In-Depth Review

Recognition and Management of Resistant Hypertension

Branko Braam, Sandra J. Taler, Mahboob Rahman, Jennifer A. Fillaus, Barbara A. Greco, John P. Forman, Efrain Reisin,
Debbie L. Cohen, Mohammad G. Saklayen, and S. Susan Hedayati

Abstract
Despite improvements in hypertension awareness and treatment, 30%–60% of hypertensive patients do not
achieve BP targets and subsequently remain at risk for target organ damage. This therapeutic gap is particularly
important to nephrologists, who frequently encounter treatment-resistant hypertension in patients with CKD. Data
Due to the number of
are limited on how best to treat patients with CKD and resistant hypertension, because patients with CKD have contributing authors,
historically been excluded from hypertension treatment trials. First, we propose a consistent definition of resistant the affiliations are
hypertension as BP levels confirmed by both in-office and out-of-office measurements that exceed appropriate provided in the
targets while the patient is receiving treatment with at least three antihypertensive medications, including a Supplemental
Material.
diuretic, at dosages optimized to provide maximum benefit in the absence of intolerable side effects. Second, we
recommend that each patient undergo a standardized, stepwise evaluation to assess adherence to dietary and Correspondence:
lifestyle modifications and antihypertensive medications to identify and reduce barriers and discontinue use Dr. Branko Braam,
of substances that may exacerbate hypertension. Patients in whom there is high clinical suspicion should be University of Alberta
Hospital, Department
evaluated for potential secondary causes of hypertension. Evidence-based management of resistant hypertension of Medicine, Division
is discussed with special considerations of the differences in approach to patients with and without CKD, including of Nephrology and
the specific roles of diuretics and mineralocorticoid receptor antagonists and the current place of emerging Immunology, 11-132
therapies, such as renal denervation and baroreceptor stimulation. We endorse use of such a systematic approach to CSB Clinical Sciences
Building, Edmonton,
improve recognition and care for this vulnerable patient group that is at high risk for future kidney and
AB, Canada T6G 2G3.
cardiovascular events. Email: branko.braam@
Clin J Am Soc Nephrol 12: 524–535, 2017. doi: 10.2215/CJN.06180616 ualberta.ca

Introduction contribution of instituting appropriate lifestyle prac-

Global recognition of hypertension, the number of
treated patients, and the proportion achieving recom-
mended BP targets have improved over the past
several decades (1,2). Nevertheless, many patients do
not reach BP goals and are labeled as having resistant
hypertension (rHTN) (3), which is particularly com-
mon among patients with CKD (4). Importantly,
patients with uncontrolled hypertension are more
likely to develop target organ damage, including
progressive CKD and ESRD. Such patients are likely
to be referred to a nephrologist for care, and treatment
to achieve BP goals may be challenging. Early recog-
nition of rHTN using a standardized definition and
adoption of a consistent approach to evaluation and
management may increase the chance of successful
implementation of therapeutic approaches that com-
bine medical treatment and lifestyle changes to pre-
vent adverse outcomes.
Accurate recognition and effective management of
rHTN are problematic, because available consensus
guidelines are inconsistent, even in their definitions of
rHTN (3,5,6). First, varied definitions render it diffi-
cult to accurately estimate prevalence and associations
with outcomes. Second, inappropriate labeling may
discourage providers from performing evaluations to
establish whether the patient’s hypertension is truly
resistant, searching for reversible causes, and pursu-
ing more effective combination therapies. The
tices to achievement of BP control may be under-
estimated or considered too time consuming to
address. Third, overdiagnosis of rHTN could lead
to specialty referral of a large proportion of patients
who could otherwise be cared for by primary pro-
viders and increase health care costs. This paper
proposes a stepwise approach for the evaluation
and identification of rHTN on the basis of the avail-
able literature and where direct evidence is lacking,
observational data. Special considerations regarding
the evaluation and management of rHTN in the
patient with concomitant CKD are also reviewed.
Definitions of rHTN
In 2008, the American Heart Association issued a
scientific statement that defined rHTN as BP that
remained above goal despite the concurrent use of
three antihypertensive agents of different classes. The
statement suggested that, ideally, one of three agents
should be a diuretic and that all agents be prescribed
at optimal dosages. In addition, patients whose BP
was controlled but required four or more medications
were also considered resistant to treatment (3). This
definition did not address other relevant factors, such
as ensuring accurate BP measurement, reinforcement
of lifestyle modifications and antihypertensive med-
ication adherence, adequate dosing and frequency,
elimination of prescription and over the counter

524 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 March, 2017
Clin J Am Soc Nephrol 12: 524–535, March, 2017 Resistant Hypertension, Braam et al. 525

medications that may interfere with BP control, and
exclusion of secondary causes (Table 1). In addition, the
importance of out-of-office BP measurement as a part of
hypertension evaluation has been increasingly recognized
and deserves consideration (7). Assessment requirements
as listed in Table 1 are necessary add ons to the definition to
make a clear distinction between apparent rHTN, in which
all of these requirements are not necessarily fulfilled, and true
rHTN. In the latter case, a thorough and complete assessment
is required.
Epidemiology and Outcomes of rHTN
Epidemiologic studies report a highly variable preva-
lence for rHTN that ranges between 2% and 40% (1,4,7–15)
depending on how rHTN was defined. Unfortunately, epi-
demiologic cohorts generally do not incorporate detailed
information regarding medication dosing, treatment
adherence, appropriate use of diuretics, and other clini-
cal factors that may affect BP. Hence, the term apparent
treatment-rHTN is used defined as BP not at goal (usually
$140/90 mmHg) when the patient is prescribed three or
more classes of antihypertensive medication or at goal after
prescription of four or more classes. The variability in
prevalence may also be related to differences in the
populations studied, and it is higher in patients with
CKD and cardiovascular disease (7,8,10). In the 2005–2008
US National Health and Nutrition Examination Survey, the
prevalence of apparent treatment-rHTN was estimated to
be 11.8% among individuals with hypertension (1), similar
to what was reported from the Antihypertensive and Lipid-
Lowering Treatment to Prevent Heart Attack Trial (ALL-
HAT), in which 12.7% of patients had apparent treatment-
rHTN (12). However, a large retrospective review of 468,000
hypertensive patients reported a prevalence of 32%, but only
one half of the patients categorized as resistant were pre-
scribed optimal antihypertensive regimens (16). Data from a
large health maintenance organization indicated that only
2.2% of patients with uncontrolled BP were taking diuretics
and two or more classes of antihypertensive medications at
maximal recommended doses, with 39.5% classified as
having uncontrolled hypertension (4). These examples
illustrate the importance of a consistent definition for
rHTN that includes important factors, such as diuretic
prescription and appropriate dosing. Consequently, the
true prevalence of rHTN may be lower than reported. A
prevalence rate in the range of 2%–10% in the general
population and primary care settings is a reasonable
estimate. The prevalence is substantially higher in patients
with CKD, estimated to be 40% of hypertensive partici-
pants in the Chronic Renal Insufficiency Cohort (CRIC)
Study. Approximately 50% had BP that was not at target
on three or more medications, and the other one half had
BP that was at target on four or more medications. Older
age, men, black race, diabetes mellitus, and higher body
mass index were independently associated with higher
likelihood of having apparent treatment-rHTN (17). Sim-
ilar findings were reported in a smaller study from The
Netherlands (18).
Despite differences in definitions, a consistent body of
evidence supports the concept that rHTN is associated
with an increased risk of adverse long–term cardiovas-
cular and kidney outcomes (9,14,19). In the ALLHAT,
participants with apparent treatment-rHTN were at
higher risk for coronary heart disease (hazard ratio
[HR], 1.44; 95% confidence interval [95% CI], 1.18 to
1.76), stroke (HR, 1.57; 95% CI, 1.18 to 2.08), all-cause
mortality (HR, 1.30; 95% CI, 1.11 to 1.52), heart failure
(HR, 1.88; 95% CI, 1.52 to 2.34), peripheral artery disease
(HR, 1.23; 95% CI, 0.85 to 1.79), and ESRD (HR, 1.95; 95%
CI, 1.11 to 3.41) compared with those without rHTN (12).
In the CRIC Study, participants with CKD and apparent
treatment-rHTN had a 38% higher risk of cardiovascular
events or all-cause mortality and a 28% higher risk of
ESRD or 50% decline in GFR (17).
Stepwise Evaluation and Approach to rHTN
A systematic approach to evaluating the patient with
suspected rHTN is illustrated in Figure 1. rHTN should be
viewed as a diagnosis of exclusion. First, the accuracy of BP
measurements using optimal technique needs to be estab-
lished (20). Common pitfalls include improper patient posi-
tioning, wrong cuff size, poor timing of measurements, and
equipment-related error. Ambulatory BP monitoring (ABPM)
is an important component of the evaluation of a patient with

Table 1. Definitions and assessment requirements for resistant hypertension diagnosis

Definition of rHTN (adapted from ref. 3)

BP confirmed by out-of-office measurements exceeding the patient’s individualized target while receiving treatment
with at least three antihypertensive medications, including a diuretic, maximized to optimal doses in the absence of
intolerable side effects
Assessment requirements
Confirm accuracy of BP by out-of-office measurements
Assess adherence to a healthy lifestyle and diet and reduce barriers
Confirm discontinuation of substances that can cause high BP
Recognize and address hypervolemic state
Address nonadherence, tolerability, and dosing (intervals and up titration) of antihypertensive medications
Consider evaluation for secondary causes of hypertension if there is high clinical suspicion
Definition of controlled rHTN
BP controlled to the patient’s individualized target while receiving treatment with at least four antihypertensive
medications, including a diuretic, maximized to optimal doses in the absence of intolerable side effects

rHTN, resistant hypertension. Modified from ref. 3, with permission.

526 Clinical Journal of the American Society of Nephrology
rHTN to assess BP variability and diurnal and nocturnal
patterns, and it can identify masked and white coat hyper-
tension. The US Preventive Services Task Force recommends
ABPM as the standard for confirmation of a hypertension
diagnosis outside of the clinical setting (21). It is important to
detect nondipping, defined as ,10% nocturnal drop in BP, in
assessing overall BP control and for prognostic significance
(22). Importantly, nondipping occurs in 49%–82% of hyper-
tensive patients with CKD and is associated with progression
of CKD (23–25). When ABPM is not feasible, home BP
monitoring may be substituted and has been shown to
correlate closely with daytime ABPM readings (26), although
it will not provide information about nocturnal patterns.
Finally, automated office measurements can reduce the white
coat effect but will miss masked hypertension. Thus, even in
the setting of goal office measurements, it might be useful to
pursue ABPM, such as when disproportionate target organ
damage is present. The importance of accurate BP assessment
was stressed in a recent statement by the American Society of
Hypertension about rHTN (27).
Second, nonadherence deserves special attention to
identify and address adherence barriers effectively. One
study screened patients’ urine samples with mass spec-
troscopy and found that only 47% of 76 patients with
Figure 1. | A systematic approach to the patient with suspected resistant hypertension.
apparent rHTN were adherent to all prescribed medica-
tions, that 16% did not take any prescribed medications,
and that 37% took ,25% (28). In another study of newly
referred, already treated, and thoroughly evaluated pa-
tients with rHTN, 10% were completely nonadherent, and
52% were partially or completely nonadherent (29). Non-
adherence may be more common among hypertensive
patients with CKD than those with normal kidney function
(30,31). This is possibly related to the increased cost and
complexity of medical regimens needed to treat CKD-
related conditions or may be a contributing cause for CKD.
Other causes of nonadherence include socioeconomic
barriers, medication side effects, motivation, and cognitive
dysfunction (32). Unfortunately, questionnaires have lim-
ited value in recognizing nonadherence in apparent rHTN
(33). Tools to identify adherence problems include non-
confrontational face-to-face interview, review of pharmacy
records for timing of prescription refills, pill counts, phone
calls between office visits, use of a clinical pharmacist
within the practice, or medication event monitoring sys-
tems that electronically document each time the patient
opens a pill bottle. Although not readily available in most
clinical settings, medication event monitoring systems
were shown to be reliable indicators of and may improve
Clin J Am Soc Nephrol 12: 524–535, March, 2017 Resistant Hypertension, Braam et al. 527

adherence (34). In extreme cases, observed medication
dosing in a controlled clinical setting may unmask non-
adherence (35). A thorough approach to the patient with
rHTN should include proactive assessment of barriers for
adherence. Urine screens with mass spectroscopy for de-
tection of antihypertensive medications can be considered
if available.
Third, other factors contributing to or exacerbating
hypertension should be considered and addressed. These
include lifestyle practices (excessive salt and alcohol intake,
sedentary lifestyle, and lack of exercise) and use of
recreational drugs and some prescription and nonprescrip-
tion medications (including complementary and alterna-
tive medications) that exacerbate hypertension (Table 2)
(3). Evaluation of salt intake and volume status is further
discussed in Special Considerations in the Patient with
CKD below.
Fourth, the diagnosis of rHTN requires that the patient is
treated with a diuretic. As detailed below (Pharmacologic
Treatment and Special Considerations in the Patient with
CKD), dose and dosing frequency should be critically
considered.
Fifth, workup for secondary hypertension should be
considered (Table 3). The initial evaluation should include
measurement of electrolytes, eGFR, urinalysis, urine pro-
tein assessment, and kidney imaging. In subjects with a
family history of autosomal dominant polycystic kidney
disease and normal serum creatinine, a renal ultrasound
should be obtained. The addition of Duplex Doppler can
provide quantitative information on renal artery velocities
to improve detection of renovascular disease. Because
several studies suggest that angioplasty alone may im-
prove BP and even cure hypertension in young persons
with fibromuscular dysplasia (36), a young patient with
rHTN but without CKD should be further studied using
renal artery imaging by computed tomography or conven-
tional angiography on the basis of clinical suspicion.
Presence and management of renovascular disease in
patients with concomitant CKD are discussed further in
Special Considerations in the Patient with CKD below.
Obstructive sleep apnea (OSA) is a common cause of
secondary hypertension. Screening tools, such as the Berlin
questionnaire, can be useful (37) followed by overnight
oximetry and polysomnography for confirmation. Several
studies showed a high prevalence of OSA among patients
with CKD ranging from 22% to 33%, and OSA is
considered a contributing factor to rHTN (38). Treatment
of OSA with continuous positive airway pressure (CPAP)
was shown to reduce BP, although to a limited degree. In a
trial of 40 patients with moderate to severe OSA and
rHTN, a combination of CPAP and medical therapy versus
medical therapy alone resulted in a significant improve-
ment in BP at 6 months: mean daytime ambulatory BP
decreased by 7/5 mmHg in the CPAP group and increased
by 3/2 mmHg in the control group (39). However, BP
reduction was not consistent across trials of CPAP treat-
ment and is usually modest, with an average lowering of 3/2
mmHg reported in a recent meta-analysis of 29 trials (40). A
combination of CPAP and weight loss may result in
greater BP reduction (41).
Several endocrine causes of secondary hypertension
should be considered on the basis of clinical presentation.
Although hyperaldosteronism is classically associated with
metabolic alkalosis and hypokalemia, normokalemia
should not preclude the diagnosis or deter further testing
in patients with a high pretest probability (32). Measure-
ment of the serum aldosterone concentration-to-plasma
renin activity ratio, which had a sensitivity of 89% and a

Table 2. Common prescription and nonprescription drugs that can raise BP

Prescription Drugs Nonprescription Drugs

Anabolic steroids Anabolic steroids

Antidepressants Caffeine
Monoamine oxidase inhibitors Cocaine
Selective serotonin reuptake inhibitor Ethanol (in excess)
Selective norepinephrine uptake inhibitors Glycyrrhizic acid (contained in some licorice, cough drops, and
chewing tobacco)
Norepinephrine transporter inhibitors NSAIDs
Calcineurin inhibitors Sympathomimetic and illicit drugs
Cyclosporin Amphetamines
Tacrolimus Cocaine
Glucocorticoids Sympathomimetic nonprescription medications
(decongestants)
Erythropoietin Nasal sprays
Contraceptives a-Adrenergic herbal supplements
Estrogen containing Ephedra (Ma-Huang)
Progesterone containing Caulophyllum thalictroides (blue cohosh)
NSAIDs Citrus aurantium
Sympathomimetics Synephrine, N-methyltyramine (bitter orange)
VEGF inhibitors 1,3-Dimethylamylamine
Tyrosine kinase inhibitors
Amphetamines (in context of ADHD)

NSAID, non-steroidal anti-inflammatory drugs; VEGF, vascular endothelial growth factor; ADHD, attention-deficit hyperactivity
disorder.
528 Clinical Journal of the American Society of Nephrology
Table 3. Potential causes of secondary hypertension
Cause
Evaluate in all patients
Parenchymal kidney disease
Secondary causes to be considered
Renal artery stenosis
Atherosclerotic
Fibromuscular dysplasia
Obstructive sleep apnea
High-aldosterone states
Primary hyperaldosteronism
Adrenal adenoma
Bilateral adrenal hyperplasia
Secondary hyperaldosteronism
Renal artery stenosis
Renin-secreting tumor
Glucocorticoid remediable aldosteronism
Cushing syndrome
Congenital adrenal hyperplasia
Apparent mineralocorticoid excess
Liddle syndrome
Gordon syndrome
Pheochromocytoma
Hyper- or hypothyroidism
Aortic coarctation
CTA, computed tomography angiogram; MRA, magnetic resonance angiography.
specificity of 71% in one study, can be useful as initial
screening (42), even for patients taking antihypertensive
medications, except for aldosterone receptor blockers,
which should be stopped 4–6 weeks before testing. Testing
for thyroid disease or pheochromocytoma should be
considered on the basis of clinical suspicion (Table 3).
After the stepwise evaluation as depicted in Figure 1 has
been completed to confirm that the hypertension is actually
resistant, the provider can formulate a therapeutic plan.
Nonpharmacologic Approaches to Management
Evidence-based studies are sparse regarding nonphar-
macologic modification of lifestyle and diet as part of
management for rHTN in patients with and without CKD
(43). Several nonpharmacologic interventions have rela-
tively well established efficacy in reducing BP in patients
with prehypertension and primary hypertension. Use in
treatment of rHTN is primarily extrapolated from these
trials. The Dietary Approaches to Stop Hypertension
(DASH) Study provides the best evidence for BP-lowering
effectiveness of dietary sodium restriction and weight loss
in those with prehypertension, with more pronounced
effects in those with hypertension (44–49).
A Cochrane review summarized the effects of modest
weight loss (24 kg over 6–36 months) by dietary inter-
vention to reduce BP. However, hard outcomes were not
studied in any of the included trials (50). Long–term
Diagnostic Testing
Basic blood chemistry, including creatinine, sodium, potassium,
bicarbonate; urinalysis with microscopic examination, urine
protein-to-creatinine and/or albumin to-creatinine ratio,
kidney ultrasound
Kidney ultrasound with Duplex Doppler, magnetic resonance
imaging, computed tomography angiography, conventional
angiography
Berlin questionnaire, overnight oximetry, polysomnography
Serum sodium and potassium concentration, serum aldosterone
concentration-to-plasma renin activity ratio, BP response to
mineralocorticoid receptor antagonist, genetic testing
Dexamethasone suppression test, 24-h urine cortisol excretion,
salivary cortisol
Clinical diagnosis
Clinical diagnosis, aldosterone and renin levels, electrolytes
Clinical diagnosis, family history, aldosterone and renin levels,
serum electrolytes
Plasma-free metanephrines, 24-h urine metanephrines and
catecholamines
Thyroid-stimulating hormone
BP measurements in both arms and legs, echocardiogram,
thoracic CTA or MRA
outcome studies of weight loss by bariatric surgery using
gastric banding revealed mixed results (51). In the Swedish
Obese Subjects Study, after a transient lowering of BP in the
first postoperative years, BP was similar in subjects who
underwent surgery compared with controls (52,53). Data
regarding gastric bypass surgery indicate better long–term
outcomes. In a small series of hypertensive obese subjects,
gastric bypass surgery was associated with persistent
hypertension in only 20% after 10 years. Similar data
were reported by the Longitudinal Assessment of Bariatric
Surgery Consortium, a multicenter observational cohort
study of ten United States hospitals in six geographically
diverse locations (54). Three years after surgery, remission
of hypertension occurred in 269 of 605 patients with
hypertension at baseline who underwent Roux-en-Y gastric
bypass surgery (38.2%) and 43 of247 patients with hyperten-
sion who received laparoscopic adjustable gastric banding
(17.4%) (54). Of note, gastric bypass as opposed to gastric
banding may also result in endocrine changes that affect BP
regulation, such as an increase in atrial natriuretic peptide
levels (55). Evidence is currently lacking whether such dif-
ferences translate into different clinical responses in patient
with rHTN with and without CKD.
Accumulating evidence supports the beneficial effects of
involving nurses and pharmacists in education, treatment,
and monitoring of hypertension (56). A recent randomized,
controlled trial of 110 diabetic subjects with uncontrolled
Clin J Am Soc Nephrol 12: 524–535, March, 2017 Resistant Hypertension, Braam et al. 529

hypertension revealed that home BP telemonitoring com-
bined with automated support improved BP control over
home BP monitoring alone, with 51% of intervention
participants achieving BP target compared with 31% of
controls (P,0.05) (57). A randomized trial of 401 partici-
pants with uncontrolled hypertension showed that an
intervention using telemonitoring under primary care
clinician supervision and optional patient decision support
improved daytime ambulatory BP by 4.3/2 mmHg com-
pared with usual care (58).
Insight on the value of multiple simultaneous lifestyle
interventions for rHTN is the subject of the TRIUMPH Trial
(Clinicaltrials.gov no. NCT02342808) (59) to be completed in
2019, which evaluates the efficacy of a center–based lifestyle
intervention using exercise training, sodium reduction, DASH
diet, and weight management compared with standardized
education and physician advice for improving BP control in
patients with rHTN (59). Patients with CKD are included if the
eGFR is .45 ml/min per 1.73 m2. Evidence is lacking
regarding the BP-reducing efficacy of other individual non-
pharmacologic interventions, including exercise, reduced al-
cohol intake, and nondietary, nonpharmacologic treatments
referred to as alternative approaches (60) in patients with
rHTN. Table 4 summarizes efficacious lifestyle modifications
in hypertensive patients that are not specific to rHTN or CKD
(47,61).
To educate and engage patients about lifestyle changes,
communication is key. Communication with patients about
cardiovascular risk requires dedicated effort and recogni-
tion of barriers to achieving effective changes (62). Even in a
research study setting, it is difficult for participants to
maintain long–term lifestyle modifications (47). Develop-
ing effective public health strategies that can be feasibly
implemented and lead to sustained lifestyle modifications
remains a challenge (61). Because data about the effective-
ness of weight loss, diet adaptations, and other nonphar-
macologic interventions in rHTN are limited, the current
knowledge gap could benefit from trials specifically aimed
at lifestyle modifications in carefully selected patients with
rHTN and CKD.
Pharmacologic Treatment
Given the reported high nonadherence rates as assessed
using mass spectroscopy in patients with apparent and
confirmed rHTN (28,29), a comprehensive therapeutic
strategy is needed. Such a strategy would aim to (1) assure
that the prescribed medications are selected and dosed
appropriately, (2) determine whether the instituted therapy
causes a measurable BP response, and (3) verify the
presence of and address barriers to adherence. Using
primary hypertension treatment algorithms (63), a patient
with rHTN would likely be treated with at least three
antihypertensive agents of different classes, including a
renin-angiotensin system blocker, a calcium antagonist, a
diuretic, and possibly, a b-blocker. As will be described,
there are data to support the addition of a mineralocorti-
coid receptor antagonist as an add-on fourth or fifth agent
if a high aldosterone state has been confirmed by labora-
tory measurements.
Optimization of intravascular volume status is essential
in the management of the patient with rHTN (30), partic-
ularly in those with CKD (64). Inadequate volume control
was reported even in patients being treated with diuretics
(65). Brain–type and atrial natriuretic peptide levels were
higher in 279 consecutive patients with rHTN (uncon-
trolled and using three or more antihypertensive medica-
tions) compared with 53 controls (normotensive or BP
controlled by less than three antihypertensive medica-
tions). Interestingly, 85% of those with rHTN were being
treated with a thiazide diuretic.
Selection of a specific diuretic, titration of dose, and
dosing frequency must each be considered for effective
management of volume. For example, furosemide has a
half-life of 30 minutes to 2 hours in patients with normal
kidney function and would need to be dosed two to three
times daily (66). Additional discussion regarding choice of

Table 4. The effect of nonpharmacologic approaches to manage hypertension

Modification Description Systolic BP Reduction

Weight reduction
DASH Diet
Reduced dietary sodium
Increased physical activity
Moderate alcohol intake
Increased potassium intake
Alternative approaches
To attain normal weight (i.e., BMI,25) 5–20 mmHg/10-kg weight loss
Rich in fruits, vegetables, low-fat dairy, 8–14 mmHg
reduced saturated and total fat, and
reduced sodium
To 65–100 mmol/d (1.5–2.4 g Na+ or 3.8–6 g 2–8 mmHg
NaCl)
Regular aerobic exercise 30 min/d most 4–9 mmHg
days of week
Limit to #2 drinksa per day for men and #1 2–4 mmHg
drink per day for women and those with
lighter weight
120 mmol/d (4.7 g/d; also included in Variable
DASH Diet)
Meditation, yoga, other relaxation Variable up to 2–10 mmHg
therapies, biofeedback, device-guided
breathing, and acupuncture

BMI, body mass index; DASH, Dietary Approaches to Stop Hypertension.

a
One drink is equivalent to 12 oz beer, 5 oz wine, or 1.5 oz 80-proof liquor, each representing, on average, 14 g ethanol.
530 Clinical Journal of the American Society of Nephrology
diuretic and dosing in the setting of CKD is presented in
Special Considerations in the Patient with CKD below.
Plasma aldosterone levels, aldosterone-to-renin ratios,
and 24-hour urine aldosterone levels are reported to be
higher in those with rHTN compared with normotensive
subjects and subjects with controlled hypertension (65).
Moreover, a low dose of spironolactone decreased BP in
patients with rHTN by 17/7, 24/10, and 26/11 mmHg at 1,
3, and 6 months after starting the drug, respectively (67).
Two recent trials support the efficacy of mineralocorticoid
inhibition in rHTN. The first confirmed the efficacy of
25 mg spironolactone (versus placebo) to decrease BP and
reach the prespecified target systolic BP of ,140 mmHg
(73% versus 41% in spironolactone versus placebo groups)
(68). The second compared the BP-lowering effect of the
addition of spironolactone, doxazosin, bisoprolol, or pla-
cebo as add-on therapy to the participant’s baseline anti-
hypertensive medications. Spironolactone (25–50 mg) was
the most effective and reduced home systolic BP by 14
mmHg, about 9 mmHg more than placebo and 5–6 mmHg
more than doxazosin or bisoprolol (69). One of 285 treated
patients experienced a serum potassium concentration
.6 mmol/L. These trials support mineralocorticoid inhibi-
tion with spironolactone as an effective addition to rHTN
treatment. Eplerenone, as a more specific aldosterone re-
ceptor antagonist, remains a desirable alternative for pa-
tients with clinically significant side effects, such as
gynecomastia or breast tenderness.
Beyond optimizing diuretic dosage and addition of a
mineralocorticoid antagonist, it may be necessary to add
additional antihypertensive agents. Direct vasodilators,
a-blockers, and central sympathetic agonists should
be reserved for the most resistant or those intolerant of
other agents due to more significant associated side
effects.
Special Considerations in the Patient with CKD
In addition to considerations already discussed for the
patient with rHTN, special attention should be given to
patients with rHTN and concomitant CKD with respect to
the definition, stepwise evaluation, and particularly, dif-
ferences in hypertension management.
Whether the definition of rHTN in the setting of CKD
should include more specific criteria has not been clearly
delineated. For example, patients with CKD are more likely
to present with sodium retention and excess volume among
other features, such as unopposed activity of the renin-
angiotensin-aldosterone system (RAAS). Therefore, opti-
mization of volume status, including attention to diuretic
selection and adequacy of dosage and dosing frequencies
as well as consideration for use of RAAS inhibitors, should
be addressed before a patient with CKD is labeled with true
rHTN.
Special considerations for the systematic approach to the
patient with rHTN and CKD include confirmation of office
elevated BP readings and interpretation of 24-hour ABPM.
In particular, questions remain regarding interpretation of
nocturnal hypertension if high 24-hour ABPM readings are
limited to nighttime or in instances where BP is at target
except for the presence of a nondipping pattern. There is a
need for additional studies on the utility of chronotherapy
in the patient with CKD and rHTN. (70)
Assessment of volume status and salt intake is particu-
larly relevant in the patient with CKD, although formal
measurements of salt excretion and volume using bioim-
pedance or labeled red blood cell techniques may be
technically challenging or unavailable. Extracellular fluid
volume expansion is prevalent and increases with the
severity of CKD (71). In 338 patients with stages 3–5 CKD,
52% were fluid expanded as assessed by bioimpedance
(72). Several small trials, including studies of patients with
rHTN and CKD, suggest that measurement of hemody-
namic parameters and volume status using thoracic bio-
impedance may be an efficacious approach to guide
medication selection and dosing (65,72–76). Until more
data become available to support the standard use of such
techniques in practice, reduction in salt intake and mon-
itoring weight may serve as surrogates of volume status.
Sodium intake can be estimated by 24-hour urinary sodium
excretion for an individual in steady state or using a
validated salt calculator, a survey of about 25 questions
(77). Patients with CKD should be instructed to monitor
their weight regularly.
Secondary causes for hypertension are more common in
patients with CKD and apparent rHTN. Although CKD per
se could be responsible for rHTN (due to underlying renal
parenchymal disease), the presence of CKD should not
discourage investigation for other causes if clinical suspi-
cion exists. OSA is frequent in the patient with CKD and
particularly relevant in CKD, because fluid overload may
contribute to swelling of the hypopharynx, palate, and
nasal cavities and result in OSA exacerbation.
Special consideration is required regarding renovascular
hypertension. On the basis of the results of the benefit of
STent placement and blood pressure and lipid-lowering for
the prevention of progression of renal dysfunction caused
by Atherosclerotic ostial stenosis of the Renal artery (STAR)
Trial (78), the STent for Renal Artery Lesions (ASTRAL)
Trial (79), and the Cardiovascular Outcomes in Renal
Atherosclerotic Lesions (CORAL) (80) Trial, which sugges-
ted that renal angioplasty/stenting does not confer addi-
tional benefit above optimal medical therapy in patients
with stable CKD, routine screening for atherosclerotic renal
artery disease should be discouraged (78–80). The CORAL
Trial emphasized the safety and efficacy of angiotensin
receptor blockers in patients with unilateral or bilateral
renal artery stenosis. Medical therapy in patients suspected
of having underlying atherosclerotic renal artery disease
should, therefore, include maximal tolerated doses of one
of these agents before defining treatment resistance. In
contrast, patients who fail optimal medical therapy, espe-
cially those with severe hypertension or recurrent episodes
of acute (flash) pulmonary edema, refractory heart failure,
recurrent AKI after treatment with angiotensin receptor
blockers or angiotensin–converting enzyme inhibitors, or
deterioration of kidney function, may benefit from percuta-
neous angioplasty and stenting, because such patients were
excluded from the three trials (81).
With respect to nonpharmacologic approaches for man-
agement, rHTN is more common and salt sensitivity of BP
is well established in patients with CKD (43). The Kidney
Disease Improving Global Outcomes guideline for man-
agement of BP in CKD advises limiting sodium intake to 2
g/d for hypertensive patients not on dialysis (82).
Clin J Am Soc Nephrol 12: 524–535, March, 2017
Nevertheless, recommendations regarding sodium restric-
tion in patients with CKD are on the basis of observational
data, and interventional studies are needed to determine
the optimal amount of sodium restriction in patients with
CKD. One small randomized, controlled trial assessed
sodium restriction for rHTN in 12 participants with CKD
(83) in a 4-week crossover design. Sodium excretion rates
were 252 and 46 mmol/d during the high– and low–
sodium intake periods, respectively. The low–sodium intake
phase was accompanied by a substantially lower systolic
and diastolic BP (223/9 mmHg) (83). In addition, caution
and close monitoring should be used when considering the
DASH diet for patients with advanced CKD or those being
treated with RAAS inhibitors given the increased risk of
hyperkalemia.
Discussion of pharmacologic treatment of the patient
with CKD and rHTN comes with several considerations.
Because of decreased GFR, higher doses of diuretics are
required in patients with CKD compared with those with
normal kidney function (84). Regarding thiazide or thiazide-
like diuretics, there is evidence that chlorthalidone is more
potent in lowering BP, possibly because of a longer half-
life, than hydrochlorothiazide (85). Moreover, recent meta-
analyses reported that chlorthalidone and other thiazide–like
diuretics were more efficacious in preventing cardiovascular
events than hydrochlorothiazide and other thiazide–type
diuretics (86,87). The longer half-life and duration of action
of chlorthalidone may be particularly valuable in patients
with variable medication adherence (88). Although there
is a widespread belief that thiazides are not effective for
patients with CKD and eGFR,30 ml/min per 1.73 m2, a
recent study showed benefit (89). To date,
hydrochlorothiazide remains the most commonly used
thiazide, particularly in combination tablets. Taken to-
gether, although there are no head to head outcomes trials,
it seems preferable to use chlorthalidone in the treatment
of rHTN in patients with CKD. With advanced CKD
(eGFR,20–30 ml/min per 1.73 m2), a loop diuretic can be
effectively used to manage hypertension with consider-
ation of dosing interval. Torsemide may be preferred,
because it has greater and more consistent bioavailability
and can be generally dosed once daily compared with
furosemide or bumetanide, which would both require twice
daily dosing. Diuretics in general and thiazides in particular
are associated with hyperuricemia, but this should not
discourage their use in patients with CKD given the
frequent presence of hypervolemia. In rare situations, the
combination of a thiazide and a loop diuretic to augment
diuresis may be considered; however, this approach can
cause extreme natriuresis and must be titrated and mon-
itored carefully.
A word of caution is needed about the application of
mineralocorticoid inhibitors for patients with CKD; they
are frequently already treated with an inhibitor of the
renin-angiotensin system and would be more prone to
develop hyperkalemia with a combination of medications
targeting the RAAS.
Role of Emerging Therapies
In recent years, several novel therapies were investigated
as potential complimentary or alternative treatments to
antihypertensive medications.
Resistant Hypertension, Braam et al. 531
Catheter–based sympathetic renal denervation (RDN)
derives its pathophysiologic basis from the observation
that bidirectional renal sympathetic nerve trafficking con-
tributes significantly to BP regulation (90). Surgical sym-
pathectomy was at one time one of the few therapies that
could provide treatment for hypertension when drug
therapy was not widely available (91). The renal artery
can now be less invasively approached using radiofre-
quency ablation (92). In 2009, a small uncontrolled trial
reported striking reductions of 22/11 and 27/17 mmHg in
office BP 6 and 12 months, respectively, after application of
this technique in 45 subjects with rHTN (92).
Subsequently, a small nonblinded, randomized, controlled
trial reported that RDN decreased BP by 25/10 mmHg after
12 months (93). The SIMPLICITY-3 Trial was the first sham
treatment–controlled trial using this approach, but it failed
to confirm earlier findings (94) Potential explanations
included technique issues (operator related and catheter
related) and trial design (better treatment adherence in both
the control and intervention groups). Although a recent
paper reported BP-lowering effect of RDN added to a
stepped care approach using antihypertensive medications
(compared with stepped care alone), there was no sham
operation control (95). In the context of RDN, other tech-
niques are now being developed with externally delivered
focused ultrasound (96), which may offer safer adjunct
treatment options.
Although the negative SIMPLICITY-3 Trial substantially
decreased interest in RDN, studies using RDN in patients
with heart failure are ongoing and may provide more
insight. Furthermore, favorable clinical effects reported for
RDN, such as improvements in insulin sensitivity (97),
microalbuminuria (98), and apnea/hypopnea index (99),
may be offset by safety concerns, such as renal artery
stenosis (100). Subsequent occurrence of reinnervation
must also be considered. Larger studies with longer
durations are needed to address these issues before RDN
can be considered for clinical use.
Another emerging technique is electrical carotid sinus
baroreceptor stimulation using implantable devices. Such
devices implanted chronically led to significant reductions
in mean systolic BP of 26 and 35 mmHg after 6 and 12 months,
respectively (101). Importantly, the safety end point was not
met; issues were related to surgery (nerve damage and wound
healing) and uncontrolled BP. Unfortunately, robust sham–
controlled studies are not available. Moreover, carotid body
stimulation has not been associated with the favor-
able metabolic effects observed for RDN. Of note, neither
catheter–based sympathetic RDN nor electrical carotid sinus
baroreceptor stimulation are Food and Drug Administration–
approved therapies.
Summary
The lack of consensus around a unified definition for
rHTN has challenged efforts to define prevalence of the
condition and outcomes. A systematic approach to evalu-
ation will improve identification of factors contributing to
poor control rates and facilitate efforts directed at better
control through modifying these factors, which include but
are not limited to nonadherence to lifestyle and dietary
modification or medications, use of substances that may
exacerbate high BP, suboptimal dosing of antihypertensives,
532 Clinical Journal of the American Society of Nephrology
lack of use or inadequate dosing of a diuretic as a cornerstone
of management, and failure to perform appropriate diagnostic
testing to exclude secondary causes. We propose that rHTN
be defined more restrictively as a BP that exceeds the
individualized BP target while the patient is receiving
treatment with at least three antihypertensive medications,
including a diuretic, at dosages optimized for maximum
benefit with absence of intolerable side effects. In addition to
office BP measurement, confirmation by above–target out-of-
office measurements should be required. Treatment of rHTN
includes attention to dietary and lifestyle modifications and
adjustments to the antihypertensive regimen, including con-
tinued vigilance to adherence barriers and avoidance of
substances that may cause high BP. For patients with CKD,
drug class effect, dose escalation, optimization of dosing
interval, and drug tolerability require additional attention,
with special emphasis on volume assessment and treatment of
hypervolemia. The role and safety of emerging novel therapies
need additional exploration before their use in clinical practice.
Acknowledgments
The authors thank all members of the American Society of Ne-
phrology (ASN) Hypertension Advisory Group (George L. Bakris,
Ellen D. Burgess, Lance D. Dworkin, Karen A. Griffin, James M.
Luther, Julie Ingelfinger, Velvie A. Pogue, Jennifer S. Pollock, George
Thomas, Peter N. Van Buren, and Matthew R. Weir) for their valuable
advice and contributions. The ASN Hypertension Advisory Group
would also like to thank Grant Olan, Senior Policy and Government
Affairs Associate of the ASN, and Rosie Hernandez for their assis-
tance during the preparation of this manuscript.
Although this paper was written by members of the (former) ASN
Hypertension Advisory Group and approved by the ASN Publi-
cations Committee, it is not an official ASN statement.
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