Nephrol Dial Transplant (2019) 1–3
doi: 10.1093/ndt/gfz123
The renin–angiotensin–aldosterone system update:
full-court press
Anthony M. Provenzano1 and Matthew A. Sparks1,2
1
Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA and 2Renal Section, Durham
VA Health Care System, Durham, NC, USA
Correspondence and offprint requests to: Matthew A. Sparks; E-mail: matthew.sparks@duke.edu
Cardiovascular disease, blood pressure and the kidneys are in-
extricably linked by the renin–angiotensin–aldosterone system
(RAAS). The RAAS plays a dominant role in the maintenance
of basal blood pressure and the pathogenesis of hypertension,
and exerts powerful effects on kidney function [1]. The last
50 years could be dubbed the RAAS years, as manipulation of
this system with pharmacologic inhibition has been the main-
stay of therapy for a wide variety of diseases including hyperten-
sion, kidney disease, diabetes and heart disease. We review
recent advances in how the RAAS is being used in a variety of
ways in these disease states. We discuss the fate of dual RAAS
blockade in diabetic kidney disease, neprilysin inhibition in
heart failure (HF), the use of angiotensin (Ang) II in septic
shock, Ang II vaccination for hypertension, the potential use of
biased agonism of the type 1 Ang receptor and the renewed in-
terest in blocking aldosterone in hypertension (Figure 1).
The biologic exploitation of the RAAS in human disease
started after the isolation of the first angiotensin-converting en-
zyme inhibitor (ACEi) from the venom of the Brazilian pit viper
Bothrops jararaca [2]. The next decade saw numerous random-
ized clinical trials utilizing RAAS blockade, demonstrating effi-
cacy in patients with hypertension, HF and diabetic kidney
disease. This also ushered the advent of a variety of pharmaco-
logic inhibitors of the RAAS including the direct renin inhibi-
tors and the angiotensin receptor blockers (ARBs), which
demonstrated similar efficacy to ACEis but with diminished
side effects including cough and angioedema. Since ACEis and
ARBs have different targets, it was tempting to use these to-
gether for a potential synergistic effect. However, large clinical
trials utilizing dual RAAS blockade in patients with diabetic ne-
phropathy did not demonstrate an overwhelming kidney and
cardiovascular benefit. In fact, they resulted in more adverse
events such as hyperkalemia. Thus, the use of dual RAAS block-
ade is not a current strategy used in proteinuric kidney disease
[3, 4].
The RAAS plays an important role in the pathophysiology
of HF with reduced ejection fraction (HFrEF) [5]. Several ran-
domized clinical trials have demonstrated efficacy of RAAS in-
hibition to improve mortality and morbidity [5]. Recently,
novel therapies have shown promise in patients with HFrEF.
C The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
V 1
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NDT DIGEST
Neprilysin, an enzyme that degrades natriuretic peptides and
Ang II, both of which are upregulated in patients with HF, has
emerged as a key target. In nonpathologic states, natriuretic
peptides increase in response to RAAS activation and counter-
act its downstream effects [6]. However, in HF, natriuretic pep-
tides are dysregulated with concomitant RAAS overactivation.
A key component of this system is neprilysin which is an endo-
peptidase that breaks down biologically active natriuretic pepti-
des. Multiple trials have attempted to study the clinical
significance of blocking neprilysin, the most significant of
which is the angiotensin–neprilysin inhibition versus enalapril
in HF [Prospective comparison of ARNI with ACEI to
Determine Impact on Global Mortality and morbidity in Heart
Failure (PARADIGM-HF)] trial [7]. This randomized clinical
trial compared the combined neprilysin inhibitor/ARB (sacuba-
tril/valsartan) with ACEi (enalapril). The primary endpoint was
a composite of cardiovascular death or HF hospitalization [7].
The study was terminated early due to the benefit of the neprily-
sin inhibitor/ARB combination, providing yet another example
of the importance of regulation of the RAAS and indicating that
there are other targets within this system that can be of pharma-
cologic benefit.
Vasopressors are a mainstay of therapy for patients with cir-
culatory collapse. Evolutionarily, this is the entire reason for the
existence of the RAAS. Thus, it is logical that Ang II itself could
be a therapeutic option in patients with low blood pressure and
septic shock. Circulatory collapse syndromes related to periph-
eral/distributive shock are some of the most difficult to treat,
with very high mortality especially when acute kidney injury
(AKI) is present and renal replacement therapy (RRT) is re-
quired. Is it possible that Ang II could have beneficial effects on
kidney function during septic shock? The mechanism for such
an effect would be through efferent arteriolar vasoconstriction
leading to increased intraglomerular pressure and preservation
of the filtration pressure. The Angiotensin II for the Treatment
of High-Output Shock (ATHOS) and ATHOS-3 trials sought
to answer this question [8, 9]. The larger of these two studies
was ATHOS-3, which looked at 344 patients and randomized
them to receive either Ang II or placebo on a background of
standard care. The primary endpoint was an increase in mean

Relative
pathophysiologic
state
is
Seps
HTN
DKD
F
HFrE
RAAS
FIGURE 1: The RAAS is being used in a variety of ways from blocking its effect in states of relative excess in hypertension (HTN), diabetic kid-
ney disease (DKD), and heart failure with reduced ejection fraction (HFrEF) to supplementing with exogenous angiotensin II during shock
and sepsis. Progress is also advancing on how intracellular signaling can be manipulated by utilizing biased agonist of the type 1 angiotensin
receptor.
arterial pressure (MAP) by 10 mmHg after 3 h on the infusion
or to a MAP of 75 mmHg. This was greater in the Ang II group,
as was the cardiovascular Sequential Organ Failure Assessment
(SOFA) score, but not the total SOFA score [9, 10]. Multiple
limitations were noted in the trial including the lack of fluid bal-
ance, lactate and peripheral capillary oxygen saturation (SpO2)
comparisons between the groups. A post hoc analysis of patients
with AKI requiring RRT at study drug initiation in the
ATHOS-3 trial suggested greater RRT liberation in the Ang II
group [11]. Therefore, this suggests that Ang II could become a
potential pressor choice in patients with septic shock. More
studies are needed to determine its efficacy in improving overall
survival and benefit in kidney outcomes.
Given the systemic effects of RAAS on multiple disease
states, global and permanent reduction in the form of a vaccine
to temper the effect of the RAAS may be beneficial. Another po-
tential benefit would be negating the need for daily oral lifetime
therapy, thus improving medication compliance and potentially
diminishing healthcare costs [12]. This strategy has been
employed in a variety of animal models of hypertension [12].
Short-term human studies have also shown that vaccines that
affect RAAS components can result in diminished blood pres-
sure in patients with hypertension. However, the long-term
effects are not yet known, and importantly, the physiologic
need for RAAS activation in states of volume depletion do ne-
cessitate caution in the broad application of this strategy.
There have also been attempts to modulate the type 1 Ang
(AT1) receptor signaling pathway. The AT1 receptor signals as
a prototypical G-protein-coupled receptor (GPCR) and mobi-
lizes either the Gi/o or G12/13 G-protein families. Recently, just
as in other GPCRs, it has been shown that the AT1 receptor can
signal through a G-independent b-arrestin pathway. Many of
the downstream signaling pathways from b-arrestin agonism
are thought to be beneficial, whereas G-protein stimulation is
maladaptive. b-arrestin signaling allows for receptor desensiti-
zation and internalization and leads to independent signaling
through the extracellular signal-regulated kinase pathway [13].
Attempts to block the G-protein and yet stimulate the b-
arrestin pathway simultaneously (termed biased agonism) are
2 A. Provenzano and M. A. Sparks
AT1 receptor
Gα β-Arrestin
Vasoconstriction Reduced AT1 receptors
Hypertrophy Decreased cell death
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Increased cell death Other effects?
Increased BP
currently being investigated as novel therapeutic targets in a
wide range of cardiovascular diseases.
The last 5 years have seen a renewed interest in aldosterone
and the mineralocorticoid receptor as a therapeutic target in hy-
pertension. The PATHWAY-2 trial demonstrated that spirono-
lactone was more efficacious in terms of blood pressure
lowering in patients with resistant hypertension compared with
bisoprolol or doxazosin [14], thus demonstrating that RAAS
inhibition even in resistant hypertension is efficacious.
The RAAS remains an important physiologic target for both
further study and therapies. From its history and through its
more recent advances, the RAAS remains an important area of
investigation to help improve the burden of not only hyperten-
sion but also hypotension, HF, fibrosis and inflammation.
Recently, the Canagliflozin and Renal Outcomes in Type 2
Diabetes and Nephropathy trial demonstrated impressive kid-
ney and cardiovascular effects of sodium-glucose cotrans-
porter-2 (SGLT2) inhibitors in patients with diabetic kidney
disease. These patients were also on concomitant RAAS inhibi-
tors [15]. As SGLT2 inhibitors have known effects on the affer-
ent arteriole and RAAS inhibitors the efferent arteriole, it is
possible that the combination has a synergistic effect. Even
though research on the RAAS has been intensely investigated
over the last half a century, there continue to be new discoveries
and progress made.
CONFLICT OF INTEREST STATEMENT
None declared.
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Received: 2.5.2019; Editorial decision: 10.5.2019
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