The Promise of Mineralocorticoid Antagonism in Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a major cause of morbidity and mortality in hospitalized patients. Despite substantial progress being made in understanding the mechanisms contributing to the pathophysiology of AKI, we have so far been unsuccessful in devising adequate therapeutic strategies against the disease. A growing body of evidence suggests that the activation of mineralocorticoid receptors (MRs) may contribute to the exacerbation of AKI. Indeed, several studies have demonstrated the potential of MR antagonists in preventing and treating certain forms of experimental AKI. However, the main drawback of these medications is their side-effect profile. This has been addressed with the development of newer nonsteroidal MR antagonists, which have a comparable therapeutic profile without the side effects. This mini review aims at providing a brief overview of the rationale, potential benefits and challenges associated with the use of MR antagonists, particularly the novel nonsteroidal MR blockers, as therapy against AKI.

Mineralocorticoid receptor antagonists in kidney transplantation

“…In kidney transplant recipients, ischaemia–reperfusion injury (IRI) impacts acute kidney injury (AKI), chronic kidney disease (CKD) and delayed graft function (DGF), all complications that may lead to kidney dysfunction and damage (proteinuria) and poor allograft survival 9 . IRI is primarily mediated via renal hypoperfusion in response to an imbalance between vasoconstrictive and vasodilator mediators in renal vasculature, leading to the activation of pro‐inflammatory and pro‐fibrotic pathways along with the release of reactive oxygen species 10 . Activation of MR by aldosterone has been linked to dose‐dependent vascular smooth muscle contraction in humans 11–13 .…”

“…9 IRI is primarily mediated via renal hypoperfusion in response to an imbalance between vasoconstrictive and vasodilator mediators in renal vasculature, leading to the activation of pro-inflammatory and pro-fibrotic pathways along with the release of reactive oxygen species. 10 Activation of MR by aldosterone has been linked to dose-dependent vascular smooth muscle contraction in humans. [11][12][13] Moreover, aldosterone-mediated MR activates pro-inflammatory and pro-fibrotic pathways.…”

Reducing Oxygen Demand to Alleviate Acute Kidney Injury

“…The expression of mineralocorticoid receptors has been detected in other tissues as well, where its activation may be pathophysiologic. Angiotensin II stimulates the biosynthesis and release of aldosterone from the adrenal cortex zona glomerulosa [148,149]. Aldosterone stimulates NHE3 and Na + ,K + -ATPase activities in cultured human renal proximal tubule cells [150,151].…”

Changing Paradigms in Acute Kidney Injury: From Mechanisms to Management

“…The role of the non-selective, calcium (Ca 2+ )-permeable cation channel of the transient receptor potential melastatin 2, and iron in mediating oxidative stress in AKI were discussed. New targets for intervention were described including autophagy, sphingolipid signaling, macrophage, complement and tubular transport mechanisms [1,2,3,4,5,6]. A major theme was to explore the contributors to progression of AKI to chronic kidney disease, and speakers provided elegant overviews of the experimental evidence and molecular mechanisms that are in play [7,8].…”

“…Advances in understanding the role of micro-RNA regulation of injury and repair pathways [4], organ cross-talk and lipid pathways were discussed. Knowledge obtained from pre-clinical models is now being applied to evaluating gene delivery approaches, remote ischemic pre-conditioning and novel approaches with lipoic acid [1] and mineralocorticoid receptor antagonism for prevention and management of AKI [5]. …”