Aldosterone Blockade and Mineralocorticoid Receptor in CKD
Aldosterone Blockade and Mineralocorticoid Receptor in CKD
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.
Aldosterone is a steroid hormone with mineralocorticoid activity that is produced primarily by the adrenal glomerulosa in response to diverse stimuli including angiotensin II, adrenocorticotropic hormone, and importantly increased serum potassium (K) levels.
Aldosterone binds to the cytosolic mineralocorticoid receptor (MR), a member of the nuclear hormone receptor family, in the distal convoluted tubule of the kidney. According to the traditional formulation, the major physiological role of aldosterone is to increase sodium reabsorption in the distal nephron in order to maintain sodium balance and volume homeostasis. Reabsorption is mediated via activation of the apical epithelial sodium channel (ENaC) and the basolateral Na+, K+ATPase. Aldosterone enhances the expression of the gene that encodes the α-subunit of ENaC. Aldosterone influences the apical targeting and function of ENaC through diverse regulatory pathways involving the serine/threonine protein kinase, serum- and glucocorticoid-regulated kinase 1 and the ubiquitin ligase Nedd4-2.
Since its isolation and characterization almost 60 years ago, clinicians and medical investigators have perceived aldosterone primarily as acting at the level of the kidney to regulate extracellular fluid volume and K metabolism—the 'traditional or classical theory'. The past two decades have witnessed a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. Consequently, these myriad 'off target' actions of aldosterone have mandated an expansion and major revision of the traditional concept of aldosterone's role. There is substantive and ever increasing evidence that aldosterone impacts the heart, the vasculature, the central nervous system, and the kidney, and that it can promote vascular remodeling, collagen formation, and endothelial dysfunction. Aldosterone has been shown to have rapid nongenomic effects, where signaling through the classic pathways of gene activation, transcription, and protein synthesis are not required. Therefore, the nongenomic responses may be rapid. These actions contribute substantively to the pathophysiology of congestive heart failure and progressive renal dysfunction. Furthermore, there is now compelling evidence that MR activation produces hypertension by promoting a direct vasoconstrictor effect on the vascular wall and by acting in the circumventricular region of the hypothalamus. All of these new insights have spurred intense investigative interest in evaluating the use of MR antagonist (MRA) as a new treatment strategy for controlling blood pressure (BP) and reducing albuminuria/proteinuria and for possibly retarding the progression of chronic renal disease.
Although the explosive growth in this field has prompted publication of several recent reviews, the breadth and expanse of this subject has prompted an in-depth consideration of several themes and topics with a relative paucity of discussion of other topics that we believe are critically important. Consequently, our review is meant to complement these earlier publications and to highlight several salient points that require critical consideration.
In this overview, we will summarize the expanding role of aldosterone/MR activation and the potential mechanisms by which it promotes both vascular and renal injury. It is becoming increasingly evident that these effects, occurring independently of hemodynamic factors, contribute substantively to enhanced cardiovascular risk and progressive renal disease. We will review the preclinical and clinical studies that investigated the use of MRA using either spironolactone (SPL) or the selective MRA eplerenone (EPL) to attenuate progressive renal disease. We will conclude with a discussion of some of the clinical implications of utilizing MR blockade in patients with incipient nephropathy as well as the possibility that this treatment regimen may be beneficial in patients with stage 5 chronic kidney disease (CKD).
As full doses of renin–angiotensin system blockers including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) attenuate but do not abrogate progression of renal dysfunction, add-on MRA therapy constitutes a rational therapeutic strategy for retarding progression of renal disease. Furthermore, because the feasibility of add-on MRA is critically dependent on our ability to minimize or avoid the risk of hyperkalemia, and because great controversy centers on the incidence and magnitude of hyperkalemia, we will also critically review the scientific data relating to the risk of hyperkalemia with add-on MRA.
Another patient cohort that comprises a substantive portion of CKD patients, are patients whose primary disorder is resistant hypertension. Consideration of MRA treatment is often ignored in this patient cohort, because the presence of the renal disease is often overshadowed by the immediacy of the primary diagnosis of resistant hypertension. Indeed, although MRA treatment of these patients with resistant hypertension with concomitant CKD is clearly indicated as the appropriate add-on treatment, its use is frequently and inappropriately withheld because of the overriding fear of inducing hyperkalemia in the setting of CKD. In this review, we address this issue and propose that greater attention be devoted to this large hypertensive cohort that inappropriately is undertreated with MRA.
We will conclude our review by considering an issue that has both immediacy and yet is frequently ignored—the 'elephant in the room'. Patients with CKD and end-stage kidney disease (ESRD) die of cardiovascular events. Consequently, the CKD and ESRD patient is enriched with respect to susceptibility to adverse cardiovascular outcomes, the very patient who theoretically stands to benefit most from add-on MRA. This therapeutic intervention is constrained by the palpable and widespread concern regarding provoking hyperkalemia in the ESRD patient. Consequently, we plan to rigorously examine the available data base in ESRD patients in order to demonstrate that the risk for developing hyperkalemia is significantly less than previously thought, and that instituting MRA in ESRD patients with appropriate laboratory surveillance is a reasonable treatment option.
Abstract and Introduction
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.
Introduction
Aldosterone is a steroid hormone with mineralocorticoid activity that is produced primarily by the adrenal glomerulosa in response to diverse stimuli including angiotensin II, adrenocorticotropic hormone, and importantly increased serum potassium (K) levels.
Aldosterone binds to the cytosolic mineralocorticoid receptor (MR), a member of the nuclear hormone receptor family, in the distal convoluted tubule of the kidney. According to the traditional formulation, the major physiological role of aldosterone is to increase sodium reabsorption in the distal nephron in order to maintain sodium balance and volume homeostasis. Reabsorption is mediated via activation of the apical epithelial sodium channel (ENaC) and the basolateral Na+, K+ATPase. Aldosterone enhances the expression of the gene that encodes the α-subunit of ENaC. Aldosterone influences the apical targeting and function of ENaC through diverse regulatory pathways involving the serine/threonine protein kinase, serum- and glucocorticoid-regulated kinase 1 and the ubiquitin ligase Nedd4-2.
Since its isolation and characterization almost 60 years ago, clinicians and medical investigators have perceived aldosterone primarily as acting at the level of the kidney to regulate extracellular fluid volume and K metabolism—the 'traditional or classical theory'. The past two decades have witnessed a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. Consequently, these myriad 'off target' actions of aldosterone have mandated an expansion and major revision of the traditional concept of aldosterone's role. There is substantive and ever increasing evidence that aldosterone impacts the heart, the vasculature, the central nervous system, and the kidney, and that it can promote vascular remodeling, collagen formation, and endothelial dysfunction. Aldosterone has been shown to have rapid nongenomic effects, where signaling through the classic pathways of gene activation, transcription, and protein synthesis are not required. Therefore, the nongenomic responses may be rapid. These actions contribute substantively to the pathophysiology of congestive heart failure and progressive renal dysfunction. Furthermore, there is now compelling evidence that MR activation produces hypertension by promoting a direct vasoconstrictor effect on the vascular wall and by acting in the circumventricular region of the hypothalamus. All of these new insights have spurred intense investigative interest in evaluating the use of MR antagonist (MRA) as a new treatment strategy for controlling blood pressure (BP) and reducing albuminuria/proteinuria and for possibly retarding the progression of chronic renal disease.
Although the explosive growth in this field has prompted publication of several recent reviews, the breadth and expanse of this subject has prompted an in-depth consideration of several themes and topics with a relative paucity of discussion of other topics that we believe are critically important. Consequently, our review is meant to complement these earlier publications and to highlight several salient points that require critical consideration.
In this overview, we will summarize the expanding role of aldosterone/MR activation and the potential mechanisms by which it promotes both vascular and renal injury. It is becoming increasingly evident that these effects, occurring independently of hemodynamic factors, contribute substantively to enhanced cardiovascular risk and progressive renal disease. We will review the preclinical and clinical studies that investigated the use of MRA using either spironolactone (SPL) or the selective MRA eplerenone (EPL) to attenuate progressive renal disease. We will conclude with a discussion of some of the clinical implications of utilizing MR blockade in patients with incipient nephropathy as well as the possibility that this treatment regimen may be beneficial in patients with stage 5 chronic kidney disease (CKD).
As full doses of renin–angiotensin system blockers including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) attenuate but do not abrogate progression of renal dysfunction, add-on MRA therapy constitutes a rational therapeutic strategy for retarding progression of renal disease. Furthermore, because the feasibility of add-on MRA is critically dependent on our ability to minimize or avoid the risk of hyperkalemia, and because great controversy centers on the incidence and magnitude of hyperkalemia, we will also critically review the scientific data relating to the risk of hyperkalemia with add-on MRA.
Another patient cohort that comprises a substantive portion of CKD patients, are patients whose primary disorder is resistant hypertension. Consideration of MRA treatment is often ignored in this patient cohort, because the presence of the renal disease is often overshadowed by the immediacy of the primary diagnosis of resistant hypertension. Indeed, although MRA treatment of these patients with resistant hypertension with concomitant CKD is clearly indicated as the appropriate add-on treatment, its use is frequently and inappropriately withheld because of the overriding fear of inducing hyperkalemia in the setting of CKD. In this review, we address this issue and propose that greater attention be devoted to this large hypertensive cohort that inappropriately is undertreated with MRA.
We will conclude our review by considering an issue that has both immediacy and yet is frequently ignored—the 'elephant in the room'. Patients with CKD and end-stage kidney disease (ESRD) die of cardiovascular events. Consequently, the CKD and ESRD patient is enriched with respect to susceptibility to adverse cardiovascular outcomes, the very patient who theoretically stands to benefit most from add-on MRA. This therapeutic intervention is constrained by the palpable and widespread concern regarding provoking hyperkalemia in the ESRD patient. Consequently, we plan to rigorously examine the available data base in ESRD patients in order to demonstrate that the risk for developing hyperkalemia is significantly less than previously thought, and that instituting MRA in ESRD patients with appropriate laboratory surveillance is a reasonable treatment option.
