1. Introduction
Aldosterone is a mineralocorticoid hormone that is up-regulated by angiotensin II, high serum potassium (K
+) levels and adrenocorticotropic hormone [
1,
2]. Aldosterone regulates extracellular fluid volume and K
+ metabolism by increasing sodium reabsorption in the principal cells of the distal nephron. Sodium reabsorption is mediated via activation of the apical epithelial sodium channel (ENaC) and the basolateral Na
+- K
+ ATPase, and aldosterone promotes the expression of the gene that encodes the a-subunit of ENaC [
2]. Apart from these classical effects, aldosterone has a deleterious impact on the heart, the vasculature and the kidney by promoting vascular remodeling, collagen formation, endothelial dysfunction and organ fibrosis overall [
3,
4,
5].
Primary aldosteronism has been acknowledged as a highly prevalent but under-recognized entity in hypertensive as well as normotensive individuals [
6], and excess aldosterone production conveys a higher risk of damage in target organs, such as the cardiovascular system and the kidneys [
7,
8]. Moreover, experimental and clinical evidence suggest that aldosterone contributes to progressive kidney disease [
8,
9,
10]. Numerous studies have demonstrated that activation of the renin–angiotensin–aldosterone system (RAAS) has a detrimental effect on the progression of CKD and inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs) can delay disease progression [
11,
12]. Interestingly, plasma aldosterone levels may rebound and increase to a significant extent following an initial decline after administration of ACEi or ARBs [
13]. This phenomenon, known as ‘aldosterone breakthrough’, could have important clinical consequences given aldosterone’s pro-fibrotic actions on the kidneys, especially in patients with established CKD. Depending on the definition used, the incidence of aldosterone breakthrough extends over a wide range from 10% after 6 months to 53% after 1 year of ACEi or ARB treatment. Nevertheless, breakthrough definition is somehow problematic, as in some studies, it is defined as any increase from an individual’s baseline serum aldosterone level, while others set an absolute cutoff value of serum aldosterone. The latter studies have detected lower risks of breakthrough [
13]. In any case, a large proportion of patients with CKD already on ACEi or ARB treatment could potentially benefit from mineralocorticoid receptor (MR) antagonist add-on therapy. Indeed, treatment with MR antagonists, especially spironolactone, has been shown to have favorable effects in patients with CKD of various etiologies by reducing albuminuria and the degree of estimated glomerular filtration rate (eGFR) decrease [
14]. Even treatment with the non-steroidal MR antagonist finerenone decreased the risk of CKD progression in patients with CKD and diabetes in the recent FIDELIO-DKD and FIGARO-DKD trials [
15,
16]. Nevertheless, data on safety and the efficacy of eplerenone on CKD progression and proteinuria reduction, especially in patients with glomerulonephritis, are scanty.
In this prospective observational study, we evaluated the effects of the MR antagonist eplerenone on proteinuria and kidney function (expressed as eGFR) in a cohort of patients with biopsy-proven GN who were treated with eplerenone (25 mg/d) for 1 year.
2. Materials and Methods
In this prospective observational cohort study, we evaluated the effects of eplerenone on proteinuria and eGFR as well as its safety in patients with biopsy-proven glomerulonephritis. All patients with biopsy-proven glomerulonephritis treated and actively monitored in our department’s outpatient clinic were screened during a 3-month period. All patients were offered treatment with eplerenone for 1 year on top of their standard treatment, and those who agreed were prescribed 25 mg of eplerenone once daily. Those who did not agree to receive eplerenone on top of their standard treatment were considered as controls.
Inclusion criteria comprised the following: age > 18 years, previous treatment with ACEi or ARB at maximum tolerated dose for at least 6 months prior to screening, proteinuria greater than 150 mg in a 24 h urine collection, serum potassium less than 5 mg/dL at screening and no evidence of active cancer. We excluded patients with hepatic dysfunction, history of allergy or non-tolerability to ACEi or ARBs, acute kidney injury in the past three months and those on active immunosuppressive treatment with corticosteroids alone or in combination with calcineurin inhibitors, anti-metabolites or monoclonal antibodies. Antihypertensive drugs apart from ACEi or ARBs were prescribed as needed to achieve a target systolic blood pressure (SBP) of less than 120 mmHg. Dosage of ACEIs and ARBs remained stable after inclusion in the study. No patient received treatment with an SGLT-2 inhibitor prior to or during the study period.
All patients were advised to follow a low-protein (approximately 0.8 g/kg/day) and low-salt (4–5 g NaCl/day) diet. Moreover, patients who received eplerenone received comprehensive dietary counseling on a low-K+ diet and avoidance of high K+ content fruits and vegetables. We did not measure urinary Na+ and K+ excretion to assess dietary compliance. If serum K+ levels increased above the threshold of 5.5 meq/L, eplerenone was discontinued.
Baseline evaluation included standard office BP measurements as suggested by the European Society of Hypertension [
17], eGFR calculation using the CKD-EPI equation and measurement of 24 h urine protein and plasma aldosterone levels. Thereafter, patients were followed in the outpatient clinic after 3, 6 and 12 months. Blood pressure and heart rate were measured three times at each visit, and a blood sample was drawn after the patient had remained seated for 30 min. At each clinic visit, including the baseline evaluation, each subject was asked to bring a 24 h urine collection for urine protein measurement.
The Human Research Committee of the University Hospital of Patras approved the study protocol (number of approval: 7251/14.12.20), and all subjects provided their written informed consent prior to inclusion in the study. The study protocol is in accordance with the Helsinki Declaration as revised in 2013.
11. Discussion
In this prospective study of eplerenone treatment on top of standard treatment with ACEi or ARBs in patients with glomerular disease, we have shown that eplerenone is effective in reducing proteinuria in patients with a higher degree of baseline proteinuria. Moreover, patients who received eplerenone maintained stable kidney function after 12 months, while those who received conservative treatment alone showed a trend of decline in eGFR.
Effectively reducing proteinuria remains the main target of therapy in patients with primary glomerulonephritis, as proteinuria almost invariably correlates with progression to end-stage kidney disease [
18]. ACEi or ARB administration remains the cornerstone of antiproteinuric treatment, while sodium glucose transporter 2 inhibitors have recently emerged as an important add-on option [
19,
20]. Other options include MRAs, either in the form of first-generation spironolactone or the second generation, and, with less adverse effects, eplerenone. Concerning spironolactone, there is evidence that when administered in combination with ACEi or ARBs, it reduces proteinuria more than standard treatment with ACEi or ARBs, even at a dose of 25 mg/day [
14]. This feature is also prominent in patients with diabetic kidney disease and albuminuria [
21]. Eplerenone has exhibited an antiproteinuric effect in experimental nephrotic syndrome [
22], and additionally, it reduces albuminuria effectively in non-diabetic CKD patients after 8 weeks of administration at a dose of 25–50 mg once daily as an add-on treatment to ACEi or ARBs [
23]. Higher doses of eplerenone up to 100 mg/day have also shown a significant effect on albuminuria, up to almost 50%, in patients with diabetic nephropathy [
24]. Treatment for longer periods, up to 1 year, has also shown benefit in albuminuria in patients with hypertension and CKD [
25]. Nevertheless, addition of spironolactone to ACEi did not further reduce proteinuria in one study that included 11 patients with membranous nephropathy and nephrotic syndrome [
26]. The beneficial anti-albuminuric effect of eplerenone in the aforementioned studies involved patients in the spectrum of modest albuminuria up to 599 mg/g (urine albumin/creatinine ratio) [
25] to higher values of over 1 gr/24 h [
23]. In our study, though, significant reduction of proteinuria after eplerenone treatment was seen mainly in patients with baseline proteinuria greater than 1000 mg/24 h, while patients with proteinuria of lesser degree showed a non-significant reduction.
Long-term preservation of kidney function is the ultimate treatment goal for patients with CKD. Previous studies have demonstrated that addition of spironolactone to treatment with ACEi or ARBs initially lowered the eGFR [
27] but stabilized kidney function in the long run [
14]. eGFR reduction directly after initiation of spironolactone has also been demonstrated in cohorts of patients with type 1 or 2 diabetes and albuminuria [
28,
29]. Concerning eGFR after eplerenone administration, the same short-term pattern is observed in diabetic as well as non-diabetic patients with CKD and albuminuria. Nevertheless, the early decrease in eGFR is less than 30% from baseline values, and treatment cessation is rarely necessary [
23,
24]. In our cohort, those treated with eplerenone showed an insignificant increase in serum creatinine 3 months after initiation of treatment, but overall, kidney function was stable during the 12 months of follow-up. On the contrary, patients who received conservative treatment showed a more pronounced but still not statistically significant decline in kidney function at the end of follow-up. Finally, overall kidney function between the two groups at the end of follow-up did not show significant difference.
Addition of spironolactone to ACEi or ARBs has been shown to reduce BP effectively in patients with diabetic as well as non-diabetic CKD and albuminuria [
14,
29]. Likewise, initiation of eplerenone on top of standard treatment has a significant lowering effect on SBP in patients with diabetic nephropathy or non-diabetic CKD [
23,
30]. However, all of the aforementioned studies included patients with a target SBP of less than 130 or 125 mmHg, while in our study, the target SBP was 120 mmHg, indicating intensified anti-hypertensive treatment. Concerning DBP, eplerenone appears to be effective in patients with CKD and proteinuria, although data are more inconsistent in patients with diabetic nephropathy and show either an important lowering or neutral effect [
23,
24,
30]. In this study, patients treated with eplerenone showed a significant overall reduction of SBP, which was more apparent 6 months after initiation of treatment. This reduction could have at least a partial positive impact on the proteinuria reduction that was shown in these patients. Diastolic BP, however, was not significantly altered. Interestingly, patients who received only standard treatment also showed a non-significant reduction in SBP, and thus the SBP values between the two groups of patients at the end of follow-up were not significantly different.
High aldosterone levels are independently associated with kidney function deterioration in patients with CKD [
9], and treatment with MRAs attenuates the progression of kidney disease [
1]. Furthermore, patients with higher aldosterone levels exhibit a greater degree of proteinuria and lower serum potassium [
9,
14]. These features are also found in patients with aldosterone breakthrough [
9,
14]. Although the incidence of aldosterone breakthrough can reach 50% of patients after 1 year of treatment with ACEi or ARBs, it was diagnosed in only 29% of patients in our cohort. More importantly, those with aldosterone breakthrough who received eplerenone showed reduction of proteinuria and better maintained kidney function in comparison to those on standard therapy. Nevertheless, this favorable outcome was not accompanied by significant BP reduction in this subgroup of patients.
Adverse effects of treatment with MRAs in patients with CKD include, but are not limited to, hyperkalemia and gynecomastia. While both of these features are prominent in patients treated with spironolactone [
14], data on eplerenone prove that this agent is better tolerated with minimal or no treatment withdrawals due to hyperkalemia [
23,
25]. In our cohort, we detected no cases of significant hyperkalemia, and no patient withdrew from eplerenone treatment due to high K
+ serum levels. This could be attributed to the comprehensive dietary counseling provided to patients, which ensured a low-K
+ diet and avoidance of certain vegetables and fruits. Moreover, none of our male patients developed gynecomastia or other pronounced female characteristics, which offers a substantial advantage over traditional treatment with spironolactone. Overall, eplerenone was well tolerated, and only two patients discontinued treatment due to reported low BP and upper limb numbness.
Limitations of our study include its single-center design and its relatively low number of patients who followed active treatment with eplerenone. Moreover, the lack of a placebo-controlled arm may have affected the final results. Furthermore, the significant reduction in SBP in the active treatment arm could have an impact on proteinuria reduction. Nevertheless, this could not be further assessed. Finally, a longer follow-up period could potentially demonstrate the beneficial effect of eplerenone on kidney function or a sustained effect on proteinuria regression more clearly. Prospective randomized placebo-controlled trials with more patients with glomerulonephritis and longer duration of intervention are needed to address this issue.
In conclusion, in this prospective study, we have shown that administration of eplerenone as an add-on treatment to ACEi or ARBs in patients with chronic glomerulonephritis can be beneficial in proteinuria reduction in those with baseline values of more than 1000 mg/24 h with a favorable safety profile.