REVIEWS

Management of hypertension in chronic

kidney disease
Raymond R. Townsend and Sandra J. Taler
Abstract | Hypertension is a common comorbidity in patients with impaired kidney function. The kidney exerts
a marked degree of control over blood pressure through various mechanisms, such as by regulating sodium
balance and hormone secretion through the activity of the reninangiotensin system. The kidney is susceptible
to injury, and if already damaged can be at risk of further loss of function as a consequence of elevated
blood pressure. Once elevated blood pressure is identified, a combination of sensible lifestyle measures,
such as sodium restriction and weight loss, with pharmacological intervention to reduce blood pressure will
usually achieve blood pressure goals. In this Review, we outline the importance of blood pressure control for
patients with chronic kidney disease (CKD), the mechanisms that affect blood pressure control, and the basis
for non-drug and drug therapies. We further discuss the rationale for <140 mmHg systolic and <90 mmHg
diastolic targets for blood pressure in patients with CKD, with consideration for tighter targets in the setting
ofproteinuria.
Townsend, R. R. & Taler, S. J. Nat. Rev. Nephrol. advance online publication 28 July 2015; doi:10.1038/nrneph.2015.114

Introduction
Strong evidence, based on more than a century of blood
pressure monitoring, clearly demonstrates that elevated
blood pressure reduces life expectancy and has a marked
influence on target organ damage, including of the heart,
brain, and kidneys. Target organ damage might occur
in one, several, or all of these organs. Previous efforts to
identify and manage hypertension have predominantly
focused on reducing mortality, heart disease, and stroke.
Preservation of kidney function in patients with hyper-
tension, however, has become a high priority for prac-
titioners over the past 30years, in conjunction with an
increased awareness of the high prevalence (~12%) of
chronic kidney disease (CKD) in the US population.1
Hypertension is the most common comorbidity in
patients with CKD, affecting 6792% of patients; the
prevalence of hypertension increases with declining renal
function.2 Control of hypertension is, therefore, a major
priority in the management of CKD and represents an
important modifiable factor in slowing further loss of
kidney function.35 Elevated blood pressure can occur as
a result of CKD but is also a potent risk factor for CKD
University of
progression, rendering it difficult to determine which
Pennsylvania, Perelman disease process precedes the other. Patients at highest
School of Medicine, risk of hypertension often share characteristics that
3400 Spruce Street,
Philadelphia, also represent risk of CKD, including older age, African
PA19104, USA descent, overweight or obesity, and concurrent diagnoses
(R.R.T.). Mayo Clinic,
Division ofNephrology
of diabetes mellitus and/or cardiovascular disease.6
and Hypertension, 200 The interaction between hypertension and CKD is
First Street Southwest, complex and as such, has sparked debate as to the optimal
Rochester, MN 55905,
USA (S.J.T.). blood pressure target for delaying the progression of
Correspondence to:
R.R.T. Competing interests
townsend@upenn.edu The authors declare no competing interests.
kidney disease. This debate is exemplified by the differ-
ences in the recommendations for blood pressure control
from KDIGO and JNC8 (Table1). Regardless of these
differences, the coexistence of hypertension and CKD
is known to greatly increase the risk of adverse cardio-
vascular and cerebrovascular outcomes, and therapy to
reduce blood pressure is therefore indicated to limit CKD
progression and protect other target organs, particularly
the heart and brain, from damage.1,3,4 The risk of these
described outcomes is further intensified in the pres-
ence of proteinuria.7 Patients with proteinuria exhibit
a greater need for effective blood pressure treatment to
prevent morbidity and mortality as compared to those
withoutproteinuria.
Numerous exogenous and endogenous factors can
influence blood pressure in patients with CKD, includ-
ing high dietary sodium intake, enhanced activity of the
sympathetic nervous system and reninangiotensin
aldosterone system (RAAS), and endothelial dysfunc-
tion.827 Furthermore, impaired kidney function might
amplify the adverse effects on blood pressure that can
be elicited by various prescription and over-the-counter
medications, such as NSAIDs.28
In this Review we address the necessity of frequent
and accurate blood pressure monitoring in patients
with CKD, the current recommendations regarding
blood pressure target levels, and the rationale behind
these recommendations. We describe the mechanisms
that underlie a rise in blood pressure in the presence of
impaired kidney function, and conclude by discussing
the current lifestyle interventions, drug treatments, and
device therapies that are available for the management of
high blood pressure in patients with CKD.

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Key points
Elevated blood pressure can occur as a result of, and be a potent risk factor for,
chronic kidney disease (CKD) progression
CKD is associated with dysregulation of various blood pressure control
systems, including the ability to excrete the daily sodium load, sympathetic
activation, reninangiotensin system activity, and endothelial function
Although controversial, the Joint National Committee recommends target blood
pressure levels <140/90 mmHg in US patients with CKD until 70years of age
Most guidelines for hypertension treatment in CKD recommend administration
of an agent that blocks the reninangiotensin system, with follow-up testing of
kidney function and serum potassium concentrations
Home and ambulatory blood pressure monitoring can improve the assessment
of overall blood pressure control in patients with CKD, as compared to office
measurements alone
Device-based methods for blood pressure reduction, such as renal denervation
and baroreceptor activation therapy, suggest safety in CKD; unequivocal
efficacy remains to be shown in sham-controlled studies
Blood pressure measurement
Automated blood pressure measurements
The growing recognition of the value of home and
ambulatory blood pressure monitoring is changing
clinical practice. Both methods can better predict risk of
cardiovascular events2932 in the general population and
in patients with CKD3335 compared to office measure-
ments. Out of office measurements might not, however,
be consistently available, and consequently many treat-
ment decisions must still be based primarily on office
readings. A standardized approach to measuring blood
pressure improves the consistency and accuracy of the
recorded readings. The use of an automated device might
be more reliable than manual auscultatory methods and
will generally provide reproducible and accurate meas-
urements.36 The BpTRU (BpTRU Medical Devices,
Canada) and Omron HEM907 (OMRON Healthcare
Europe B.V., The Netherlands) devices have both been
validated in the office setting.3640
Ambulatory blood pressure monitoring
Ambulatory blood pressure monitoring provides a vast
amount of additional data compared to office recordings,
including nocturnal measurements and data on blood
pressure variability. Nocturnal blood pressure and circa-
dian blood pressure rhythm is often abnormal in patients
with CKD, and is usually characterized by a loss of the
normal nocturnal 1020% fall in systolic and diastolic
pressures. This effect is commonly observed in patients
with advanced CKD who might even exhibit a rise in
nocturnal blood pressure. Symptoms of elevated noc-
turnal blood pressure might include nocturnal or early
morning headaches that typically occur in the posterior
occipital region, snoring, daytime somnolence associated
with undiagnosed obstructive sleep apnoea, and noct-
uria.41 The level of nocturnal blood pressure has been
linked to rates of cardiovascular disease and target organ
damage,42 including progression of CKD.43,44 The under-
lying mechanism of this rise in nocturnal blood pressure
is associated with reduced diuresis during the daytime
and consequently enhanced pressure natriuresis at
night.45 Beyond circadian blood pressure patterns, alarge
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body of epidemiologic literature supports an associ-
ation between blood pressure variability (on a single day
and on different days or visits) and the progression of
cardiovascular and renal organ damage and/or events,
and mortality.4648 However, clinical evidence to support
that a reduction in blood pressure variability leads to
improved outcomes is, however, lacking.49,50
Home blood pressure monitoring
A growing literature attests to the value of home blood
pressure monitoring in the CKD population. 33,35,51,52
Patients with CKD are likely to achieve as much, if not
more, benefit using home blood pressure monitor-
ing than the general hypertensive population. Specific
guideline-based targets for home blood pressure values
are not currently available, but values <135/85 mmHg, as
suggested by the American Heart Association, American
Society of Hypertension, and Preventive Cardiovascular
Nurses Association, are consideredreasonable.53
Home blood pressure monitoring is very useful in
patients undergoing dialysis as it can help indicate the
adequacy of outpatient management between dialysis
sessions.54 Current practice in the USA is to aim for
daytime home blood pressure values <140/90 mmHg.55
Ambulatory blood pressure monitoring in patients
undergoing dialysis is currently considered to be more
useful for research purposes than clinical practice, and
little guidance exists as to target blood pressure values.
A comprehensive clinical review of home blood pressure
monitoring in CKD, including in patients undergoing
dialysis, has been previously published elsewhere.33
Patients who use home blood pressure monitor-
ing are statistically more likely to be at or below target
blood pressure levels,56 as compared to those who do
not perform home monitoring. This effect might be as
a result of improved motivation in self care and better
adherence to treatment regimens in those who reliably
obtain home blood pressure measurements, as opposed
to those who are treated based only on office measure-
ments. Furthermore, the direct feedback of seeing ones
own blood pressure values might motivate patients to
maintain better adherence to medications. The optimal
use of a home blood pressure monitor is essential to
produce accurate and reproducible results (Box1).
Ensuring an adequate cuff size is very important
when purchasing a home blood pressure monitor.
Patients with CKD tend to be overweight or obese,57 and
in most instances a large arm cuff is needed but might
be sold separately. The frequency of home monitoring
will depend on whether one is confirming a diagno-
sis of hypertension, assessing adequacy of treatment,
or considering conditions such as masked hyperten-
sion. Guidance regarding the frequency and timing of
home monitoring blood pressure has been previously
reviewedelsewhere.53
Target blood pressure in CKD
Patients with CKD are at high risk of cardiovascular
events and mortality.5860 Beyond prevention of cardiovas-
cular events, the rationale for treatment ofhypertension
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Table 1 | Blood pressure targets and treatment recommendations in CKD
Guideline Blood pressure Blood pressure Recommended first line
target in CKD target in CKD medication
without proteinuria* with proteinuria
USA JNC891 <140/<90 mmHg <140/<90 mmHg ACEI or ARB
KDIGO76 <140/<90 mmHg <130/<80 mmHg ACEI or ARB
NICE 80
<140/<90 mmHg <130/<80 mmHg ACEI or ARB
CHEP 78
<140/<90 mmHg <140/<90 mmHg ACEI; ARB if ACEI intolerant
ESC/ESH79 <140 mmHg <130 mmHg ACEI or ARB
ASH/ISH 123
<140/<90 mmHg <140/<90 mmHg
ARB or ACEI
ISHIB124 <130/<80 mmHg <130/<80 mmHg Diuretic or CCB
*Proteinuria defined as either +1 (by dipstick); >500 mg protein per 24 h; or >200 mg albumin per 24 h
(orthe equivalent of these values in a spot urine determination that employs a protein-to-creatinine or
albumin-to-creatinine ratio). The NICE recommendations in CG182125 are to use ACEIs or ARBs when
proteinuria is present; otherwise the guidance in CG12780 is to follow general recommendations for blood
pressure control when proteinuria is absent. ASH/ISH guidelines acknowledge that some authorities still
recommend <130/<80 mmHg for CKD with proteinuria. Abbreviations: ACEI, angiotensin-converting-enzyme
inhibitor; ARB, angiotensin-receptor blocker; ASH/ISH, American Society of Hypertension/International
Society of Hypertension; CHEP, Canadian Hypertension Education Program; CKD, chronic kidney disease;
ESC/ESH, European Society of Cardiology/European Society of Hypertension; ISHIB, International Society
of Hypertension in Blacks; KDIGO, Kidney Disease: Improving Global Outcomes; NICE, National Institute for
Heath and Care Excellence; USA JNC8, USA Eighth Joint National Committee.
in CKD is to slow ongoing renal injury and to delay
progression to end-stage renal disease (ESRD) and the
need for renal replacement therapy.61,62 Hypertension
accelerates renal injury when impaired autoregulation
allows the transmission of high systemic pressures to the
glomeruli, resulting in high perfusion pressures63,64 and
accelerated glomerulosclerosis.65,66 Inturn, renal injury
can cause hypertension, due in partto inefficient sodium
removal.8 Additional contributions to hypertension come
from an activated RAAS and an overactive sympathetic
nervoussystem.
US recommendations
Data obtained from three randomized controlled
trials (MDRD, AASK, and REIN-2) 6769 and subse-
quent meta-analyses3,70,71 provided the basis for setting
blood pressure targets in the USA. None of these
studies included patients with type1 diabetes mellitus
and very few patients had diabetic nephropathy. All
three trials were negative, failing to show benefit from
lower blood pressure targets of 125130/7580 mmHg
compared to <140/90 mmHg in reducing cardiovas-
cular events, slowing progression of CKD to ESRD,
or reducing mortality. The AASK trial prospectively
considered the impact of proteinuria on CKD progres-
sion, but did not demonstrate a slower progression of
CKD to ESRD for those assigned lower blood pressure
targets.68 The MDRD trial showed a benefit of lower
blood pressure targets on CKD progression, but these
data were generated in a posthoc analysis and the use of
angiotensin-converting-enzyme inhibitor (ACEI) treat-
ment was not balanced between the study arms of the
trial.67 Secondary evidence based on posthoc analyses
and follow-up studies support a benefit of lower blood
pressure targets in patients with CKD and proteinuria,70
but a more definitive, prospective study has not yet
been performed. Furthermore, increased cardiovas-
cular morbidity and mortality were noted when blood
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pressures were lowered <130/70 mmHg,72 but the inci-
dence of stroke did not increase.73 The ACCORD trial of
patients with type2 diabetes mellitus and overall normal
kidney function failed to demonstrate a cardiovascular
protective effect of a lower blood pressure target (<120
versus <140 mmHg systolic).74 The incidence of stroke
in this cohort was reduced as a result of lower blood
pressure, but this benefit occurred at the expense of a
greater number of serious adverse effects such as
hypotensionfrom the antihypertensive agents. Renal
outcomes were not included as primary or second-
aryoutcomes in the ACCORD trial, but the creatinine
level and estimated glomerular filtration rate (eGFR)
were examined and were not improved by the lower
treatment targets.74 Acomparison of mortality rates in
two groups of veterans with CKD who achieved systolic
blood pressure <140 mmHg found that the mortality
hazard ratio was higher in patients with treated systolic
blood pressure <120 mmHg than in patients with treated
systolic blood pressure 120139 mmHg (HR = 1.70; range
1.631.78).75 These data were obtained from a retrospec-
tive observational analysis based on achieved pressures
and, therefore, are at risk of confounding.75
International recommendations
The 2012 KDIGO clinical practice guideline for the
management of blood pressure in CKD was the first
modern guideline to consider a higher blood pressure
goal of 140/90 mmHg in patients with CKD without
albuminuria or proteinuria.76 This guideline was based
on the same limited clinical trial evidence described
above and in some cases a lack of ideal evidence. The
KDIGO panel stopped short of raising the blood pres-
sure target for patients with albuminuria or proteinuria,
and acknowledged that this decision was based solely
on expert opinion. Other consensus groups similarly
raised blood pressure targets for patients with CKD,
including the American Diabetes Association (target
<140/80 mmHg),77 Canadian Hypertension Education
Program (target <140/90 mmHg for CKD),78 and the
European Society of Cardiology/European Society of
Hypertension (target <140 mmHg systolic for CKD).79
The National Institute for Health and Clinical Excellence
(NICE) advised pharmacologic treatment in patients
with blood pressures >140/90 mmHg in the setting of
target organ damage (including renal disease) or with
a 10year cardiovascular risk >20%, which would
generally include patients with CKD. 80 A separate
NICE CKD guideline was updated and released in July
2014 81 using the KDIGO classification system. This
guideline recommended treatment at blood pressures
140/90 mmHg, and suggested treating to a target
range of 120139/<90 mmHg. In addition, the NICE
guidelines recommend drug therapy for blood pressures
130/80 mmHg in patients with albuminuria (defined
by an albumin-to-creatinine ratio 70 mg/mmol), and
suggest a target range of 120129/<80 mmHg. Overall,
there remains a propensity to maintain lower blood pres-
sure targets for those with more severe proteinuria based
on posthoc analyses and expert opinion, with targets
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Box 1 | Optimal use of home blood pressure measurements
Check the home monitoring device against a reliable blood pressure device
used in the providers office
A general practitioner or nurse should observe the patient perform a blood
pressure check
The directions supplied with the blood pressure monitor should be read
carefully prior to making a reading
Patients must be aware of the requirements to void the bladder and avoid
cigarettes and caffeine use before measuring, to be sat quietly in a position
that enables back support, foot support on the floor, and elbow placement at
heart level, and the value of duplicate or triplicate measurements
Blood pressure measurements should be encouraged at set times of the day
and not limited to times when the patient feels in bad or good health or mood,
as these situations might not be representative of general health
A blood pressure monitor with a memory or the ability to download data to a
computer is desirable to reduce reporting bias wherein a patient might feel
pressured to only report their better blood pressure measurements
typically being more loosely applied to those who are
elderly or frail.
While disagreement remains on blood pressure targets
for patients with CKD, the majority of guidelines favour
a general target of <140 mmHg systolic and <90 mmHg
diastolic (Table1). This goal might be challenging for
those with advanced CKD who are more likely to have
resistant hypertension and might already be taking mul-
tiple anti-hypertensive agents. This hypothesis was con-
firmed in an analysis of National Health and Nutritional
Examination Survey data, where more patients with
CKD remained with uncontrolled hypertension com-
pared to patients without CKD, even when higher blood
pressure targets were used.82
Our own approach is to first aim for a systolic blood
pressure 130140 mmHg and a diastolic blood pressure
<90 mmHg in patients with CKD without proteinuria
or albuminuria. Long-acting agents should be selected
to reduce dosing frequency and smooth drug effect,
but the majority of patients will require twice daily
dosing. Although the data to support lower blood pres-
sure targets are weak and somewhat circumstantial, we
propose to aim for lower targets (<130/80 mmHg) in
patients with proteinuria (>1 g and especially >3 g per
24 h) until more definitive results from clinical trials
are available. In this setting, the patient must be able to
tolerate lower blood pressure levels without developing
symptoms of hypoperfusion.
Pathogenesis of hypertension in CKD
The role of the kidney in CKD-associated hypertension
is complex because the kidney both contributes to, and is
damaged by the hypertensive processes. In simple terms,
blood pressure is a physiologic parameter regulated along
four axessodium regulation, the sympathetic nervous
system, humoral systems, and autoregulatory systems.
These axes provide independent and inter-associated
input into pressure regulation (Figure1). Although these
systems are discussed individually in the following section,
these pathways are also interdependent. The kidney acts
as an excretory organ, a component in the sympathetic
axis, a source of circulating constrictors and dilators, and
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as a target of blood pressure itself and is therefore poised
to have a substantial role in blood pressure dysregulation
in the presence of impaired kidney function.
Sodium
The regulation of sodium excretion is a fundamental
function of the kidney. The kidneys filter >25,000 mmol
sodium per day and generate a urine typically containing
~150 mmol over 24 h, thus excreting <1% of the filtered
sodium load.83 The smallest deviation from this precise
matching of input and output over months and years can
result in volume-mediated hypertension or devastating
volume depletion.
The means by which sodium can increase blood pres-
sure is equally complex. Dietary or parenteral intake
of sodium chloride causes an initial volume expansion
and increases cardiac filling before ventricular systole
(preload). A complex choreography ensues whereby
renin activity is diminished, aldosterone concentra-
tions fall, and the increase in cardiac output is translated
into diminished filtered sodium recovery and increased
sodium excretion.84 Other pathways also contribute to
this process that involve changes in eicosanoids, includ-
ing 20-hydroxyeicosotetraenoic acid (20-HETE) and
kininogens.8,9 Increases in 20-HETE drive diuresis under
salt loading conditions, and failure to generate increases
in 20-HETE is seen in salt-sensitive hyper tension. 10
Kinin activation promotes vasodilation and natri-
uresis, and failure to generate kinins under salt loading
contributes to hypertension.11
In addition to volume-associated increases in cardiac
output, sodium chloride administration potentiates
the pressor action of vasoconstrictors, such as norepi-
nephrine.12 An increased sodium intake results in stiffer
arterial vessels, alterations in nitric oxide release, and the
promotion of inflammatory processes that contribute to
blood pressure elevation.13 Some patients show no dis-
cernible change in their blood pressure when challenged
by low and high sodium diets and are said to be resis-
tant to sodium-mediated increases in blood pressure.
The ability to maintain a normal blood pressure in the
faceof a sodium challenge decreases with progressive
loss of kidney function, and a decline in glomerular fil-
tration rate (GFR) is associated with a greater sensitivity
of blood pressure to salt.14
Sympathetic nervous system
The contribution of the sympathetic nervous system to
blood pressure regulation is one of the most difficult
factors to measure. Circulating levels of plasma norepi-
nephrine (noradrenaline) provide an approximate index
to sympathetic activity, but more precise measures, such
as muscle sympathetic nerve activity and regional or
whole-body norepinephrine spillover, are restricted to
a handful of laboratories worldwide.15
Initial studies in ESRD demonstrated increased
muscle sympathetic nerve activity in patients under-
going haemodialysis with resistant hypertension, which
returned to lower values after bilateral nephrectomy.16
Early stage impairment of kidney function can also
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Autoregulation
Blood pressure
Sodium Sympathetic
nervous system
Humoral
systems
Figure 1 | Integration of the processes and pathways that
regulate blood pressure. Blood Nature Reviews | Nephrology
pressure is regulated by
inter-connected systems that although linked, function
independently of each other. These systems fall broadly
into the four illustrated categories. Most medications and
lifestyle recommendations for managing blood pressure
focus primarily on one system. For example, diuretic
therapy and dietary sodium restriction act mainly through
reducing the input of sodium into blood pressure control.
Both diuretic therapy and a substantial reduction in dietary
sodium intake, however, can increase plasma renin activity
(the humoral system) and sympathetic nervous system
activity, underscoring both the interdependence of these
systems, as well as providing a logical basis for additional
therapeutic interventions that when added to a diuretic
typically result in additive blood pressure control. Such
additional interventions include drugs that counteract renin
system activation, such as angiotensin-converting-enzyme
inhibitors and angiotensin-receptor blockers.
elicit an increase in muscle sympathetic nerve activ-
ity.17 Efferent nerves (to the kidney) and afferent nerves
(tothe brainstem) are found around the renal arteries,
with the majority being efferent. At low levels of stimula-
tion, efferent renal nerves promote increased renal renin
secretion. Stimulation of the efferent nerves results in a
reduction in urinary sodium excretion (anti-natriuresis)
and maximal stimulation of the efferent nerves mediates
an increase in renal vascular resistance.18 The kidneys,
therefore, receive direction from, and generate input to,
the sympathetic nervous system.
Humoral Systems
Plasma renin activity
The contact between the afferent arteriole, the distal
convoluted tubule, and the base of the glomerulus
forms a unit known as the juxtaglomerular apparatus.
When afferent arteriolar stretch is reduced by haemor-
rhage or volume loss through the intestines, the RAAS
within the juxtaglomerular apparatus is activated, and
plasma renin activity increases.85 Sympathetic activa-
tion further potentiates this effect through activation of
the 1-adrenoreceptor, which further stimulates renin
secretion. When sodium is consumed or volume is other-
wise increased, the afferent arteriolar stretch increases
and renin activity is suppressed.85 The operating charac-
teristics of this mechanism are shifted in patients with
CKD such that the renin system is more active for any
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level of volume.19 In addition to the well-known constric-
tor effects, angiotensin II (the end product of activation
of this system) can also potentiate sodium reabsorp-
tion, enhance neurotransmitter release at synaptic
clefts in the sympathetic nervous system, and stimulate
aldosteronerelease.86
Aldosterone
Aldosterone potentiates sodium reabsorption in the
distal nephron in exchange for the secretion of potas-
sium. An excess effect of aldosterone was recognized as
a potential cause of hypertension shortly after the initial
identification of aldosterone.20 Classic experiments per-
formed in the 5/6th nephrectomy rat model demonstrated
a pronounced increase in serum aldosterone concentra-
tion that contributes both to elevated blood pressure
and parenchymal damage.21 Limited data from human
studies suggest that aldosterone concentrations increase
as kidney function declines.22 Aldosterone exerts its
effect either through the mineralocorticoid receptor or
directly on the vasculature.23
Other factors
A multitude of other factors have been reported to
mediate blood pressure elevation in CKD. These factors
include endothelins, oxidative stressors, and inflam-
matory mediators.2426 Endothelins, such as ET-1, are
vasoconstrictors that can also elicit inflammatory and
fibrotic effects.24 Oxidative stressors include reactive
oxygen species, which promote vasoconstriction, the
release of renin, and increased urinary protein excre-
tion.25 Inflammatory mediators include cytokines, such
as TNF and IFN, which impair endothelial function.26
Autoregulation
The final system of blood pressure regulation is directly
associated with the endothelium and the vascular wall.
Processes that can impair the release of nitric oxide from
the endothelium, or that reduce the bioavailability of
nitric oxide either by limiting its substrate (arginine) or
by oxidizing it within the cell before release, impair an
important vasodilatory response.27 In addition, processes
that can stiffen the arterial or arteriolar wall, such as vas-
cular calcification87 or excessive collagen accumulation,88
are both known to be more active in patients with CKD
and promote an increase in blood pressure.
Treatment of hypertension
Non-pharmacologic therapy
Sodium intake contributes to drug resistance, in par-
ticular in patients with a reduced GFR.89 Dietary inter-
vention should be a mainstay of treatment but requires
formal patient dietary education provided in one-on-one
individualized sessions in order to be effective. Dietary
sodium restriction is particularly effective in patients
with proteinuria, with one study showing that a restric-
tion of daily sodium intake to <100 mmol can reduce
proteinuria by 22%.90 Diuretic therapy will usually be
needed in conjunction with dietary efforts, especially as
CKD becomes more advanced.
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Pharmacologic therapy
Many guidelines for patients with CKD now recommend
either initiating antihypertensive treatment with an ACEI
or an angiotensin-receptor blocker (ARB), or adding an
ACEI or ARB to the patients current regimen.76,78,79,91
The evidence to support this rationale has been primar-
ily derived from patients with some degree of elevated
protein or microalbumin excretion, as it has not been
shown to benefit those without proteinuria.71 ACEIs or
ARBs function as RAAS blockers, which reduce intra-
glomerular pressure and thereby reduce proteinuria.65
Aconcurrent reduction in GFR will produce an increase
in serum creatinine of up to 30%.92 Greater increases in
serum creatinine should be investigated and might be
caused by volume contraction, use of nephrotoxic agents
such as NSAIDs, or bilateral renovascular disease.28,93
The combination of an ACEI and an ARB is discour-
aged following the results of three randomized trials
that demonstrated harm from combined administra-
tion compared to use of ACEI or ARB therapy alone.9496
The combination of an ACEI or ARB with an aldosterone
antagonist is also generally discouraged, but might be
effective in some clinical circumstances, including
heart failure9799 and severe proteinuria;100 this scenario,
however, should be the exception rather than the rule.
Careful monitoring of serum potassium and creatinine
levels must be performed in these patients.
Most other antihypertensive agents can be used alone
or in combination after consideration of their metabo-
lism and dosing requirements according to the level of
renal function. Most patients with CKD should be treated
with a diuretic as their first or second agent to manage
volume and sodium retention.101 Patients with auto-
somal dominant polycystic kidney disease are an excep-
tion to this consensus, where concern exists that diuretic
therapy will stimulate renin production and subsequently
stimulate cyst growth.102,103 In other patients, the addi-
tion of a diuretic might correct nocturnal non-dipping
and restore the circadian rhythm of blood pressure.104
Non-dihydropyridine calcium channel blockers might
elicit antiproteinuric effects105 whereas dihydropyridine
calcium channel blockers are more effective in lowering
blood pressure and can be used in combination with an
ACEI or ARB without a negative effect on proteinuria.106
Dihydropyridine calcium channel blockers combined
with an ACEI or an ARB might be more effective in
slowing the progression of nephropathy than an ACEI or
ARB in combination with a diuretic.107 This observation is
particularly valid in black patients.108 -Blockers are often
indicated for coexisting cardiac disease.109
The treatment approach for patients with hypertension
and advancing CKD is similar to that for patients with
resistant hypertension. The use of noninvasive haemo-
dynamic measurements has been shown to provide more
effective control of hypertension than clinical judgment
alone, enabling drugs to be titrated on the basis of serial
measurements when multiple agents are needed. 110
Higher diuretic doses might be needed as GFR progres-
sively declines. A loop diuretic is indicated when eGFR is
<30 ml/min/1.73 m2. In this setting, torasemide might be
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effective in a once daily dosing format, whereas other loop
diuretics, such as furosemide and bumetanide, require
twice daily dosing to effectively control hypertension. In
select cases, the combination of a loop diuretic and a thia-
zide diuretic might be effective,111 but the result of com-
bining these agents can be potent. This approach must
therefore be used with caution and serum electrolytes and
blood pressure must be closely monitored.
Patients receiving RAAS blockade require serum
potassium and creatinine monitoring as hyperkalaemia
will be a more notable concern as renal function declines.
ACEIs and ARBs have been increasingly and safely used
in patients with advanced CKD to delay disease pro-
gression.112,113 Discontinuing RAAS blockade in patients
with low levels of renal function, however, might delay
initiation of dialysis and prolong time to transplan-
tation while preparations are underway to evaluate
transplantationsuitability.
Device interventions
Renal denervation
The surface of the renal artery contains a rich network
of afferent and efferent neural fibers. Destruction of
these fibers by radiofrequency ablation has resulted in
dramatic reductions in blood pressure in some,114,115 but
not all studies116 of drug resistant hypertension. Renal
denervation seems to be reasonably safe and well toler-
ated, even in patients with CKD.116 A study of 15 patients
with CKD stage 34 that underwent renal denerva-
tion found a reduction in systolic blood pressure of
33 mmHg at 6months;117 this study, however, was open
label and did not include a control group. The Symplicity
Hypertension 3 trial demonstrated that patients with
eGFR >60 ml/min/1.73 m2 had a better blood pressure
response to renal denervation than the sham treatment
group, although this difference was not observed in
patients with eGFR <60 ml/min/1.73 m2.117 The effec-
tiveness of renal denervation for hypertension remains
to be determined, and no approved devices are currently
available for this procedure in the USA.
Baroreflex activation therapy
An alternative treatment strategy for drug resistant
hypertension has been to pace the carotid barorecep-
tors by applying electrodes directly to the surface of the
carotid artery bifurcation to increase their activity.118
When the pacing generator source is turned on, blood
pressure markedly declines over a few seconds.119 As
with renal denervation, initial studies in patients with
resistant hypertension were very promising,120 but the
Pivotal Trial failed to meet all the primary efficacy end
points.121 Limited uncontrolled studies in patients with
CKD show good procedural safety and moderate reduc-
tions in blood pressure,122 but this therapy, like renal
denervation, remains unproven in the USA.
Conclusions
Hypertension is a major risk factor for CKD progres-
sion, cardiovascular events, and target organ damage
and can also occur as a consequence of a progressive
www.nature.com/nrneph
 REVIEWS

decline in renal function. The use of automated office
measurements and out of office measures, includ-
ing ambulatory blood pressure monitoring and home
readings, improves measurement accuracy and better
predicts the risk of cardiovascular events. US and inter-
national guidelines recommend blood pressure control
to <140/90 mmHg, with some preference to maintain
a target <130/80 mmHg for patients with proteinuria.
Pending additional studies, our own approach is to
first aim for a systolic blood pressure 130140 mmHg
and diastolic blood pressure <90 mmHg, with attempts
to further lower to <130/80 mmHg if tolerated in those
with proteinuria, while incorporating the use of an ACEI
or ARB in the regimen. Multiple mechanisms contrib-
ute to hypertension in CKD and their contributions
might differ between patients. Consequently medication
regimens to reduce blood pressure often contain mul-
tiple agents that block several aspects of blood pressure
control, and tend to work better when patients can be
motivated to implement lifestyle measures, such as salt
reduction and weight loss. Newer treatment approaches
that use devices to reduce blood pressure seem to be
reasonably safe from limited clinical studies of patients
with CKD, but have yet to demonstrate greater efficacy
than sham or control procedures. These procedures have
not yet entered the mainstream of hypertension care in
CKD. Elevated blood pressure is a manageable condition
in patients with CKD, and efforts expended in control-
ling CKD might yield substantial renal and cardiovascu-
lar benefits for our patients. Further studies are needed
to clarify the most optimal blood pressure targets and
treatment regimens.

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Author contributions
Both authors researched data for the article, provided
substantial contributions to discussion of its content,
wrote the article and undertook review and/or editing
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