Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

Kawanami, Daiji; Yuasa, Takashi; Muta, Yoshimi; Oda, Naoki; Nagata, Dai; Takahashi, Hiroyuki; Tanabe, Makito

doi:10.3389/fphar.2021.754239

Cited by 28 publications

(20 citation statements)

References 143 publications

(180 reference statements)

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“…Consistent with this proposal, other investigators showed that MR activation induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria and MR blockade reduces podocyte damage and proteinuria [ 33 , 52 , 53 ]. In addition, MR blockade has a potent anti-inflammatory and antifibrotic properties [ 54 , 55 , 56 ]. These preclinical studies shed light on the mechanisms by which MR antagonism reduces renal disease and are relevant to results of recent large-scale studies in patients with CKD and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II

Huang

Guzelce

Gholami

et al. 2023

IJMS

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Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8–10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12–14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

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Section: Discussionmentioning

confidence: 99%

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II

Huang

Guzelce

Gholami

et al. 2023

IJMS

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“…In fact, they activate the MR in individuals with the genetic variant S810L, causing early severe hypertension [ 40 ]. This alters the effect on proteinuria and kidney damage, with finerenone having a greater effect than spironolactone and eplerenone [ 38 , 39 ]. Furthermore, in pre-clinical studies, finerenone was shown to have a homogeneous distribution between the kidney and heart, while spironolactone and eplerenone are preferentially concentrated in the kidney, which increases the risk of hyperkalemia ( Table 1 ) [ 4 , 20 , 28 , 37–39 ].…”

Section: Mr Antagonistsmentioning

confidence: 99%

Cardiorenal benefits of finerenone: protecting kidney and heart

et al. 2023

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Persons with diabetes and chronic kidney disease (CKD) have a high residual risk of developing cardiovascular (CV) complications despite treatment with renin-angiotensin system blockers and sodium-glucose cotransporter type 2 inhibitors. Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis. Finerenone is a nonsteroidal selective mineralocorticoid antagonist. Recent clinical trials, such as FIDELIO-DKD and FIGARO-DKD and the combined analysis FIDELITY have demonstrated that finerenone decreases albuminuria, risk of CKD progression, and CV risk in subjects with type 2 diabetes (T2D) and CKD. As a result, finerenone should thus be considered as part of a holistic approach to kidney and CV risk in persons with T2D and CKD. In this narrative review, the impact of finerenone treatment on the CV system in persons with type 2 diabetes and CKD is analyzed from a practical point of view. Key messages: Despite inhibition of renin-angiotensin system and sodium-glucose cotransporter type 2, persons with type 2 diabetes (T2D) and chronic kidney disease (CKD) remain on high cardiovascular (CV) residual risk. Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis that is not targeted by traditional treatments. Finerenone is a nonsteroidal selective mineralocorticoid antagonist that decreases not only albuminuria, but also the risk of CKD progression, and CV risk in subjects with T2D and CKD.

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“…References for this section: [41][42][43][44][45] The mineraolcorticoid receptor is an important contributor to the development of diabetic kidney disease. Mineralocorticoid receptor overactivation is assumed to promote kidney inflammation and fibrosis in diabetic individuals.…”

Section: Mineralocorticoid Receptor Antagonism In Diabetic Kidney Dis...mentioning

confidence: 99%

Diabetic kidney disease in type 2 diabetes: a consensus statement from the Swiss Societies of Diabetes and Nephrology

Zanchi¹,

Jehle²,

Lamine³

et al. 2023

Swiss Med Wkly

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Diabetic kidney disease is highly prevalent in patients with type 2 diabetes and is a major cause of end-stage renal disease in Switzerland. Patients with diabetic kidney disease are among the most complex patients in diabetes care. They require a multifactorial and multidisciplinary approach with the goal to slow the decline in glomerular filtration rate (GFR) and cardiovascular morbidity. With this consensus we propose an evidence-based guidance to health care providers involved in the care of type 2 diabetic patients with diabetic kidney disease. First, there is a need to increase physician awareness and improve screening for diabetic kidney disease as early intervention may improve clinical outcomes and the financial burden. Evaluation of estimated GFR (eGFR) and spot urine albumin/creatinine ratio is recommended at least annually. Once it is diagnosed, glucose control and optimisation of blood pressure control with renin-angiotensin system blockers have been recommended as mainstay management of diabetic kidney disease for more than 20 years. Recent, high quality randomised controlled trials have shown that sodium-glucose cotransporter-2 (SGLT2) inhibition slows eGFR decline and cardiovascular events beyond glucose control. Likewise, mineralocorticoid receptor antagonism with finerenone has cardiorenal protective effects in diabetic kidney disease. Glucagon-like peptide-1 (GLP1) receptor agonists improve weight loss if needed, and decrease albuminuria and cardiovascular morbidity. Lipid control is also important to decrease cardiovascular events. All these therapies are included in the treatment algorithms proposed in this consensus. With advancing kidney failure, other challenges may rise, such as hyperkalaemia, anaemia and metabolic acidosis, as well as chronic kidney disease-mineral and bone disorder. These different topics and treatment strategies are discussed in this consensus. Finally, an update on diabetes management in renal replacement therapy such as haemodialysis, peritoneal dialysis and renal transplantation is provided. With the recent developments of efficient therapies for diabetic kidney disease, it has become evident that a consensus document is necessary. We are optimistic that it will significantly contribute to a high-quality care for patients with diabetic kidney disease in Switzerland in the future.

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Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

Cited by 28 publications

References 143 publications

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II

Cardiorenal benefits of finerenone: protecting kidney and heart

Diabetic kidney disease in type 2 diabetes: a consensus statement from the Swiss Societies of Diabetes and Nephrology

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