131The Central Role of the Renin-Angiotensin-Aldosterone
System
The RAAS has powerful effects on control of the blood pressure and on target organ
damage due to hypertension. It also controls fluid and electrolyte balance through
coordinated effects on the heart, blood vessels, and kidneys. The system is largely
mediated by kidneys, and abnormal activation of the RAAS plays a pivotal role in
CKD-related hypertension.
In the classic pathway of the RAAS, renin release results in the subsequent gen-
eration of angiotensin II and aldosterone secretion. Angiotensin I has little effect on
blood pressure and angiotensin II is the main effector of the RAAS. The activation
of RAAS causes angiotensin II-mediated vasoconstriction as well as aldosterone-
mediated salt retention, thus, resulting to increase both total peripheral resistance
and blood volume. Angiotensin II can also potentiate sodium reabsorption and
enhance sympathetic nervous system (SNS) activity.
While plasma renin activity is typically found to be markedly elevated only in
patients with renal artery stenosis, many patients with CKD have “inappropriately
normal” renin levels (i.e., lower levels would be expected, considering their
degree of hypertension and fluid overload). There is also evidence of an intrarenal
RAAS that is regulated independently of the systemic RAAS [ 20 ]. In the kidney,
all of the RAAS components are present, and intrarenal angiotensin II is formed
by independent multiple mechanisms. Inappropriate activation of the intrarenal
RAAS is also an important contributor to the pathogenesis of CKD-related hyper-
tension [ 20 ].
Markedly increased plasma renin activity has been well documented in hemodi-
alysis patients with uncontrolled hypertension despite optimized ultrafiltration [ 21 ].
Treatment of such patients with bilateral nephrectomy or RAAS inhibitors has been
shown to result in lowered blood pressure, suggesting the failing kidney as the
source of excess renin activity [ 21 , 22 ]. Increased renin activity occurs probably due
to renin secretion in poorly perfused areas such as cysts and scars or after microan-
giopathic damage or tubulointerstitial inflammation.
A high incidence of hypertension (50–75%) occurs early in the course of autoso-
mal polycystic kidney disease, and in this setting, activation of the RAAS is an
important factor in the pathogenesis of hypertension. The release of excess renin is
believed to be from renal ischemia due to compression of the renal vasculature by
enlarging cysts in polycystic kidney disease.
Aldosterone not only potentiates sodium reabsorption in the distal nephron
through the mineralocorticoid receptor but also directly affects vascular system by
inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis, and
endothelial dysfunction [ 23 ]. Aldosterone may play a significant role in the devel-
opment in CKD-related hypertension [ 24 , 25 ]. However, limited data from human
studies suggest that aldosterone levels increase as kidney function declines.
8 Pathophysiological Insights of Hypertension in Patients with Chronic Kidney Disease