Secondary Hypertension [1st ed.] 9783030455613, 9783030455620

Table of contents :
Front Matter ....Pages i-x
Renal Parenchymal Disease (Michel Burnier, Francesca Viazzi, Giovanna Leoncini, Grégoire Wuerzner, Roberto Pontremoli)....Pages 1-19
Atherosclerotic Renovascular Disease (Peter W. de Leeuw, Costas Tsioufis)....Pages 21-32
Fibromuscular Dysplasia: From a Rare Cause of Renovascular Hypertension to a More Frequent Systemic Arterial Disease (Marco Pappaccogli, Alexandre Persu, Alberto Morganti)....Pages 33-57
Primary Aldosteronism (Gian Paolo Rossi)....Pages 59-78
Familial Hyperaldosteronism (Alessio Pecori, Silvia Monticone, Isabel Losano, Giovanni Cavaglià, Jacopo Pieroni, Franco Veglio et al.)....Pages 79-93
Monogenic Forms of Hypertension (Filippo Ceccato, Franco Mantero)....Pages 95-107
Pheochromocytoma and Paraganglioma (Andrzej Januszewicz, Aleksander Prejbisz, Piotr Dobrowolski, Magdalena Januszewicz)....Pages 109-125
Hypertension in Cushing’s Syndrome (Filippo Ceccato, Mattia Barbot, Carla Scaroni, Marco Boscaro)....Pages 127-139
Vascular Disease (Stéphane Laurent)....Pages 141-148
Obstructive Sleep Apnea (Joanna Kanarek-Kucner, Jacek Wolf, Krzysztof Narkiewicz)....Pages 149-158
Drug-Induced Hypertension (Aurélien Lorthioir, Ines Belmihoub, Laurence Amar, Michel Azizi)....Pages 159-166
Hypertension in Acromegaly (Peter Kamenický, Philippe Chanson)....Pages 167-179
Organ Damage (Enrico Agabiti Rosei, Damiano Rizzoni, Claudia Agabiti-Rosei, Anna Paini, Maria Lorenza Muiesan)....Pages 181-195
Secondary Hypertension and Cardiovascular Risk: An Overview (Gino Seravalle, Giuseppe Mancia, Guido Grassi)....Pages 197-209

Citation preview

Updates in Hypertension and Cardiovascular Protection Series Editors: Giuseppe Mancia · Enrico Agabiti Rosei

Alberto Morganti Enrico Agabiti Rosei Franco Mantero   Editors

Secondary Hypertension

Updates in Hypertension and Cardiovascular Protection Series editors: Giuseppe Mancia Milan, Italy Enrico Agabiti Rosei Brescia, Italy

The aim of this series is to provide informative updates on both the knowledge and the clinical management of a disease that, if uncontrolled, can very seriously damage the human body and is still among the leading causes of death worldwide. Although hypertension is associated mainly with cardiovascular, endocrine, and renal disorders, it is highly relevant to a wide range of medical specialties and fields – from family medicine to physiology, genetics, and pharmacology. The topics addressed by volumes in the series Updates in Hypertension and Cardiovascular Protection have been selected for their broad significance and will be of interest to all who are involved with this disease, whether residents, fellows, practitioners, or researchers. More information about this series at http://www.springer.com/series/15049

Alberto Morganti  •  Enrico Agabiti Rosei Franco Mantero Editors

Secondary Hypertension

Editors Alberto Morganti Center of Clinical Physiology and Hypertension, Policlinic Hospital University of Milan Milan Italy

Enrico Agabiti Rosei Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Franco Mantero Department of Medicine, Endocrine Unit University of Padua Padova Italy

ISSN 2366-4606     ISSN 2366-4614 (electronic) Updates in Hypertension and Cardiovascular Protection ISBN 978-3-030-45561-3    ISBN 978-3-030-45562-0 (eBook) https://doi.org/10.1007/978-3-030-45562-0 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

In memory of Professor Alberto Zanchetti, teacher and mentor of all of us.

Preface

It is common belief that secondary forms of hypertension are rare whereas in 95% of patients the cause of high blood pressure is unknown, which is said, euphemistically, “essential.” Thus, many clinicians are reluctant to embark on expensive, timeconsuming, and potentially risky diagnostic procedures that most of the times turn out negative. However, there is increasing evidence from epidemiological studies that the prevalence of secondary hypertensions is much higher than previously thought accounting for 20–25% of all hypertensive patients, meaning that worldwide there are some 200 million people in whom the cause of high blood pressure is not recognized. There are additional, very good reasons for searching patients with secondary hypertension. First is that for equal blood pressure levels these patients are exposed to a greater risk of suffering major cardiovascular events than patients with essential hypertension and for this reason they require particular care. Second is that these patients are curable with appropriate interventions and liberated from the burden of a lifetime pharmacological therapy or, at least, have a chance to be treated with more specific and effective medications. Obviously for picking up patients with secondary hypertension, a good deal of clinical skill is required to appreciate the often vague and subtle symptoms and signs that characterize these individuals. A full comprehension of the mechanisms responsible for the development and maintenance of high blood pressure is also needed. This book was conceived to inform readers on the most updated advances in the epidemiological, pathophysiological, diagnostic, and therapeutic aspects of secondary hypertension provided by a group of the most respected European scholars in this field. We aim to offer an opportunity to expand readers’ knowledge in an intricate area of cardiovascular medicine hoping that the new acquisitions may be translated to a better treatment of the many patients with secondary hypertension. Milan, Italy Brescia, Italy Padova, Italy

Alberto Morganti Enrico Agabiti Rosei Franco Mantero

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Contents

Renal Parenchymal Disease������������������������������������������������������������������������������   1 Michel Burnier, Francesca Viazzi, Giovanna Leoncini, Grégoire Wuerzner, and Roberto Pontremoli Atherosclerotic Renovascular Disease��������������������������������������������������������������  21 Peter W. de Leeuw and Costas Tsioufis  Fibromuscular Dysplasia: From a Rare Cause of Renovascular Hypertension to a More Frequent Systemic Arterial Disease������������������������  33 Marco Pappaccogli, Alexandre Persu, and Alberto Morganti Primary Aldosteronism�������������������������������������������������������������������������������������  59 Gian Paolo Rossi Familial Hyperaldosteronism����������������������������������������������������������������������������  79 Alessio Pecori, Silvia Monticone, Isabel Losano, Giovanni Cavaglià, Jacopo Pieroni, Franco Veglio, and Paolo Mulatero  Monogenic Forms of Hypertension������������������������������������������������������������������  95 Filippo Ceccato and Franco Mantero Pheochromocytoma and Paraganglioma �������������������������������������������������������� 109 Andrzej Januszewicz, Aleksander Prejbisz, Piotr Dobrowolski, and Magdalena Januszewicz  Hypertension in Cushing’s Syndrome�������������������������������������������������������������� 127 Filippo Ceccato, Mattia Barbot, Carla Scaroni, and Marco Boscaro Vascular Disease������������������������������������������������������������������������������������������������ 141 Stéphane Laurent Obstructive Sleep Apnea ���������������������������������������������������������������������������������� 149 Joanna Kanarek-Kucner, Jacek Wolf, and Krzysztof Narkiewicz Drug-Induced Hypertension ���������������������������������������������������������������������������� 159 Aurélien Lorthioir, Ines Belmihoub, Laurence Amar, and Michel Azizi

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Hypertension in Acromegaly���������������������������������������������������������������������������� 167 Peter Kamenický and Philippe Chanson Organ Damage �������������������������������������������������������������������������������������������������� 181 Enrico Agabiti Rosei, Damiano Rizzoni, Claudia Agabiti-­Rosei, Anna Paini, and Maria Lorenza Muiesan Secondary Hypertension and Cardiovascular Risk: An Overview �������������� 197 Gino Seravalle, Giuseppe Mancia, and Guido Grassi

Renal Parenchymal Disease Michel Burnier, Francesca Viazzi, Giovanna Leoncini, Grégoire Wuerzner, and Roberto Pontremoli

Introduction Hypertension and chronic kidney disease (CKD) are highly inter-related and aggravate each other. Kidneys are involved in the development and maintenance of primary hypertension, and renal diseases represent the most common cause of secondary hypertension in children and the second most common form of secondary hypertension in adults [1]. In fact, renal parenchymal diseases account for 2–5% of all causes of hypertension, with renal vascular disease and ischemic nephropathy accounting for another 1–3%. On the other hand, increased blood pressure (BP) of any etiology can lead to renal damage, and especially when accompanied by proteinuria, it is an important factor for CKD progression. The purpose of this chapter is to review the epidemiology and the pathophysiology of hypertension in CKD and the role of hypertension in the progression of renal diseases. In addition, we shall discuss the role of CKD in special clinical situation such as resistant hypertension, dialysis, and renal transplantation.

M. Burnier (*) · G. Wuerzner Service of Nephrology and Hypertension, University Hospital (CHUV), Lausanne, Switzerland e-mail: [email protected]; [email protected] F. Viazzi · G. Leoncini · R. Pontremoli Department of Internal Medicine, University of Genoa and Ospedale Policlinico San Martino-IST, Genoa, Italy e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2020 A. Morganti et al. (eds.), Secondary Hypertension, Updates in Hypertension and Cardiovascular Protection, https://doi.org/10.1007/978-3-030-45562-0_1

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Epidemiology CKD affects approximately 10% of the population worldwide mainly due to the aging of the population. Indeed, the steady increase in life expectancy has undoubtedly an impact on CKD prevalence, as aging is associated with a progressive loss of renal function (about 0.7–1  mL/min/1.73  m2/year after the age of 40  years). However, recent demographic trends contribute to increase the CKD prevalence increasing the prevalence of several well-known risk factors for renal damage such as diabetes mellitus, hypertension, smoking, and obesity as well as public health policies. In Europe, the prevalence of CKD ranges from 3.3% in Norway to 17.3% in northeast Germany [2]. Overall, the prevalence of hypertension is high among CKD patients and increases with the decline of glomerular filtration rate (GFR). In the Chronic Renal Insufficiency Cohort (CRIC) study [3], a longitudinal study of 3939 adults aged 21–74 years, 92% of patients with an estimated GFR (eGFR) 60  mL/min/1.73  m2 had elevated BP. The National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) [4], a community-based health screening of over 115,000 adults with risk factors for CKD, yielded similar prevalence estimates showing an overall prevalence of hypertension of 86.2%. The observed prevalence of hypertension gradually increased with advancing CKD stages from 79.1% in stage 1 to 95.5% in stages 4 and 5. In the National Health and Nutrition Examination Survey (NHANES) of a nationally representative sample of non-institutionalized adults aged 20  years or older, the age-adjusted prevalence of hypertension in the United States CKD population was 59.1% for the period 2013–2014 (Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System—United States. Website: http://www.cdc.gov/ckd). Hypertension is very common also among patients on hemodialysis or peritoneal dialysis and in renal transplant recipients [5]. Furthermore, in patients on hemodialysis, the intermittent removal of fluid leads to large differences in BP values between pre-, post-, and inter-dialysis periods, making it harder to define and detect the presence of hypertension as will be discussed later in this chapter. The prevalence of hypertension in CKD is also influenced by the type of nephropathy, being highest in renal vascular diseases (93%), in established diabetic nephropathy (87%), and in polycystic kidney disease (74%) compared to a lower prevalence in glomerulonephritis and tubule-interstitial disease [6]. Moreover, clinic BP measurements might be misleading, since masked hypertension may occur in up to 30% and apparent treatment resistant hypertension in up to 40% of patients with CKD [7]. Thus, 24-h ambulatory blood pressure monitoring (ABPM) may be a useful tool to diagnose hypertension accurately and to assess achievement of BP goals in renal patients. Unsurprisingly, the control of hypertension becomes more difficult as CKD worsens, and it has recently been emphasized that severe renal impairment represents the most common cause of treatment-resistant hypertension [8].

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CKD is frequently observed in patients with arterial hypertension since the same factors that promote the development and progression of atherosclerosis can also promote CKD.  However, estimating the prevalence of CKD attributable to hypertension alone is very difficult since subjects with presumed hypertensionrelated renal damage rarely undergo renal biopsy. Assessment of hypertensionrelated kidney damage requires the evaluation of GFR as well as quantification of albuminuria. Knowledge of both these markers allows renal and cardiovascular (CV) risk assessment at the same time. In fact, the coexistence of CKD in hypertension is accompanied by a further significant increase in CV risk, which reinforces the need for a simultaneous protection of both the renal and the CV system. However, it must be pointed out that several studies have reported a low incidence rate of end-stage renal disease (ESRD) in hypertensive patients without underlying primary intrinsic renal disease. Accordingly, in Multiple Risk Factor Intervention Trial (MRFIT) and Kaiser Permanente of Northern California, two large population studies, the overall rate of developing ESRD in hypertensive subjects without evidence of primary renal disease was low at 15.6 and 14.3 cases per 100,000 person-years, respectively [9, 10]. Furthermore, in both the studies, the risk of ESRD was associated with increasing BP levels throughout BP readings above the optimal level, therefore even with modest elevations. Nevertheless, these results underline the association of hypertension with the development and progression of CKD.

Pathophysiology of Hypertension in CKD The development and progression of hypertension in CKD patients have traditionally been attributed to the interaction of several different mechanisms (Table  1). While volume expansion due to reduced nephron mass and impaired natriuresis have been considered a major driver leading to steady elevation of BP, an increased activity of the renin–angiotensin–aldosterone system [11] and inappropriate activation of the sympathetic nervous system [12] are responsible for increased peripheral resistance. As the degree of renal impairment increases, intrarenal arterial wall stiffness ensues leading to loss of renal autoregulation and transmission of systemic hypertension to glomeruli [13]. The resulting glomerular hypertension fosters the onset of glomerular sclerosis and proteinuria, setting off a vicious circle which finally leads to diffuse tubular-interstitial fibrosis and ESRD [14] (Fig.  1). Other factors such as insulin resistance, obesity, and imbalance between decrease in vasodilator prostaglandin and vasoconstrictor agents such as endothelin may also play a role [15, 16]. Conversely, the discovery of several monogenic forms of hypertension [17] leading to an increased renal reabsorption of sodium and kidney cross-transplantation studies [18] demonstrates the crucial role of the kidney in the development of hypertension.

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Table 1  Features associated with high blood pressure in chronic kidney disease

Systemic hypertension

• Reduced nephron number and extracellular fluid volume expansion • Arterial stiffness • Renin–angiotensin–aldosterone system stimulation • Increased sympathetic activity • Endothelin • Decrease in vasodilatory prostaglandins • Obesity and insulin resistance • Sleep apnea • Smoking • Hyperuricemia • Drugs: Steroids, erythropoietin, nonsteroidal antiinflammatory agents • Parathyroid hormone secretion/increased intracellular calcium/hypercalcemia • Renal vascular disease and ischemic nephropathy • Aldosterone-induced fibrosis • Asymmetric dimethylarginine • Advanced glycation end products (diabetes) • Heritable factors

Primary renal disease renal mass reduction

Ageing diabete mellitus enviroment (diet) hereditary factors

Glomerular hypertension

Endothelial injury • Release of vasoactive factors • Vascular lipid deposition • Intracapillary thrombosis

Mesangial injury • Accumulation of macromolecules • Increased matrix production • Increased celll proliferation

Epithelial injury • Proteinuria • Reduced permeability to water

Glomerular sclerosis

Fig. 1  Role of glomerular hypertension in the initiation and progression of renal structural injury. (Modified from ref. [14] with permission)

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Hypertension as a Risk Factor for Kidney Function Loss in CKD Albuminuria is a well-established marker of renal damage and carries strong prognostic power for both CV events and risk of future renal function worsening [19, 20]. Several studies have shown that a reduction in albuminuria obtained with optimal BP control is associated with better cardio-renal outcome while an increase in urine albumin excretion over time entails worse prognosis [21, 22]. Thus, changes in albuminuria under treatment have been taken to indicate parallel changes in risk and albuminuria reduction has been proposed as a treatment target in itself [23]. However, recent studies seem to indicate that, even in the presence of diabetes, albuminuria is minimal or modest in a large proportion of patients presenting with declining renal function [24]. Furthermore, while for risk stratification, GFR and albuminuria provide important information, and these parameters do not fully account for the rather complex and heterogeneous histological features encountered in patients with CKD, with fibrosis and ischemia variably involving glomeruli and the interstitium. Type and degree of renal lesions may influence the interaction between antihypertensive therapy and outcome and account for the considerable inter-individual variation observed in clinical practice [25]. Despite these limitations, clinical and experimental evidence over the past decades has consistently shown the effectiveness of antihypertensive treatment, especially with the use of renin–angiotensin–aldosterone system inhibitors (RAAS-is) in retarding progression to ESRD [26]. A recently published retrospective study while confirming that long-term, strict control of BP is associated with a reduction of albuminuria suggested that the related benefit in terms of GFR preservation may be smaller than that anticipated because of a paradoxical worsening in renal function at very low BP levels [27]. As a matter of fact, several other studies seem to confirm these data, indicating a weakening or even the disappearance of renal benefit when very low BP values are achieved [28, 29]. This could probably be due to the inability to maintain intraglomerular pressure gradient and therefore filtration when BP is lowered in the context of low angiotensin II levels. Low BP values and maximal pharmacologic inhibition of the RAAS have consistently been shown to improve renal outcome in CKD patients presenting with the traditional “albuminuric” phenotype. However, whether a similar therapeutic strategy should be applied to those presenting with no or minimal albuminuria is currently debated. On the basis of results from recent epidemiological studies, it has been proposed that antihypertensive treatment should be individualized both in terms of target BP values and possibly in terms of drugs combination [30]. Recently, a large trial has compared two different therapeutic regimens aiming at lowering systolic BP to either below 140 or below 120 mmHg in a large group of patients at high CV risk, including patients with CKD [31]. A more intensive

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BP reduction was generally associated with better CV outcome and lower mortality although no benefit on renal endpoints was evident, and some renal function worsening was even present in specific subgroups. These results have led to a reduction in target BP values recommended by International Guidelines although some authors have criticized the interpretation and clinical applicability of the Sprint trial due to some methodological limitations in the study, especially regarding the technique of BP recording [32]. Based on this evidence, some International Guidelines have recently revised recommendations on optimal BP values indicating a systolic BP value below 130 mmHg for high-risk patients such as those with diabetes and CKD [33]. Interestingly though, current European Guidelines also recommend, for the first time, a threshold below which BP should not be lowered in these patients to prevent a paradoxical increase in morbidity and mortality [26]. Considering the positive correlation between the degree of albuminuria and risk of renal progression, patients with proteinuria should be maintained at a BP value below 130 mmHg and possibly even lower. In the absence of albuminuria, a BP target below 130 mmHg but above 120 mmHg seem to be wise [34]. Real-life data seem to confirm that a J-curve describes the relationship between BP reduction and renal morbidity [35] (Fig. 2). In conclusion, optimal BP reduction by antihypertensive treatment currently remains the most effective and safe intervention to convey renal and CV protection in patients with CKD. RAAS-I should be considered the treatment of choice although ideal BP values remain a matter of debate. Lower targets are recommended in the presence of overt albuminuria, a condition that entails greater risk of renal 6

Odds Ratio for development of CKD

Fig. 2  A paradoxical J-shaped curve relationship has been described between BP reduction and risk of renal function deterioration in patients with type 2 diabetes. Both high and low BP values over time are associated with an increased risk (OR, odds ratios) of developing CKD. (Modified from ref. [35], free open access, authors’ own work)

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progression. A paradoxical J-curve relationship between BP reduction and renal morbidity may limit the benefit of aggressive treatment strategies, especially in the frail, elderly patients with non-albuminuric renal impairment.

Special Conditions Resistant Hypertension in CKD According to ESC/ESH hypertension guidelines, hypertension is considered as resistant to treatment when “the recommended treatment strategy fails to lower office SBP and DBP values to less than 140 mmHg and/or less than 90 mmHg, respectively, and the inadequate control of BP is confirmed by ABPM or HBPM in patients whose adherence to therapy has been confirmed” [26]. The treatment should include a diuretic and all components of the treatment regimen should be adequately dosed, taking into consideration drug intolerances. The prevalence of true resistant hypertension in the general hypertensive population is difficult to estimate with figures ranging between 5% and more than 30%, but the real figure is probably below 10% [35–39]. Among the many demographic and clinical factors associated with true resistant hypertension, reduced renal function appears to be an important risk factor [40, 41]. Thus, when compared to hypertensive patients without renal disease, hypertensive patients with CKD have a twofold higher prevalence of true resistant hypertension [3, 42–46], as reviewed recently by Rossignol et  al. [44] Of note, in CKD patients, the prevalence of resistant hypertension increases as estimated glomerular filtration rate (GFR) declines and proteinuria increases [45]. However, in a recent analysis of the populationbased Three-City survey in France, which included 8695 participants older than 65  years, the speed of kidney function decline was associated more strongly than kidney function itself with the risk of apparent treatment resistant hypertension [47]. Many factors associated with the development of CKD contribute to the development of resistant hypertension in patients with an impaired renal function. Thus, age and CKD-induced premature vascular aging leading to rigid arterial walls impaired baroreflex sensitivity and autonomic dysfunction belong to the important factors leading to resistant hypertension in patients with an impaired renal function. However, the reduced capacity to excrete sodium and water leading to salt retention and volume overload is probably the main characteristic of CKD patients with resistant hypertension [48]. In accordance with this hypothesis, the recent results of the Nephrotest cohort, a large population of patients with CKD stage 1–5, in whom thorough renal explorations were performed, including measurements of GFR and of extracellular water, are particularly interesting [49]. Indeed, in this analysis, a lower GFR, a higher body mass index, diabetic status, and African origin were associated with hypertension severity but not with BP control, whereas a higher extracellular water, older age, and a higher albuminuria were independent determinants of both resistant and uncontrolled hypertension during CKD [49]. These data

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therefore confirm the important role of volume overload in the pathophysiology of resistant hypertension, an observation made also in non-CKD patients [50], and hence justify the intensive use of diuretics in the management of CKD patients with resistant hypertension. The development of resistant hypertension in patients with renal impairment has important clinical implications not only in terms of progression towards endstage renal disease but also in terms of cardiovascular outcome. Thus, apparent treatment-­resistant hypertension increases the risk of end-stage renal disease [51, 52]. However, a reduced renal function and the presence of albuminuria are also associated with an increased risk of cardiovascular events and total and cardiovascular deaths [53]. The association of CKD and resistant hypertension further increase the cardiovascular and the mortality risk [37, 46]. Thus, in patients with hypertensive nephropathy followed for 5 years, the presence of a true resistant hypertension increases twofold to threefold the risk of fatal and nonfatal cardiovascular events, end-stage renal disease, or death when compared with patients with hypertensive nephropathy but a well-controlled BP [46]. As most patients with resistant hypertension should already receive a blocker of the renin–angiotensin system, a calcium channel blocker, and a diuretic as per 2018 ESC/ESH guidelines [26], the major additional therapeutic step to improve BP control in CKD patients is to intensify diuretic therapy. In patients with CKD 1–3a, this can be done with the addition of spironolactone, which has been found to be more effective than an alpha- or a beta-blocker [50]. In patients with more advanced CKD stages 3b–5, the first step may be to prescribe loop diuretics, which have a preserved efficacy and dose–response when renal function is reduced. As of today, the use of spironolactone in more advanced CKD stages is not recommended because of the high risk of hyperkalemia, particularly when patients receive simultaneously a blocker of the renin–angiotensin system. However, this attitude may change in the future with the development of new potassium binders, which may help controlling hyperkalemia and using spironolactone as well as blockers of the renin–angiotensin system more widely as recommended in the guidelines. Indeed, a large study has demonstrated the ability of the potassium-binding polymer patiromer to maintain serum potassium within the normal range in patients with diabetic nephropathy treated with a blocker of the renin–angiotensin system [54]. In patients with resistant hypertension, a specific study is ongoing, the AMBER study (ClinicalTrials.gov identifier NCT03071263), which will evaluate if patiromer used concomitantly with spironolactone in patients with resistant hypertension and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management [55]. This study should include about 290 patients with CKD 3b and true resistant hypertension. Until these data are available, both blockers of the renin– angiotensin system and spironolactone could be used in combination with a potassium binder if this latter is available. The alternative is to use beta-blockers or alpha-blockers, such as clonidine [56], or eventually consider a device-guided therapy such as renal denervation [57].

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Hypertension in Patients on Dialysis Hypertension has a high prevalence among patients with end-stage renal disease on dialysis, be it in hemodialysis or in peritoneal dialysis [58]. In cohorts of hemodialysis patients, an inverse relationship of BP recorded before or after dialysis with mortality was initially described, which lead to the concept of reverse epidemiology [59]. According to this concept, low BP was supposed to be more dangerous than an elevated BP in dialysis patients. However, this phenomenon was not found when BP was measured outside of the dialysis unit either with self-­measured home BP recordings or with 24 h interdialytic ambulatory BP monitoring [60]. In that case, the elevated BP is associated linearly with an increased mortality at levels >160 mmHg systolic, but between 120 and 160 mmHg systolic, the relation between out-of-office BP and mortality is highly variable with a W rather than a U shape, as illustrated in Fig. 3 [61]. As lowering BP in dialysis patients has been associated with major reduction in cardiovascular morbidity and mortality [62], it is still strongly recommended to lower any elevated BP in dialysis patients. However, the management of hypertension in dialysis patients is confronted to three important issues as discussed recently in a European Consensus paper [5]. The first two concern the most adequate timing for measuring BP in patients on hemodialysis and the best methods to measure BP.  Indeed, BP is regularly controlled before, during, and immediately after dialysis. BP values collected at these time points are important for the monitoring of the patients’ hemodynamic stability during hemodialysis sessions. However, do they have any prognostic value for the long-­ term outcome of these patients? Recent data suggest that the answer is no, except perhaps for a low BP (