***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Aims Mineralocorticoid receptor antagonists ( MRAs ) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction ( HFrEF ) , but their use is limited by hyperkalaemia and /or worsening renal function ( WRF ) . BAY 94 - 8862 is a highly selective and strongly potent non-steroidal MRA . We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease ( CKD ) . Methods and results This r and omized , controlled , phase II trial consisted of two parts . In part A , the safety and tolerability of oral BAY 94 - 8862 [ 2.5 , 5 , or 10 mg once daily ( q.d . ) ] was assessed in 65 patients with HFrEF and mild CKD . In part B , BAY 94 - 8862 ( 2.5 , 5 , or 10 mg q.d . , or 5 mg twice daily ) was compared with placebo and open-label spironolactone ( 25 or 50 mg/day ) in 392 patients with HFrEF and moderate CKD . BAY 94 - 8862 was associated with significantly smaller mean increases in serum potassium concentration than spironolactone ( 0.04–0.30 and 0.45 mmol/L , respectively , P < 0.0001–0.0107 ) and lower incidences of hyperkalaemia ( 5.3 and 12.7 % , respectively , P = 0.048 ) and WRF . BAY 94 - 8862 decreased the levels of B-type natriuretic peptide ( BNP ) , amino-terminal proBNP , and albuminuria at least as much as spironolactone . Adverse events related to BAY 94 - 8862 were infrequent and mostly mild . Conclusion In patients with HFrEF and moderate CKD , BAY 94 - 8862 5–10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of haemodynamic stress , but it was associated with lower incidences of hyperkalaemia and WRF BACKGROUND We evaluated the role of aldosterone as a mediator of renal inflammation and fibrosis in a rat model of aldosterone/salt hypertension using the selective aldosterone blocker , eplerenone . METHODS Unnephrectomized , Sprague-Dawley rats were given 1 % NaCl ( salt ) to drink and r and omized to receive treatment for 28 days : vehicle infusion ( control ) ; 0.75 microg/hour aldosterone subcutaneous infusion ; or aldosterone infusion + 100 mg/kg/day oral dose of eplerenone .  Blood pressure and urinary albumin were measured and kidneys were evaluated histologically . Renal injury , inflammation , and fibrosis were assessed by immunohistochemistry , in situ hybridization , and reverse transcription-polymerase chain reaction ( RT-PCR ) . RESULTS Aldosterone/salt induced severe hypertension compared to controls ( 220 + /- 4 mm Hg vs. 131 + /- 4 mm Hg , P < 0.05 ) , which was partially attenuated by eplerenone ( 179 + /- 4 mm Hg , P < 0.05 ) . In aldosterone/salt treated rats , renal histopathologic evaluation revealed severe vascular and glomerular sclerosis , fibrinoid necrosis and thrombosis , interstitial leukocyte infiltration , and tubular damage and regeneration .  Aldosterone/salt increased circulating osteopontin ( 925.0 + /- 80.2 ng/mL vs. 53.6 + /- 6.3 ng/mL ) and albuminuria ( 75.8 + /- 10.9 mg/24 hours vs. 13.2 + /- 3.0 mg/24 hours ) compared to controls and increased expression of proinflammatory molecules . Treatment with eplerenone reduced systemic osteopontin ( 58.3 + /- 4.2 ng/mL ) , albuminuria ( 41.5 + /- 7.2 mg/24 hours ) , and proinflammatory gene expression : osteopontin ( OPN ) , monocyte chemoattractant protein-1 ( MCP-1 ) , interleukin-6 ( IL-6 ) , and interleukin-1beta ( IL-1beta ) . CONCLUSION These findings indicate that aldosterone/salt-induced renal injury and fibrosis has inflammatory components involving macrophage infiltration and cytokine up-regulation . Attenuation of renal damage and inflammation by eplerenone supports the protective effects of aldosterone blockade in hypertensive renal disease IMPORTANCE Steroidal mineralocorticoid receptor antagonists , when added to a renin-angiotensin system blocker , further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events . OBJECTIVE To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone , given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled , parallel-group study conducted at 148 sites in 23 countries . Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014 . Of 1501 screened patients , 823 were r and omized and 821 received study drug . INTERVENTIONS Participants were r and omly assigned to receive oral , once-daily finerenone ( 1.25 mg/d , n = 96 ; 2.5 mg/d , n = 92 ; 5 mg/d , n = 100 ; 7.5 mg/d , n = 97 ; 10 mg/d , n = 98 ; 15 mg/d , n = 125 ; and 25 mg/d , n = 119 ) or matching placebo ( n = 94 ) for 90 days . MAIN OUTCOMES AND MEASURES The primary outcome was the ratio of the urinary albumin-creatinine ratio ( UACR ) at day 90 vs at baseline . Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate . RESULTS The mean age of the participants was 64.2 years ; 78 % were male . At baseline , 36.7 % of patients treated had very high albuminuria ( UACR ≥300 mg/g ) and 40.0 % had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower . Finerenone demonstrated a dose-dependent reduction in UACR . The primary outcome , the placebo-corrected mean ratio of the UACR at day 90 relative to baseline , was reduced in the finerenone 7.5- , 10- , 15- , and 20-mg/d groups ( for 7.5 mg/d , 0.79 [ 90 % CI , 0.68 - 0.91 ; P = .004 ] ; for 10 mg/d , 0.76 [ 90 % CI , 0.65 - 0.88 ; P = .001 ] ; for 15 mg/d , 0.67 [ 90 % CI , 0.58 - 0.77 ; P<.001 ] ; for 20 mg/d , 0.62 [ 90 % CI , 0.54 - 0.72 ; P < .001 ] ) . The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups ; incidences in the finerenone 7.5- , 15- , and 20-mg/d groups were 2.1 % , 3.2 % , and 1.7 % , respectively . There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30 % or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups . CONCLUSIONS AND RELEVANCE Among patients with diabetic nephropathy , most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker , the addition of finerenone compared with placebo result ed in improvement in the urinary albumin-creatinine ratio . Further trials are needed to compare finerenone with other active medications . TRIAL REGISTRATION clinical trials.gov Identifier : NCT1874431 
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Interestingly , recent evidence suggests that MR signaling is increased by Rac1 activation , independent of lig and binding to MR , and that Rac1 was shown to be activated by angiotensin II and diabetic conditions [ 5 ] .
There are many convincing data suggesting that MRAs may provide additional reno-protective effects in patients experiencing the aldosterone escape phenomenon during RAS blockade treatment [ 6 ] .