IJCA-20595; No of Pages 5 International Journal of Cardiology xxx (2015) xxx–xxx

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Review

The renal effects of mineralocorticoid receptor antagonists☆ Stefano Bianchi a,⁎, Valentina Batini b, Roberto Bigazzi b a b

Unità Operativa di Nefrologia e Dialisi II, Livorno, Italy Dipartimento di Medicina Clinica ed Unità Operativa di Nefrologia e Dialisi I, Livorno, Italy

a r t i c l e

i n f o

Article history: Received 4 December 2014 Accepted 17 May 2015 Available online xxxx Keywords: Chronic kidney disease Mineralocorticoid receptor antagonists Glomerular filtration rate Proteinuria Hyperkalemia

a b s t r a c t Beyond its well known classic effects on renal water and electrolytes metabolism, an increasing amount of experimental and clinical evidence suggests that aldosterone contributes to the pathogenesis and progression of kidney disease. The binding of aldosterone on epithelial and non-epithelial cells of the kidney induces many deleterious effects, such as podocyte apoptosis and injury, mesangial cell proliferation and deformability and tubulointerstitial inflammation, finally resulting in glomerular fibrosis and sclerosis. Moreover, aldosterone acting by fast non-genomic mechanisms, may induce other potential deleterious effects on kidney function and structure. Indeed, many experimental studies have shown that aldosterone participates to the progression of kidney disease through hemodynamic and direct cellular actions and that antagonists of aldosterone may retard the progression of kidney disease, independently of effects on blood pressure. Therefore, blockade of the aldosterone pathway may prove to be a beneficial therapy for kidney disease. In this brief review we summarize the reported data that support an independent role of aldosterone in inducing kidney damage both in human and experimental models, and interventional studies that highlight how strategies aimed to antagonize its action may favorably modify the progressive decline of renal function in patient with kidney disease and in patients with extrarenal disease frequently associated with kidney function impairment. © 2015 Published by Elsevier Ireland Ltd.

1. Introduction Aldosterone action, after its release from the zona glomerulosa of the adrenal gland, was believed since its isolation and characterization more than 50 years ago [1] to be limited to just few classical target organs, mainly of epithelial origin (kidney, colon and salivary and sweat glands), where the hormone induces the biochemical modifications required to maintain volume and electrolyte homeostasis by acting through genomic pathways. Targeting the tubular cells of the distal nefron of the kidney, aldosterone increases sodium reabsorption by binding to the intracellular mineralocorticoid receptor (MR) that translocates to the nucleus, where it upregulates the transcription of genes encoding Na/K-ATPase and epithelial sodium channel subunits. In the end, aldosterone promotes volume expansion, thereby increasing blood pressure. Recently however, this historical view has been modified, leading to a better understanding of the multitude of effects of aldosterone on the kidney, besides the classical effects on sodium and potassium transport in the renal tubules. MR, which mediates the genomic effects of aldosterone, is expressed in many other residing cells of the kidney. In fact it occurs also in podocytes, mesangial cells, fibroblasts, endothelial cells, ☆ Authorship: All authors had access to and participated in writing this manuscript. ⁎ Corresponding author at: Via Roberto Bracco, 1, 57127 Livorno, Italy. E-mail address: [email protected] (S. Bianchi).

etc. [2]. Binding of aldosterone to MR affects negatively the physiology of all the above cells by inducing podocyte apoptosis, mesangial proliferation and deformability, finally resulting in inflammation, fibrosis and sclerosis of the glomerular and interstitial structure [3]. On the other hand, MR blockade by MR antagonist (MRA) induces a remission of glomerulosclerosis [4] and decreases cardiac hypertrophy in a chronic kidney disease (CKD) model [5]. Furthermore, aldosterone is also synthetized in many extraadrenal tissues, including the kidney [6,7]. It is also likely that aldosterone acts in a paracrine fashion and by rapid non-genomic mechanisms [8]. Considered for years solely as a friendly ‘renal hormone’, aldosterone is now recognized as a key player in many pathological conditions, such as cardiovascular and kidney diseases, hypertension, metabolic syndrome, etc. The recognition of its direct effect on renal hemodynamic, inflammation, fibrogenesis, endothelial function, fibrinolysis and oxidative stress supports a broader implication of aldosterone than previously anticipated. 2. Most harmful effects of renin–angiotensin–aldosterone system on the kidney are mediated by aldosterone and abrogated by MRA There is great amount of evidence that renin–angiotensin–aldosterone system (RAAS) plays an important role in the pathogenesis and progression of renal diseases. Blockade of RAAS through angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker

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Please cite this article as: S. Bianchi, et al., The renal effects of mineralocorticoid receptor antagonists, Int J Cardiol (2015), http://dx.doi.org/ 10.1016/j.ijcard.2015.05.125

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(ARB) is considered the most effective therapy in slowing progression of CKD. ACEi and ARB, however, provide only imperfect protection since they sometimes fail to prevent end-stage renal failure [9]. Moreover, ACEi and ARB reduce effectively aldosterone levels during acute therapy, while the suppression of aldosterone is variable and unsustained over the long term treatment. It is possible that RAAS inhibition strategies may be suboptimal, because serum aldosterone levels may increase during RAAS blockade with ACEi or ARB (aldosterone breakthrough). This phenomenon may be associated with more severe renal damage and seems to be independent of the RAAS inhibition dosage. Although angiotensin II has been identified as the primary mediator of the system, many recent studies have raised the possibility that aldosterone, independent of renin–angiotensin, contributes in mediating renal injury. Indeed, CKD is characterized by elevated levels of aldosterone, and this has been demonstrated both in animals [10] and humans [11,12]. In rats with subtotal nephrectomy and adrenalectomy, proteinuria, hypertension and structural renal injury were less pronounced than in rats with intact adrenal glands [13]. A causal role of aldosterone in CKD is also indicated by the findings reported by Quinkler et al. [14] on kidney biopsies of patients with CKD. Serum aldosterone was correlated negatively with creatinine clearance and positively with renal scarring, and in the biopsies of patients with higher proteinuria, the MR was increased 5-fold. In a study performed in the general Japanese population, normotensive individuals without any sign of kidney disease were followed for more than 9 years [15]. Adverse renal outcome was predicted by a higher baseline aldosterone-to-renin ratio. Similarly, the prospective Framingham offspring study [16] showed that the baseline aldosterone concentration in healthy individuals was significantly associated with the development of CKD during follow-up. Green and collaborators [10] have attracted renewed attention to the role of aldosterone as independent cause of renal damage. In 1996 they demonstrated that aldosterone was able to reverse the renal protective effects of RAAS blockade in the 5/6 nephrectomy rat. They found that pharmacologic blockade of RAAS with ARB, which was associated with suppression of aldosterone secretion, reduces proteinuria and renal lesions, all of which were almost completely reversed when aldosterone was infused concurrently. Rocha et al. also demonstrated that renal-protective effects of ACEi were reversed by the infusion of aldosterone in stroke-prone spontaneously hypertensive rat. The authors found that treatment with captopril prevented the development of proteinuria and glomerular sclerosis while reducing endogenous aldosterone levels, whereas subsequent aldosterone infusion reversed almost completely these protective effects of captopril [17]. Shibata and collaborators demonstrated that uninephrectomized rats, treated with exogenous aldosterone infusion for weeks, exhibited higher proteinuria than control rats and reduced expression of nephrin, a transmembrane protein of the slit diaphragm, with consequent significative glomerular damage. Such injury was prevented by treatment with the MRA eplerenone [3] [Table 1]. The prevention of kidney injury by the administation of MRA in animal model of hypertension [18], nephron reduction [4] and diabetes [19] suggests the significant involvement of MR in these pathophysiological processes. Therefore, aldosterone may contribute to renal impairment via direct and indirect effects. Direct effects are mediated through the MR by causing tubulointerstitial inflammation and subsequent fibrosis. Indirect effects could be the consequence of non-genomic effect of this hormone (Fig. 1). Aldosterone exerts deleterious renal hemodynamic effects by elevating renal vascular resistance and glomerular capillary pressure, two conditions that have been demonstrated to cause proteinuria and accelerated kidney injury. Rising doses of aldosterone in rabbits cause dose-dependent constriction in both arterioles, with a higher sensitivity in efferent arterioles. The result is an increase of intraglomerular pressure with consequent proteinuria and renal damage. These vasoconstrictor actions are presumably non-genomic since maximum reduction of the arteriole's lumen happens in less than 10 min [8]. Furthermore it has been shown that the infusion of aldosterone for

Table 1 Potential beneficial effects of mineralocorticoid receptor antagonists on kidney function and structure. ↓ Glomerular podocyte injury ↑ Glomerular expressions of slit diaphragm–associated molecules (nephrin and podocin) ↓ Desmin, a damaged podocyte marker ↓ Monocyte and macrophage infiltration ↓ Tubulointerstitial inflammation and fibrosis ↓ Plasminogen activator inhibitor-1 and transforming growth factor-β1 ↓ Connective tissue growth factor ↓ Proinflammatory cytokines (osteopontin and monocyte chemoattractant protein-1) ↓ Vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) ↓ Reactive oxygen species production Vasodilatation or pre-glomerular afferent and mostly post-glomerular efferent arterioles ↓ Intraglomerular pressure and glomerular filtration rate (acute effect) Stabilization of glomerular filtration rate (long-term effect) ↓ Proteinuria (acute and long-term effect)

1 week to normotensive dogs determined a 20% to 24% increase of glomerular filtration rate (GFR), which was associated with an increase of renal perfusion pressure [20]. In all, these studies suggest that MRA may reduce GFR, at least acutely, due to direct effects on the renal microcirculation. 3. Effects of MRA in patients with chronic kidney disease There is an increasing amount of evidence indicating that aldosterone can induce renal damage also in humans and this hypothesis was first postulated since the description of the syndrome characterized by excess of aldosterone synthesis. In 1964 Conn et al. in the reported study of 145 patients with primary hyperaldosteronism, a condition characterized by excessive and largely autonomous aldosterone secretion, showed that high plasma aldosterone levels were in most cases associated with proteinuria and reduced renal function. For some time these renal symptoms have been attributed only to the deleterious effects of high blood pressure rather than to the direct effects of aldosterone on renal function and structure [21]. A higher prevalence of proteinuria and renal damage has been recently confirmed in patients with primary aldosteronism [22]. These conditions were significantly ameliorated after treatment with MRA [23]. On the basis of the effect of aldosterone in inducing kidney damage and the potential role of MRA in antagonizing these negative effects, recent interest has developed in therapeutic strategy aimed to reduce proteinuria and retard the progression of CKD by using MRA. Aldosterone has become a therapeutic target in patients with CKD since the publication in 2001 of the paper of Chrysostomou et al. In an uncontrolled study, these authors reported that the addition of spironolactone to ACEi in a small group of proteinuric patients with CKD induced a dramatic reduction of proteinuria, without any negative effects on renal function [24]. In a short-term study, Bianchi et al. observed that spironolactone effectively reduced proteinuria in non-diabetic CKD patients, already treated with ACEi and/or ARB, after only two weeks of treatment. It is noteworthy that in this study baseline levels of aldosterone were significantly correlated with the degree of reduction in proteinuria [25]. In diabetic patients with CKD and high levels of aldosterone, notwithstanding an active treatment with ACEi, Sato et al. [26] reported a significant reduction of proteinuria after 24 weeks of treatment with spironolactone. Of note, the decrease of proteinuria was more pronounced among patients with aldosterone breakthrough. The effect of spironolactone in decreasing proteinuria has been observed to persist 6–12 months in patients with CKD on long-term therapy with ACEi and/or ARB [12,27,28]. Similar findings were observed in studies that have used the more selective MRA eplerenone. Epstein et al. showed that eplerenone reduced proteinuria more effectively than an ACEi in patients with type

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Fig. 1. Schematic representation of the effects of aldosterone on the kidney. Aldosterone can act through the well-established pathway via the MR on epithelial cells inducing the “classic” effect on water and electrolytes reabsorption and excretion (left); with the same genomic mechanism, aldosterone interacts with MR of epithelial and non-epithelial cells inducing many deleterious effects, leading in the end to glomerular fibrosis and sclerosis (middle); finally, aldosterone can induce many other effects, mainly hemodynamic, interacting with a MMR through rapid, “nongenomic” pathway (right). MR: mineralocorticoid receptor; MMR: membrane mineralocorticoid receptor; AngioII: angiotensin II.

2 diabetes mellitus. A combination of eplerenone and ACEi was more effective than either drug given alone in reducing proteinuria [29]. The investigators also observed a rapid decrease in GFR in spironolactonetreated patients which leveled off over time. Conversely, in the placebo group, the investigators observed a progressive, linear decline in GFR. Other investigators have reported an early reduction in GFR after initiation of treatment with spironolactone [12,28]. The mechanisms responsible for this reduction in GFR are unclear. However, this phenomenon is reminiscent of the initial fall in GFR seen in patients with CKD treated with ACEi or ARB, whereby an initial rapid decrease in GFR is usually followed by stabilization of kidney function. Whereas the pattern of rapid reduction followed by stabilized GFR translates into improved long-term renal survival with ACEi and ARB, this remains to be proven with MR blockade. In fact, while the GFR showed significant improvement after an initial decrease in some studies [12], it remained significantly lower in the spironolactone group compared with the placebo group at the end of 1 year of treatment in the study published by van den Meiracker et al. [28]. Larger, long-term studies are needed to demonstrate whether or not the stabilization of renal function with MRA is persistent over time and leads to benefits in the long term renal outcome. 4. Effects of MRA on renal function in patients with heart failure Worsening of renal function is a common finding in patients with heart failure (HF) and it is associated with increased mortality both in-hospital and ambulatory patients [30]. The treatment with RAAS inhibitors in patients with HF is often associated with a significant decrease of GFR. In studies in which patients with postinfarction HF were treated with both ACEi or ARB, the decline of renal function developed mostly in the early phase of treatment, and has been reported both during hospitalization and after discharge. The occurrence of renal impairment in these patients significantly and independently correlated with mortality [31,32]. An early reduction of GFR has been also observed in clinical studies that have investigated the effects of MRA on cardiovascular outcome in patients with HF. In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), the authors

reported that patients with HF after myocardial infarction treated with the selective MRA eplerenone, when compared with those receiving placebo, showed an early significant reduction in GFR. This moderately more frequent worsening of renal function did not affect its clinical benefit on cardiovascular outcomes [33]. The EMPHASIS-HF study randomized patients with NYHA class II functional symptoms to either eplerenone or placebo. Patients treated with eplerenone when compared with those receiving placebo exhibited an early, modest, but statistically significant decline in GFR; however, other predictors of this biochemical change included older age, baseline GFR, baseline potassium, hypertension, diabetes mellitus, etc. [34]. Moreover, the rate of discontinuation and hospitalization because of reduced GFR during treatment did not differ between treatment groups and no death was directly attributed to reduced GFR. The early and mild decline in renal function observed in eplerenone-treated group of patients is similar with that observed in the Randomized ALdactone Evaluation Study (RALES) wich enrolled patients with more severe HF to treatment with spironolactone or placebo [35]. The mechanisms responsible for the acute adverse renal effects of RAAS inhibitors are complex and likely multifactorial. The hemodynamic effects of ACEi and ARB on the intraglomerular circulation (reduction of glomerular pressure and filtration due to the effect of these drugs on glomerular afferent and efferent arterioles) are well known and remain a primary reason for their use in patients with CKD [9]. The common association in these patients between initiation of RAAS inhibitors and a fall in GFR is not associated with further renal damage and warrants continued use of the drugs, because it is associated with long-term stability of renal function. If this clinical behavior is also what we could observe in patients with HF is still undetermined and it is not clear whether worsening renal function in patients with HF exposed to RAAS inhibitors predicts a worse prognosis or merely reflects the acute pharmacological action of these drugs on the kidney. The mechanisms responsible for the acute adverse renal effects of MRA in patients with HF did not probably differ from those observed in patients treated with ACEi and ARB. Aldosterone acts on glomerular hemodynamic in a fashion similar to angiotensin II, inducing a fast increase of glomerular perfusion and filtration that could be abrogated by the administration of MRA [8]. This effect on glomerular hemodynamics is probably only

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acute and transient, because no further subsequent deterioration occurred over time. The decrease of GFR observed shortly after the initiation of treatment with MRA is associated with worsened outcomes in patients treated with MRA compared with that observed in patients without any renal impairment. However, the significant decrease in mortality and hospitalization for HF observed with the use of MRA was significantly greater in patients with worsening of renal function than in the group of patients with stable GFR. Therefore, balancing pro and con consequences on clinical outcomes, cardiologists should not be deterred from using MRA when a decrease of renal function occurs. 5. Main side effects of MRA treatment in patients with CKD Hyperkalemia Hyperkalemia (HK), a potentially life-threatening condition, is undoubtedly the most feared complication of MRA treatment in patients with CKD and in those with HF, especially when these drugs are administered in addition to ACEi or ARB. A meta-analysis of Navaneethan et al. has shown that in patients with CKD the association of MRA with ACEi or ARB compared with ACEi or ARB alone, significantly increases the risk of HK [36]. Similar results have been reported in patients with HF treated with MRA, where the occurrence of HK nonetheless did not eliminate the survival benefit of treatment [33]. The risk of HK increases in patients with baseline reduced renal function and everyone should be careful whether to administer MRA when the GFR b45 ml/min/1.73 m2. Therefore a careful follow-up strategy of patients undergoing this treatment is crucial. Serum potassium levels should be frequently checked, especially during the first phases of therapy in order to identify those patients at higher risk of developing hyperkalemia. Checking serum potassium levels at the end of the first week of treatment, then every two weeks during the first months appears a reasonable strategy in patients at high risk to develop HK [12]. Besides, a close monitoring of serum potassium levels would allow to adjust the therapy with the introduction of a diet low in potassium, additional diuretic therapy, or lowering the dose of MRA, before stopping MRA treatment. Also the use of potassium-binding resins could be useful. On this regard, interesting results come from the PEARL-HF study where the authors have pioneered the use of a novel intestinal non-absorbed polymeric potassium binder, RLY5016. One hundred and five patients with chronic HF and a history of HK were treated with spironolactone. These patients were randomized to treatment with RLY5016 or placebo for 4 weeks. 66 out of 105 enrolled had GFR b 60 ml/min/1.73 m2. At the end of the study, compared with placebo, RLY5016 significantly lowered serum potassium levels. In the sixty-six patients with reduced GFR, the difference in serum potassium between groups was even greater, and the incidence of hyperkalaemia was 6.7% in treated patients and 38.5% in the placebo group, respectively. From the point of view of a practicing cardiologist, it is noteworthy that the use of the resin allowed to increase the dose of spironolactone in 91% of treated patients vs. 74% of the placebo group [37]. 5.1. Gynecomastia Gynecomastia and other unfavorable sexual side effects due to binding of aldosterone to androgen and progesterone receptors has been frequently reported as a side effect of therapy with spironolactone, to the point that it has limited its use in the clinical practice. In a population of 165 patients with stages III–V CKD, randomized to receive aldosterone or placebo, 6 of 83 patients treated with spironolactone developed gynecomastia but only one patient had to discontinue the medication [12]. Other experiences in patients with CKD has confirmed this finding [29,30]. In the RALES study the incidence was 9% in patients treated with spironolactone and 1% in the placebo arm [38]. The use of selective MRA eplerenone, equally potent as spironolactone but with lower affinity for androgen and progesterone receptors than spironolactone, drastically

minimizes the risk of gynaecomastia and other unfavorable sexual side effects, as demonstrated in the EPHESUS study [39]. 6. Conclusions Experimental and clinical data show that the activation of the MR represents a significant moment in causing renal damage and its progression. Therapeutic strategies that aim at MR blockade play an important role in reducing proteinuria and slowing the progression of chronic renal disease. The acute reduction of renal function observed when a MRA is administerd to patients with CKD or with HF seems to represent a transient hemodynamic effect, with no relevant negative implication in the long-term phase of treatment. The use of these drugs should be carefully pondered in patients with baseline reduced renal function where it should be reserved to patients that can be aware of the potential benefits as well as the potential side effects and should be subjected to a strict follow-up and close clinical observation. Conflict of interest None. References [1] S.A. Simpson, J.F. Tait, A. Wettstein, et al., Isolation from the adrenals of a new crystalline hormone with especially high effectiveness on mineral metabolism, Experientia 9 (1953) 333–335. [2] H. Kiyomoto, K. Rafiq, M. Mostofa, et al., Possible underlying mechanisms responsible for aldosterone and mineralocorticoid receptor-dependent renal injury, J. Pharmacol. Sci. 108 (2008) 399–405. [3] S. Shibata, M. Nagase, S. Yoshida, et al., Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1, Hypertension 49 (2007) 355–364. [4] J.C. Aldigier, T. Kanjanbuch, L.J. Ma, et al., Remission of existing glomerulosclerosis by inhibition of aldosterone, J. Am. Soc. Nephrol. 16 (2005) 3306–3314. [5] L. Michea, A. Villagran, A. Urzua, et al., Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and prevents oxidative stress in uremic rats, Hypertension 52 (2008) 295–300. [6] J.M.C. Connell, E. Davies, The new biology of aldosterone, J. Endocrinol. 186 (2005) 1–20. [7] S.M. MacKenzie, J.M. Connell, E. Davies, Non-adrenal synthesis of aldosterone: a reality check, Mol. Cell. Endocrinol. 350 (2012) 163–167. [8] S. Arima, K. Kohagura, H.L. Xu, et al., Non-genomic vascular action of aldosterone in the glomerular microcirculation, J. Am. Soc. Nephrol. 14 (2003) 2255–2263. [9] KDIGO, 2012 clinical practice guideline for the evaluation and management of chronic kidney disease, Kidney Int. Suppl. 3 (2013) 73–90. [10] E. Greene, S. Kren, T.H. Hostetter, Role of aldosterone in the remnant kidney model in the rat, J. Clin. Invest. 98 (1996) 1063–1068. [11] R.J. Hene, P. Boer, H.A. Koomans, et al., Plasma aldosterone concentration in chronic renal failure, Kidney Int. 21 (1982) 98–101. [12] S. Bianchi, R. Bigazzi, V.M. Campese, Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease, Kidney Int. 70 (2006) 2116–2123. [13] Z.Y. Quan, M. Walser, G.S. Hill, Adrenalectomy ameliorates ablative nephropathy in the rat independently of corticosterone maintenance level, Kidney Int. 41 (1992) 326–333. [14] M. Quinkler, D. Zehnder, K.S. Eardley, et al., Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria, Circulation 112 (2005) 1435–1443. [15] S. Terata, M. Kikuya, M. Satoh, et al., Plasma renin activity and the aldosterone-torenin ratio are associated with the development of chronic kidney disease: the Ohasama Study, J. Hypertens. 30 (2012) 1632–1638. [16] C.S. Fox, P. Gona, M.G. Larson, et al., A multi-marker approach to predict incident CKD and microalbuminuria, J. Am. Soc. Nephrol. 21 (2010) 2143–2149. [17] R. Rocha, P.N. Chander, A. Zuckerman, et al., Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats, Hypertension 33 (1999) 232–237. [18] J. Du, Y.Y. Fan, H. Hitomi, et al., Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats, Am. J. Physiol. Renal. Physiol. 297 (2009) 802–808. [19] G. Fujisawa, K. Okada, S. Muto, et al., Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats, Kidney Int. 66 (2004) 1493–1502. [20] J.E. Hall, J.P. Granger, M.J. Smith Jr., et al., Role of renal hemodynamics and arterial pressure in aldosterone “escape”, Hypertension 6 (1984) 183–192. [21] J.W. Conn, R.F. Knopf, R.M. Nesbit, Clinical characteristics of primary aldosteronism from an analysis of 145 cases, Am. J. Surg. 107 (1964) 159–172. [22] G.P. Rossi, G. Bernini, G. Desideri, et al., Renal damage in primary aldosteronism: results of the PAPY study, Hypertension 48 (2006) 232–238. [23] V.G. Fourkiotis, O. Vonend, S. Diederich, et al., Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism, Eur. J. Endocrinol. 168 (2012) 75–81.

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The renal effects of mineralocorticoid receptor antagonists.

Beyond its well known classic effects on renal water and electrolytes metabolism, an increasing amount of experimental and clinical evidence suggests ...
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