Mineralocorticoid receptor antagonists in kidney transplantation: time to consider?
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Although patient survival is significantly improved by kidney transplantation (KT) in comparison with dialysis, it remains significantly lower than that observed in the general population. Graft function is one of the major determinants of patient survival after KT. Mineralocorticoid receptor antagonists (MRAs) could be of particular interest in this population to improve graft function and treat or prevent cardiovascular (CV) complications. In KT, ischaemia/reperfusion injury is a major factor involved in delayed graft function, which is often associated with inferior long-term graft survival. Preclinical studies suggest that MRAs may prevent ischaemia/reperfusion-related lesions in addition to having a protective effect in preventing calcineurin inhibitor-induced nephrotoxicity. Clinical data also support the anti-proteinuric effect of MRAs in chronic kidney disease (CKD). Taken together, MRAs may hence be of particular benefit in improving short- and long-term graft function. Numerous randomized controlled trials (RCTs) have shown the efficacy of MRAs in both heart failure and resistant hypertension. As these comorbidities are frequent in kidney transplant recipients before transplantation or during follow-up, MRAs could represent a useful therapeutic option in those with mild renal function impairment. However, CKD patients are under-represented in RCTs and the CV effects of MRAs in kidney transplant recipients have yet to be specifically assessed in large-scale trials. Available evidence indicates a good safety profile for MRAs in patients with a glomerular filtration rate (GFR) >30 mL/min/1.73 m2. However, as for all patients prescribed an MRA, creatinine and potassium should also be closely monitored following MRA initiation in kidney transplant patients. Given the current evidence suggesting that MRAs prevent ischaemia/reperfusion-related lesions and calcineurin inhibitor-induced nephrotoxicity in kidney transplant recipients as well as CV events in patients at high risk of CV complications (such as those in kidney transplant recipients), trials are urgently needed to fully assess the clinical impact of MRA use in this population.Keywords:
MRAS
Eplerenone
Over the last decade a wealth of studies have shed new light on the role of aldosterone in the pathogenesis of cardiovascular diseases. It is now evident that in addition to its classical role in increasing sodium reabsorbtion in the kidney , aldosterone also exhibits several nonepithelial effects such as the induction of inflammation, fibrosis and necrosis in various organs. Herein we review the experimental evidences for the protective effects of mineralocorticoid receptor blockade in the prevention and treatment of target organ damage, both in animals and in humans. We also discuss the pharmacological and clinical differences between the two available mineralocorticoid receptor blockers, spironolactone and eplerenone. Keywords: Aldosterone, eplerenone, spironolactone, mineralocorticoid receptor, mineralocorticoid receptor antagonists
Eplerenone
Mineralocorticoid
Pathogenesis
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Mineralocorticoid
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Eplerenone
Mineralocorticoid
Blocking (statistics)
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Mineralocorticoid
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Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRATM), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.
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Mineralocorticoid
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Mineralocorticoid
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We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.
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End organ damage
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Summary 1. The importance of mineralocorticoid receptor (MR) antagonists in the treatment of cardiovascular disease has been emphasised by two recent clinical trials, one using spironolactone and the other using a new selective MR antagonist, namely eplerenone. 2. Eplerenone has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of eplerenone to the MR were investigated using chimeras created between the ligand‐binding domains (LBD) of the MR and the GR. These chimeras had been used previously to investigate aldosterone and spironolactone binding specificity to the MR. 3. Eplerenone competed strongly for [ 3 H]‐dexamethasone binding to a MR/GR chimera containing amino acids 804–874 of the MR and weakly to a chimera containing amino acids 672–803 of the MR. Within the 804–874 region, eplerenone competed for [ 3 H]‐dexamethasone binding to a chimera containing amino acids 820–844 of the MR, although the calculated affinity was approximately 10‐fold lower than for binding to the full‐length MR LBD. Similar results were obtained using another MR antagonist, namely spironolactone. Modelling of eplerenone binding to the MR LBD, based on the GR LBD crystal structure, suggests that amino acids 820–844 affect the overall shape of the ligand‐binding pocket and that eplerenone acts as an MR antagonist because it fails to stabilize the active conformation of the receptor. 4. In contrast with results with the MR antagonists eplerenone and spironolactone, amino acids 820–844 are sufficient in themselves to confer high‐affinity aldosterone binding to the MR, suggesting that the binding determinants of the two antagonists are similar to each other but differ from those of aldosterone.
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Mineralocorticoid
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Mineralocorticoid
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