Download Full Reviews Definition, identification and treatment of resistant

Nephrol Dial Transplant (2014) 29: 1327–1335
doi: 10.1093/ndt/gft346
Advance Access publication 17 September 2013
Full Reviews
Definition, identification and treatment of resistant
hypertension in chronic kidney disease patients
Yelena R. Drexler and Andrew S. Bomback
Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Correspondence and offprint requests to: Andrew S. Bomback; E-mail: [email protected]
A B S T R AC T
Resistant hypertension, the inability to achieve goal blood
pressure despite the use of three or more appropriately dosed
antihypertensive drugs (including a diuretic), remains a
common clinical problem, especially in patients with chronic
kidney disease (CKD). While the exact prevalence and prognosis of resistant hypertension in CKD patients remain
unknown, resistant hypertension likely contributes significantly to increased cardiovascular risk and progression of kidney
disease in this population. We review the identification and
evaluation of patients with resistant hypertension, including
the importance of 24-h ambulatory blood pressure monitoring
in the identification of ‘white-coat’, ‘masked’ and ‘non-dipper’
hypertension, the latter of which has particular clinical and
therapeutic importance in patients with resistant hypertension
and CKD. We then discuss treatment strategies for resistant
hypertension that target the pathophysiologic mechanisms
underlying resistance to treatment, including persistent
volume excess, incomplete renin-angiotensin-aldosterone
system blockade and inadequate nocturnal blood pressure
control. Finally, we propose a treatment algorithm for evaluation
and treatment of resistant hypertension in patients with CKD.
Keywords: algorithm, chronic kidney disease, resistant
hypertension
INTRODUCTION
Resistant hypertension is defined as blood pressure (BP) that
remains above goal despite adherence to treatment with at
least three antihypertensive agents prescribed at optimal doses,
ideally including a diuretic [1]. By this definition, patients
with resistant hypertension include those who are able to
© The Author 2013. Published by Oxford University Press on
behalf of ERA-EDTA. All rights reserved.
achieve BP control but require four or more antihypertensive
medications at full doses to do so. While somewhat arbitrary
in terms of the number of medications required, this definition
helps identify those patients who are at highest risk for the
adverse outcomes associated with persistently elevated blood
pressure and who may benefit most from therapy.
The prevalence of resistant hypertension is unknown, in
part due to the feasibility of conducting a large, forced titration
study to answer this question appropriately. However, data
from the National Health and Nutrition Examination Survey
(NHANES) from 2003 to 2008 suggest that 12.8% of the antihypertensive-treated population meets the criteria for resistant
hypertension [2]; this number may rise to >50% in nephrology
clinics [3]. Indeed, in the first study to specifically address this
question in 300 hypertensive chronic kidney disease (CKD)
patients referred to a nephrology clinic, 38% met the definition
of resistant hypertension after 6 months of blood pressure
management, with a higher prevalence of diabetic nephropathy and higher levels of proteinuria emerging among the patients with resistant hypertension [4]. A number of factors
may contribute to the pathogenesis and higher prevalence of
resistant hypertension in CKD, including impaired sodium
handling, increased activity of the renin-angiotensin-aldosterone (RAAS) and sympathetic systems, impaired nitric oxide
synthesis and endothelium-mediated vasodilation, and increased arterial stiffness [5–8]. The relationship between these
factors has important implications for the identification and
treatment of resistant hypertension in CKD (non-end stage
renal disease) patients, the topic of this review.
DEFINITION
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood
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Pressure (JNC 7), published in 2003, identifies a treatment
goal of <140/90 mm Hg for patients with hypertension and no
other compelling conditions, and includes a separate recommendation for a goal BP of <130/80 mm Hg for all patients
with CKD, defined as either reduced glomerular filtration rate
(GFR) or the presence of albuminuria (>300 mg/day or 200
mg/g creatinine) [9]. Likewise, a number of guidelines recommend a lower target blood pressure for patients with hypertension who are at high risk for cardiovascular disease, which
includes those with CKD [10, 11].
Data supporting a goal of <130/80 to slow progression of
CKD or to reduce cardiovascular disease risk in CKD are not
robust. Indeed, the greatest benefit of targeting a blood pressure of <130/80 has been demonstrated in patients with advanced, proteinuric CKD and stems from two large trials of
patients with predominantly non-diabetic CKD and mean
GFR <60 mL/min/1.73 m2, the Modification of Diet in Renal
Disease Study (MDRD) and the African American Study of
Kidney Disease (AASK) [12, 13]. In the primary analysis of
both studies, randomization to a low blood pressure group
(mean arterial pressure <92 mm Hg, equivalent to BP <125/
75) versus the usual blood pressure group (mean arterial pressure <107 mm Hg, equivalent to BP <140/90) did not result in
slowing progression of CKD at 3 years in MDRD and at 4
years in AASK [12, 13]. However, in subgroup analysis, both
studies revealed trends favoring lower BP goals in patients
with higher baseline proteinuria. As we await updates in the
JNC and other guidelines, the most conservative approach is
to classify proteinuric CKD patients with BP >130/80 and
non-proteinuric CKD patients with BP >140/90 as above goal.
I D E N T I F I C AT I O N
In the evaluation and treatment of patients with apparent resistant hypertension, ‘pseudo-resistant’ hypertension, or the
appearance of treatment resistance, must first be distinguished
from true resistant hypertension. Factors that can contribute
to elevated blood pressure readings in a patient who does not
truly have resistant hypertension include improper blood pressure measurement technique, difficult to compress heavily calcified or atherosclerotic arteries in the elderly, poor adherence
to prescribed treatment and the phenomenon of ‘white-coat’
hypertension [14]. Poor adherence to therapy is a common
cause of apparent treatment resistance. Retrospective cohort
studies suggest that ∼40% of patients with newly diagnosed
hypertension will discontinue treatment during the first year,
and only 40% will continue with therapy during the first 5 or
10 years of follow-up [15–17]. Poor adherence to treatment
can be identified through the use of self-report tools, pharmacy refill rates and pill counts. A number of methods can be
used to improve adherence, including selection of medications
with low side effect profiles, simplification of the medication
regimen through once daily dosing and use of fixed-dose combinations, and improved communication between patients and
physicians regarding patient knowledge, awareness, beliefs
and attitudes [18]. Given the high rates of treatment discontinuation, interventions to enhance medication adherence
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therefore have the potential to overcome a significant component of apparent treatment resistance.
Two additional causes of pseudo-resistance are related to
the antihypertensive regimen itself: (i) suboptimal dosing of
medications or inappropriate combinations of agents and (ii)
clinician inertia, a failure to change or increase dose regimens
in order to obtain adequate treatment of poorly controlled
hypertension despite awareness of the condition. Studies conducted among primary care physicians suggest that many physicians have higher BP thresholds for initiation and
modification of drug therapy than the recommended treatment goals, and many are not familiar with the JNC guidelines
[19]. Perhaps a greater understanding of what determines physicians’ thresholds for making treatment decisions, and education regarding treatment guidelines and available medical
decision algorithms, can improve adherence to evidence-based
recommendations and attainment of treatment goals.
Confirmation of true resistant hypertension should include
the accurate measurement of office blood pressure, with attention to environment, body and arm position, appropriate
cuffs, and the recommendation that multiple measurements
be obtained at least 1 min apart and averaged out [20]. Nonetheless, office blood pressure measurement has shortcomings,
and the use of out-of-office monitoring including home and
24-h ambulatory blood pressure monitoring (ABPM) is becoming increasingly important. ABPM, which involves readings taken at preset intervals throughout the day and night to
capture the diurnal rhythm and variability of blood pressure
over 24 h, can help detect ‘white-coat’ hypertension, an elevation in blood pressure that occurs during clinic visits, with
normal blood pressure in non-clinic settings and absence of
target organ damage [21]. The confirmation of white-coat
hypertension, a common cause of pseudo-resistance, identifies
patients who are relatively low risk and therefore unlikely to
benefit from additional antihypertensive therapy. In one study
of patients with apparent resistant hypertension, 28% were
found to have normal awake ambulatory blood pressure when
ABPM was used to complement office BP measurements [22].
Twenty-four-hour ABPM has, in fact, been shown to be the
best method for estimating a patient’s hypertension-related
cardiovascular risk [23]. ABPM can identify patients with
‘masked’ hypertension, which is defined as elevated ambulatory blood pressure but normal clinic blood pressure, and has
been associated with an increased risk of cardiovascular
events. In a study of 466 patients with apparent responder
hypertension based on clinic measurements, ambulatory BP
monitoring found 27% to have ‘masked’ hypertension, which
over a follow-up period of 5 years was associated with a relative
risk of 2.28 (95% CI, 1.1–4.7; P < 0.05) of fatal and nonfatal
cardiovascular events, compared with true responder hypertension [24].
Moreover, ABPM provides clinicians with the ability to
capture nighttime blood pressures and to identify the presence
of a ‘non-dipping’ pattern, which is the diminution or reversal
of the normal 10–20% nocturnal fall in blood pressure
that occurs in both normotensive and hypertensive individuals. Nighttime blood pressure is a potent predictor of cardiovascular risk, and in a cohort study of 7458 patients,
Y.R. Drexler and A.S. Bomback
Resistant hypertension in CKD
increased cardiovascular morbidity and mortality in both
hypertension and in CKD [34, 36].
Obesity is another common co-morbidity seen in both resistant hypertension and CKD, and may mediate hypertension
through a number of mechanisms including impaired sodium
excretion, enhanced sympathetic nervous system activity, increased aldosterone secretion due to visceral adiposity and obstructive sleep apnea (OSA) [14]. Severe OSA, in particular,
has been linked to resistant hypertension in patients with advanced CKD, though an independent association between
severe OSA and resistant hypertension has thus far only been
demonstrated in dialysis patients [37].
T R E AT M E N T
The approach to treatment of resistant hypertension in patients with CKD should aim to address the multitude of
factors that contribute to the pathogenesis of hypertension in
this population, including impaired handling of sodium and
volume expansion, increased activity of the renin-angiotensinaldosterone system, enhanced sympathetic activity and reduced
endothelium-dependent vasodilation. Particular focus should
be lent to patterns of elevated blood pressure that have been
found to be more prevalent in this population and to increase
the risk of target organ damage, including elevated nighttime
BP and the presence of non-dipping.
Volume
Salt restriction has been shown to lower blood pressure in
patients with and without hypertension. In the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial, sodium
reduction from 100 to 50 mmol per day generally had twice the
effect on blood pressure as reduction from 150 to 100 mmol per
day [38]. The effect of dietary sodium restriction on the degree
of BP reduction appears to be particularly robust in patients
with resistant hypertension. In a small, randomized crossover
trial of patients with resistant hypertension, a low (50 mmol/
day) compared with high (250 mmol/day) sodium diet decreased mean office systolic BP (SBP) by 22.7 mm Hg and led
to significant reductions in daytime, nighttime and 24-h ambulatory blood pressure [39].
Thus, patients with resistant hypertension, as well as
those with CKD, demonstrate particularly salt-sensitive
hypertension. Patients with CKD have an impaired ability to
effectively excrete sodium and will respond to a sodium load
by raising blood pressure in order to re-establish salt
balance; this ‘pressure natriuresis’ comes at the expense of
hypertension-related target organ damage [8]. In addition,
dietary sodium intake has been shown to interact with the
RAAS, particularly aldosterone, in both animal models and
human studies, to mediate hypertension, vascular and tissue
damage and kidney disease [40]. In a study of patients with
resistant hypertension and high 24-h urinary aldosterone,
urinary protein excretion increased significantly with progressively greater salt intake, suggesting that aldosterone
excess and high dietary sodium intake interact to increase
proteinuria [41]. Indeed, in a randomized, double-blind,
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FULL REVIEW
nighttime BP was found to be a stronger predictor than
daytime blood pressure of total and cardiovascular mortality
[25]. Similarly, non-dipping has been shown to confer an ∼2fold greater risk of cardiovascular mortality compared with a
normal dipping pattern, independent of the presence of hypertension (i.e. even with a normal 24-h blood pressure) [26]. In a
study of 556 patients with resistant hypertension, a nondipping pattern was present in 65% and was an independent
predictor of the composite end point of fatal or nonfatal cardiovascular events, all-cause mortality and cardiovascular
mortality (hazard ratio, 1.74; 95% CI, 1.12–2.71) [27].
ABPM takes on greater importance in the CKD population
with hypertension, as both non-dipping and masked hypertension are more common among patients with CKD. In the
AASK Cohort Study, a remarkable 80% of the participants
were non-dippers, and of the 377 participants with controlled
clinic BP, 70% had masked hypertension [28]. Higher nighttime BP and masked hypertension were associated with increased severity of target organ damage, including higher
prevalence of left ventricular hypertrophy (LVH) and proteinuria and lower estimated GFR. Accordingly, in a large cohort
of 436 hypertensive patients with CKD, ABPM has been
shown to be a better predictor of renal and cardiovascular end
points compared with office BP measurements, with nighttime
systolic BP emerging as a stronger predictor than daytime systolic BP among the components of ABPM [29]. As this study
suggests, the prognostic role of ABPM is superior to that of
office BP among CKD patients. However, ABPM is associated
with increased time, effort and expense, and prospective
studies that randomize CKD patients to therapeutic interventions based on ABPM rather than office BP are required before
ABPM can be recommended as standard of care in all CKD
patients [30].
In addition to the above considerations, a number of
factors can impair control of preexisting hypertension and
contribute to the development of resistance, particularly in
CKD patients. Renal artery stenosis, most commonly caused
by atherosclerosis, has a reported prevalence in the Medicare
population of 0.5% overall but 5.5% in those with CKD [31].
Moreover, as this represents symptomatic renovascular
disease, and renal artery stenosis is usually asymptomatic, the
true disease burden is likely higher. While the frequency of resistant hypertension resulting from renovascular disease is
unknown, hypertension and symptomatic disease of the extrarenal vasculature are strongly associated with prevalent renovascular disease, and hemodynamically significant renal artery
stenosis may contribute to treatment resistance [32]. Increased
arterial stiffness is a common finding in patients with CKD
and has also been associated with resistant hypertension [33].
Increased arterial stiffness in CKD may be a consequence of a
number of pathologic mechanisms, including vascular calcification, chronic volume overload, inflammation, endothelial
dysfunction, oxidative stress and activation of the RAAS, and
has been shown to progress in a stepwise manner across the
stages of CKD [34, 35]. This association carries important
consequences for both identification and treatment of resistant
hypertension, as arterial stiffness has been associated with
FULL REVIEW
placebo-controlled crossover study in proteinuric patients
without diabetes, salt restriction itself exerted an antihypertensive and antiproteinuric effect and further enhanced the
antiproteinuric effects of RAAS blockade to nearly the same
magnitude as, and in an additive manner with, diuretics
[42]. While this study and others have demonstrated the
beneficial impact of sodium restriction on intermediate renal
outcomes in CKD, it is important to note that no large
cohort studies have shown sodium restriction to reduce BP
or long-term cardiovascular and overall mortality specifically in CKD patients [43]. Therefore, the recommendation for
sodium restriction in the treatment of hypertension in CKD
and in the reduction of cardiovascular and overall mortality
in CKD patients remains largely opinion-based.
The salt-excreting handicap of CKD and resulting extracellular volume expansion also provides the basis for treating
hypertensive CKD patients with diuretics. Studies of resistant
hypertension suggest that, even in the absence of CKD, this
group of patients manifest increased extracellular volume, as
measured by brain-type natriuretic peptide (BNP) and atrial
natriuretic peptide (ANP) [44]. Therefore, use of appropriate
diuretics is a cornerstone of therapy in patients with CKD and
resistant hypertension [9]. Nonetheless, diuretics remain underutilized and underdosed, and a change in diuretic therapy
may help a significant proportion of patients with resistant
hypertension achieve BP goals [14]. For example, while the
major trials supporting the use of diuretic therapy used
chlorthalidone at 25 mg/day, the weaker hydrochlorothiazide
(HCTZ) at doses of 12.5–25 mg/day remains the most commonly prescribed antihypertensive medication worldwide
[45]. However, when evaluated with 24-h ambulatory BP
monitoring, the antihypertensive efficacy of HCTZ at doses of
12.5–25 mg/day has been shown to be inferior to that of other
commonly prescribed drug classes [45]. Chlorthalidone is approximately twice as potent as HCTZ with a much longer duration of action (8–15 h for HCTZ compared with >40 h for
chlorthalidone) [46]. In clinical studies using 24-h ABPM,
chlorthalidone 25 mg/day results in greater reductions in 24-h
mean SBP compared with HCTZ 50 mg/day, primarily due to
its effect on reducing nighttime mean SBP [47]. Therefore,
strong consideration should be given to using chlorthalidone
over HCTZ, especially given the growing importance of nocturnal blood pressure on cardiovascular outcomes and kidney
disease progression in patients with CKD.
Thiazide diuretics are most effective in patients with a GFR
>50 mL/min/1.73 m2, although chlorthalidone can be effective
to a GFR of 30–40 mL/min/1.73 m2 in the absence of severe
hypoalbuminemia [14]. A loop diuretic is preferred for patients with advanced CKD. Typically, loop diuretics such as
furosemide and bumetanide should be dosed at least twice
daily given their short duration of action and the potential for
intermittent natriuresis leading to a reactive increase in the
RAAS (with ensuing sodium retention) if dosed once daily
[48]. The longer-acting torsemide can be dosed once or twice
daily. Consideration should also be given to combining
the loop diuretic with a diuretic that acts more distally in the
nephron, such as a thiazide or a low-dose potassium-sparing
diuretic [49].
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Adequate RAAS blockade
Targeting the RAAS with angiotensin-converting enzyme
(ACE) inhibitors and angiotensin-receptor blockers (ARBs) is
a well-established therapeutic strategy to target hypertension,
slow the progression of CKD and reduce morbidity and mortality in heart failure. However, many patients progress despite
treatment, and clinical trials of ACE inhibitors and ARBs
suggest that after an initial decline, plasma aldosterone levels
will increase in 30–40% of patients over the long term, a phenomenon known as ‘aldosterone breakthrough’ [50]. Aldosterone breakthrough has been linked to adverse outcomes such
as LVH, impaired exercise capacity, urinary albumin excretion
and a more rapid decline in GFR [50]. This breakthrough is
particularly important given the recent shift in our understanding of the role of aldosterone in mediating hypertension
and target organ damage. Namely, the classical view that aldosterone acts primarily upon epithelial tissues to regulate
intravascular volume and sodium and potassium homeostasis
has been broadened by the identification of the mineralocorticoid receptor (MR) in non-epithelial tissues including the
heart, kidney, vasculature and brain. A number of studies in
both animals and humans have demonstrated the widespread
effects of aldosterone in mediating vascular damage, inflammation and tissue fibrosis, mainly in the presence of a highsalt environment that potentiates the deleterious effect of MR
activation [51].
One therapeutic option to target incomplete blockade of
the RAAS is dual blockade with the combination of ACE inhibitors and ARBs, which has been shown to confer modest BP
reductions of an average of 4/3 mm Hg compared with monotherapy as well as proteinuria reductions of 30 and 39% compared with monotherapy with ACE inhibitors and ARBs,
respectively [52]. However, improved cardiovascular and renal
outcomes have not been consistently demonstrated despite
these additional reductions in BP and proteinuria. An alternative strategy is to use ‘ultrahigh’ doses of ACE inhibitors or
ARBs. Several small, short-term clinical studies in patients
with hypertension and CKD have found significant incremental
reductions in proteinuria after treatment with ARBs at higher
than conventional doses, albeit without additional blood pressure changes [53]. One large, randomized, open-label trial of
360 patients with non-diabetic proteinuric CKD followed for >3
years found that ‘optimal’ antiproteinuric doses of benazepril
and losartan, achieved through uptitration from conventional
doses of 10 mg/day for benazepril and 50 mg/day for losartan,
were associated with a 51 (P = 0.03) and 53% (P = 0.02) reduction, respectively, in the combined primary end point of doubling of serum creatinine, end stage renal disease or death [54].
However, optimal antiproteinuric efficacy was obtained in 57%
of patients with a losartan dose of 100 mg/day, which would be
considered a standard dose. These data suggest that while most
patients achieve maximal antihypertensive and antiproteinuric
efficacy at conventional doses of ACE inhibitors and ARBs,
some patients with hypertension and CKD may require higher
doses to achieve a more optimal degree of RAAS blockade. Theoretically, these resistant patients are displaying a form of aldosterone breakthrough.
Y.R. Drexler and A.S. Bomback
Chronotherapy
Both resistant hypertension and CKD are associated with
the phenomenon of non-dipping, an absence of the normal
nocturnal decline in BP. In the AASK Cohort Study, 80% of
the participants were non-dippers, and those in the highest
Resistant hypertension in CKD
tertile of nighttime systolic BP were more likely to have LVH,
higher prevalence of proteinuria and higher risk of CKD progression [28]. In patients with all degrees of hypertension, particularly true resistant hypertension, the presence of a nondipping profile has been shown to confer an ∼2-fold increased
risk of cardiovascular morbidity and mortality [26, 27]. In
both resistant hypertension and CKD, a common pathophysiologic mechanism may involve the impaired capacity to
excrete sodium during the daytime, leading to higher nocturnal BP and the absence of dipping [59].
In this setting, investigators have evaluated whether
chronotherapy—the strategy of bedtime, rather than morning,
dosing of antihypertensive medications—can have an impact
on the circadian rhythm of BP, including 24-h ambulatory BP
control and the prevalence of non-dipping. In a study of 250
patients with resistant hypertension, patients who were randomly assigned to the strategy of changing one drug but administering the new drug at bedtime demonstrated a
statistically significant ambulatory blood pressure reduction
(9.4/6.0 mm Hg for systolic/diastolic BP, P < 0.001) compared
with the strategy of changing one drug but continuing all medications in a single morning dose (Figure 1) [60]. The effect
was larger on the nocturnal than on the diurnal mean BP, and
the prevalence of non-dipping decreased from 84 to 43% over
the 12-week study period. The benefit of chronotherapy has
also been demonstrated in resistant hypertension by moving
all non-diuretic antihypertensive drugs from morning to
bedtime dosing without changing any medications or doses
[61]. Thus, chronotherapy offers an opportunity to improve
nocturnal BP control and the non-dipper pattern without
changing the total number of medications.
F I G U R E 1 : Chronotherapy of hypertension (data from Hermida
et al. [60]). Switching blood pressure medications from morning to
bedtime dosing can lead to significant improvements in systolic and
diastolic blood pressure. This chronotherapy strategy has also recently
been shown, in a large study of CKD patients with resistant hypertension, to improve cardiovascular morbidity and mortality.
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Hence, suppressing the RAAS with mineralocorticoid receptor blockers (MRBs), such as spironolactone and eplerenone,
has gained renewed interest as a treatment for resistant hypertension in patients with and without CKD. While hyperaldosteronism has previously been considered an uncommon cause
of resistant hypertension, recent studies have found significantly
higher aldosterone levels and an elevated aldosterone to renin
ratio (ARR) in over a third of patients with resistant hypertension, despite persistent extracellular volume expansion [44]. In
this setting, MRBs have emerged as effective therapy for patients
with resistant hypertension, with and without CKD. The strongest evidence for the efficacy of MRBs in resistant hypertension
comes from two studies. In 2007, the Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA) showed that fourth-line add-on therapy with
spironolactone, at a median treatment duration of 1.3 years and
a starting dose of 25 mg/day, resulted in a mean reduction in
SBP of 21.9 mm Hg (95% CI: 20.8–23.0 mm Hg) and in diastolic BP of 9.5 mm Hg (95% CI: 9.0–10.1 mm Hg) [55]. Subsequently, the randomized, double-blind, placebo-controlled
Addition of Spironolactone in Patients with Resistant Arterial
Hypertension (ASPIRANT) trial demonstrated a mean decrease
in daytime systolic ambulatory BP of 5.4 mm Hg (P = 0.02), as
well as significant decreases in ABPM nighttime systolic (8.6
mm Hg, P = 0.01), 24-h ABPM systolic (9.8 mm Hg, P = 0.004)
and office systolic BP values (6.5 mm Hg, P = 0.01), with spironolactone 25 mg/day at 8 weeks of therapy [56].
The efficacy and safety of MRBs in patients with resistant
hypertension who have stages 2 and 3 CKD has been evaluated
in several small retrospective studies, which have shown significant and sustained BP reductions with spironolactone and
eplerenone at low doses [57, 58]. In a study of 36 patients with
mean estimated glomerular filtration rate (eGFR) 48.6 mL/
min/1.73 m2, the addition of spironolactone at a mean dose
23.6 mg/day or eplerenone at a mean dose 60.4 mg/day resulted in a significant decrease in SBP from 162 ± 22 to
138 ± 14 mm Hg after 1 year of follow-up, and led to discontinuation of at least one antihypertensive medication during
follow-up in 44% of patients [57]. These studies have also provided important data on the risk of hyperkalemia in this group
of patients. In a cohort of 46 patients with mean eGFR
56.5 ± 16.2 mL/min/1.73 m2 who had spironolactone (25 mg/
day) or eplerenone (50 mg/day) added to a stable antihypertensive regimen, including a maximally dosed RAAS blocker
and an appropriately dosed diuretic, a baseline eGFR ≤45 mL/
min/1.73 m2 and a baseline serum potassium >4.5 mEq/L
were the strongest predictors of hyperkalemia (defined as
serum potassium >5.5 mEq/L) [58]. With close monitoring of
potassium, the use of MRBs in patients with early stage CKD,
or with later stage CKD and a low baseline potassium level
and/or concomitant use of diuretics, can be a safe and effective
therapeutic strategy for resistant hypertension.
FULL REVIEW
Data regarding chronotherapy in hypertensive patients
with CKD are promising. In an uncontrolled, 8-week clinical
trial of 32 non-dipper patients with CKD treated with a mean
2.4 antihypertensive medications at baseline, shifting one antihypertensive drug from morning to bedtime dosing restored a
‘dipper’ profile in 87.5% of subjects with significant reductions
in systolic and diastolic nocturnal BP [62]. Moreover, urinary
protein excretion decreased as well, from 235 ± 250 to
167 ± 206 mg/day (P < 0.001), a change that correlated with
the improvement in the night/day BP ratio. Subsequently, in a
prospective, randomized, open-label trial of 661 hypertensive
patients with CKD, Hermida et al. [63] found that bedtime
dosing of at least one antihypertensive medication resulted in
significant improvements in nocturnal BP control, attainment
of ‘dipper’ status and controlled ambulatory BP, lower adjusted
risk of cardiovascular events (adjusted HR, 0.31; 95% CI, 0.21–
0.46; P < 0.01) and lower risk for a composite outcome of cardiovascular death, myocardial infarction and stroke (adjusted
HR, 0.28; 95% CI, 0.13–0.61; P < 0.001). Bedtime treatment
was also associated with a greater percent reduction in
albumin excretion from baseline (26.9 versus 15.6% in patients
on morning treatment, P = 0.018). The bedtime treatment
group also demonstrated slower decline in GFR (0.4 mL/min/
1.73 m2 versus 2.3 mL/min/1.73 m2, P = 0.043), but the absolute differences were small and progression of CKD was not
studied as an outcome. Given these data, a reasonable strategy
in patients with resistant and/or non-dipping hypertension
and CKD is to change one antihypertensive medication to
bedtime dosing.
T R E AT M E N T A L G O R I T H M S
Current guidelines recommend initiating treatment with a diuretic, either alone or in combination with an agent that has a different mechanism of action, such as an agent that targets the
RAAS. Additional agents with complementary mechanisms of
action are then added, in a stepwise fashion, until BP control is
achieved [1]. However, limited guidance is provided to clinicians in terms of choice of add-on therapy and individualization
of treatment. As a result, as seen in a large general hypertensive
cohort, 21% of patients are prescribed ≥3 medications [64].
Several treatment algorithms have been proposed that
target the underlying physiology mediating resistance to
therapy. In a renin test-guided therapeutic (RTGT) algorithm,
ambulatory plasma renin activity (PRA) values obtained from
a routine blood sample, regardless of antihypertensive therapy
or diet, were used to guide addition and/or subtraction of
drugs [65]. Hypertensive patients with low ambulatory PRA
(<0.65 ng/mL/h) were presumed to have persistent salt/
volume excess that would respond primarily to natriuretic
anti-volume (‘V’-type) drugs, including diuretics, aldosterone
antagonists, calcium channel blockers or alpha blockers. Patients with PRA ≥0.65 ng/mL/h were considered to have an
excess of renin-angiotensin system-related vasoconstrictor activity that would respond to anti-renin (‘R’-type) drugs, including beta blockers, ACE inhibitors or ARBs. For example,
in a patient treated with a diuretic and either an ACE inhibitor
1332
or ARB, which stimulate renin secretion, a suppressed PRA
<0.65 ng/mL/h would suggest stopping or downtitrating the
‘R’ drug and uptitrating or adding a ‘V’ drug. Compared with
clinical hypertension specialists’ care (CHSC), RTGT resulted
in a 10 mm Hg greater decline in SBP (P = 0.03), generally via
subtracting ‘R’ drugs from low-renin patients while adding
them to the medium- and high-renin groups and subtracting
‘V’ drugs from high-renin patients while adding them to the
other groups. Additional studies have similarly found that
baseline PRA can predict the blood pressure response to addon therapy with beta blockers and thiazide diuretics (higher
renin predicting greater BP response to atenolol, and lower
renin predicting greater BP response to HCTZ) [66] as well as
spironolactone [56], supporting the use of this physiologybased algorithm to provide clues regarding patients’ sodiumvolume and/or renin status in order to optimize BP control. In
clinical practice, lower PRAs are associated with poorer blood
pressure control and use of more antihypertensive medications
[64], suggesting that patients with low-renin hypertension can
perhaps benefit most from this approach.
Additional algorithms for resistant hypertension also rely
on targeting the known physiologic mechanisms mediating
hypertension, including salt/volume excess, the RAAS and the
sympathetic nervous system (SNS). In patients with resistant
hypertension despite a combination regimen directed at both
salt/volume excess and the RAAS, the first step would be to
identify patients in whom persistent salt/volume excess is sustaining hypertension and who would benefit from bolstering
the diuretic regimen [67]. While the presence of edema is an
important clinical clue, patients with both resistant hypertension and CKD may manifest occult extracellular volume expansion. As discussed above, suppressed ambulatory PRA,
interpreted in the context of existing antihypertensive therapy,
can indicate this occult volume excess and need for more diuresis. The second option in this algorithm is the addition of
medications directed at SNS-mediated hypertension, mainly
α- and β-blockers, in clinical circumstances that suggest
hypertension driven by the SNS, such as sleep apnea. In a
retrospective study assessing the efficacy of this approach in 27
patients with resistant hypertension, 89% were able to achieve
BP control, including 54% in whom the diuretic regimen was
strengthened, with the most frequent medication adjustment
being the addition of a potassium-sparing diuretic [68].
We propose a screening and treatment algorithm that
follows these physiologic approaches to resistant hypertension
(Figure 2). Remaining areas of uncertainty that will likely
enhance this algorithm include (i) whether to screen for aldosterone breakthrough in all patients treated with RAAS blockade prior to initiating treatment with aldosterone antagonists
[50] and (ii) whether chronotherapy should be utilized as a
generalized approach or be limited to those patients with resistant hypertension and a 24-h BP profile of non-dipping.
CONCLUSION
Despite increased awareness and multiple treatment strategies for hypertension, resistant hypertension remains a
Y.R. Drexler and A.S. Bomback
FULL REVIEW
F I G U R E 2 : A physiology-based algorithm for resistant hypertension in CKD, from identification to treatment.
common clinical problem. In the evaluation of patients with
apparent resistant hypertension, clinicians should first identify potential causes of pseudo-resistance. Consideration
should be given to 24-h ABPM given the gaps in our definition of resistant hypertension, including ‘white-coat’ and
‘masked’ hypertension and the presence of a ‘non-dipping’
pattern, common both in resistant hypertension and in
CKD. Treatment should aim to address the many physiologic mechanisms underlying resistant hypertension in
this population. We propose a physiology-based algorithm
for resistant hypertension in CKD, from identification to
treatment, aimed at improving blood pressure control and,
ultimately, long-term renal and cardiovascular outcomes.
Resistant hypertension in CKD
C O N F L I C T O F I N T E R E S T S TAT E M E N T
None declared.
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Received for publication: 20.3.2013; Accepted in revised form: 8.7.2013
FULL REVIEW
Nephrol Dial Transplant (2014) 29: 1335–1341
doi: 10.1093/ndt/gft371
Advance Access publication 5 September 2013
Ultrafiltration for the treatment of congestion: a window into the
lung for a better caress to the heart
Gian Paolo Rossi1, Lorenzo A. Calò1, Giuseppe Maiolino1 and Carmine Zoccali2
1
Department of Medicine-DIMED, Clinica Medica 4, Hypertension and Nephrology Unit, University of Padova, Padova, Italy and 2CNR-IBIM,
Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
Correspondence and offprint requests to: Gian Paolo Rossi; E-mail: [email protected]
A B S T R AC T
A significant proportion of patients treated for acute decompensated heart failure (ADHF) suffer from worsening renal
function, which is often associated with medical therapy resistance and poor outcome. In this setting, haemofiltration has
been used for more than 30 years, despite inconclusive
© The Author 2013. Published by Oxford University Press on
behalf of ERA-EDTA. All rights reserved.
evidence for its advantages. In the last decade, a major technological advances have made available a new technique, ultrafiltration, which works at lower blood flow rates and requires
only a venous access. As in a first proof-of-concept study (EUPHORIA), ultrafiltration proved to be efficacious in fluid
removal in ADHF patients; this treatment was further investigated in randomized controlled trials. The RAPID-CHF trial
demonstrated that ultrafiltration was more effective than
1335