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The double challenge of resistant hypertension and chronic

kidney disease
Patrick Rossignol, Ziad A Massy, Michel Azizi, George Bakris, Eberhard Ritz, Adrian Covic, David Goldsmith, Gunnar H Heine, Kitty J Jager,
Mehmet Kanbay, Francesca Mallamaci, Alberto Ortiz, Raymond Vanholder, Andrzej Wiecek, Carmine Zoccali, Grard Michel London,
Bndicte Stengel, Denis Fouque, for the ERA-EDTA EURECA-m working group, Red de Investigacin Renal (REDINREN) network, and
Cardiovascular and Renal Clinical Trialists (F-CRIN INI-CRCT) network

Lancet 2015; 386: 158898 Resistant hypertension is dened as blood pressure above goal despite adherence to a combination of at least three
INSERM Centre optimally dosed antihypertensive medications, one of which is a diuretic. Chronic kidney disease is the most frequent
dInvestigations Cliniques of several patient factors or comorbidities associated with resistant hypertension. The prevalence of resistant
(CIC)-1433, and INSERM
U1116, Nancy, France
hypertension is increased in patients with chronic kidney disease, while chronic kidney disease is associated with an
(Prof P Rossignol MD); Institut impaired prognosis in patients with resistant hypertension. Recommended low-salt diet and triple antihypertensive
Lorrain du Cur et des drug regimens that include a diuretic, should be complemented by the sequential addition of other antihypertensive
Vaisseaux, CHU Nancy, drugs. New therapeutic innovations for resistant hypertension, such as renal denervation and carotid barostimulation,
Vandoeuvre ls Nancy, France
(Prof P Rossignol); Universit de
are under investigation especially in patients with advanced chronic kidney disease. We discuss resistant hypertension
Lorraine, Nancy, France in chronic kidney disease stages 35 (ie, patients with an estimated glomerular ltration rate below 60 mL/min per
(Prof P Rossignol); Association 173 m and not on dialysis), in terms of worldwide epidemiology, outcomes, causes and pathophysiology, evidence-
Lorraine pour le Traitement de based treatment, and a call for action.
lInsusance Rnale,
Vandoeuvre ls Nancy, France
(Prof P Rossignol); Division of Introduction contribute to impaired renal function and uraemia.
Nephrology, Ambroise Par Resistant hypertension is dened as blood pressure (BP) Pharmaceutical treatment, admission to hospital, and
University Hospital (APHP), above goal despite adherence to a combination of at least costly interventions, such as major cardiovascular surgery
University of Paris Ouest-
three optimally dosed antihypertensive medications, one or renal replacement therapy, are often necessary.
Yvelines (UVSQ), of which is a diuretic (panel 1). Chronic kidney disease is Data describing the epidemiology, prevalence, clinical
Boulogne-Billancourt, Paris, the most frequent of several patient factors and characteristics, and outcomes of resistant hypertension
France (Prof Z A Massy MD); comorbidities that can be secondary causes of resistant in patients with chronic kidney disease are scarce and
INSERM U1018, Research
Centre in Epidemiology and
hypertension. Prevalence of resistant hypertension poorly documented, and adding to the data available
Population Health (CESP), increases with reduced kidney function and raised should be a goal for future research. This review is based
UVSQ, Villejuif, France albuminuriaie, signs of chronic kidney disease. Chronic on a detailed scientic literature search of resistant
(Prof Z A Massy); APHP, Hpital
kidney disease is characterised by an initial injury followed hypertension in chronic kidney disease, and it
Europen Georges Pompidou,
Unit dHypertension by a progressive decline in the glomerular ltration rate summarises diagnostic criteria, epidemiology, morbidity
artrielle, Paris, France (GFR; chronic kidney disease stages 15 or 5D; panel 1), and mortality, causes, pathophysiology, evidence-based
(Prof M Azizi MD); Universit leading to kidney failure and the need for renal treatment, and key unmet needs.
Paris Descartes, Paris, France
replacement therapy. The clinical phenotype changes with
(Prof M Azizi); INSERM
CIC-1418, Paris, France each stage, and chronic kidney disease-related Epidemiology of resistant hypertension and
(Prof M Azizi); Department of complications (such as cardiovascular complications) association with chronic kidney disease
Medicine, University of Chicago The prevalence of true resistant hypertension is unknown
Medicine, Chicago, IL, USA
because most studies did not include key diagnostic criteria
(Prof G Bakris MD); Department
Search strategy and selection criteria (eg, antihypertensive medication doses, treatment
Internal Medicine, Ruperto
Carola University of The Cochrane Library, MEDLINE, Embase, and Cochrane adherence, and systematic exclusion of measurement
Heidelberg, Germany
Database Systematic Reviews were searched, up to May 23, artifacts). Several large population-based studies1416 and
(Prof E Ritz MD); Parhon
2015. The following search terms were used: hypertension in electronic medical record studies1719 recorded the prevalence
University Hospital,
Grigore T Popa University of combination with the terms resistant or uncontrolled and of apparent treatment-resistant hypertension, which was
Medicine, Iasi, Romania chronic kidney disease or chronic kidney insuciency, or dened as uncontrolled BP in patients taking three or more
(Prof A Covic FRCP); Renal and antihypertensive medication classes or four or more drugs
Transplantation Department,
chronic kidney disease AND hypertension AND socioeconomic
Guys and St Thomas AND cost of illness. Publications in the past 5 years were regardless of BP level (panel 1). 0514% of people treated
Hospitals, London, UK selected, but commonly referenced and highly regarded older for hypertension have apparent treatment-resistant
(Prof D Goldsmith FRCP); publications were not excluded. The reference lists of articles hypertension in the studies summarised in table 2. Based
Internal Medicine on data from the general population, only 50% of
IV-Nephrology and
identied by this search strategy were cross-referenced, and
Hypertension, Saarland relevant papers were selected. Review articles are cited to individuals with apparent treatment-resistant hypertension
University Medical Centre, provide readers with more details and more references than would be prescribed optimum antihypertensive therapy21
Homburg, Germany
space permits in this narrative review. Additional publications and around 40% of apparent treatment-resistant
(Prof G H Heine MD); ERA-EDTA hypertension could be white-coat hypertension or caused
Registry, Department of were proposed by members of the writing team.
by medication non-adherence.22 Thus, true resistant

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hypertension might be present in less than half of the Medical Informatics, Academic
patients with apparent treatment-resistant hypertension, Panel 1: Denitions of resistant hypertension and chronic Medical Center, University of

but the evidence is inadequate to precisely quantify the kidney disease Amsterdam, Amsterdam,
Netherlands (K J Jager MD);
prevalence. As compared with people without chronic Resistant hypertension Department of Medicine,
kidney disease, prevalence of resistant hypertension is The accepted denition of resistant hypertension is a seated Division of Nephrology, Koc
twice as high in people with chronic kidney disease18,19 and University School of Medicine,
oce systolic blood pressure (SBP) 140 mm Hg or diastolic Istanbul, Turkey
increases both with decreased estimated GFR (eGFR) and blood pressure (DBP) 90 mm Hg on maximally tolerated (M Kanbay MD); Nephrology,
raised albuminuria.16 In the CRIC study,20 42% of doses of three or more antihypertensive agents, one of which Hypertension and Renal
3612 patients with established chronic kidney disease had must be a diuretic appropriate for the level of kidney Transplantation Unit, Ospedali
apparent treatment-resistant hypertension. Riuniti, Reggio Calabria
function.1,2 Most guidelines also stipulate the need for (F Mallamaci MD); CNR
daytime ambulatory blood pressure measurement (ABPM) (National Research Council of
Outcomes readings of SBP 135 mm Hg or DBP 85 mm Hg on the Italy) Institute of Clinical
Whereas the associations between hypertension, same regimen13 to conrm resistant hypertension by Physiology (IFC), Clinical
cardiovascular risk, and progression of chronic kidney Epidemiology and
excluding white coat hypertension. True resistant Pathophysiology of Renal
disease are well established,8,23 few studies have assessed hypertension is a diagnosis of exclusion because all other Diseases and Hypertension,
the long-term prognosis of resistant hypertension in potential causes (eg, pseudoresistance associated with poor Ospedali Riuniti, Reggio
patients with or without chronic kidney disease.2429 In adherence, endocrine and vascular causes, and white coat Calabria, Italy (F Mallamaci,
Prof C Zoccali MD); Division of
18 036 patients with incident hypertension treated with hypertension) must all rst be excluded.1,2 Most Nephrology, IIS-Fundacion
three or more antihypertensive agents, the risk of a epidemiological studies lack key elements (eg, medication Jimenez Diaz, Madrid, Spain
composite endpoint including death, cardiovascular doses, adherence, and aetiology assessments are mostly (Prof A Ortiz MD); School of
events, and chronic kidney disease over 38 years of follow- lacking, while ABPM is scarcely used) to dene true resistant Medicine, Universidad
Autonoma de Madrid, Madrid,
up was 180% in the 2521 patients with apparent treatment- hypertension, thus it was proposed to consider an additional Spain (Prof A Ortiz); Red de
resistant hypertension, and 135% in those without category of apparent treatment-resistant hypertension, as Investigacion Renal
resistant hypertension (adjusted hazard ratio [HR] 147, dened by an uncontrolled blood pressure (BP) on three or (REDINREN), Madrid, Spain
95% CI 133162, p<0001).24 Patients with hypertensive more antihypertensive medication classes or use of four or (Prof A Ortiz); Insituto Reina
Soa de Investigaciones
nephropathy (n=100) with true resistant hypertension more medications regardless of BP level. Nefrolgicas (IRSIN), Madrid,
(according to both oce and ambulatory blood pressure Spain (Prof A Ortiz); Nephrology
monitoring [ABPM]) had a higher risk of fatal and non- Chronic kidney disease Section, Department of
fatal cardiovascular events (HR 198, 95% CI 114343) Chronic kidney disease is dened as abnormalities of kidney Internal Medicine, University
and end-stage renal disease or death (266, 162437) structure or function, present for more than 3 months, with Hospital Ghent, Belgium
implications for health (which is intended to reect the (Prof R Vanholder MD);
compared with 118 patients with hypertensive nephropathy Department of Nephrology,
and controlled BP who were prospectively followed up over notion that a variety of abnormalities of kidney structure or Transplantation and Internal
57 months.25 Lower baseline eGFR identied a very high function might exist, but not all have implications for health Medicine, Medical University of

cardiovascular risk prole in 531 patients with true of individuals, and therefore need to be contextualised) and Silesia, Katowice, Poland
is classied based on cause, estimated glomerular ltration (Prof A Wiecek MD); INSERM
resistant hypertension over a median follow-up of U970, Hpital Europen
49 years. The adjusted HR for fatal or non-fatal rate, and albuminuria category.4 Georges Pompidou, Paris
cardiovascular events was 427 (95% CI 1791020, Substantial discrepancies exist in international guidelines to (Prof G M London MD); UVSQ,
UMRS 1018, Paris-South
p<0001), for all-cause mortality 437 (1581220, p<001), dene target BP in chronic kidney disease (table 1), especially University, Villejuif, France
and for cardiovascular mortality was 495 (1391754, when signicant albuminuria is present. To avoid unnecessary (B Stengel MD); and
p<005) for each log10 lowering of eGFR.26 The REGARDS confusion, BP levels for dening resistant hypertension Department of Nephrology,
study and secondary analyses of the ALLHAT trial noted should be consistent with those of the general population Nutrition, and Dialysis, Centre
Hospitalier Lyon Sud, Carmen-
that apparent treatment-resistant hypertension increased (ie, oce SBP 140 mm Hg or DBP 90 mm Hg). CENS, Universit de Lyon, Lyon,
the risk of end-stage renal disease.28,29 However, these France (Prof D Fouque MD)
studies were limited in generalisability because the Correspondence to:
denition of resistant hypertension diered between all patients with resistant hypertension should undergo Prof Patrick Rossignol, Centre
patients with chronic kidney disease (130/80 mm Hg) and screening for secondary forms of hypertension (panel 2).3 dInvestigations Cliniques,
INSERM CHU de Nancy, Institut
patients without chronic kidney disease (140/90 mm Hg), Because chronic kidney disease is the most common Lorrain du Cur et des Vaisseaux
dierent methods were used to dene resistant cause of resistant hypertension, its presence might Louis Mathieu, 54500 Vandoeuvre
hypertension (ie, oce vs ABPM), and standardised discourage screening for other secondary causes of ls Nancy, France
control groups were not available. hypertension. However, some secondary causes of

hypertension are more frequent in chronic kidney

Investigation of causes and pathophysiological disease and should still be evaluated. Atherosclerotic
insights renal artery stenosis is present in 05% of the
Other secondary causes US Medicare population, but is present in 55% of those
According to the 2013 European Society of Hypertension patients with chronic kidney disease.30 Endocrine forms
(ESH) and European Society of Cardiology (ESC) of secondary hypertension (eg, primary aldosteronism,
guidelines for the management of arterial hypertension, phaeochromocytoma, and Cushings disease) might be Vol 386 October 17, 2015 1589

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Target BP* in CKD without Target BP in CKD with Target BP in diabetes Target BP in elderly Denition of resistant hypertension
albuminuria or proteinuria albuminuria or proteinuria (mm Hg) people (mm Hg)
(mm Hg) (mm Hg)
KDIGO5 140/90 130/80 As for non-diabetics No specic targets NA
CHEP6 <140/90 (in non-diabetic CKD) <140/90 (in non-diabetic CKD) <130/80 Aged 80 years; <150, NA
<130/80 (in diabetes) <130/80 (in diabetes) systolic BP
JNC 87 <140/90 <140/90 <140/90 Aged 60 years; <150/90, NA
<140/90 if in diabetes and
CKD or CKD alone
JNC 78 <130/80 <130/80 <130/80 No specic targets Failure to achieve goal BP in patients who
adhere to full doses of an appropriate three
drug regimen that includes a diuretic
ISH and ASH9 <140/90 <140/90 <140/90 Aged 80 years; <150/90, BP 140/90 mm Hg with use of three drugs
<140/90 if in diabetes and (ACEi or ARB, CCB, and a diuretic) in full or
CKD or CKD alone maximally tolerated doses
NICE1012 <140/90 (in non-diabetic CKD) <130/80 <140/80, <130/80 with Aged 80 years; <150/90 BP >140/90 mm Hg after treatment with
<130/80 (in diabetes) kidney, eye, or the optimal or best tolerated doses of an
cerebrovascular damage ACE inhibitor or an ARB plus a CCB plus a
NHFA13 <130/80 <125/75 <130/80 No specic targets NA
ESC and ESH3 <140, systolic BP <130, systolic BP <140/85 Aged 80 years; <150/90 BP 140/90 mm Hg with appropriate
lifestyle measures and three drugs (a
diuretic and two other drugs belonging to
dierent classes, not necessarily including
an MRA) at adequate doses

BP=blood pressure. CKD=chronic kidney disease. ACE=angiotensin-converting enzyme. ARB=angiotensin receptor blocker. CCB=calcium channel blocker. CKD=chronic kidney disease. MRA=mineralocorticoid
receptor antagonist. KDIGO=Kidney Disease Improving Global Outcomes. CHEP=Canadian Hypertension Education Program. JNC=Joint National Committee. ISH=International Society of Hypertension.
ASH=American Society of Hypertension. NICE=National Institute for Health and Clinical Excellence. ESC= European Society of Cardiology. ESH=European Society of Hypertension. *BP targets apply to seated
oce BP measurements. No specic recommendations are given for elderly people with CKD and diabetes or diabetes alone. ISH and ASH generally recommend a BP target of <140/90 mm Hg for CKD, but
acknowledge that some experts still recommend less than 130/80 mm Hg in albuminuria. Note that NICE CKD guidelines additionally dene target systolic BP ranges (CKD without either diabetes or
albuminuria: 120139 mm Hg; CKD and albuminuria with or without diabetes: 120129 mm Hg). Recommendations refer to type 2 diabetes.

Table 1: Target blood pressure (BP) in chronic kidney disease and denition of resistant hypertension by various groups

dicult to diagnose in the presence of advanced chronic urine analysis study38 found that 23% (4) of patients
kidney disease (table 3). The concommittent use of other referred for renal denervation were completely non-
pharmacological agents or illicit drugs that interfere with adherent to their prescribed antihypertensive treatment.
the pharmacodynamic eects or the pharmacokinetics of Patients with chronic kidney disease are especially prone
antihypertensive treatment could also aect resistant to non-adherence39,40 because of the size and complexity of
hypertension. Patients with chronic kidney disease might their multiple drug regimens (often more than 20 pills per
need glucocorticoids or calcineurin inhibitors to treat the day). Additionally, drug-related side-eects, costs, and poor
cause of their chronic kidney disease, erythropoietin for education on the benets of antihypertensive treatment
anaemia, or VEGF-targeting drugs for kidney cancer, all can contribute to non-adherence.41 In addition, multiple
of which could interfere with BP control.34 In addition, changes in therapeutic regimens in response to
patients with chronic kidney disease might be more comorbidities, complications, or hospital admissions
sensitive to the potential pressor eects of non-steroidal might confuse patients with chronic kidney disease, who
anti-inammatory drugs or oral contraceptives.35 are often old and frequently suer from cognitive disorders
and depression.42 Finally, physicians can contribute to poor
Non-adherence to drug therapy management of resistant hypertension in patients with
Inadequate control of BP is often attributable to poor drug chronic kidney disease through omission of salt-restriction
adherence. Inadequately controlled BP due to poor drug recommendations, prescriptions for diuretics, or
adherence is not strictly consistent with the denition of reluctance to increase the dose of BP medication.43
resistant hypertension, but it is one of the causes of
apparent treatment-resistant hypertension.36 A mass Factors associated with chronic kidney disease
spectrometry urine toxicology screening of antihypertensive that aect resistant hypertension
drugs reported that 53% (40) of patients with resistant Eect of arterial ageing and autonomic dysfunction
hypertension were non-adherent to treatment. Of these, In the general population, older patients (over 60 years
70% (28) were incompletely adherent and 30% (12) were old) are more likely to present with resistant
completely non-adherent. Reduced adherence was not hypertension than younger patients. Ageing itself is
attributed to a particular antihypertensive class.37 Another linked to decreased kidney function and is also

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Study, country, and time period Participants with CKD denition, GFR % prevalence of Denition % prevalence % prevalence of apparent
treated HT n, age in mL/min per 173 m2 uncontrolled BP of apparent of apparent treatment-resistant HT in
years (% prevalence) 140/90 mm Hg treatment- treatment- participants treated for HT
resistant resistant HT
HT* in
treated for
Without CKD With CKD
General population studies
McAdam et al17 GE electronic medical record USA 21 460 18 ICD-9 code (29%) 67% 2 124% 122% 204%
Persell14 NHANES USA 200308 3710 20 eGFR <60 (199%) 41% 1 128% 120% 247%
Stengel et al15 Three-City France 200304 1298 (49% with eGFR <45 (42%) 69% 2 51% 33% 157%
treated HT) 69
Tanner et al16 REGARDS USA 200309 13 384 45 eGFR <60 (292%) 30% 1 143% 125% 232%
Gijn-Conde et Madrid Health Area 6 Hypertension 48 744 all ages CKD hospital discharge 44% 1 129% 124% 246%
al18 registry Spain 2008 codes (39%)
Weitzman et al19 MHS Hypertension registry Israel 172 432 18 eGFR <60 (266%) 36% 1 05% 05% 16%
Chronic kidney disease cohort study
Muntner et al20 CRIC USA 200307 3612 (85% with eGFR 2070 (100%) 33% 1 .. .. 42%
treated HT) 2174

CKD=chronic kidney disease. GFR=glomerular ltration rate. BP=blood pressure. HT=hypertension. ICD 9=9th International Classication of Disease code.17 NHANES=National Health and Nutrition Examination
Survey. REGARDS=Reasons for Geographic and Racial Dierences in Stroke. MHS=Maccabi Health Services. CRIC= Chronic Renal Insuciency Cohort. *1=systolic/diastolic BP 140/90 mm Hg with concurrent use
of three or more antihypertensive drugs or use of four regardless of BP level, 2=systolic/diastolic BP 140/90 mm Hg (130/80 mm Hg for those with CKD or diabetes) with concurrent use of three or more
antihypertensive medications including a diuretic. Prevalence of apparent treatment-resistant HT calculated in all Three-City study participants. Prevalence of apparent treatment-resistant HT calculated in all
CRIC study participants (treated and untreated).

Table 2: Worldwide prevalence of apparent treatment-resistant hypertension overall and by chronic kidney disease status

associated with an increase in systolic and diastolic BP,

and with poor BP control in patients with chronic Panel 2: Resistant hypertension general work-up
kidney disease.44 Many older patients have isolated Resistant hypertension
systolic hypertension that is related to arteriosclerosis. Failure to reach goal BP in patients who adhere to full doses of an appropriate three-drug
Chronic kidney disease is associated with premature regimen, which includes a diuretic (ideally an RAS blocker, CCB, and a diuretic)
vascular ageing, characterised by accelerated
arteriosclerosis or atherosclerosis and endothelial Work-up
dysfunction.45 Vascular changes appear in the early (1) Conrm treatment resistance
stages of chronic kidney disease, although they are Obtain home or ABPM readings to exclude white coat eect
most pronounced in advanced stages (stages 5 or 5D). (2) Check for barriers to successful treatment
Systolic hypertension is the most common form of Adverse eects of ongoing treatment
hypertension in patients with chronic kidney disease,44 Non-adherence to treatment
and raised systolic BP is independently associated with Insucient treatment (type and dose adapted to eGFR)
risk of progression to chronic kidney disease Interfering pressor substance or medication
stages 55D. Increased risk of chronic kidney disease Excessive salt intake or excess alcohol intake
was observed at systolic BP greater than 140 mm Hg,
(3) Screen for secondary hypertension and propose treatment for causal factors
but the highest risk was conferred at pressures of
150 mm Hg or over.46 In chronic kidney disease, BP=blood pressure. RAS=renin angiotensin system. CCB=calcium channel blocker. ABPM=ambulatory blood pressure
uncontrolled (especially systolic) hypertension results measurement. eGFR=estimated glomerular ltration rate.

from advanced arteriosclerosis, rigid arteries, and

impaired baroreex sensitivity and autonomic baroreceptor unloading, which contributes to frequent
dysfunction.47,48 Rigid arterial walls were shown to orthostatic hypotension and circulatory instability.
attenuate baroreceptor control of eerent sympathetic Hypoxaemia of renal tissue due to kidney damage
activity and vagal activation.48 Reduced baroreex activates the CNS via aerent nerves, which also
sensitivity maintains high sympathetic activity directed contributes to high sympathetic activity. Impaired
to the heart, blood vessels, and kidney, which baroreex sensitivity, high BP variability, and postural
contributes to high BP. Patients with chronic kidney instability are aggravated by the need to use multiple
disease have an inadequate vasoconstrictor response to antihypertensive medications.49,50 Vol 386 October 17, 2015 1591

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First-line tests Potential confounding factors in CKD Additional or conrmatory tests Potential confounding factors in CKD
Renal artery stenosis Renal duplex Doppler None Magnetic resonance angiography; spiral Systemic brosis and gadolinium (used
ultrasonography CT angiography in magnetic resonance angiography);
nephrotoxic eects of iodinated
radiocontrast agents (CT angiography)
Primary aldosteronism ARR under standardised conditions Renal failure and false-positive (high) Oral sodium loading,* saline infusion, Risk of volume overload (sodium
(correction of hypokalaemia and or low ARR; risks associated to diuretic udrocortisone suppression, or captopril loading), risk of potassium overload
withdrawal of drugs that aect the withdrawal for 6 weeks31 test; adrenal CT scan, adrenal vein (udrocortisone or captopril use);
RAA system) sampling nephrotoxic eects of iodide
Phaeochromocytoma and Urinary fractionated metanephrines False-positive results for plasma-free MRI or CT scan of the abdomen and Systemic brosis and gadolinium (used
paraganglioma or plasma-free metanephrines metanephrine and normetanephrine pelvis; I-labelled metaiodobenzyl- in magnetic resonance angiography);
levels,32 oligoanuria, or anuria impede guanidine scanning or nephrotoxicity of iodinated
assessment of urinary values F-uorodeoxyglucose PET scan; genetic radiocontrasts (CT angiography)
screening for pathogenic mutations
Cushings syndrome 24 h urinary cortisol; excretion, late Falsely low results for oligoanuria Dexamethasone suppression tests; False-negative results due to reduced
night salivary cortisol CT scan, brain MRI clearance of dexamethasone in CKD33

*12 g/day salt diet for 3 days in the absence of contraindication such as heart failure. 2 L 09% intravenous saline in 4 h. ARR=aldosteronerenin ratio. CKD=chronic kidney disease. RAA=renin angiotensin

Table 3: Approaches to rule out the main causes of secondary hypertension according to the 2013 European Society of Hypertension and the European Society of Cardiology guidelines
for the management of arterial hypertension3 and potential confounders caused by the presence of chronic kidney disease

Eect of volume overload: excess sodium intake have unique clinical needs that are outside the scope of
and salt retention this Review.
Subclinical volume overload is present in more than 20% Patients with chronic kidney disease and resistant
of patients with chronic kidney disease.51 Clinically hypertension should, by denition, receive at least three
unapparent volume expansion is an important antihypertensive drugs of dierent classes at maximum
contributor to resistant hypertension, but the value of tolerated doses including a diuretic.3,57 The National
guiding resistant hypertension treatment based on Institute for Health and Care Excellence (NICE)
subclinical extracellular uid excess has not yet been guidelines recommend the use of triple combination
tested. Excess salt intake can exacerbate resistance to therapy that includes a thiazide or a thiazide-like diuretic,
antihypertensive therapy.52 Evidence shows that most a reninangiotensin system (RAS) blocker, and a calcium
patients with chronic kidney disease are salt-sensitive channel blocker.57 The rst step is to optimise the dosage
ie, they respond to an increase in their sodium intake by of the ongoing treatment or to give appropriate
a rise in BPand diuretics do not help; excess sodium antihypertensive drug combinations.58
abrogates the antiproteinuric eects of angiotensin-
converting enzyme inhibitors (ACEi) or angiotensin Step 1: optimisation of ongoing treatment,
receptor blockers (ARB), thereby exacerbating especially sodium depletion
proteinuria.53 Conversely, eorts to reduce salt intake can Salt reduction to improve BP control
be benecial because of synergism with the actions of In a randomised trial59 in patients with chronic kidney
thiazides,54 ACEi,55 or ARB,56 resulting in improved BP disease stages 34 and poorly controlled hypertension, a
control and less proteinuria. low-sodium diet (100 mmol/dayie, 24 g sodium per
day or 6 g of salt per day) was associated with substantial
Treatment options reductions in BP (systolic BP decreased by 9.7 mm Hg
The goals of antihypertensive therapy in patients with and diastolic BP decreased by 3.9 mm Hg), the need for
chronic kidney disease are to lower BP, reduce the risk of antihypertensive medication, and extracellular volume.
cardiovascular disease, and slow the progression of chronic The KDOQI guideline on hypertension in patients with
kidney disease.5 Multidrug regimens are usually necessary chronic kidney disease recommends limiting sodium
to achieve BP goals by interfering with the dierent intake to 24 g per day (ie, 6 g of salt) in patients not on
pathways involved in the pathogenesis of hypertension in dialysis.60 This recommendation is a notable dietary
patients with chronic kidney disease.5 Individualisation of restriction, since a no added salt daily diet contains
treatment should take into account cardiovascular disease roughly 4 g sodium. The amount of sodium present in a
or other comorbidities, age, sex, ethnicity, the presence of no added salt diet already exceeds the amount that the
proteinuria, and risk of drugdrug interactions. The route kidney of a patient with chronic kidney disease can
of drug excretion should be considered and doses adjusted excrete irrespective of diuretic administration. Sodium
according to GFR level.5 Additional considerations might intake is reduced in a low protein diet as a consequence
be appropriate for patients with end-stage renal disease of the selection of low-sodium foods, which results in a
undergoing dialysis or post-transplantation. These patients better-controlled BP.61 24 h urine sodium excretion

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monitoring is the best method of recording sodium Step 2: addition of further antihypertensive
intake, and should be done in patients with resistant treatment
hypertension. Although spot urine sodium or After optimisation of the ongoing treatment, the next
sodium:creatinine ratio have been used as indicators of step is to consider the addition of other antihypertensive
daily salt intake in many epidemiological hypertension drugs. No clinical trials have systematically compared the
studies,62 large uctuations in excretion during the day various available treatment options. Proteinuria can be
reduce the reliability and predictive value of individual lowered by dual RAS blockade with ACEi and ARBs or
measurements. Some data challenge the validity of urine with direct renin inhibitors to a greater extent than either
sodium excretion for estimating sodium intake, RAS blocker alone.7274 However, this combination has
suggesting that sodium might bind to skin proteins not been shown to improve BP control, or improve
without exerting an osmotic power in healthy individuals cardiovascular outcomes7274 compared with single RAS
and patients with chronic kidney disease.63,64 Thus, blockade in patients with resistant hypertension,70
sodium might be underestimated in experimental and although it might preserve renal function in patients
clinical studies. with diabetes and chronic kidney disease to some extent,
BP control can also be improved by increasing diuretic according to a recent network meta-analysis.75
dosage, or by switching to a more potent, thiazide-like Additionally, this combination increases the risk of
diuretic with a longer duration of action than the hyperkalaemia, hypotension and acute renal failure.7274
existing drug, eg, chlorthalidone and indapamide Dual RAS blockade is discouraged by the NICE and ESH
instead of hydrochlorothiazide or bendroumethiazide, guidelines and the European Medicines Agency.3,57
when GFR is 30 mL/min or over. Non-potassium The suggested fourth line therapy is to add
sparing diuretics can also reduce the risk of mineralocorticoid receptor antagonists3 (MRA, 125 to
hyperkalaemia that is exacerbated by a RAS blocker.5 25 mg per day spironolactone or 25 to 50 mg per day
Loop diuretics should be prescribed when GFR is less eplerenone, to be adapted according to eGFR level) in
than 30 mL/min65,66 as recommended by NICE and patients with GFR of 30 mL/min or over and plasma
Kidney Disease: Improving Global Outcomes (KDIGO) potassium concentrations 45 mmol/L or lower, or in
guidelines.67,68 However, small studies have shown that patients with other indications, such as heart failure with
thiazides maintain their short-term and mid-term left ventricular dysfunction. MRA reduces BP and left
natriuretic and antihypertensive eects in patients with ventricular hypertrophy in patients with resistant
GFR of less than 30 mL/min.67,69 Loop diuretics are also hypertension and an eGFR 5060 mL/min,76,77 but it
indicated in the presence of oedema or volume overload doubles the risk of hyperkalaemia when added to ACEi
due to nephrotic syndrome or heart failure.5,65 or ARB in patients with moderate chronic kidney disease
Furosemide and bumetanide should be administered (eGFR 3090 mL/min per 173 m).78 The long-term
twice daily (preferentially concurrent with sodium eects of MRA on renal and cardiovascular outcomes,
ingestion) because of their short duration of action, mortality, and safety in patients with chronic kidney
whereas longer-acting torasemide can be administered disease remain to be established. ESH guidelines do not
once daily. Higher loop diuretic doses might be needed recommend the routine use of MRA in patients with
in patients with severe chronic kidney disease with or chronic kidney disease, especially in combination with
without albuminuria.5,65 However, counter-regulatory RAS blockers, because of the risk of further renal
rebound sodium retention could abolish the ecacy of impairment and hyperkalaemia.3 KDIGO guidelines also
loop diuretics in patients with chronic kidney disease in outline their potential risks.5 The results of the
both the short and long term.68 To overcome this PATHWAY-2 study,79 which included patients with
phenomenon, the diuretic dose or dosing frequency resistant hypertension on a triple combination therapy
could be increased, or sequential nephron blockade (ie, an ACEi, a CCB, and a diuretic), with eGFR of more
using a combination of loop diuretics and thiazides than 45 mL/min, and plasma potassium concentrations
might be needed for patients with resistant within normal range, showed that 12 weeks of treatment
hypertension,70 especially in the presence of oedema or with spironolactone 2550 mg was the most eective
heart failure. However, careful monitoring of renal add-on, fourth-line drug as compared with bisoprolol
function, serum electrolytes, and uid status is needed (510 mg) and doxazosin modied release (48 mg).
to detect dehydration, hypokalaemia, hyponatremia, We suggest low dose spironolactone (12525 mg/day)
hypovolaemia, or renal dysfunction. or eplerenone (2550 mg/day) in patients with eGFR
Replacement of ACEi and ARB with other 30 mL/min per 173 m or over and plasma potassium
antihypertensive drugs in patients with advanced chronic concentrations of 45 mmol/L or lower, because of their
kidney disease (stages 4 to 5) should be considered when ecacy in reducing BP in patients with resistant
there are no contraindications, such as heart failure71 or hypertension.77 Specic doses should be adapted
when discontinuation of the drug is expected to relieve according to eGFR. The presence of comorbidities such
side-eects such as hyperkalaemia, acute kidney injury, as heart failure with left ventricular dysfunction should
or symptomatic hypotension. also be considered. Early and close monitoring of plasma Vol 386 October 17, 2015 1593

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potassium and creatinine concentrations is needed when might have been accentuated by the use of an invasive
MRA, and other potassium-sparing diuretics, are used in procedure in the sham group, which could have increased
patients who are receiving concomitant RAS blockers.5 adherence to medication and diet. Finally, the
If BP remains uncontrolled, further stepwise treatment antihypertensive treatment was not standardised, and
options include (1) a blocker (preferably with an hepatic uncontrolled medication changes might also have
elimination route [ie, metoprolol, carvedilol, nebivolol, aected the BP results: 22% (118) of 535 patients had
and propranolol] to avoid drug accumulation which could medication changes 26 weeks before screening and
lead to an increased risk of bradyarrhythmias, (2) an medication changes were documented in another 39%
blocker, and (3) centrally acting agonists, which (211) of the patients between baseline and the 6-month
preferably do not require dose adjustments (ie, endpoint assessment. Additional results from the
methyldopa or clonidine).3,5 blockers are the drug of DENERHTN85 and Desch86 trials do not concur with the
choice and can be used at any stage, especially in patients negative results of SYMPLICITY HTN-3. In the
with co-existing coronary artery disease, heart failure, or DENERHTN trial, oral antihypertensive treatment before
arrhythmias. Direct vasodilators such as hydralazine or and after renal denervation was controlled, and the trial
minoxidil are sometimes used, but could induce severe showed a decrease of about 6 mm Hg ambulatory BP for
uid retention and tachycardia, especially minoxidil renal denervation compared with the same medical
which has other side-eects (eg, hirsutism, pericardial therapy alone in patients with resistant hypertension and
eusion).3,5 eGFR 40 mL/min or higher. Desch and colleagues
Complex multidrug therapeutic regimens increase the conducted a sham controlled, randomised trial of renal
likelihood of drug-related side-eects, which could denervation with the Symplicity renal denervation
contribute to non-adherence. When possible, xed-dose catheter (n=71) in patients with resistant hypertension
combinations should be prescribed to reduce the pill and eGFR 45 mL/min or higher. The primary outcome,
burden, which might improve adherence to treatment in 24 h ambulatory systolic BP at 6 months, was not
association with home BP monitoring, regular signicantly reduced versus the control group with
appointments, and involvement of health-care maintained antihypertensive treatment in the intention-
professionals in conjunction with the patient and their to-treat cohort (p=015). By contrast, the dierence of
family. 56 mm Hg between the two groups was signicant in
terms of 24 h (p=0042) and daytime systolic BP
Procedures and device-based therapies (p=0012) in the per-protocol analysis.86 These results
Procedures and devices for neural modulation could be explained by the fact that the Desch trial was
Catheter-based radiofrequency denervation of the renal slightly underpowered and should be interpreted with
arteries is a potential treatment for patients with resistant caution, as acknowledged by the authors. Scarce data are
hypertension and eGFR higher than 45 mL/min per available regarding denervation procedures in patients
173 m, but the evidence of ecacy is inconclusive with resistant hypertension and chronic kidney disease.
See Online for appendix (appendix). The initial non-randomised or randomised, In a small cohort of patients with chronic kidney disease
open-label studies recorded large BP reductions in stages 3 and 4 and resistant hypertension (n=15), the
response to renal denervation, as measured during oce eGFR was stable over a 3-month follow-up.87 Another
visits or by ABPM.80,81 These studies were limited by pilot study (n=27) in patients with chronic kidney disease
small sample sizes, limited assessment of ambulatory stages 3 and 4 and resistant hypertension showed that
BP, absence of blinding, and lack of sham control treatment of hypertension with renal denervation
procedures. The double-blind SYMPLICITY HTN-3 decreased BP and slowed or halted the decline of renal
randomised, controlled study82,83 did not show a function over 1-year of follow-up.88 Other small studies
signicant reduction in oce and ambulatory BP in reported stability of acute kidney injury markers, a
patients with resistant hypertension at 6 or 12 months decrease in proteinuria, and an increase in renal ow on
after renal-artery denervation with the single electrode duplex ultrasound after renal denervation. Additional
Symplicity radiofrequency catheter (Medtronic, well designed and conducted randomised studies are
Mountain View, CA, USA), as compared with a sham needed to investigate the long-term antihypertensive,
control. Incomplete denervation of the renal nerves antiproteinuric, and renoprotective ecacy and the
could be a reason for the absence of ecacy, but safety of renal denervation with dierent catheters in
straightforward methods to conrm intraprocedural patients with chronic kidney disease and resistant
completeness of the ablation are lacking.84 Heterogeneity hypertension.89
and variability observed in the performance of the renal Carotid baroreceptor activation is another method for
denervation procedure aected the BP results. The neural modulation in resistant hypertension (appendix).
number of ablation attempts and radiofrequency delivery A signicant improvement in oce BP control was
in all four quadrants of the renal artery were associated demonstrated in a double-blind, randomised, controlled
with greater reductions in BP. Moreover, medication trial.90 Improvements in left ventricular hypertrophy91 and
adherence was not monitored, and the placebo eect arterial stiness92 were shown in other cohorts. In a small

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cohort (n=23) of patients with chronic kidney disease

(61% in stages 3 and 4) and resistant hypertension, carotid Panel 3: Recommendations for research in resistant hypertension in chronic
baroreceptor activation reduced oce BP signicantly kidney disease
(p<001) and improved both kidney function and urinary Obtain a better epidemiological picture of resistant hypertension for each chronic
albumin excretion (the latter to a greater extent for kidney disease stage, through more accurate phenotyping of true resistant
chronic kidney disease stages 34 vs chronic kidney hypertensionnot only apparent treatment-resistant hypertension
disease stages 12 patients) after 6 months of follow-up.93 Measure the socioeconomic eect of resistant hypertension in chronic kidney disease
However, further randomised studies in larger groups are through a dedicated plan (appendix)
needed to establish clinical uses for this expensive and Undertake large-scale randomised outcome trials in resistant hypertension
invasive treatment. The Economic Evaluation of throughout the chronic kidney disease spectrum to dene: (1) the optimum blood
Baroreceptor STIMulation for the Treatment of Resistant pressure targets with subsequent renements of the resistant hypertension
HyperTensioN (ESTIM-rHTN) trial, funded by the French denition(s) (eg, in advanced chronic kidney disease stages, or elderly patients),
Ministry of Health, is ongoing and aims to study (2) preferred fourth line and further drug combinations, and (3) the ecacy of
baroreceptor activation in patients with resistant procedures and device-based therapies
hypertension and eGFR 30 mL/min per 173 m or higher Identify public sources of funding for this research, since almost all antihypertensive
(NCT02364310). drugs are generic or soon will be, and advanced chronic kidney disease has always
been an unattractive investment area for the pharmaceutical industry
Renal artery stenting in atherosclerotic renal artery Perform rigorous strategy trials (eg, randomised registry trials) with less stringent
stenosis regulatory constraints, since most drugs are already approved
During the past 10 years, three randomised, controlled Test new antihypertensive pharmacological agents in patients with resistant
studies in roughly 1900 patients with atherosclerotic hypertension and chronic kidney diseaseeg, dual neprilysinangiotensin receptor
renal artery stenosis, mostly with chronic kidney disease, inhibitors (LCZ696), fourth generation dihydropyridine based-non-steroidal MRA
were published (appendix).9496 Contrary to some (nerenone), guanylate cyclase analogues (currently deployed in heart failure trials),
expectations, the addition of percutaneous renal artery and new endothelin-1 receptor antagonists
angioplasty and stenting to standard medical therapy was Monitor treatment adherence objectively and systematically
not benecial over standard care alone in terms of
progression of chronic kidney disease, mortality, or BP
reduction, except in the CORAL study, in which a modest reduction of salt content in food, overcoming therapeutic
dierence in systolic BP favouring the stent group inertia, promotion of polypills to facilitate drug adherence,
(23 mm Hg, 95% CI 44 to 02, p=003) was dedicated reimbursement policies, and providing funding
observed.95 Better methods to identify patients who might for home BP monitors should be encouraged. Together,
benet from renal angioplasty are needed (eg, fractional these measures should contribute to the improvement of
ow reserve studies), because the degree of renal artery outcomes in patients with resistant hypertension and
stenosis is not the most important determinant of chronic kidney disease, which are two major, unmet,
outcome in patients after renal angioplasty.97 The medical needs.
presence of resistant hypertension, rapid decline in GFR Contributors
(especially after therapy with ACEi or ARBs), and ash All authors contributed to the design and concept, performed the searches
pulmonary oedema might be relevant indications. The required for their assigned sections, wrote a section, read, revised and
critiqued the successive versions, and approved the nal manuscript.
ANDORRA (Renal Artery Stenting in Patients With PR coordinated the eort and integrated the sections and comments.
Documented Resistant Hypertension and Atherosclerotic
Declaration of interests
Renal Artery Stenosis) trial, funded by the French PR has received speaker honoraria from CVRx. MA has received
Ministry of Health, is ongoing and aims to recruit honoraria for advisory board meetings from Vessix, Boston Scientic
patients with RH, eGFR greater than or equal to Corporation, Cordis, Actelion, has received speakers honoraria from
20 ml/min per 173 m and an angiographically proven Cordis, CVRx, Servier, was involved as investigator in Symplicity HTN-2
(Ardian/Medtronic) and Reduce-HTN (Vessix/Boston Scientic
atherosclerotic renal artery stenosis 60% or over Corporation) trials and has received a research grant from Servier. GB has
(NCT02539810). received grant support from the Investigator Initiated Grant/Research
Support-Takeda (direct funding to University of Chicago), was a principal
Conclusions investigator on clinical trials sponsored by Medtronic, Relypsa, Bayer
(direct funding to University of Chicago), has acted as an adviser or
Our review of the literature highlights the absence of consultant for Takeda, AbbVie, CVRx, Janssen, Eli Lilly, Boehringer-
robust evidence to guide the clinical care of patients with Ingelheim, Medtronic, Bristol-Myers Squibb, Novartis, GlaxoSmithKline,
resistant hypertension in the setting of chronic kidney Bayer, Tengion, Elcelyx, and ZS Pharma. AC has received honoraria for
disease. Several key priorities for research need to be advisory board from AbbVie, ZS Pharma and speakers fees from AbbVie,
Amgen, and has acted as a consultant for Fresenius Medical Care. DG has
addressed to optimise resistant hypertension management received speaking and consulting honoraria from Merck, Pzer, Sano,
in chronic kidney disease worldwide (panel 3). Moreover, Sandoz, Amgen, AbbVie, Keryx, Relypsa, Astellas, and Novartis. AO has
we believe that stronger commitment of policy makers acted as a consultant for Genzyme, Servier, has received speakers fees
from Shire, Amgen, Fresenius Medical Care, and has received research
through public health eorts (eg, earlier diagnosis of
support from Fresenius Medical Care and Abbvie. RV has acted as a
resistant hypertension in chronic kidney disease, Vol 386 October 17, 2015 1595

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consultant Baxter, Bellco, and has received speakers fees from Nipro and 16 Tanner RM, Calhoun DA, Bell EK, et al. Prevalence of apparent
Amgen. AW has received speaking and consulting honoraria from treatment-resistant hypertension among individuals with CKD.
Amgen, Fresenius Medical Care, Boehringer Ingelheim, Astellas, Roche Clin J Am Soc Nephrol 2013; 8: 158390.
and Apotex. BS has received grant support from Amgen, Baxter, Fresenius 17 McAdam-Marx C, Ye X, Sung JC, Brixner DI, Kahler KH. Results of
Medical Care, GlaxoSmithKline, MSD, Eli Lilly, and Sano- Genzyme as a retrospective, observational pilot study using electronic medical
part of the CKD-REIN study Public-Private Partnership, and has received records to assess the prevalence and characteristics of patients with
lecture fees from MSD. DF has acted as a consultant for Genzyme, Baxter, resistant hypertension in an ambulatory care setting. Clin Ther
2009; 31: 111623.
Astellas, Fresenius Kabi, and has received speakers fees from Shire,
Amgen, Fresenius Medical Care. ZAM, ER, GHH, KJJ, MK, FM, CZ, and 18 Gijn-Conde T, Graciani A, Banegas JR. Resistant hypertension:
demography and clinical characteristics in 6,292 patients in a primary
GML declare no competing interests.
health care setting. Rev Esp Cardiol (Engl Ed) 2014; 67: 27076.
Acknowledgments 19 Weitzman D, Chodick G, Shalev V, Grossman C, Grossman E.
We thank Wendy Gattis Stough for the editing of the manuscript. Prevalence and factors associated with resistant hypertension in a
large health maintenance organization in Israel. Hypertension 2014;
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