Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease

Alexandrou, Maria‐Eleni; Papagianni, Αikaterini; Τσάπας, Απόστολος; Loutradis, Charalampos; Boutou, Afroditi; Piperidou, Alexia; Papadopoulou, Dorothea; Ruilope, Luis; Bakris, George L.; Sarafidis, Pantelis A.

doi:10.1097/hjh.0000000000002187

Cited by 73 publications

(42 citation statements)

References 75 publications

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“…Aldosterone is known to affect volume status by the regulating renal sodium reabsorption and exert profibrotic effects through increased production of TGF-beta, reactive oxygen, species, PAI-1 and increased collagen gene expression and synthesis [41,42] and, the use of MRI has been demonstrated to reduce inflammation and fibrosis at kidney level [43][44][45]. Several studies have shown that the addition of aldosterone receptor blockade to ACEI or ARB blockade can lead to further reduction in albuminuria including in DKD [46][47][48], however long-term data on the efficacy of mineralocorticoid receptor antagonists on hard endpoints, for example the development of ESKD or patient survival, are still lacking.…”

Section: Limitations Of Raas Inhibitionmentioning

confidence: 99%

Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations

et al. 2020

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Diabetic kidney disease (DKD) affects approximately one-third of patients with diabetes and taking into consideration the high cardiovascular risk burden associated to this condition a multifactorial therapeutic approach is traditionally recommended, in which glucose and blood pressure control play a central role. The inhibition of renin–angiotensin–aldosterone RAAS system represent traditionally the cornerstone of DKD. Clinical outcome trials have demonstrated clinical significant benefit in slowing nephropathy progression mainly in the presence of albuminuria. Thus, international guidelines mandate their use in such patients. Given the central role of RAAS activity in the pathogenesis and progression of renal and cardiovascular damage, a more profound inhibition of the system by the use of multiple agents has been proposed in the past, especially in the presence of proteinuria, however clinical trials have failed to confirm the usefulness of this therapeutic approach. Furthermore, whether strict blood pressure control and pharmacologic RAAS inhibition entails a favorable renal outcome in non-albuminuric patients is at present unclear. This aspect is becoming an important issue in the management of DKD since nonalbuminuric DKD is currently the prevailing presenting phenotype. For these reasons it would be advisable that blood pressure management should be tailored in each subject on the basis of the renal phenotype as well as related comorbidities. This article reviews the current literature and discusses potentials and limitation of targeting the RAAS in order to provide the greatest renal protection in DKD.

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Section: Limitations Of Raas Inhibitionmentioning

confidence: 99%

Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations

et al. 2020

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“…Remnant rat models have shown that the addition of aldosterone increases proteinuria and glomerulosclerosis in the kidney, even reversing the protection seen with ACEI/ARB treatment ( Greene et al, 1996 ). Steroidal MRAs, such as eplerenone and spironolactone, have been shown to decrease proteinuria in CKD patients and have long been used for the management of hypertension and HF, but have safety concerns due to the risk of hyperkalemia ( Alexandrou et al, 2019 ; Barrera-Chimal et al, 2019 ). The aldosterone-salt model used for this study, as well as the similar DOCA-salt model, have been used historically to test the potential benefits of some MRAs, including non-steroidal MRAs such as esaxerenone and BR-4628, a precursor to finerenone ( Schupp et al, 2011 ; Arai et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have found that MRA therapy significantly decreases the urine albumin-to-creatinine ratio (UACR), showing efficacy in the treatment of patients with CKD ( Barrera-Chimal et al, 2019 ). Two recent meta-analysis reviews of randomized controlled trials that evaluated the effects of combination treatment of MRAs and ACEI/ARB concluded that MRAs either alone or in combination with ACEI/ARB resulted in significant antiproteinuric effects compared with ACEI/ARB therapy alone ( Alexandrou et al, 2019 ; Zuo and Xu, 2019 ). However, patients with CKD, heart failure (HF), or cardiometabolic syndrome, or those taking ACEI/ARB therapy are at risk of developing hyperkalemia ( Palmer, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury

Jaisser

Tan²,

Chi³

et al. 2021

Front. Pharmacol.

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The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.

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“…The first meta-analysis looking at the role of spironolactone and eplerenone in chronic kidney disease patients already treated with RAS inhibitors showed that MRA reduce proteinuria and increase the risk of hyperkalemia [55]. In the latest meta-analysis, the use of MRA (spironolactone, eplerenone, finerenone) alone or on top of RAS inhibitors had a significant antiproteinuric effect in chronic kidney disease patients [56]. Compared to placebo, MRA decreased UACR by 24.6%, urine protein-creatinine ratio by 53.9% and 24 h albuminuria by 32.5%.…”

Section: Mineralocorticoid Receptor Antagonists (Mra)mentioning

confidence: 99%

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

et al. 2021

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Diabetes mellitus is a global health issue and main cause of chronic kidney disease. Both diseases are also linked through high cardiovascular morbidity and mortality. Diabetic kidney disease (DKD) is present in up to 40% of diabetic patients; therefore, prevention and treatment of DKD are of utmost importance. Much research has been dedicated to the optimization of DKD treatment. In the last few years, mineralocorticoid receptor antagonists (MRA) have experienced a renaissance in this field with the development of non-steroidal MRA. Steroidal MRA have known cardiorenal benefits, but their use is limited by side effects, especially hyperkalemia. Non-steroidal MRA still block the damaging effects of mineralocorticoid receptor overactivation (extracellular fluid volume expansion, inflammation, fibrosis), but with fewer side effects (hormonal, hyperkalemia) than steroidal MRA. This review article summarizes the current knowledge and newer research conducted on MRA in DKD.

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Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease

Cited by 73 publications

References 75 publications

Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations

Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations

The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

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