Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms

Abstract

The past two decades have witnessed a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. There is substantive evidence that mineralocorticoid receptor (MR) activation promotes myriad 'off target' effects on the heart, the vasculature, and importantly the kidney. In the present review, we summarize the expanding role of MR activation in promoting both vascular and renal injury. We review the recent clinical studies that investigated the efficacy of MR antagonism (MRA) in reducing proteinuria and attenuating progressive renal disease. We also review in-depth both the utility and safety of MRA in the end-stage renal disease (ESRD) patient undergoing dialysis. Because the feasibility of add-on MRA is critically dependent on our ability to minimize or avoid hyperkalemia, and because controversy centers on the incidence of hyperkalemia, we critically review the risk of hyperkalemia with add-on MRA. Our present analysis suggests that hyperkalemia supervening in MRA-treated patients is overstated. Furthermore, recent studies demonstrating the efficacy of new non-absorbed, orally administered, potassium [K+]-binding polymers suggest that a multi-pronged approach encompassing adequate surveillance, moderate or low-dose MRA, and K-binding polymers may adequately control serum K in both chronic kidney disease and ESRD patients.

Focal Segmental Glomerulosclerosis

“…This approach may have less effect on reducing glomerular capillary pressure, but aldosterone antagonists are potent antifibrotic agents. Recent data have shown that aldosterone is positioned upstream of multiple profibrotic pathways and that angiotensin 2 is only one of many stimuli to aldosterone production (131). This combination confers a risk for hyperkalemia, particularly with reduced GFR; this may be controlled with dietary restriction and diuretics, although close monitoring may be required.…”

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials

“…2 While treatment with MRA might be thought to be of limited efficacy in patients on ACEi or ARB therapy, detailed study of patients on this treatment reveals that in many cases use of ACEi and ARB decreases levels of circulating aldosterone only for a period of weeks. In 10-50% of patients' circulating aldosterone concentrations return to pre-treatment levels (a phenomenon termed 'aldosterone breakthrough').…”

“…4 Strong evidence suggests that ACEi and ARB drugs do not effectively inhibit aldosterone production in all patients and that aldosterone may also be a mediator of renal and cardiovascular damage in patients with CKD. 2 Mineralocorticoid receptors are present in the brain, heart and blood vessels as well as the kidney, and there is evidence of aldosterone production within these tissues. 5 Local mineralocorticoid receptor activation by aldosterone causes numerous pathological effects on the cardiovascular system including endothelial injury, inflammation, oxidative stress and fibrosis in the heart and vasculature, as well as the development of hypertension and autonomic dysfunction.…”

“…1 The importance of the renin-angiotensinaldosterone system (RAAS) in the progression of CKD and in the development of cardiovascular disease associated with this condition is widely recognized. 2,3 The renal and cardiovascular benefits of inhibition of the RAAS have been demonstrated in multiple large trials of angiotensinconverting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), largely attributed to the prevention of the multiple adverse effects of angiotensin II. 4 Strong evidence suggests that ACEi and ARB drugs do not effectively inhibit aldosterone production in all patients and that aldosterone may also be a mediator of renal and cardiovascular damage in patients with CKD.…”

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

“…28 Studies over the past two decades have shown that aldosterone plays an independent role as a mediator of kidney injury and progression of chronic kidney disease. 29 Aldosterone has been shown to exert its effects through genomic or non-genomic pathway. 30 Genomic effects of aldosterone are generally thought to be mediated by the MR and involve transcription, while aldosterone can also exert rapid nongenomic effects that are not blocked by inhibitors of transcription.…”