eplerenone may result in hyperkalemia and worsening of kidney function. Antiandrogenic effects, including gynecomastia, breast pain, and sexual side effects, are seen with use of spironolactone and nonselective first generation MRAs. Risk of hyperkalemia was reported to be 2-7% of patients treated with steroidal MRAs (51–53). Gynecomastia and breast pain was reported by 10-14% of patients receiving spironolactone, as opposed to <1% of patients on placebo or treated with eplerenone (52–54). The finerenone side effect profile appears to be more favorable than steroidal MRAs, especially when compared to spironolactone. The incidence of hyperkalemia and decrease in eGFR was lower in patients treated with finerenone as compared to those treated with spironolactone (55–57). While the risk of hyperkalemia in patients with CKD treated with finerenone was higher than in placebo group, the overall safety profile of finerenone was similar to placebo (58).

STEROIDAL MRAS AND TARGET ORGAN DAMAGE IN PA

Both spironolactone and eplerenone are efficacious in normalizing BP and serum potassium in tightly controlled clinical trial settings (8; 59–61). Data from several large retrospective cohort studies, however, suggest that steroidal MRA doses used in clinical practice are often not equally effective in preventing target organ damage. For example, in an Italian retrospective cohort study of 107 patients with PA and 894 patients with primary hypertension followed for a median of 11.8 years, patients with PA treated medically had higher risk of atrial fibrillation compared with the surgical PA group or those with primary hypertension (62). Similar results were reported from a Taiwanese cohort: after follow-up for 6.3±4.0 years, MRA-treated patients with lateralized PA (N=313) had higher risks of major CVEs, atrial fibrillation, and HF than patients with primary hypertension (N=1210), or those with clinical cure after unilateral adrenalectomy (N=272) (63).

In a single-center, US cohort of 602 patients with PA treated with steroidal MRAs and 41,853 age-matched patients with primary hypertension, patients with PA had an adjusted 10-year cumulative 14·1 [95% CI 10·1-18·0] excess incidence of CVEs per 100 people, as well as higher adjusted risks for incident mortality (hazard ratio [HR] 1·34 [95% CI 1·06-1·71]), diabetes (1·26 [1·01-1·57]), and atrial fibrillation (1·93 [1·54-2·42]) (64). Patients with PA treated with MRAs were also found to have a higher adjusted risk of incident chronic kidney disease as compared to those with either surgically treated PA or primary hypertension (29). Similarly, in a study of hypertensive patients without known cardiovascular disease, patients with PA on insufficient MRA treatment (n=130; as indicated by persistent volume expansion and renin suppression) had a 10-year cumulative incidence of new onset atrial fibrillation of 26.5 cases per 100 patients, a 2.55-fold increased risk compared to hypertensive controls and despite adjustment for baseline BP (65). Notably, the excess cardiovascular and renal risks in both studies were buffered in the small subset of patients with medically-treated PA in whom plasma renin was no longer suppressed. These groups were treated with higher average doses of MRAs or surgical adrenalectomy, suggesting that the target organ damage was offset by eliminating the inappropriate MR activation. Given the retrospective nature of the studies and small group of patients with normalized renin, other contributors to the observed cardiovascular and renal morbidity and mortality differences cannot be excluded. Potential confounders include differences in salt intake, intensity of follow up, medication compliance, and/or PA severity.

Taken together, available data suggest that, to mitigate the added cardiovascular and renal risk of PA, medical treatment should target renin normalization, as a surrogate for adequate MR blockade. Nevertheless, clinicians rarely pursue renin targets after initiation of MRA therapy. In a study of 30,777 patients with hypertension treated with steroidal MRAs between 2000-2020, only 163 patients (123 with PA) had renin followed after MRA initiation (66). After a median follow-up of 124 (interquartile range, 65-335) days, normalization of renin was achieved in 43% of patients. The odds of achieving target renin in PA decreased with lower baseline serum potassium, lower MRA doses, and use of beta-blockers. Efforts to reverse renin suppression can be further limited by MRA side effects, underlying renal insufficiency, and PA severity. Initiation of MRA therapy contributes to an acute reversal of PA-induced intravascular volume expansion and renal hyperfiltration (67–69), and a subsequent decline in the estimated glomerular filtration rate (eGFR). Older age and higher PA severity increase the risk of acute eGFR decline (68; 69), and mandate conservative MRA dose titration. Long-term, however, adequate doses of MRAs have reno-protective effects, and MRA use should be attempted whenever possible (29; 68).

Additionally, the risk of target organ complications rendered by PA dissipates gradually following initiation of therapy, and this process likely depends on the disease severity and duration. This was recently exemplified by a large Korean study of patients with PA and primary hypertension, which found that the risk of new-onset atrial fibrillation was persistently higher in the first 3 years after unilateral adrenalectomy or initiation of steroidal MRA therapy, but it declined gradually, to reach levels similar to that observed in patients with primary hypertension 3 years into therapy (70). Similarly, spironolactone therapy reduced the common carotid intima-media thickness to a lesser extent compared to unilateral adrenalectomy at 1 year, but the benefits were similar at 6 years from therapy initiation (71). A progressive decline in common carotid intima-media thickness was also observed in patients treated with eplerenone, despite elevations in aldosterone levels (60). In a meta-analysis of 4 prospective cohort studies, steroidal MRA therapy was equivalent to unilateral adrenalectomy at reducing the LV mass after an average of 4-year follow-up, despite more modest effects on hypertension (37). Taken together, these data emphasize the importance of overcoming the inappropriate MR activation that occurs in PA rather than focusing exclusively on BP control.

STEROIDAL MRAS AND TARGET ORGAN DAMAGE IN PRIMARY HYPERTENSION

The MR is expressed as a nuclear receptor in several non-epithelial tissues/cell types including the kidney, heart, endothelial cells, vascular smooth muscle cells, and inflammatory cells – especially macrophages and fibroblasts (72). Physiological effects of aldosterone activation induce salt and water retention and directly impact BP. Pathological MR overactivation also influences target gene expression in inflammatory and fibrotic pathways, directly inducing target organ damage in the heart, blood vessels, and kidneys in animal and translational models (72; 73). Furthermore, MR-mediated damage in the heart and kidneys occurs independently of systemic BP effects, and is intensified by high sodium intake (72). Even in the absence of PA, steroidal MRAs have emerged as promising pharmacological agents in ameliorating inflammation and fibrosis in resistant hypertension, CKD, and HF, beyond their role as potassium-sparing diuretics.

Randomized controlled trials (RCTs) have demonstrated significant BP lowering with steroidal MRAs in resistant hypertension, making them the preferred 4^th anti-hypertensive medication (9; 40; 41). Small studies have shown that steroidal MRAs decrease arterial stiffness through a BP-independent effect (74–76). Multiple landmark RCTs have shown that steroidal MRA use in patients with HF with reduced ejection fraction (HFrEF), a state of secondary aldosteronism and MR overactivation, lead to remarkably reduced risk of HF hospitalizations and cardiovascular mortality (52; 77; 78). Subgroup analyses of these trials demonstrated reduction in levels of pro-fibrotic collagen biomarkers among participants randomized to MRAs, confirming the pathological role of MR overactivation in cardiac disease (79; 80). Steroidal MRAs are an integral part of guideline-directed medical therapy for patient with HFrEF, particularly with an eGFR >30 ml/min/1.73m² and serum potassium levels <5.0 mEq/L (81). The effectiveness of steroidal MRAs in reducing risk of CVEs in patients with HF with preserved ejection fraction (HFpEF) remains unclear (82; 83), though there are demonstrable improvements in LV modeling and indices of LV function (51; 72; 84; 85), and the ongoing FINEARTS-HF Trial (NCT04435626) is evaluating the effect of the non-steroidal MRA finerenone on the composite of cardiovascular death and total HF events in patients with HFpEF.

Several short-term, small, RCTs evaluated add-on steroidal MRAs in patients with diabetic or non-diabetic CKD who were already on a renin-angiotensin system blocker (i.e., angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)) (72; 86; 87). These trials demonstrated striking reductions in proteinuria, decrease in tubular markers of renal injury and fibrosis, and slowing of eGFR decline in participants randomized to MRAs. These effects occurred independently of systemic BP changes, presumably counteracting the ‘aldosterone escape’ that occurs with renin-angiotensin system blockade alone, decreasing vasoconstriction and intraglomerular pressures, increasing renal blood flow, and decreasing fibrosis and glomerulosclerosis (72; 86; 87).

Despite RCT evidence supporting the target organ benefits of steroidal MRAs, observational studies have demonstrated significant prescription inertia or discontinuation of MRAs in real-world clinical practice, attributed to acute kidney injury, hyperkalemia, and the anti-androgenic effects of steroidal MRAs (88–90). Addition of steroidal MRAs to an ACEI/ARB is associated with two-fold higher risk of hyperkalemia and acute kidney injury in short-term trials of patients with CKD, and these risks are likely cumulative (91). The cardiovascular benefits of combing a steroidal MRA and renin-angiotensin system blocker are superior to dual renin-angiotensin system blockade, but the long-term renal benefits remain unclear. A phase-II RCT showed that patiromer, a potassium-binder, enabled safe and persistent spironolactone use in patients with resistant hypertension and CKD over a 12-week period compared to placebo; however, long-term results are lacking (92). Evidence of cardiovascular benefit in patients with advanced CKD and end stage renal disease is also inconclusive. A recent Cochrane meta-analysis demonstrated a 55% reduction in all-cause mortality and 65% reduction in cardiovascular mortality, without significantly increasing the risk of hyperkalemia, with steroidal MRA use in patients with end stage renal disease; however, these studies were at high risk of bias and the evidence remains uncertain (86; 91). Thus, while the use of MRAs with renin-angiotensin system blockade is very attractive for CKD and end stage renal disease management, we await the results of larger longer term clinical trials to ascertain safety and conclude robust cardiovascular and renal benefit.

NON-STEROIDAL MRAS AND TARGET ORGAN DAMAGE IN DIABETIC KIDNEY DISEASE

Two recent RCTs “Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes” (FIDELIO-DKD) (93) and “CVEs with Finerenone in Kidney Disease and Type 2 Diabetes” (FIGARO-DKD) (94) evaluated the effects of finerenone, a non-steroidal MRA, on CVEs and progression of diabetic kidney disease (DKD) in patients with type 2 diabetes. FIDELIO-DKD was a double-blind RCT that enrolled 5,734 patients with CKD and type 2 diabetes. Subjects were randomly assigned to receive finerenone or placebo in 1:1 ratio. Subjects either had albuminuria (urinary albumin-to-creatinine ratio [UACR] of 30 to less than 300 mg/g); eGFR of 25 to <60 mL/min/1.73m² and diabetic retinopathy, or UACR of 300 to 5000 mg/g and an eGFR of 25 to <75 mL/min/1.73m². All participants received maximally tolerated renin-angiotensin system blockade prior to randomization. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in eGFR from baseline, or death from renal causes. The secondary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF. Patients were followed for a median of 2.6 years. The primary outcome event occurred in 17.8% vs 21.1% of participants in the finerenone vs placebo group, respectively (HR 0.82; 95% CI 0.73-0.93; P = 0.001). The secondary composite outcome occurred in 13.0% vs 14.8% in the respective groups (HR 0.86; 95% CI 0.75-0.99; P = 0.03).

FIGARO-DKD was a similar study to FIDELIO-DKD with slightly different inclusion criteria and assessed CVEs as the primary endpoint. The study randomized 7,437 patients with DKD to finerenone or placebo. Subjects had UACR of 30 to <300 mg/g and eGFR of 25-90 mL/min/1.73m² or UACR 300 to 5000 mg/g and eGFR ≥60 mL/min/1.73m². Patients received maximally tolerated renin-angiotensin system blockade prior to randomization. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF. Secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Patients were followed for a median of 3.4 years. The primary outcome event occurred in 12.4% in the finerenone group and 14.2% in the placebo group (HR 0.87; 95% CI 0.76-0.98; P=0.03), with the benefit driven primarily by a lower incidence of hospitalization for HF (HR 0.71; 95% CI 0.56-0.90). The secondary composite outcome occurred in 9.5% and 10.8 % in the finerenone and placebo groups, respectively (HR 0.87; 95% CI 0.76-1.01). Adverse events, including acute kidney injury, were similar in both groups in both studies; however, hyperkalemia was higher with finerenone than with placebo. No fatal episodes of hyperkalemia occurred in either study. These important studies demonstrate that use of finerenone as compared to placebo reduced UACR, risk of CKD progression, and CVEs in DKD patients with CKD and moderate albuminuria or stage 1/2 CKD with severely elevated albuminuria. Based on these studies, the American Diabetic Association recently updated their guidelines and now recommend finerenone (level A) in patients with CKD who are at increased risk for CVEs or CKD or are unable to use a sodium–glucose cotransporter 2 inhibitor (95).

POTENTIAL ROLE FOR NON-STEROIDAL MRAS IN THE TREATMENT OF PA AND FUTURE DIRECTIONS FOR RESEARCH

Of the existing steroidal MRAs (spironolactone, eplerenone, canrenone and mexrenone), only sprinolactone and eplerenone are available in the US for treatment of PA. Spironolactone is the most commonly used MRA, but has high affinity for androgen and glucocorticoid receptors leading to antiandrogenic side effects in men (5). Eplerenone has lesser affinity for androgen receptors but also as a significantly lower affinity for MRs and is less potent. Third generation MRAs –apararenone, esaxerenone and finerenone –are devoid of non-MR activity (96). In the US, finerenone is the only clinically available drug in this class. Recent studies with finerenone in the DKD population only demonstrated very minor reductions in systolic BP, in the range of 2-3 mmHg; nonetheless, this may be due to the low dosage of finerenone used and the absence of diagnosed PA or even resistant hypertension among participants (93; 94). Finerenone is a potent inverse agonist of the MR receptor, with minimal affinity for progesterone, estrogen, androgen or glucocorticoid receptors (97) and could be a possible treatment for PA without the side effects of traditional MRAs. The effect of esaxerenone on PA is being studied in a Japanese population in a phase 3 trial (NCT2885662) and could be potentially useful in this PA population. It may be that non-steroidal MRA treatment could be better tolerated and thus better facilitate renin normalization, as a surrogate for adequate MR blockade, in patients with PA. Whether this might provide adequate protection against end-organ complications, despite more modest BP lowering than with steroidal MRAs, is not yet clear.

CONCLUSIONS

PA is a common cause of hypertension, and particularly resistant hypertension, but is grossly underrecognized. Furthermore, patients with PA are at elevated risk of target organ damage to the heart and kidney, necessitating early recognition and targeted treatment. Steroidal MRAs are highly effective at reducing BP in patients with resistant hypertension and PA, and at lowering the risk of target organ damage in several disease states including PA, HFrEF, and CKD. Nonetheless, steroidal MRAs are underutilized, in part due to adverse antiandrogenic side effects. Non-steroidal MRAs, which have much more tolerable side effect profiles, have demonstrated substantial reductions in adverse renal and cardiovascular outcomes among patients with DKD. However, BP-lowering effects of these agents were nominal in DKD. Future studies will determine the effectiveness of non-steroid MRAs in patients with PA for reducing their markedly elevated risk for target organ damage.