C H A P T E R

14
Pathophysiology of Hypertension
in Chronic Kidney Disease
Yonghong Huan, Debbie L. Cohen and Raymond R. Townsend
Renal, Hypertension and Electrolyte Division, University of Pennsylvania, Philadelphia,
Pennsylvania, USA

SCOPE OF THE PROBLEM AND PUBLIC Ambulatory blood pressure monitoring (ABPM) pro-
HEALTH IMPLICATIONS vides superior BP measurements compared to office BP
measurements in CKD patients. ABPM not only pro-
The prevalence of CKD continues to increase. An vides more data on BP readings but also information
estimated 26 million adults in the US have CKD.1 on diurnal BP rhythm, which normally has a 10–20%
Hypertension is the most common comorbidity in CKD. dip during sleep, compared to awake BP. The abnormal
More than 80% of patients with CKD have coexistent diurnal BP rhythm of non-dipping (less than 10% dip
hypertension. More severe stages of CKD are associ- in sleep BP) or reverse-dipping (higher asleep BP than
ated with more severe hypertension,2 which is usually awake BP) has been associated with worse cardiovascu-
more difficult to control and requires a greater num- lar outcomes.10 ABPM measurements are often abnor-
ber of medications to reach target blood pressure (BP) mal in CKD. CKD patients frequently have an altered
goals.3 Patients with more severe hypertension are also circadian rhythm with an increased rate of non-dipping
more likely to develop CKD.4 Patients with CKD also and reverse dipping.11 The prevalence of non-dippers
have an increased risk of CVD. Based on data from the and reverse-dippers increases progressively as stage
USRDS, it is estimated that hypertension occurs in 23.3% of CKD progresses. Masked hypertension is defined as
of individuals without CKD, and 35.8% of stage 1, 48.1% patients who have normal office BP readings but ele-
of stage 2, 59.9% of stage 3, and 84.1% of stage 4 and 5 vated BP readings on ABPM or home BP. Masked hyper-
CKD patients.5 Although most CKD patients require tension is more common in CKD and has been shown to
multiple antihypertensive agents to control BP, nonad- be present in studies using ABPM in this population. In
herence does not appear to be more common in CKD the African American Study of Kidney (AASK) Disease
patients compared to the general population.6 Cohort Study, of the 61% of participants with controlled
Rates of awareness and control of hypertension have clinic BP, 70% had masked hypertension. Target organ
improved in the general population and also appear to damage (proteinuria and left ventricular hypertrophy)
be improving in patients with CKD. Recent studies have was more common in those with elevated nighttime
shown that both awareness and control of hypertension in BP, masked hypertension, or sustained hypertension.
the general population compared to earlier decades have Masked hypertension, particularly nocturnal BP con-
improved from 69% to 80% and 27% to 50%, respectively.7 trol, may account for the disappointing results from the
Reports from CKD patients enrolled in prospective obser- AASK study where despite excellent in office BP control
vational studies have shown similar improvements in there was still progression of kidney disease.
the rates of awareness and BP control in the CKD popu- The likelihood of hypertension in CKD patients is
lation.3,6 CKD patients have also been shown to be more also influenced by the type of underlying renal disease.
likely to be receiving adequate treatment for hypertension Classically patients with tubulointerstitial diseases have
when compared to prior decades.8,9 had lower prevalence of elevated blood pressure than

P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease.

DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00014-7 163 2015 Elsevier Inc. All rights reserved.
© 2012
164 14.  Pathophysiology of Hypertension in Chronic Kidney Disease

those with glomerular diseases.12 Hypertension was TABLE 14.1  Changes that Lead to Increased Blood
reported in one study to be present in 93% of patients Pressure in CKD
with renal artery stenosis, 87% of patients with diabetic Increases in: Decreases in:
nephropathy (87%), and 74% of patients with polycystic
kidney disease.13 Salt retention Prostaglandins
African Americans have a higher incidence of hyper- Volume expansion Nitric oxide
tension and CKD than Caucasians, and are at greater RAAS activation Kinins
risk of developing progressive CKD and ESRD than any
Aldosterone Genetic factors
other racial group.14 African Americans develop car-
diovascular disease approximately 5 years earlier and Sympathetic activity
have higher mortality rates compared to Caucasians Exogenous drugs
of similar ages.15,16 This is largely due to the increased Ouabain-like factors
prevalence and severity of both hypertension and CKD
Obesity and insulin resistance
in African Americans. African Americans with risk vari-
ants of APOL1 (the gene that codes apolipoprotein L1) Metabolic syndrome
have a higher risk of hypertension-attributable kidney Parathyroid hormone
disease.17,18 Endothelin
Treatment of hypertension in the patient with CKD
Renal artery stenosis
can often be challenging, as these patients often have
severe hypertension, requiring the use of multiple med- Vascular damage from prior hypertension
ications to achieve target blood pressure goals. Target Vascular stiffening
blood pressure goals have traditionally been lower
Reactive oxygen species
in patients with CKD than the general population.
The targets for BP are evolving, but in general BP Genetic factors
should be less than 140/90 mm Hg for patients with
CKD and lower, in the range of 130/80 mm Hg for
patients with CKD and proteinuria.19 The ongoing NIH
sponsored Systolic Blood Pressure Intervention Trial Endothelial dysfunction
(SPRINT) will likely provide more definitive answers Inflammation, oxidative stress

Re al
on the treatment goal of BP in patients with hyperten-
e

ni dos
m

n- te
sion and CKD.
olu

an ro
/V

gi ne
ot
m

en
diu

sin
So

PATHOPHYSIOLOGY OF HYPERTENSION Increased

IN CKD BP in CKD

Sy
m
pa
The pathogenesis of hypertension in CKD is es

th
ur

et
s
complex and involves many factors. There are an po

ic
x

ac
/E
increasing number of factors that are implicated in the gs tiv
ity
u
Dr
blood pressure regulation in CKD (Table 14.1). Factors
that contribute to hypertension in CKD are shown in
Large artery stiffness
Figure 14.1. Increased wave reflection
Several large cohorts have shown that in addition
to blood pressure itself, arterial stiffness and increased FIGURE 14.1  Input of various factors on blood pressure in CKD.
pulse wave reflection are prominent in CKD and ESRD,
and are independent risks for death, CKD progression
and cardiovascular endpoints.20–22 SODIUM RETENTION AND FLUID
The increase in blood pressure results from four RETENTION
basic interrelated mechanisms by which blood pressure
is regulated: 1) sodium and fluid retention, 2) RAAS The maintenance of sodium and fluid homeosta-
hyperactivation, 3) sympathetic nervous system hyper- sis by the kidneys has long been implicated as the key
activation, and 4) vascular endothelial dysfunction. All regulator of blood pressure. A defect in kidney function
these factors are potentially modifiable. Treatment of is considered to be a prerequisite in the development
hypertension in CKD should take these into account of hypertension.23 The normal kidneys are very sensi-
when medication selection is considered. tive to blood pressure changes. A subtle change of 1 to

IV. PATHOPHYSIOLOGY
 Sympathetic Nervous System Hyperactivation 165
3 mm Hg in mean arterial pressure can result in prompt to changes in dietary sodium intake. Increased sodium
changes in sodium and fluid excretion or retention in intake leads to suppressed renin activity and reduced
normal people. In people with normal kidneys, this angiotensin II production, which ensures a prompt, pre-
autoregulatory mechanism accurately adjusts sodium cise, and effective elimination of sodium by the kidneys
and fluid balance across a wide range of blood pressure. to maintain normal blood pressure. However, inappro-
The rapid response of the kidneys in handling sodium priate suppression of RAAS activity in the presence of
and fluid is the result of changes in tubular sodium and sodium loading has been implicated in the hyperten-
fluid reabsorption, rather than total renal blood flow sion associated with CKD.31 The presence of volume
or GFR. In CKD, however, the tubular reabsorption of expansion in CKD patients further potentiates the vaso-
sodium and fluid is often not suppressed adequately, active effects of RAAS activation. Some of the increase
resulting in inappropriate sodium and fluid retention in RAAS activation appears to be the result of increased
and the development of elevated blood pressure. sympathetic input into the juxtaglomerular apparatus
The kidneys are very effective in handling sodium through the β1-adrenoreceptor.28
and fluid balance by excreting during periods of sur- The role of increased RAAS activation in the hyper-
plus and retaining during periods of deficit. In normal tension of CKD is supported by several lines of evi-
kidneys, variations in dietary sodium intake usually dence. First, CKD patients often do not have normal
result in less than 10% fluctuation in extracellular fluid suppression of plasma renin activity, given their usual
and intravascular volume, and only subtle changes state of sodium retention and volume expansion.32
in blood pressure.24 In CKD, however, blood pres- Second, CKD patients often have a good antihyper-
sure becomes more responsive to variations in dietary tensive response to both ACEIs and ARBs.33,34 In addi-
sodium intake, often increasing significantly with tion, bilateral nephrectomy results in blood pressure
increasing dietary sodium intake.25 In a study with normalization in many CKD patients.35 Third, a direct
patients of GFR ranging from 3 to 75 mL/min, the “salt- relationship between plasma renin activity and blood
sensitive” component of BP (defined as Salt Sensitivity pressure is often seen in CKD patients.36 Aside from
Index = Change in MAP (mm Hg)/Change in Dietary the hemodynamic consequences of renin activation,
Sodium Intake (meq/day)) increased exponentially as the excess angiotensin II produced likely contributes to
the GFR declined.26 The salt sensitivity index increased progressive renal functional loss and other target organ
from 0.01 at GFR of 60 mL/min, to 0.05 at GFR of damage through its stimulation of aldosterone release,
30 mL/min, and to above 0.1 for GFR of 10 mL/min. potentiation of the effects of various growth factors and
Sodium retention and volume expansion is a in particular its stimulating effects on the fibrogenic
common concomitant of the hypertension of CKD. The cytokine transforming growth factor-β.37,38
ability to excrete sodium and fluid decreases progres- A component related to renin system activation is
sively as kidney function declines. If coexisting heart aldosterone. Hostetter’s group demonstrated a large
failure is present, this further adds to the challenge of increase in aldosterone occurs in the 5th/6th nephrec-
maintaining normal volume status. Sodium intake tomy rat model.39 Aldosterone contributes to blood
increases blood pressure to a great extent as kidney pressure elevation in CKD through its effects to stimu-
function declines, and to an even greater extent than late sodium reabsorption, which occurs both through
simple volume expansion would predict at the lowest epithelial sodium transport channels, as well as through
levels of kidney function.26 This finding suggests that upregulation of sodium absorption in the sodium chlo-
the effect of sodium intake on blood pressure is likely ride channels (the thiazide-sensitive channels) of the
enhanced by the CKD milieu. distal tubule.40 Other actions of aldosterone that con-
Independent of blood pressure increasing effects tribute to increased blood pressure in CKD patients
through volume, high sodium intake also results in include inhibition of nitric oxide action, hyperfiltration
increased arterial stiffness, reductions in nitric oxide, and proteinuria, inflammation and hypertrophy at the
and promotion of inflammatory processes.27 Moreover glomerular level, and podocyte injury related to reac-
sodium intake amplifies the hypertensive effects of tive oxygen species generated by aldosterone.41
angiotensin II28 and norepinephrine (noradrenaline).29

SYMPATHETIC NERVOUS SYSTEM

RAAS HYPERACTIVATION HYPERACTIVATION

The RAAS is recognized as an important regulator The neural control of the kidneys is mostly sympa-
of blood pressure.30 Renin activity and angiotensin II thetic,42 and the sympathetic nervous system appears
production are normally regulated closely in response to be hyperactive in CKD.43 Like the RAAS, the kidneys

IV. PATHOPHYSIOLOGY
166 14.  Pathophysiology of Hypertension in Chronic Kidney Disease

are both the source and target of neurogenic activity.44 large organ, having both an antithrombotic function, as
Activation of the renal efferent sympathetic nerves, well as a significant role in regulating vascular smooth
which carry central sympathetic input into kidneys, muscle tone through a series of locally acting mediators.
results in renin secretion and renal tubular sodium One of the most potent vasoactive mediators generated
reabsorption. There is a fairly extensive network of sen- by the endothelium is nitric oxide (NO). Figure 14.2 is a
sory nerve fibers in the kidneys, and evidence indicates schematic showing the regulatory pathways involved in
renal sympathetic activation plays a role in hyperten- local generation of NO in the endothelium. Asymmetric
sion in CKD through direct vascular constriction and the dimethyl arginine (ADMA), an inhibitor of NO produc-
aforementioned interactions with the RAAS and renal tion and availability, is elevated in CKD and ESRD, and
sodium handling. The recent results of impressive blood was noted recently to be an independent predictor of
pressure reduction in drug-resistant hypertension with death in ESRD patients.55 NO activity is impaired by
renal nerve ablation support the importance of the sym- oxidative stress, which is commonly found in CKD.56
pathetic system in the pathogenesis of hypertension.45–48 Oxidative stress denatures NO into peroxynitrite
In addition, pilot studies showing similarly impressive (ONOO−), and dissociates tetrahydrobiopterin (“BH4”), a
blood pressure lowering with renal sympathetic dener- necessary cofactor for NO action, from NO. The substrate
vation in patients with CKD49 and ESRD50 further sup- for NO generation is L-arginine. In CKD, urea competes
port the important role of sympathetic hyperactivity in with L-arginine for uptake into endothelial cells, creat-
hypertension associated with CKD. ing a relative L-arginine deficiency.56 In addition, ADMA
Sympathetic activation in CKD is manifested in and symmetric dimethylarginine (SDMA) concentra-
several ways. Direct measures of muscle sympathetic tions are elevated in CKD, partly because of diminished
activity through microneurography in dialysis patients degratory pathways (such as dimethylargininedimethyl-
show increased neuronal firing consistent with activa- aminohydrolase which metabolizes ADMA), and partly
tion.51 Bilateral nephrectomy dramatically reduces both through decreased renal excretion. ADMA competes with
blood pressure in drug-resistant hypertensive patients NOS inhibiting the generation of NO, and SDMA inhib-
treated with dialysis, as well as muscle sympathetic its endothelial NO production by limiting the availability
nerve activity.51 A relatively new aspect in catecholamine of its main substrate, L-arginine, as well as stimulating
metabolism has emerged from the work of Desir and pro-inflammatory mediators such as IL-6 and TNF-alpha,
colleagues who isolated an enzyme, renalase, from the which participate in blood pressure increase through
kidney which degrades catecholamines. Reduced kidney inflammatory pathways that damage vessels.57
function is associated with less renalase activity, reduc- Vascular endothelial dysfunction appears to be char-
ing catecholamine clearance and potentially allowing acteristic of CKD.56 One of the most important vascu-
more effect because of greater catecholamine exposure.52 lar endothelial functions is the ability to produce local
Another sympathetic mechanism is an increase in vasodilator NO. Several pathways have been proposed
renin secretion induced by renal sympathetic activity to explain the endothelial dysfunction linked with the
mediated by beta-1 receptors, which can be blocked by impaired NO production, including oxidative stress,
beta-blockers. The increases in tubular sodium reab- L-arginine deficiency, and formation of ADMA and
sorption and renal vascular resistance are mediated by N-monomethylarginine (L-NMMA).
alpha receptors and can be blocked by alpha-blockers. Oxidative stress is a particularly potent means to
Central agents such as clonidine reduce renal sympa- reduce endothelial function and potentiate hyperten-
thetic activity and renin activity. Several studies attest sion. Cellular oxidation generates several species that
to the efficacy of beta-blocker therapy in hypertensive are important signaling molecules. One potent stimu-
patients with CKD.53,54 However, the association of lus to reactive oxygen species generation is angiotensin
more heart failure with alpha1-adrenoreceptor blocking II. This is particularly evident when angiotensin II is
agents has limited enthusiasm for use of this class of infused in an animal model that is deficient in antioxi-
drugs as first- or even second-line agents except in men dants. Angiotensin II infusion in such animals results in
with prostate hypertrophy symptoms. an increase in blood pressure and urinary protein excre-
tion, and kidney function declines substantially more
than in other animal models such as the DOCA-salt form
VASCULAR ENDOTHELIAL of hypertension.58 Other sources of oxidant stress include
DYSFUNCTION xanthine oxidase and NADPH oxidase. Evidence regard-
ing the importance of xanthine oxidase is the reduction
A great deal of effort has gone into understanding in the rate of kidney function loss when allopurinol is
the role of disordered endothelial function in the patho- given to patients with CKD,59 and the reduction in blood
genesis of atherosclerosis and hypertension in the set- pressure that occurs when adolescents with hyperurice-
ting of impaired kidney function. The endothelium is a mia are treated with allopurinol.60

IV. PATHOPHYSIOLOGY
 Conclusion 167

ADMA ARGININE BLOOD SURFACE

ENDOTHELIAL CELL

NITRIC OXIDE
E
CITRULLIN ARGININE SYNTHASE**

NO
ONOO
PROTEIN
DDAH ADMA
NADPH
O2 OXIDASE
DMA PRMTs

NO NO

VASCULAR SMOOTH MUSCLE CELL VASCULAR

GTP C-GMP
GC
RELAXATION

MUSCLE CELL VASCULAR SMOOTH MUSCLE CELL

FIGURE 14.2  Schema showing nitric oxide (NO) generation from arginine (transported into the endothelial cell by specialized proteins) via
endothelial nitric oxide synthase (NOS). NOS also produces reactive oxygen species, such as peroxynitrite (ONOO−), as does nicotinamide ade-
nine dinucleatide phosphate oxidase (NADPH oxidase), which through peroxidation of NO renders it unable to function as a vasodilator signal.
NO, once formed, is released across the endothelial cell surface largely in response to shear stress from the blood surface. Once uptake by vas-
cular smooth muscle occurs, NO stimulates guanylate cyclase (GC) to promote the conversion of guanosine-5′-triphosphate (GTP) to cyclic gua-
nosine monophosphate (cGMP), which results in vasodilatation of the smooth muscle. Other processes include the methylation of cell proteins
by protein-arginine methyltranserases (PRMTs) which generates asymmetric dimethylarginine (ADMA) as the protein is hydrolyzed. ADMA is
largely metabolized within cells by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which generates dimethylarginine (DMA)
and citrulline, although some ADMA may escape intracellular degradation and is released into the blood. ADMA inhibits endothelial func-
tion by competing with arginine as a substrate for NOS. In CKD, DDAH activity is diminished, the generation of reactive oxygen species is
enhanced, and the availability of NO is reduced, which all promote endothelial dysfunction.

Several other systems are also active to a pathologic in CKD patients. There are several rare phenotypes in
degree in some patients with CKD. Among those tar- which the link between the kidneys and hypertension
gets amenable to potential drug treatment are endothe- has been described, shedding light on important intra-
lin61 and aldosterone.62 Endothelin levels are elevated in renal blood pressure regulation pathways.66 Aside from
many CKD patients with uncontrolled blood pressure. diagnostic value, however, there has been little benefit
Elevated BP may respond to treatment with an endothe- achieved to date from genetic studies with respect to
lin antagonist,61,63 though this class of drugs is techni- guiding intervention.
cally only FDA approved for the treatment of pulmonary
hypertension.
CONCLUSION

DRUGS AND OTHER EXPOSURES Hypertension is highly prevalent in CKD and

increases progressively as kidney function declines. The
The anemia accompanying CKD is often treated pathogenesis of hypertension in CKD is complex and
by erythropoiesis-stimulating agents which increase multifactorial. Sodium and fluid retention and salt sen-
BP.64 In addition, lead, non-steroidal anti-inflammatory sitivity, sympathetic dysfunction and abnormalities in
drugs, calcineurin inhibitors and the use of illicit com- endothelial function are the prominent features which
pounds such as cocaine are also potential contributors contribute to hypertension, and which potentiate the
to blood pressure increases in patients with CKD.65 hypertensive effects of other factors.
Finally, there is also some progress in our under- There remain a number of unanswered questions
standing of the genetic underpinnings of hypertension regarding the pathogenesis of hypertension in CKD.

IV. PATHOPHYSIOLOGY
168 14.  Pathophysiology of Hypertension in Chronic Kidney Disease

An important goal for the future is defining the role of 14. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL,
BP in circumstances of significant genetic risks. Besides a Stamler J. End-stage renal disease in African-American and white
men. 16-year MRFIT findings. JAMA 1997;277(16):1293–8.
few identified Mendelian forms of secondary hyperten- 15. Gillum RF. The epidemiology of cardiovascular disease in black
sion due to monogenic mutations, most hypertension Americans. N Engl J Med 1996;335(21):1597–9.
in CKD patients is related to much more complicated 16. Clark LT, Emerole O. Coronary heart disease in African
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of Kidney Disease and Hypertension (AASK) cohort.67 In Am Soc Nephrol 2011;22(11):2098–105.
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larly outside the clinic, given the significant incidence of Bowden DW, Kao WH, et  al. Apolipoprotein L1 gene variants
masked hypertension and nocturnal increases in blood associate with hypertension-attributed nephropathy and the rate
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IV. PATHOPHYSIOLOGY