Renal Denervation: Treatment and Device-Based Neuromodulation [2 ed.] 3031389336, 9783031389337

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Richard R. Heuser · Markus P. Schlaich · Dagmara Hering · Stefan C. Bertog   Editors

Renal Denervation Treatment and Device-Based Neuromodulation Second Edition

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Renal Denervation

Richard R. Heuser  •  Markus P. Schlaich Dagmara Hering  •  Stefan C. Bertog Editors

Renal Denervation Treatment and Device-Based Neuromodulation Second Edition

Editors Richard R. Heuser University of Arizona Phoenix, AZ, USA Dagmara Hering Department of Hypertension and Diabetology Medical University of Gdańsk Gdańsk, Poland

Markus P. Schlaich Dobeny Hypertension Centre, Royal Perth Hospital University of Western Australia Perth, WA, Australia Stefan C. Bertog CardioVasculäres Centrum Frankfurt Frankfurt, Germany

ISBN 978-3-031-38933-7    ISBN 978-3-031-38934-4 (eBook) https://doi.org/10.1007/978-3-031-38934-4 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023, Springer-Verlag London 2015 This work is subject to copyright. All rights are solely and exclusively licensed 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 Paper in this product is recyclable.

To my Granddaughter Anastasia We miss you every day —Richard R. Heuser To my wife Ute as well as Uta, Siegfried, Silva, Benjamin, and Niklas —Stefan C. Bertog

Preface

We were contacted 6 years after our publication of the first edition of renal denervation requesting an update to our original textbook on renal denervation. I would like to thank Springer publication and in particular Grant Westin for supporting us in this new endeavor. The question I had right away is “why to write another textbook.” Many of us in healthcare glean most of our medical information from downloading articles rather than reading textbooks. That being said, according to Springer our first edition of “Renal Denervation” generated a lot of interest and many downloads of our chapters. There were many challenges that we had to go through with the second edition. One of them was the Covid-19 crisis and the associated work challenges for everyone involved. The slow down with Covid-19 has resulted in limited resources for anything other than patient care in the throes of this worldwide pandemic. Our thanks to all of our authors for participating in this worthy endeavor. When you describe any new treatment, it is always about needs and there certainly is a need in treating hypertension. Arterial hypertension is the most important contributor to cardiovascular disease with 70% of Americans and Europeans aware of this. The SPRINT trial opened up our eyes to the fact that many patients are not getting adequate treatment for hypertension and if renal denervation works clinically, this would be one way to approach this inadequacy in cardiovascular care worldwide. At the time of our original textbook, over 60 companies were pursuing renal denervation. With some of the initial randomized controlled trials having discouraging results, there was a sharp reduction in this entrepreneurial explosive growth. Recently, however, this has changed with several novel sham-controlled randomized trials showing promising results, in not just the short term but up to 3-year follow-up. We also know that a significant advance has evolved looking at the renin-angiotensin-aldosterone system to suggest that renal denervation may also interrupt sympathetic mediated neurohormone pathways as part of its mechanism of action to reduce blood pressure. The biggest impetus for us as clinicians is that patients frequently do not take medication if they have high blood pressure. Now we have seven trials suggesting that arterial renal denervation produced clinically meaningful and lasting blood pressure reduction, independent of concomitant antihypertensive medications. With long-term safety and efficacy profile, renal denervation looks to be an adjunctive treatment modality to medication and lifestyle modification for the management of patients with hypertension. Our newer edition discusses some other treatments such as targeting the carotid body sinus as well as pacemaker-mediated blood pressure reduction. Also, there may be some evidence that approaching the nerves in the collecting system of the kidney may also be an alternative to approaching the nerves paralleling the renal arteries. Phoenix, AZ, USA Perth, WA, Australia  Gdańsk, Poland  Frankfurt, Germany 

Richard  R. Heuser Markus  P. Schlaich Dagmara Hering Stefan  C. Bertog

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Contents

Part I Physiology, Anatomy, Pivotal Hypertension Trials and Considerations for Trial Design 1 Renal  Nerves: Roles in Homeostasis and Pathophysiology�������������������������������������   3 Roman Tyshynsky, Lucy Vulchanova, and John Osborn 2 Animal  and Human Experience in Quantifying the Effects of Renal Denervation on Sympathetic Nervous System Activity ���������������������������  11 Dagmara Hering, Richard R. Heuser, and Murray Esler 3 Preclinical  Model and Histopathology Translational Medicine and Renal Denervation�����������������������������������������������������������������������������������������������  21 Yu Sato, Kenichi Sakakura, Maria E. Romero, Frank D. Kolodgie, Renu Virmani, and Aloke V. Finn 4 Appraisal  of Randomized Sham-­Controlled Trial Data on Renal Denervation for the Management of Hypertension���������������������������������  37 Stefan C. Bertog, Aung Myat, Alok Sharma, Kolja Sievert, Kerstin Piayda, Iris Grunwald, Markus Reinartz, Anja Vogel, Iloska Pamela, Natalia Galeru, Judith Anna Luisa Steffan, Gerhard Sell, Johann Raab, Erhard Starck, Andreas Zeiher, Wolfgang Stelter, Dagmara Hering, Deepak L. Bhatt, and Horst Sievert 5 Renal  Denervation Lowers Blood Pressure in Sham Controlled Studies: Meta-Analysis�������������������������������������������������������������������������������������������������������������  47 Vasilios Papademetriou, Fotis Tatakis, Panagiotis Tsioufis, and Konstantinos Tsioufis 6 Endpoints  for Clinical Effects of Renal Denervation: What Is the Best Surrogate?�������������������������������������������������������������������������������������������������������������������  57 Kevin A. Friede, Marat Fudim, and Paul A. Sobotka Part II Renal Denervation for Indications Other Than Hypertension 7 An  Overview on Hypertension Mediated Organ Damage �������������������������������������  79 Marcio G. Kiuchi and Markus P. Schlaich 8 Renal  denervation for Diabetes and Metabolic syndrome �������������������������������������  89 Revathy Carnagarin, Marcio G. Kiuchi, Leslie Marisol Lugo-­Gavidia, and Markus P. Schlaich 9 Renal  Denervation for Chronic Kidney Disease �����������������������������������������������������  97 Marcio G. Kiuchi, Revathy Carnagarin, Leslie Marisol Lugo Gavidia, Dagmara Hering, and Markus P. Schlaich

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10 Obstructive  Sleep Apnea, Resistant Hypertension and Renal Denervation ��������� 107 Adam Witkowski and Jacek Kądziela 11 Potential  Role of Renal Denervation in Management of Atrial Fibrillation��������� 113 Tim A. Fischell 12 Potential  of Renal Denervation in the Management of Ventricular Arrhythmias ��������������������������������������������������������������������������������������������������������������� 119 Emanuel M. Ebin and Venkatakrishna N. Tholakanahalli 13 Renal  Denervation and Kidney Pain Syndromes����������������������������������������������������� 125 Leslie Marisol Lugo-Gavidia, Márcio Galindo Kiuchi, Revathy Carnagarin, and Markus P. Schlaich Part III Renal Denervation Devices 14 Symplicity  SPYRAL™: Device and Procedural Tips and Tricks��������������������������� 141 Joachim Weil 15 ReCor  Medical Paradise™ System: Device and Procedural Tips and Tricks������� 151 Victor Zeijen and Joost Daemen 16 Alcohol-Mediated  Renal Sympathetic Neurolysis for the Treatment of Hypertension: The Peregrine™ Infusion Catheter��������������������������������������������� 155 Stefan C. Bertog, Alok Sharma, Dagmara Hering, Felix Mahfoud, Atul Pathak, Roland E. Schmieder, Kolja Sievert, Vasilios Papademetriou, Michael A. Weber, Kerstin Piayda, Melvin D. Lobo, Manish Saxena, David E. Kandzari, Tim A. Fischell, and Horst Sievert 17 Role  of Afferent Nerves in High Blood Pressure and Approaching Renal Denervation Via the Collecting System: The Verve Medical System���������� 171 Dagmara Hering and Richard R. Heuser Part IV Measurement of Renal Sympathetic Nerve Activity and Guided Denervation 18 Sensing  Renal Nerve Activity Before, During and After Denervation: SyMap ������������������������������������������������������������������������������������������������������������������������� 181 Jie Wang, Yue-Hui Yin, Yue Wang, Wei Ma, and Weijie Chen Part V New Device-Based Concept for the Diagnosis and Treatment of Hypertension 19 Transcatheter  Carotid Body Denervation: First-in-Man Results and Future Directions������������������������������������������������������������������������������������������������� 193 Melvin D. Lobo 20 Carotid  Baroreceptor Amplification for Treatment of Resistant Hypertension��������������������������������������������������������������������������������������������������������������� 199 Wilko Spiering Part VI Unresolved Topics 21 Patient  Selection for Renal Denervation������������������������������������������������������������������� 209 Julien Doublet, Romain Boulestreau, Julie Gaudissard, Philippe Gosse, and Antoine Cremer

Contents

Contents

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22 Testing  for Secondary Hypertension and Difficult to Control Patients����������������� 217 Omar Azzam, Márcio Galindo Kiuchi, Revathy Carnagarin, and Markus P. Schlaich 23 Drug  Adherence in Hypertension Management������������������������������������������������������� 229 Dan Lane, Michel Burnier, and Pankaj Gupta 24 Patient  Preference for Therapies in Hypertension��������������������������������������������������� 237 Filip M. Szymanski and Anna E. Platek 25 Renal  Denervation Cost Analysis and Consideration��������������������������������������������� 241 Julie Bulsei and Isabelle Durand-Zaleski 26 What  Needs to Be Shown Before Renal Denervation Can Be Used in Clinical Practice?��������������������������������������������������������������������������������������������������� 247 Manish Saxena and Melvin D. Lobo Index������������������������������������������������������������������������������������������������������������������������������������� 255

Part I Physiology, Anatomy, Pivotal Hypertension Trials and Considerations for Trial Design

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Renal Nerves: Roles in Homeostasis and Pathophysiology Roman Tyshynsky, Lucy Vulchanova, and John Osborn

Introduction The kidneys play a central role in the regulation of body fluid homeostasis. Processes throughout the nephron contribute to this regulation, including the glomerular filtration of blood, and the exchange of solutes and water between tubules and peritubular capillaries. These processes result in the excretion of excess water, solutes, and waste in the urine, and are regulated by intrinsic renal mechanisms and hormonal controllers such as the renin-angiotensin-aldosterone system. Renal function is also under the control of sensory and sympathetic innervation of the kidney [1], which will be the focus of this chapter. Increased renal sympathetic (efferent) nerve activity results in sodium retention via a decrease in glomerular filtration rate and an increase in tubular sodium reabsorption. Furthermore, renal sympathetic nerves stimulate the release of renin, initiating the renin-angiotensin-aldosterone system, leading to sodium retention and constriction of the peripheral vasculature. These synergistic actions of renal sympathetic nerves are consistent with the hypothesis that chronically increased renal nerve activity leads to hypertension. This hypothesis and successful renal denervation (RDN) procedures on animal models of hypertension form the theoretical framework that supports RDN as a treatment for hypertension in humans [1, 2]. Catheter-based renal nerve ablation (CBRNA) for the treatment of hypertension is producing promising results in clinical trials [3, 4]. This technique indiscriminately ablates sensory and sympathetic nerves traveling from and to the kidney, respectively. Moreover, unpredicted outcomes of CBRNA clinical trials, including improved glucose metabolism, reduced incidences of cardiac arrhythmias, and reduced

R. Tyshynsky · L. Vulchanova · J. Osborn (*) University of Minnesota, Minneapolis, MN, USA e-mail: [email protected]; [email protected]; [email protected]

sympathetic activity to skeletal muscle have sparked renewed interest in understanding the role of renal nerves in disease states [5]. These findings suggest that renal sensory (afferent) nerves, which relay information to the central nervous system to modulate sympathetic activity to several organs, may contribute to the additional therapeutic effects of CBRNA. Here we present the current knowledge of the anatomy and physiology of renal sympathetic and sensory nerves in the regulation of renal function in physiological and pathophysiological states.

Renal Nerves in Homeostasis Sympathetic (Efferent) Renal Nerves As illustrated in Fig. 1.1 (left side), postganglionic sympathetic (efferent) renal nerves originate from paravertebral and prevertebral ganglia (i.e. superior mesenteric, celiac, and aorticorenal sympathetic ganglia). These nerves form neuroeffector junctions with their renal targets, which include the juxtaglomerular cells of the afferent arterioles to stimulate renin release, the renal tubules to enhance sodium reabsorption, and the afferent arteriole to regulate renal vascular resistance and glomerular filtration rate [6–9]. The current understanding of the sympathetic innervation of the kidney and its functions are discussed in our recent review [1]. Renal sympathetic fibers release norepinephrine as the primary neurotransmitter and co-transmitters such as adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY), among others [10]. Although the details regarding the role of adrenergic (i.e. norepinephrine) versus purinergic (i.e. ATP) and peptidergic (i.e. VIP, NPY) signaling are still under investigation, the primary summatory results of increased efferent activity to the kidneys are: (1) vasoconstriction of the afferent arterioles resulting in increased renal vascular resistance and decreased glomerular

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_1

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Fig. 1.1  Anatomy of renal nerve pathways and roles in homeostasis. Sympathetic (efferent) renal nerves receive central input from the PVN and RVLM, whose neurons synapse onto neurons in the intermediolateral (IML) column of the spinal cord. These preganglionic neurons project to postganglionic neurons in the sympathetic ganglia, which project to their neuroeffector sites in the kidney. Sympathetic renal nerves maintain hemodynamics by causing renin release by juxtaglomerular cells, constricting peripheral vasculature to increase vascular

resistance, and increasing sodium reabsorption by the tubules. Bilateral dorsal root ganglia neurons project both to the kidney and to neurons of dorsal horn of the spinal cord. These neurons then project centrally to the nucleus of the solitary tract (NTS), as well as the RVLM and PVN. While the function of sensory renal nerves in homeostasis are not fully elucidated, they are known to be mechanosensitive and chemosensitive, and initiate reflexes, both sympathoinhibitory and sympathoexcitatory. (Adapted from Osborn, Tyshynsky, and Vulchanova [1])

filtration rate, (2) activation of the renin angiotensin system by stimulation of renin release, and (3) increased tubular sodium reabsorption [1]. The activity of renal sympathetic postganglionic neurons is driven by preganglionic neurons whose cell bodies are located in the intermediolateral (IML) cell column of the spinal cord (Fig. 1.2). The rostral ventrolateral medulla (RVLM) of the brainstem and the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of renal sympathetic nerve activity (RSNA), as they send excitatory projections to renal preganglionic neurons and are under the influence of a number of sensory inputs to the brain related to cardiovascular and body fluid homeostasis [11–16]. For example, reductions in central blood volume increase RSNA in response to decreased activity of cardiopulmonary baroreceptor input to the brainstem [17], resulting in sympathetically mediated afferent arteriolar constriction (i.e., decreased glomerular filtration), activation of the renin angiotensin sys-

tem, and increased tubular sodium reabsorption, all of which act to restore blood volume. This renal sympathoexcitatory pathway is also modulated by several circulating hormones such as angiotensin II and aldosterone [18–20]. It is believed that, under normal physiological conditions, the integration of neural and hormonal inputs within these hypothalamic and brainstem circuits regulate RSNA to maintain body fluid and cardiovascular homeostasis [21].

Sensory (Afferent) Renal Nerves The kidney is also richly innervated by sensory nerves that respond to changes in the internal renal environment (Fig. 1.1, right side). The greatest emphasis has been placed on the sensory innervation of the pelvis because of the high density of sensory fibers in the smooth muscle, epithelial, and subepithelial layers of the pelvis compared to other renal

1  Renal Nerves: Roles in Homeostasis and Pathophysiology

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b

Fig. 1.2  Role of Brain-Kidney Axis and Kidney-Brain Axis in pathology. Overactivity of the Brain-Kidney Axis (a) can initiate hypertension and renal inflammation via increases in renin release, sodium reabsorption, vascular resistance, and trafficking or activation of macrophages, T-cells, and the release of cytokines in the kidney. Consequently, renal inflammation is a cause of increased sensory renal nerve activity, acti-

vating the Kidney-Brain Axis (b). Because the Kidney-Brain Axis projects to central areas that regulate sympathetic activity to many organs, overactivity of the Kidney-Brain Axis is one cause of hypertension, and is hypothesized to lead to other conditions, including cardiac arrhythmias, diabetes. (Adapted from Osborn, Tyshynsky, and Vulchanova [1])

structures [21–25]. However, anterograde tracing experiments have demonstrated that sensory fibers are associated with all branches of the intrarenal arteries as well as a sparse association with intrarenal veins [22]. More recent studies have emphasized the potential importance of previously overlooked innervation of cortical structures in the kidney, including the afferent and efferent arterioles [26], as well as glomeruli [27]. The function of these cortical sensory fibers is largely still a question. The primary modalities of sensory renal nerves are mechanosensation to sense increased stretch in the pelvic wall and other structures, and chemosensation to respond to extreme ischemia and/or sensing changes in body fluid composition (e.g. sodium, potassium osmolarity, pH) [21, 26, 28, 29]. The role of renal sensory nerves under normal physiological conditions is still unclear. Most of what is known is based on physiological investigations of pelvic sensory renal nerves in anesthetized animals and has led to the concept of the “renorenal reflex” [30]. This hypothesis states that activation of pelvic afferent nerves reflexively decreases RSNA resulting in natriuresis and diuresis. It is hypothesized that this reflex is important in the homeostatic regulation of arterial

pressure in response to signals within the kidney (i.e., increased pelvic pressure) that signal volume expansion. However, it is important to note that studies investigating this sympathoinhibitory renorenal reflex have largely been done on anesthetized animals. In contrast, a recent study demonstrated that activation of renal sensory nerves in the unanesthetized decerebrate rat results in a sympathoexcitatory, rather than sympathoinhibitory, response [31]. This is consistent with the reports that intrarenal administration of a known activator of sensory nerves, such as bradykinin, increases arterial pressure and heart rate in conscious rats [32, 33]. This renal sympathoexcitatory reflex likely results in the activation of sensory pathways that converge at the RVLM of the brainstem and the PVN of the hypothalamus, both of which are important for the regulation of sympathetic activity to the kidney as well as other organs [3, 34–37]. It is likely that specific subsets of renal sensory nerves, based on location and sensorymodality, elicit different sympathetic responses where some are sympathoexcitatory and others are sympathoinhibitory and these responses are likely key to the maintenance of homeostasis. This is an

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active area of scientific investigation. Furthermore, it has been hypothesized that pathological states may influence the predominance of sympathoinhibitory or sympathoexcitatory response [30].

Renal Nerves in Pathophysiology  ympathetic Renal Nerves: The Brain-Kidney S Axis in Pathological States Classical View The discovery that increased RSNA results in an elevation of arterial pressure via increased renin release, sodium reabsorption, and vascular resistance led to the idea that CBRNA could be performed as an effective therapy for the treatment of hypertension, targeting this “Brain-Kidney Axis” as a source of hypertension (Fig.  1.2a). This concept was bolstered by numerous preclinical studies in which surgical renal denervation attenuated the development of several models of hypertension [38–41]. However, the technical challenge of recording RSNA in unanesthetized animals and humans has made it difficult to provide direct evidence of the activation of the “Brain-Kidney Axis” in hypertension, although a handful of animal studies have successfully recorded RSNA during the development of experimental hypertension [42]. RSNA has been shown to increase in obesity-­induced hypertension in rabbits [43], but it remains either unchanged or decreased in angiotensin-induced hypertension (as well as the angiotensin-salt model [44–46]. In contrast, indirect measurements of RSNA such as renal norepinephrine spillover, have been shown to be elevated in humans with essential hypertension [47]. Thus, elevated RSNA and the resulting increases in renin release, sodium reabsorption, and renal vascular resistance, all of which contribute to increased arterial pressure, are classically thought to cause hypertension.

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obstruction [51], and reduction in T-cell accumulation and renal fibrosis in the AngII-induced mouse model of hypertension [52]. Studies from our laboratory suggest that renal nerves mediate the trafficking and/or activation of macrophages in the kidney in the DOCA-salt rat model of hypertension. TRDN also prevents the increase of pro-inflammatory cytokines (IL-2, IL-6) and chemokines (GRO/KC, MCP-1) in this model [39]. However, TRDN did not reverse established renal inflammation in DOCA-salt hypertensive rats. Although these experiments employed TRDN to ablate both sympathetic and sensory renal nerves, these effects are largely believed to be due to the ablation of the Brain-Kidney Axis.

 ensory Renal Nerves: The Kidney-Brain Axis S in Pathological States Just as renal nerves can cause renal inflammation, renal inflammation (regardless of its cause), can, in turn, activate the Kidney-Brain Axis, resulting in a chronic activation of the sympathetic nervous system and its resulting pathologies (Fig. 1.2b). Here we summarize how this may contribute to hypertension as well as other sympathetically driven disease states.

Hypertension It is well-established that cytokines released from immune cells infiltrating the kidney as a result of the Brain-Kidney Axis of hypertension can increase the activity of sensory fibers in the kidney [53–55]. Thus, increased RSNA that can cause hypertension and renal inflammation can also lead to an increase in sensory renal nerve activity, potentially further exacerbating the disease state. Renal denervation techniques are being used to investigate these interactions. While CBRNA nonselectively ablates both sensory and sympathetic renal nerves, investigators have employed techniques to specifically ablate sensory renal nerves to study the contriRenal Nerves and Inflammation bution of the Kidney-Brain Axis in preclinical models of In addition to the classical view that activation of the Brain-­ hypertension. Kidney Axis causes hypertension, there may also be a relaDorsal rhizotomy is one such technique that has been tionship between the activity of renal nerves and renal used to target sensory renal nerves and spare sympathetic inflammation (Fig. 1.2a). This hypothesis was supported by renal nerves [56], resulting in the attenuation of hypertension early experiments in which total renal denervation (efferent in the phenol renal injury model [57, 58], the Goldblatt + afferent; TRDN) protected kidneys from infection fol- model of renal artery stenosis [59, 60], and the cyclosporine lowing the injection of colon bacilli in dogs and decreased A-induced model of hypertension [61]. While this technique proteinuria in four out of five patients with nephritis who spares sympathetic renal nerves where CBRNA and TRDN underwent surgical TRDN [48, 49]. More recent studies in do not, it is not specific to sensory nerves from the kidney preclinical models further support the hypothesis that the alone, ablating all sensory input from all organs at the tarBrain-Kidney Axis is involved in renal inflammation and geted spinal levels. fibrosis. They have demonstrated effects of TRDN such as To target sensory nerves innervating the kidney specifiamelioration of glomerulonephritis [50], prevention of cally, our laboratory has developed a more selective method interstitial fibrosis and inflammation following ureteral for the targeted ablation of renal sensory nerves using periax-

1  Renal Nerves: Roles in Homeostasis and Pathophysiology

onal capsaicin treatment (Afferent Renal Denervation; ARDN) [33]. We have employed this technique, in combination with radio telemetric measurement of arterial pressure in freely moving animals that are subjected to a renal inflammatory model of hypertension, the DOCA-salt model. Our results show that the effect of TRDN on DOCA-salt hypertension is mediated by the ablation of sensory renal nerves rather than the sympathetic renal nerves, since TRDN and ARDN attenuate hypertension by the same magnitude [39]. This same result has been shown in the DOCA-salt model in mouse [62], and the 2K-1C model in rat and mouse [63–65]. Consistent with the hypothesis that sensory renal nerve activity drives hypertension in these models, Rossi and colleagues have directly measured elevated RSNA in the non-clipped kidney of unanesthetized 2K-1C rats and this was normalized by the TRDN of the clipped kidney [66]. These results indicate that sensory renal nerves elicit sympathoexcitatory responses in the 2K-1C model, suggesting that pathological conditions may cause a sympathoexcitatory state to predominate in sensory renal nerves. However, some preclinical models that are ameliorated by TRDN are unaffected by ARDN, such as the Dahl salt-­ sensitive rat [41]. This difference in the efficacy of ARDN in different models of hypertension suggests that some causes of hypertension are driven by sympathetic renal nerves, while others are driven by sensory renal nerves. Discerning which axis predominates in animal models and human patients is needed to develop even more targeted renal nerve-­ based therapies in the future.

 ther Clinical Conditions O In addition to hypertension, it is likely that the activation of the Kidney-Brain Axis and renal inflammation may contribute to other clinical conditions that involve the chronic activation of the sympathetic nervous system, and CBRNA may be used to effectively treat these conditions. For example, some patients undergoing CBRNA for hypertension in clinical trials saw improvements in glucose metabolism, and reduced incidences of cardiac arrhythmia and apnea [5]. Furthermore, CBRNA has been proposed as an indication for patients with chronic and end-stage renal disease because such diseases cause an increase in muscle sympathetic nerve activity [3, 35–37]. These effects support the hypothesis that the Kidney-Brain Axis may be responsible for increases in sympathetic nerve activity that can lead to other conditions, including cardiac arrhythmias and diabetes. Further investigations into the mechanisms and physiological effects of sensory renal nerve activation are necessary to better understand how the Kidney-Brain Axis contributes to hypertension and other conditions, and to inform the improvement of renal denervation procedures for the treatment of these conditions.

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Given the importance of the Brain-Kidney Axis in the maintenance of hemodynamics, and the preclinical results suggesting that some models of hypertension are driven by Kidney-Brain Axis hyperactivity, it may be beneficial to selectively ablate sensory renal nerves to treat some patients’ conditions. A recent study investigating the effects of CBRNA in sheep indicated that although the procedure was successful in lowering arterial pressure in a chronic kidney disease model in sheep, the sheep that received TRDN had a compromised ability to respond to hemorrhagic and septic shock with compensatory hemodynamic processes, likely due to the loss of the Brain-Kidney Axis [67]. These regulatory processes may be preserved with advancements in CBRNA techniques to selectively target sensory renal nerves under conditions of increased activity of the Kidney-Brain Axis. Unfortunately, there are currently no diagnostic tests or biomarkers available to identify if a patient’s hypertension is driven primarily by afferent renal nerves. This is an active area of investigation.

 he Emergence of Catheter-Based Renal T Nerve Ablation for the Treatment of Hypertension and Other Diseases CBRNA as a treatment for hypertension is centered around the concept that renal nerve overactivity can cause hypertension, a concept first established in 1945 by chronic renal nerve stimulation in dogs [68]. Consequently, clinical trials investigating the efficacy of CBRNA for the treatment of hypertension in patients are currently underway, as reviewed extensively [3, 4]. These procedures typically involve the advancement of a catheter via the patient’s femoral artery into their renal arteries and employ ablation techniques targeted to and near the adventitial layer of the renal artery to ablate renal nerves (Fig.  1.3). A variety of ablation techniques have been introduced for CBRNA procedures, producing similar reductions in arterial pressure 6 months after the outpatient procedure. These include the the ReCor ParadiseTM catheter (ultrasound), Medtronic SpyralTM ablation catheter (radiofrequency), and the Ablative Solutions PeregrineTM catheter (alcohol) [3, 69]. Some of the major advantages of CBRNA over medication for the treatment of hypertension are its long-lasting decrease in arterial pressure, and the avoidance of issues related to drug resistance and patient adherence to medication. Clinical trial results suggest that, although ablation of the Brain-Kidney Axis mediates some of the beneficial effects of CBRNA, ablation of the Kidney-Brain Axis also contributes to clinical benefits of CBRNA [5]. Further investigations into the roles of renal nerves in the maintenance of homeostasis

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12. Ciriello J, Calaresu FR. Central projections of afferent renal fibers in the rat: an anterograde transport study of horseradish peroxidase. J Auton Nerv Syst. 1983;8:273–85. 13. Kuo DC, Nadelhaft I, Hisamitsu T, de Groat WC. Segmental distribution and central projectionsof renal afferent fibers in the cat studied by transganglionic transport of horseradish peroxidase. J Comp Neurol. 1983;216:162–74. 14. Wyss JM, Donovan MK. A direct projection from the kidney to the brainstem. Brain Res. 1984;298:130–4. 15. Knuepfer MM, Akeyson EW, Schramm LP. Spinal projections of renal afferent nerves in the rat. Brain Res. 1988;446:17–25. 16. Ammons WS. Renal afferent input to thoracolumbar spinal neurons of the cat. Am J Physiol - Regul Integr Comp Physiol. 1986. https:// doi.org/10.1152/ajpregu.1986.250.3.r435 17. Dorward PK, Riedel W, Burke SL, Gipps J, Komer PI. The renal sympathetic baroreflex in the rabbit. Arterial and cardiac baroFig. 1.3 Catheter-based renal nerve ablation. Although different receptor influences, resetting, and effect of anesthesia. Circ Res. devices employ different techniques to ablate the renal nerves, the gen1985;57:618–33. eral concept behind each technique remains the same. A catheter is 18. Huang BS, Leenen FHH. Sympathoexcitatory and pressor responses advanced to the renal artery, and ablative energies (radiofrequency, to increased brain sodium and ouabain are mediated via brain ANG ultrasound) or chemical (alcohol) are delivered radially to the periadII. Am J Physiol - Hear Circ Physiol. 1996. https://doi.org/10.1152/ ventitial space. These techniques produce long-lasting effects [3, 5], ajpheart.1996.270.1.h275 ablating both sympathetic and sensory nerves. 19. Kawano Y, Ferrario CM.  Neurohormonal characteristics of cardiovascular response due to intraventricular hypertonic NaCl. Am J Physiol  - Hear Circ Physiol. 1984. https://doi.org/10.1152/ and in pathological conditions will help to better inform the ajpheart.1984.247.3.h422 continuing development and refinement of renal denervation 20. Tobey JC, Fry HK, Mizejewski CS.  Differential sympathetic responses initiated by angiotensin and sodium chloride. Am J techniques. Physiol - Regul Integr Comp Physiol. 1983. https://doi.org/10.1152/ ajpregu.1983.245.1.r60 21. Kopp UC.  Role of renal sensory nerves in physiological and References pathophysiological conditions. Am J Physiol - Regul Integr Comp Physiol. 2015;308:R79–95. 1. Osborn JW, Tyshynsky R, Vulchanova L. Function of renal nerves 22. Marfurt CF, Echtenkamp SF. Sensory innervation of the rat kidney and ureter as revealed by the anterograde transport of wheat germ in kidney physiology and pathophysiology. Annu Rev Physiol. agglutinin-horseradish peroxidase (WGA-HRP) from dorsal root 2021;83. ganglia. J Comp Neurol. 1991;311:389–404. 2. Osborn JW, Foss JD. Renal nerves and long-term control of arterial 23. Kopp UC, Cicha MZ, Smith LA, Mulder J, Hökfelt T. Renal sympressure. Compr Physiol. 2017;263–320. pathetic nerve activity modulates afferent renal nerve activity by 3. Kiuchi MG, Esler MD, Fink GD, et  al. Renal denervation PGE2-dependent activation of α1- and α2-adrenoceptors on renal update from the international sympathetic nervous system sensory nerve fibers. Am J Physiol - Regul Integr Comp Physiol. summit: JACC state-of-the-art review. J Am Coll Cardiol. 2007;293:1561–72. 2019;73:3006–17. 4. Weber MA, Mahfoud F, Schmieder RE, et  al. Renal denervation 24. Liu L, Barajas L.  The rat renal nerves during development. Anat Embryol (Berl). 1993;188:345–61. for treating hypertension: current scientific and clinical evidence. 25. Kopp UC, Grisk O, Cicha MZ, Smith LA, Steinbach A, Schlüter JACC Cardiovasc Interv. 2019;12:1095–105. T, Mähler N, Hökfelt T.  Dietary sodium modulates the interac5. Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, tion between efferent renal sympathetic nerve activity and afferent Esler MD. Renal denervation as a therapeutic approach for hyperrenal nerve activity: role of endothelin. Am J Physiol - Regul Integr tension: novel implications for an old concept. Hypertension. Comp Physiol. 2009;297:337–51. 2009;54:1195–201. 6. Burnstock G, Loesch A. Sympathetic innervation of the kidney in 26. Ditting T, Tiegs G, Rodionova K, Reeh PW, Neuhuber W, Freisinger W, Veelken R. Do distinct populations of dorsal root ganglion neuhealth and disease: emphasis on the role of purinergic cotransmisrons account for the sensory peptidergic innervation of the kidney? sion. Auton Neurosci Basic Clin. 2017;204:4–16. Am J Physiol Renal Physiol. 2009;297:F1427–34. 7. Nakamura A, Johns EJ.  Effect of renal nerves on expression of renin and angiotensinogen genes in rat kidneys. Am 27. Tyshynsky R, Sensarma S, Riedl M, Bukowy J, Schramm LP, Vulchanova L, Osborn JW. Periglomerular afferent innervation of J Physiol  - Endocrinol Metab. 1994. https://doi.org/10.1152/ the mouse renal cortex. Front. Neurosci. 2023;17:974197. ajpendo.1994.266.2.e230 8. Kobayashi H, Takei Y.  Innervation in the JGA.  In: Renin-­ 28. Stella A, Zanchetti A.  Functional role of renal afferents. Physiol Rev. 1991;71:659–82. Angiotensin Syst. Comp. Asp; 1996. p. 37–40. 9. Osborn JL, Roman RJ, Ewens JD. Renal nerves and the development 29. Genovesi S, Pieruzzi F, Wijnmaalen P, Centonza L, Golin R, Zanchetti A, Stella A. Renal afferents signaling diuretic activity in of Dahl salt-sensitive hypertension. Hypertension. 1988;11:523–8. the cat. Circ Res. 2011;73:906–13. 10. Gaál K, Forgács I, Bácsalmásy Z. Effect of adenosine compounds (ATP, cAMP) on renin release in  vitro. Acta Physiol Acad Sci 30. Kopp UC. Neural control of renal function, 2nd edition. Colloq Ser Integr Syst Physiol From Mol to Funct. 2018;10:i–106. Hung. 1976;47:49–54. 11. Simon OR, Schramm LP.  Spinal superfusion of dopamine 31. DeLalio LJ, Stocker SD. Impact of anesthesia, sex, and circadian cycle on renal afferent nerve sensitivity. Am J Physiol - Hear Circ excites renal sympathetic nerve activity. Neuropharmacology. Physiol. 2020;1. 1983;22:287–93.

1  Renal Nerves: Roles in Homeostasis and Pathophysiology 32. Smits JF, Brody MJ. Activation of afferent renal nerves by intrarenal bradykinin in conscious rats. Am J Physiol Integr Comp Physiol. 2017;247:R1003–8. 33. Foss JD, Wainford RD, Engeland WC, Fink GD, Osborn JW.  A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am J Physiol Integr Comp Physiol. 2015. https://doi.org/10.1152/ajpregu.00427.2014 34. Blankestijin PJ.  Sympathetic hyperactivity in chronic kidney disease. Nephrol Dial Transplant. 2004;19:1354–7. 35. De Beus E, De Jager R, Joles JA, Grassi G, Blankestijn PJ.  Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation? J Hypertens. 2014;32:1751–61. 36. Park J, Campese VM, Nobakht N, Middlekauff HR. Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease. J Appl Physiol. 2008;105:1873–6. 37. Sata Y, Schlaich MP.  The potential role of catheter-based renal sympathetic denervation in chronic and end-stage kidney disease. J Cardiovasc Pharmacol Ther. 2016;21:344–52. 38. Asirvatham-Jeyaraj N, Fiege JK, Han R, et al. Renal denervation normalizes arterial pressure with no effect on glucose metabolism or renal inflammation in obese hypertensive mice. Hypertension. 2016;68:929–36. 39. Banek CT, Knuepfer MM, Foss JD, Fiege JK, Asirvatham-Jeyaraj N, Van Helden D, Shimizu Y, Osborn JW.  Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension. 2016;68:1415–23. 40. Banek CT, Gauthier MM, Van Helden D, Fink GD, Osborn JW. Renal inflammation in DOCA-salt hypertension: role of renal nerves and arterial pressure. Physiol Behav. 2019;73:1079–86. 41. Foss JD, Fink GD, Osborn JW.  Differential role of afferent and efferent renal nerves in the maintenance of early- and late-­ phase Dahl S hypertension. Am J Physiol Integr Comp Physiol. 2016;310:R262–7. 42. Hart EC, Head GA, Carter JR, Wallin BG, May CN, Hamza SM, Hall JE, Charkoudian N, Osborn JW. Recording sympathetic nerve activity in conscious humans and other mammals: guidelines and the road to standardization. Am J Physiol  - Hear Circ Physiol. 2017;312:H1031–51. 43. Armitage JA, Burke SL, Prior LJ, Barzel B, Eikelis N, Lim K, Head GA. Rapid onset of renal sympathetic nerve activation in Rabbits fed a high-fat diet. Hypertension. 2012;60:163–71. 44. Barrett CJ, Ramchandra R, Guild SJ, Lala A, Budgett DM, Malpas SC.  What sets the long-term level of renal sympathetic nerve activity: a role for angiotensin II and baroreflexes? Circ Res. 2003;92:1330–6. 45. Yoshimoto M, Miki K, Fink GD, King A, Osborn JW. Chronic angiotensin II infusion causes differential responses in regional sympathetic nerve activity in rats. Hypertension. 2010;55:644–51. 46. Yoshimoto M, Onishi Y, Mineyama N, Ikegame S, Shirai M, Osborn JW, Miki K.  Renal and lumbar sympathetic nerve activity during development of hypertension in dahl salt-sensitive rats. Hypertension. 2019;74:888–95. 47. Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116:976–90. 48. Page IH, Heuer GJ. The effect of renal denervation on patients suffering from nephritis. J Clin Invest. 1935;14:443–58. 49. Muller E, Petersen W.  Ueber den anteil des vegetativen nervensystems an den infections-schaden der nierengefasse. Deutsch Deselisch Int Med. 1932;44. 50. Veelken R, Vogel E-M, Hilgers K, Amann K, Hartner A, Sass G, Neuhuber W, Tiegs G.  Autonomic renal denervation ame-

9 liorates experimental glomerulonephritis. J Am Soc Nephrol. 2008;19:1371–8. 51. Kim J, Padanilam BJ.  Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol. 2013;24:229–42. 52. Xiao L, Kirabo A, Wu J, et al. Renal denervation prevents immune cell activation and renal inflammation in Angiotensin II-induced hypertension. Circ Res. 2015;117:547–57. 53. Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, Vinh A, Weyand CM. Inflammation, immunity, and hypertension. Hypertension. 2011;57:132–40. 54. Schiffrin EL. Inflammation, immunity and development of essential hypertension. J Hypertens. 2014;32:228–9. 55. Chiu IM, Von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci. 2012;15:1063–7. 56. Lappe RW, Webb RL, Brody MJ. Selective destruction of renal afferent versus efferent nerves in rats. Am J Physiol - Regul Integr Comp Physiol. 1985. https://doi.org/10.1152/ajpregu.1985.249.5.r634 57. Campese VM, Kogosov E, Koss M. Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat. Am J Kidney Dis. 1995;26:861–5. 58. Campese VM, Kogosov E.  Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension. 1995;25:878–82. 59. Wang Q, Fan XP, Chen Z, Zhao QH, Chen SQ, Wan ZH. Role of afferent renal nerves in 2K2C Goldblatt hypertension. Sheng Li Xue Bao. 1995;47:366–72. 60. Wyss JM, Aboukarsh N, Oparil S.  Sensory denervation of the kidney attenuates renovascular hypertension in the rat. Am J Physiol  - Hear Circ Physiol. 1986. https://doi.org/10.1152/ ajpheart.1986.250.1.h82 61. Zhang W, Victor RG.  Calcineurin inhibitors cause renal afferent activation in rats: a novel mechanism of cyclosporine-induced hypertension. Am J Hypertens. 2000;13:999–1004. 62. Baumann DC, Van Helden D, Evans L, Osborn J.  SPARC: renal denervation attenuates DOCA-salt hypertension in the mouse. FASEB J. 2020;34:1. 63. Lopes NR, Milanez MIO, Martins BS, et al. Afferent innervation of the ischemic kidney contributes to renal dysfunction in renovascular hypertensive rats. Pflugers Arch Eur J Physiol. 2020;472:325–34. 64. Ruiz Lauar MR, Evans L, Van Helden D, Fink GD, Banek CT, Menani JV, Osborn JW. Renal and hypothalamic inflammation in renovascular hypertension: Role of afferent renal nerves. Am. J. Physiol. - Regul. Integr. Comp. 2023. 65. Ong J, Kinsman BJ, Sved AF, Rush BM, Tan RJ, Carattino MD, Stocker SD.  Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice. J Neurophysiol. 2019;122:358–67. 66. Rossi NF, Pajewski R, Chen H, Littrup PJ, Maliszewska-Scislo M. Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-­ clip hypertensive rats. Am J Physiol - Regul Integr Comp Physiol. 2016;310:R197–208. 67. Singh RR, Sajeesh V, Booth LC, McArdle Z, May CN, Head GA, Moritz KM, Schlaich MP, Denton KM. Catheter-based renal denervation exacerbates blood pressure fall during hemorrhage. J Am Coll Cardiol. 2017;69:951–64. 68. Kottke F, Kubicek W, Visscher M. The production of arterial hypertension by chronic renal artery-nerve stimulation. Am J Physiol. 1945;145:38–47. 69. Mahfoud F, Renkin J, Sievert H, et  al. Alcohol-mediated renal denervation using the peregrine system infusion catheter for treatment of hypertension. JACC Cardiovasc Interv. 2020;13:471–84.

2

Animal and Human Experience in Quantifying the Effects of Renal Denervation on Sympathetic Nervous System Activity Dagmara Hering, Richard R. Heuser, and Murray Esler

Introduction

nerves (calcitonin gene-related peptide [CGRP] and substance P [SP]). Various experimental models of hypertension and human It is worth considering findings from animal studies showstudies found that disruption of renal sympathetic nerves has ing that the measurement of renal tissue NE content cannot considerable pathophysiologic consequences resulting in be used to immediately verify the completeness of acute blood pressure (BP) reduction. However, the BP response to RDN at the time when performed, as it generally requires arterial renal denervation (RDN) in human hypertension is 2–3 days to occur [5]. It has been shown that renal vasoconvariable. Insufficient procedural effectiveness resulting in strictor response to renal sympathetic nerve stimulation and incomplete nerve disruption has been suggested to explain basal urinary sodium excretion returns toward normal values treatment-related variation or non-response to RDN. Among 14–24 days after RDN when renal tissue NE content is still several methods for studying the sympathetic nervous sys- 400,000 patients, compared with non-resistant hypertension, patients with resistant hypertension were found to be at 32% increased risk of developing end-stage kidney disease, 24% increased risk of coronary artery disease, 46% increased heart failure, 14% increased risk of stroke, and 6% increased risk of death [12]. It is therefore imperative that resistant hypertension is properly identified as this would enable targeted cost-effective screening for secondary causes in a population that significantly stands to benefit from definitive interventions.

Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA, Australia Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_22

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Forms of Secondary Hypertension

2. Early onset hypertension, especially in females, suggestive of fibromuscular dysplasia There are several established causes of secondary hyperten- 3. Unexplained acute and sustained rise in creatinine after commencement of an angiotensin-converting enzyme sion as summarized in Table  22.1. Theses can be broadly (ACE) inhibitor, angiotensin II receptor blocker (ARB), divided into endocrine, vascular, renal, sleep-disordered or direct renin inhibitor. breathing, and iatrogenic causes. The most common causes 4 - Severe hypertension in a patient with known atheroscleof secondary hypertension vary by age group, with renal rotic disease at other sites parenchymal disease and coarctation of the aorta accounting for the bulk of causes in children and adolescents, while 5- Severe hypertension in a patient with an atrophic kidney or kidney size asymmetry endocrine disorders and, for instance, obstructive sleep apnoea more prevalently feature in the younger to middle-­ 6- Sudden, unexplained, recurrent episodes of flash pulmonary oedema (more common in bilateral renal artery aged adult cohort, and atherosclerotic renal artery disease stenosis) more so in older adults. 7 - Severe hypertension and sudden or unexplained heart In the evaluation of a patient with suspected secondary failure and impaired renal function hypertension, identification of clinical and biochemical clues consistent with known disease processes, and an understand- 8- Abdominal systolic-diastolic bruit that lateralises to one side; a modestly sensitive but highly specific finding [14] ing of their prevalence by age demographic, might identify patients who would benefit from screening for secondary hypertension, and guide the choice of confirmatory investi- Features suggestive of other causes of secondary hypertengations with greatest yield. As an example, the following sion will be mentioned in their respective following clues point to the likelihood of renovascular hypertension, sections. and constitute class 1 (Level of Evidence: B) recommendations for performing diagnostic studies [13]:

Renovascular Hypertension (RVH)

1. Onset of accelerated, malignant, or grade 3 hypertension (blood pressure ≥180 mm Hg systolic and/or 110 mm Hg diastolic) after the age of 55 years, suggestive of atherosclerotic disease Table 22.1  Causes of secondary hypertension Renovascular hypertension Atherosclerotic Fibromuscular dysplasia Endocrine Primary aldosteronism Cushing’s syndrome Pheochromocytoma/paraganglioma (PPGL) Hypothyroidism/Thyrotoxicosis Hyperparathyroidism Apparent Mineralocorticoid Excess Familial hyperaldosteronism type 1 and type 2 Renal Glomerulonephritis Chronic kidney disease Liddle’s syndrome Gordon’s syndrome Obstructive sleep apnea Coarctation of the aorta Iatrogenic Hormonal (glucocorticoids, non-steroidal anti-inflammatory drugs, contraceptive pills etc) Cancer therapies (e.g., tyrosine kinase inhibitors, VEGF blockade) Calcineurin inhibitors (cyclosporine and tacrolimus) Illicit substances Amphetamines, cocaine etc. VEGF vascular endothelial growth factor

Renovascular hypertension (RVH) is a common type of secondary hypertension that is defined as hypertension in the setting of renal artery stenotic or occlusive disease that lowers renal perfusion pressure to a level that activates the renin-­ angiotensin-­aldosterone system. While prevalence is low in mild-moderate hypertension, it may be as high as 38% in white patients with severe hypertension in the US [15]. The overwhelming majority (90%) are caused by atherosclerotic disease, referred to atherosclerotic renovascular hypertension (ATS-RVH), with remainder predominantly caused by fibromuscular dysplasia (FMD-RVH) [16]. While ATS-RVH is the dominant form in older patients (>55  years), FMD-­ RVH is the prevailing form of RVH in patients of younger age and early onset hypertension [17]. Guidelines and consensus statements across several invested societies (American College of Cardiology/American Heart Association, the European Society of Cardiology, and Society of Cardiovascular Angiography and Interventions) strongly advocate screening for RAS if features of secondary hypertension are present, alternative causes are unlikely, and a corrective procedure would be planned if a significant lesion was found [13, 18]. Patients with hypertension often have concurrent established atherosclerotic disease, including of the renal arterial bed. There is a possibility of a bidirectional relationship between the two disease states in an individual patient. It is understandably often challenging to conclude that a renal artery stenotic lesion contributes to the pathogenesis of

22  Testing for Secondary Hypertension and Difficult to Control Patients

hypertension (i.e., renovascular hypertension). Certainty of such is perhaps only possible retrospectively if revascularization achieves improvement or resolution of hypertension [19]. Their finding does not necessarily warrant an intervention given the lack of evidence for clear cut benefit with interventional approaches, and the procedural risks [20]. Notwithstanding, the incidental finding of a renal artery lesion may predate the development of hypertension, and therefore warrants surveillance once detected, alongside monitoring for new (incident) secondary hypertension which is potentially reversible in this context [21]. Moreover, there is a high prevalence of (>50% luminal) atherosclerotic renal artery disease in patients with abdominal aortic aneurysm, aorto-occlusive disease, or lower-­ extremity occlusive diseases who are often comorbid by hypertension [22]. Previously utilised tests such as Captopril renal renography and plasma renin activity are no longer utilised in screening or renal artery stenosis. Instead, screening is largely reliant on non-invasive forms of imaging which include duplex ultrasonography, computed tomography, and magnetic resonance imaging.

Fibromuscular Dysplasia FMD is classified by angiographic appearances into the following two phenotypes: 1. Multifocal FMD, accounting for >80% of cases, and has a classical appearance described as “string of beads”, due to alternating fibromuscular webs and aneurysmal dilatation. This form is usually histologically associated with medial fibroplasia. 2. Focal FMD, accounts for roughly 10% of cases, and assumes a concentric, smooth, band-like focal or tubular stenosis. Unlike the multifocal form, this is usually associated with intimal fibroplasia [23]. As patients with FMD-RVH tend to be younger, there is conceivably much to gain from accurate and timely diagnosis and classification. Most patients with multifocal FMD achieve adequate BP control with pharmacotherapy alone, using an average of 2 antihypertensive agents, and therefore risks from revascularization may outweigh benefits. Patients with focal FMD on the other hand, are more likely to have difficult-to-treat hypertension and ischaemic nephropathy complications. Hypertension cure rates after revascularization vary widely between studies, averaging around 36% based on a large meta-analysis by Trinquart et al., more commonly in the focal FMD subgroup [24] (Table 22.2). Catheter-based digital subtraction angiography (DSA) remains the ‘gold standard’ for accurate assessment of renal FMD. The finding of a pressure gradient threshold of 10% of

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Table 22.2  Clinical signs of renal artery fibromuscular dysplasia Early onset hypertension (180/110 mm Hg) hypertension Resistant hypertension Unilateral small kidney without causative urological abnormality Abdominal bruit in the absence of atherosclerotic disease or risk factors for atherosclerotic disease Suspected renal artery dissection/ infarction Presence of FMD in at least one other vascular territory FMD fibromuscular dysplasia. Adapted with slight modification from Gornik et al. [17]

the mean (aortic) pressure, or a trans-lesional gradient of >20  mm Hg, can be used to decide whether the lesion is hemodynamically significant and guide the decision to proceed with angioplasty, although this is essentially an extrapolation from experience with atherosclerotic renal artery stenosis [17, 25]. Non-invasive testing by means of Computed tomographic angiography (CTA) is the study of choice when clinical suspicion of FMD as a cause of secondary hypertension arises. Magnetic resonance angiography (MRA) offers an alternative where CTA is contraindicated. CTA provides better spatial resolution and offers superior sensitivity in detecting renal FMD than MRA, hence it is preferable for screening if the index of suspicion is high. The risk of a false negative with both modalities remains significant, especially in the case of distal / intrarenal portions of the renal artery [26]. Duplex ultrasound, while non-invasive, more affordable, and devoid of radiation exposure, has several limitations as it is time consuming, affected by patient’s body habitus, and is highly operator dependent. It is therefore only cautiously recommended as a screening test for exclusion of renal FMD in specialized centres with extensive experience in evaluation FMD [17]. While peak velocity of >200 cm/sec is commonly considered to reflect a stenosis of >60%, and a peak velocity > 300 cm/sec considered to represent a hemodynamically significant threshold, estimations of degree of stenosis by Duplex is fraught with inaccuracy and therefore should perhaps not be relied on in diagnosing, or indeed surveillance of, renal FMD [27].

 therosclerotic Renovascular Hypertension A (ATS-RVH) Unlike FMD, atherosclerotic renal artery stenosis more commonly affects aorto-ostial and the proximal sections of the main renal arteries (Fig. 22.1). This form of renal artery stenosis is most commonly observed in more advanced age groups (>55–65 years) and is often part of systemic atherosclerosis involving several vascular beds [28]. Unilateral disease constitutes somewhere between 53% and 80% in revascularisation randomised controlled trials, meaning that

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spective study of 131 patients with luminal narrowing >50%, a resistive index >80% reliably identifies patients with renal-­ artery stenosis in whom angioplasty or surgery will not improve renal function, BP, or kidney survival [34]. This likely reflect the correlation between elevated resistive index and established arteriosclerotic renal disease [35]. The utility of an 80% cut off in predicting renal outcomes was replicated by a subsequent study which examined patients who underwent open or percutaneous intervention for ATS-­ RVH.  There was also a strong, independent relationship between pre-operative resistive index with mortality, but not with blood pressure response [36]. However, it must be remembered that this parameter is highly operator dependent, and influenced by patient factors such as obesity. Fig. 22.1  Aortogram illustrating relatively high-grade, bilateral athComputed tomographic angiography (CTA) is the erosclerotic lesions located at the ostia of the renal arteries in a 63-year-­ most reliable form of non-invasive testing for the diagnosis old man. [Adapted from Textor SC.  Progressive hypertension in a patient with “incidental” renal artery stenosis. Hypertension. RAS.  It has a sensitivity of 97%, and specificity of 96% when assessed in small groups of patients, and therefore if 2002;40(5):595–600 [21], with permission. Hypertension] negative, affords the attending clinician a degree of confia significant proportion of patients have bilateral disease dence to forgo the need for invasive catheter-based evaluation [37]. [29–31]. Magnetic resonance angiography (MRA) with Catheter-based DSA, as with FMD-RVH, remains the enhancement is highly sensitive in detecting ‘gold-standard’ for diagnosis and quantitative assessment of gadolinium-­ renal artery stenosis due to atherosclerotic disease. In RAS of the proximal/ main renal arteries [38]. It’s main limi­addition to excellent depiction of vascular anatomy through tation however is the risk of gadolinium related nephrogenic direct injection of contrast medium into the renal artery, it systemic fibrosis in patients with moderate-severe renal enables the measurement of pressure gradients across ste- impairment, a prominently featured comorbidity in this popnotic lesions, which correlates with severity of the lesion and ulation cohort. Use of gadolinium, especially a group 1 agent predicts successful intervention [25, 32]. Non-invasive diag- (gadodiamide), is probably best avoided in patients with an nostic techniques which use angiographic and haemody- eGFR 410 pmol/L (15 ng/ dL) in their diagnostic algorithms. This however may come at the cost of a missed diagnosis (and consequently missed 1. sustained blood pressure elevation >150/100 mm Hg on therapeutic opportunity), considering that both forms of PA each of three measurements obtained on different days, (BAH to a greater extent) can be associated with modest 2. resistant hypertension elevations in PAC [43, 51]. 3. hypertension accompanied by spontaneous or diuretic-­ It should therefore be performed under ‘ideal’ testing induced hypokalaemia conditions that enhance the test’s sensitivity and specificity; 4. hypertension and adrenal incidentaloma these include: 5. hypertension and family history of early onset hypertension and/or premature (< 40 years) cerebrovascular event 1. normal serum potassium (with supplementation if 6. hypertension and first-degree relatives with confirmed PA required) 7. hypertension and sleep apnoea 2. unrestricted salt diet 3. patient is ambulant for at least 2 h, and seated for 5–15 min The Endocrine Society through an extensive review of the prior to testing literature, has devised an algorithm for detection, confirma- 4. non-interfering antihypertensive medications as required tion, subtyping, and treatment of PA (Fig. 22.2). to maintain acceptable control of BP: Fig. 22.2  Algorithm for the detection, confirmation, subtype testing, and treatment of PA. [Adapted from J. W. Funder et al.: Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab.2016;101(5):1889– 1916, with permission. © Endocrine Society.] Cross-­ filled circles indicate the quality of the evidence, such that ⊕○○○ denotes very low-quality evidence; ⊕⊕○○, low quality; ⊕⊕⊕○, moderate quality; and ⊕⊕⊕⊕, high quality [47]

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• non-dihydropyridine calcium antagonist (e.g., Verapamil) • alpha blocker (e.g., Prazosin) • vasodilator (e.g., Hydralazine) • alpha-2/imidazoline receptor antagonist (Moxonidine) 5. where feasible (safe), a washout of interfering antihypertensive medications for at least 2 weeks, and preferably 4 weeks in the case of mineralocorticoid receptor antagonists (MRAs)

Confirmation Confirmatory testing is performed following a positive ARR to definitively confirm or exclude the diagnosis of PA, and consequently rationalise the decision to proceed with subtyping into unilateral or adrenal forms. International guidelines recommend performing one of four tests: oral sodium loading, intravenous saline suppression, fludrocortisone suppression, or a captopril challenge test [52]. Fludrocortisone suppression is the most reliable of all four, however it is expensive and time consuming. Saline suppression test is the most widely utilised confirmatory test and can be performed with the patient either seated or recumbent. The seated SST has been shown to have a sensitivity of 88%, far more superior than that of the recumbent SST, and ideal specificity of 94%. It is the therefore the preferred confirmatory test [53]. PA is essentially excluded if PAC fails to suppress to 4. Ratios of 2 tests)

Overnight 1-mg DST

Late night salivary cortisol (> 2 tests)

Consider caveats for each test (see text) Use 48-h, 2-mg DST in certain populations (see text) Normal (CS unlikely)

ANY ABNORMAL RESULT

Exclude physiologic causes of hypercortisolism (Table 2) Consult endocrinologist Perform 1 or 2 other studies shown above Suggest consider or repeating the abnormal study Suggest Dex-CRH or midnight serum cortisol in certain populations (see text)

Discrepant (Suggest additional evaluation)

ABNORMAL Cushing’s syndrome

Normal (CS unlikely)

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Phaeochromocytoma/Paraganglioma (PPGL)

Screening Tests

Catecholamine-secreting tumours are rare, and are estimated to account for 10HU on unenhanced CT, and and screened for in patients with hypertension in the followmarked enhancement with intravenous contrast medium CT. ing settings [64]: MRI distinguishes a pheochromocytoma from other • classic triad of episodic headache, sweating, and adrenal tumours by the characteristic hyper-intensity on T2-weighted imaging, as other tumours tend to be isointense. tachycardia • presence of the ‘five P’: paroxysmal hypertension, palpi- However, MRI provides lower spatial resolution compared to CT. tations, perspiration, pallor, pounding headache I-123 MIBG scintigraphy might be of diagnostic value • onset of hypertension at a young age (10 cm in diameter), but are less reliable for sporadic forms of pheochromocytoma [68]. pheochromocytoma

When to Screen?

22  Testing for Secondary Hypertension and Difficult to Control Patients

FDG-PET and 68-Ga DOTATATE PET are mainly utilised in the diagnosis of metastatic PPGLs. They are less sensitive in detecting the primary tumour in non-metastatic settings where they are superseded by CT/MRI [69].

Parenchymal Renal Disease The relationship between renal disease and hypertension is bidirectional and could be described as a pathophysiologic vicious cycle. Several renal pathologies can cause and exacerbate hypertension, and hypertension itself is a major cause of chronic kidney disease [70, 71]. Moreover, there is a positive correlation between chronic kidney disease (CKD) ­progression and hypertension, with prevalence rising as glomerular filtration rate declines [72]. IgA nephropathy, the most common form of primary glomerulonephritis, is often associated with emergence of hypertension at some stage through the disease course, and infrequently presents with malignant hypertension [57]. The mechanisms that underpin the pathogenesis of renal hypertension include, but are not limited to: sodium retention, increased activity of the RAS, enhanced sympathetic nerve activation and secondary hyperparathyroidism [73, 74]. Erythropoietin-stimulating agents used to treat CKDassociated anaemia are also established as a cause of hypertension in this cohort [75]. The usual first sign of renal hypertension is the finding of an elevated creatinine and correspondingly reduced glomerular filtration rate on baseline biochemical screening. The most useful step in evaluation that follows is an assessment of the urine sediment with particular attention to presence of pathological levels of albuminuria/proteinuria, and/or microhaematuria. This is usually followed by a renal tract ultrasound study, and were indicated, a renal biopsy to determine the form of suspected primary glomerulonephritis.

Obstructive Sleep Apnoea Obstructive sleep apnea (OSA) is characterised by repetitive apnea or hypopnea due to obstruction of the upper airway during sleep, and is a common and often underappreciated cause of secondary hypertension. There is strong correlation between severity of OSA and the risk for hypertension, a stronger correlation with diastolic than systolic hypertension [76, 77] and with resistant HTN [78] OSA is associated with increased sympathetic nervous system activity evidenced by elevated catecholamines and increased muscle sympathetic nerve activity [79, 80]. Diagnosing OSA guides the appropriate initiation of continuous positive airway pressure which has additive BP-lowering effects to antihypertensives and weight loss [81].

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The presence of hypertension, or indeed resistant hypertension, in an overweight or obese patient should prompt screening for OSA, especially when accompanied by a history of daytime sleepiness. Other symptoms that raise suspicion include snoring and/or choking during sleep, and morning headaches. In clinic, screening begins with performance of an evaluation tool such as the Epworth sleepiness scale or the STOP-Bang questionnaire which predict the high likelihood of OSA [82]. However, none of these tools should replace formal sleep apnea testing. They should be supplemented with a physical examination assessing for obesity, a crowded oropharynx, craniofacial abnormalities, and increased neck and/or waist circumference. The gold standard for confirmation and grading of severity of OSA is in-laboratory polysomnography, although unattended home sleep apnea testing is a reasonable alternative.

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O. Azzam et al. stent placement: renal fractional flow reserve. Catheter Cardiovasc Interv. 2007;69(5):685–9. 33. Drieghe B, Madaric J, Sarno G, et al. Assessment of renal artery stenosis: side-by-side comparison of angiography and duplex ultrasound with pressure gradient measurements. Eur Heart J. 2008;29(4):517–24. 34. Radermacher J, Chavan A, Bleck J, et al. Use of Doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis. N Engl J Med. 2001;344(6):410–7. 35. Ikee R, Kobayashi S, Hemmi N, et  al. Correlation between the resistive index by Doppler ultrasound and kidney function and histology. Am J Kidney Dis. 2005;46(4):603–9. 36. Crutchley TA, Pearce JD, Craven TE, et al. Clinical utility of the resistive index in atherosclerotic renovascular disease. J Vasc Surg. 2009;49(1):148–55. 55 e1-3; discussion 55 37. Echevarria JJ, Miguelez JL, Lopez-Romero S, et al. Arteriographic correlation in 30 patients with renal vascular disease diagnosed with multislice CT. Radiologia. 2008;50(5):393–400. 38. Postma CT, Joosten FB, Rosenbusch G, et al. Magnetic resonance angiography has a high reliability in the detection of renal artery stenosis. Am J Hypertens. 1997;10(9 Pt 1):957–63. 39. Schieda N, Blaichman JI, Costa AF, et  al. Gadolinium-based contrast agents in kidney disease: comprehensive review and clinical practice guideline issued by the Canadian Association of Radiologists. Can Assoc Radiol J. 2018;69(2):136–50. 40. European Society of Urogenital Radiology. ESUR Guidelines on Contrast Media v10.0 [Available from: https://www.esur.org/fileadmin/content/2019/ESUR_Guidelines_10.0_Final_Version.pdf]. Accessed Sept 9, 2021. 41. Conn JW, Louis LH. Primary aldosteronism: a new clinical entity. Trans Assoc Am Phys. 1955;68:215–31. discussion, 31-3 42. Reincke M, Fischer E, Gerum S, et al. Observational study mortality in treated primary aldosteronism: the German Conn's registry. Hypertension. 2012;60(3):618–24. 43. Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension. 2003;42(2):161–5. 44. Gallay BJ, Ahmad S, Xu L, et al. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis. 2001;37(4):699–705. 45. Kim HY, Kim SG, Lee KW, et al. Clinical study of adrenal incidentaloma in Korea. Korean J Intern Med. 2005;20(4):303–9. 46. Dudenbostel T, Calhoun DA.  Resistant hypertension, obstructive sleep apnoea and aldosterone. J Hum Hypertens. 2012;26(5):281–7. 47. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889–916. 48. Young WF.  Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol. 2007;66(5):607–18. 49. Stowasser M, Gordon RD, Gunasekera TG, et al. High rate of detection of primary aldosteronism, including surgically treatable forms, after 'non-selective' screening of hypertensive patients. J Hypertens. 2003;21(11):2149–57. 50. Rossi GP, Cesari M, Cuspidi C, et  al. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension. 2013;62(1):62–9. 51. Stowasser M, Gordon RD.  Primary aldosteronism—careful investigation is essential and rewarding. Mol Cell Endocrinol. 2004;217(1–2):33–9. 52. Stowasser M, Gordon RD. Primary aldosteronism. Best Pract Res Clin Endocrinol Metab. 2003;17(4):591–605. 53. Stowasser M, Ahmed AH, Cowley D, et  al. Comparison of seated with recumbent saline suppression testing for the diag-

22  Testing for Secondary Hypertension and Difficult to Control Patients nosis of primary aldosteronism. J Clin Endocrinol Metab. 2018;103(11):4113–24. 54. Lim V, Guo Q, Grant CS, et al. Accuracy of adrenal imaging and adrenal venous sampling in predicting surgical cure of primary aldosteronism. J Clin Endocrinol Metab. 2014;99(8):2712–9. 55. Kline G, Leung A, So B, et al. Application of strict criteria in adrenal venous sampling increases the proportion of missed patients with unilateral disease who benefit from surgery for primary aldosteronism. J Hypertens. 2018;36(6):1407–13. 56. Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281–93. 57. Sevillano AM, Cabrera J, Gutierrez E, et al. Malignant hypertension: a type of IgA nephropathy manifestation with poor prognosis. Nefrologia. 2015;35(1):42–9. 58. Nieman LK, Biller BM, Findling JW, et  al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526–40. 59. Findling JW, Raff H. DIAGNOSIS OF ENDOCRINE DISEASE: differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome). Eur J Endocrinol. 2017;176(5):R205–R16. 60. Singh Y, Kotwal N, Menon AS.  Endocrine hypertension— Cushing's syndrome. Indian J Endocrinol Metab. 2011;15(Suppl 4):S313-6. 61. Pacak K, Linehan WM, Eisenhofer G, et  al. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134(4):315–29. 62. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. 63. Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993;329(21):1531–8. 64. Young WF Jr. Adrenal causes of hypertension: pheochromocytoma and primary aldosteronism. Rev Endocr Metab Disord. 2007;8(4):309–20. 65. Lenders JW, Pacak K, Walther MM, et  al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287(11):1427–34. 66. Sawka AM, Prebtani AP, Thabane L, et al. A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma. BMC Endocr Disord. 2004;4(1):2. 67. Kudva YC, Sawka AM, Young WF Jr. Clinical review 164: the laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab. 2003;88(10):4533–9.

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Drug Adherence in Hypertension Management

23

Dan Lane, Michel Burnier, and Pankaj Gupta

Non-adherence in Hypertension Hypertension is one of the leading causes of mortality worldwide. It is estimated to account for 1.16 million deaths in 2019 [1], and over 1.28 billion people are affected by the disease [2]. Yet, 79% of those are estimated to have uncontrolled hypertension [2]. For those with diagnosed and treated hypertension, non-adherence is recognized as a frequent contributor to uncontrolled blood pressure (BP) together with medical inertia and poor access to drug therapies [3]. A 2017 systematic review of 28 studies involving 12,603 patients determined that 45.2% of hypertensive patients were non-adherent [4]. Further still, 83.7% of patients with uncontrolled BP were non-adherent. Non-­ adherence to antihypertensive medications has major clinical consequences [5]. Indeed, non-adherent patients have a higher risk of mortality and or developing cardiovascular complications such as stroke, heart failure or myocardial infarction. The main contributors to non-adherence are classified by: patient mannerisms (e.g., treatment misconceptions, forgetfulness etc.), physician conduct (e.g., poor communication, lack of monitoring etc.), society and environment (e.g., media, transportation links, etc.), and health care provisions (e.g., symptoms from poorly tolerated medications, medication cost, etc.) [5]. Adherence, therefore, can be thought of as a complex problem not only because of the high number of potential causes but also because it is a dynamic process that varies over time.

D. Lane ∙ P. Gupta (*) The Department of Chemical Pathology and Metabolic Diseases, Leicester Royal Infirmary, Leicester, UK Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK e-mail: [email protected] M. Burnier Service of Nephrology and Hypertension, University Hospital, Lausanne, Switzerland

 easuring Drug Adherence: Methods M and Considerations Although most physicians tend to recognize that medication adherence is an important issue in the management of patients with chronic asymptomatic diseases such as hypertension or dyslipidaemia, their major concern relies in their ability to detect poorly adherent patients. As shown in Fig. 23.1, simple methods tend to be relatively unreliable, and methods providing the best information tend to be more expensive and demanding in terms of infrastructures. The ideal method to assess drug adherence should “provide a reliable capture, storage, analysis, and communication of dosing history data in ways that make it difficult or impossible for patients or trial staff to censor or otherwise manipulate the data” [6]. Interestingly, the prevalence of poor adherence to medications varies depending on the method used to measure it. Thus, self-reports, questionnaires (like the widely used Morisky Scale [7]) and pill counts overestimate adherence and are prone to bias. Systematic reviews have shown that non-adherence rates are typically higher in studies that use chemical adherence tests (CAT) [8, 9] or electronic monitoring [10]. In recent years, several new objective ways of measuring drug adherence have been developed including CAT or digital medicines with ingestible sensors inserted in pills [5]. The ability to assess medication adherence accurately is crucial as it leads to a better understanding of the issues. Yet, large clinical trials have been slow to adopt some of these new technologies, except perhaps for the Medication Event Monitoring System, which has been the gold-standard to measure medication adherence in real-time in new drug developments and was recognized by the Food and Drug Association. In recent years, much emphasize has been focused on the detection of non-adherence in patients with apparent resistant hypertension, a clinical situation in which partial or complete non-­adherence has been found to be particularly high [11, 12].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_23

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Fig. 23.1  Objective and subjective adherence testing measures

I ntroduction to Chemical Adherence Testing in Hypertension CAT has fast become an important tool in the clinician’s arsenal to differentiate those with true resistant hypertension from those who are non-adherent. Adherence, defined as participating with the agreed upon treatment prescription [13], can be objectively and accurately determined by CAT. Essentially, a patient’s urine, blood, or other biomatrix, are analysed to determine medication presence, and therefore determine whether the medication has been ingested. These techniques were researched on in the early 2010s [11, 14, 15], and were known to be used in clinics from 2014 in the UK.  The basis of these methods typically involves hyphenated mass spectrometry [16], which include a separation system (e.g., liquid chromatography (LC), gas chromatography (GC)) and a detection system (e.g., tandem mass spectrometry (MS/MS), high-resolution mass spectrometry (HRMS). The most common of these combinations are LC-MS/MS, which have been steadfast in clinical laboratories over the last 20 years and are capable of exquisite sensitivity, specificity, and selectivity over a large dynamic range of compounds (from small drugs like metformin to large proteins like haemoglobin). The overhaul to these platforms has seen CAT recommended in the recent European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 clinical guidelines [3]. By involving the techniques both clinically and in research, undue procedures and treatment escalation may be avoided. The evolution of adherence testing by hyphenated mass spectrometry has been rapid and continuous. The following sections will discuss the technical and clinical aspects, as

well as limitations and where the technology will likely progress to.

 etermination of Drug Levels Using Mass D Spectrometry The only measures that confirm medicine consumption are direct observed therapy (DOT), digital pills (which are both more expensive and labour intensive), and CAT using blood or urine. As urine and blood samples (among others) may be sent via the post, CAT may be absorbed into the service of a centralised laboratory like any other pathology test. Burns et  al (2019) showed most antihypertensive drugs were suitably stable in urine so that postal delivery under no special conditions (e.g., on dry ice) and delivery under 3-days had no impact on the ability to detect by LC-MS/ MS [17]. In brief, nifedipine, hydralazine, bendroflumethiazide, and captopril are known to be unstable at room temperature [17, 18]. Long-term freezer stability has been demonstrated for antihypertensive drugs in blood [18], though little data exists on room temperature storage. It is thought the blood delivery through existing framework (i.e., room temperature if on-­site, on ice if by courier) between the clinic and laboratory is suitable. With the advent of dry blood sampling for adherence testing [19], no special conditions would be required [20]. Mass spectrometry is a powerful instrument. Picograms (10−12 grams) of medications may be detected in human biomatrices (sampling typically needs  0.1) and is the most widespread. The system is pictured in Fig.  23.2. In brief, cylindrical metal rods are organised symmetrically, each pair charged similarly  – negative opposite negative, positive opposite positive. Applying a small radio frequency voltage to the metal rods may stabilise the flight path of an ion travelling through the centre of the rods. The ions’ m/z is intrinsically proportional to the applied voltage, so each set of rods (4 being quadrupole, 8 being octupole, and so on) can scan for specific ions to either stabilise or destabilise trajectories towards the detector. These are essentially mass filters. Between each filter situates a collision cell. Depending on the system, energy is introduced (e.g., collision with an inert gas), and ions are fragmented into small pieces which are indicative of their larger pieces. These are known as the parFig. 23.2  Triple quadrupole mass spectrometry (MS/MS) schematic. The red arrows track the movement of the analyte/ion path. Reused with permission from Gupta et al. [39]

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ent and daughter ions, or the precursor and product ions. The transition from parent to daughter is generally unique to a given ion, and multiple transitions may be monitored simultaneously in a mode known as multiple reaction monitoring (MRM). This increases resolution between ions and increases confidence in differentiating ions that could have the same parent ions. If the fragmentation does not match the expected pattern, an analyst may confirm interference. QTOF-MS offers high resolution, being capable of resolving m/z of 10−3 (m/z > 0.001). The schematic of QTOF-MS is outlined in Fig. 23.3. Briefly, like in MS/MS, a quadrupole and collision cell select and fragment parent ions. The final MS system is the main difference. Daughter ions are entered into a pulser, which applies a constant energy to accelerate the ions along a flight path. As force is proportional to mass and acceleration, ions with small mass move with higher velocity and reach the detector in less time—vice versa for high mass ions. These platforms can be operated in an untargeted mode where continual data is collected—the main benefit of using these instruments. Data sets may be sifted through to identify compounds outside the original scope i.e., additional research questions may be asked where sufficient consent is given. In the context of adherence testing, where consent is necessary, this untargeted mode may be unnecessary (at least in the current state of consenting). Perhaps in opt-out systems, like organ donation is in many countries, the power of QTOF-MS and other HRMS platforms may be increased. At present, QTOF-MS and LC-MS/ MS offer similar sensitivity and specificity, so cost is often the main decision point for acquiring a platform. In terms of detecting common antihypertensive drugs, most are good candidates by mass spectrometry. Depending on the matrix (urine or blood), different compounds may be better detected. For example, extensively metabolised drugs like ACE inhibitors may be seen primarily as their metabolite in urine (e.g., ramiprilat, enalaprilat) and primarily as their prodrug in blood (e.g., ramipril, enalapril). Some medications are scarcely renally excreted (e.g., spironolactone), hence, either blood should be used, or metabolites must be targeted. These medications make up the minority. With the

First MS

Collision cell

Second MS

Fragmentation

Selection of daughter ion

Derivitised Analyte

ESI; API Ionisation source

Selection of parent lon

Detector (electron multiplier)

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Fig. 23.3 Quadrupole time-of-flight mass spectrometry (QTOF-MS) schematic. The red arrows track the movement of the analyte/ion path

high sensitivity of MS platforms, 12 months), follow up renal denervation studies (as outlined by Liang et al. (2021) [23], medication changes were largely unchanged after the follow-­up as illustrated in Table 23.1. Krum et al. (2009) found no change in the number of drugs after RDN (though their protocol asked medication changes to be limited where necessary) [24]; EnligHTN I decreased (4.24–4.16 medications per patient) [25]; Simplicity HTN-1 increased (5.1–5.6) [26]; Simplicity HTN-2 decreased (5.1–4.6) [27]; RAPID did not stipulate 12-month data [28]. In SYMPLICITY HTN-3 the number of pills only slightly changed at 6 months (5.0–5.1), and we do not have follow-up data [29]. In REDUCE-HTN the number of pills per day did not significantly change (raw data not reported) [30]. In EnligHTN III a net decrease was mentioned but raw data were not reported [31] and in the Global SYMPLICITY Registry a very small decrease (4.5–4.4) was observed [32]. In the short-term follow-ups (6  months) of note, the ENCOReD study saw prescriptions reduced from 4.7 to 4.4 [33]. In the RADIANCE-HTN SOLO trial, the percentage of patients receiving antihypertensive medications 2  months after the intervention were 48% in the renal denervation group and 61% in the control group (p value non-significant) [34]. In the more recent SPYRAL HTN-ON MED proof-of-­ concept randomised trial, adherence to antihypertensive drugs was 65.8% at baseline and 60.5% at 6 months with no difference between the renal denervation and the control group [35]. In the RADIANCE-HTN TRIO, the number of patients receiving additional antihypertensive medications after the 2-month measurement of ambulatory BP and patients with reduction in antihypertensive medications did not differ significantly between RDN and controls although a slight trend was observed in favour of RDN.  The Table 23.1  Changes to antihypertensive medication after renal denervation intervention from long-term follow-up trials. Only studies including numeric data (not percentage) have been included Long-term renal denervation studies EnligHTN I (2014) Simplicity HTN-1 (2014)a Simplicity HTN-2 (2014)b Simplicity HTN-3 (2014) Global SYMPLICITY Registry (2019)

Baseline prescriptions (mean) 4.24 5.10

Follow-up prescriptions (mean, months) 4.16 (12-months) 5.60 (36-months)

4.60

5.10 (36-months)

5.10

5.00 (6 months)

4.50

4.40 (12-months)

Prescription changes were discouraged until 12-months Prescription changes were discouraged until 6-months

a

b

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RADIANCE-HTN TRIO trial will publish further follow-up data soon (as of the time of writing, circa 2021-end) [36]. The main point here is that adherence will still be relevant even after interventions such as RDN as the majority of patients with resistant hypertension that are treated with RDN require either the continuation or the prescription of drug therapies to control BP. Research has shown adherence is still a problem for these patients [22]. Few RDN studies monitored adherence during the study period, and often adherence was only screened (using subjective methods) prior to commencing the trial. Patel et al. (2016) used CAT to show that 23.5% of patients referred for the procedure were not taking their medications in the first instance [7]. In the recently published RADIANCE-HTN TRIO a randomised, multicentre, single-blind, sham-­ controlled trial, full adherence to the combination medications remained high at 2 months among patients (by CAT), with no difference between the renal denervation and sham groups (42 [82%] of 51 vs 47 [82%] of 57) [36]. The power of confounding adherence by objective measures in studies like those is still a pertinent topic, especially as RDN gains traction once again. This, along with other confounding issues (e.g., poor trial design, heterogeneity between interventions etc.), have likely contributed to the slow and cautious interest of RDN in resistant hypertension.

Issues and Future Research Though CAT is increasingly considered the recommended approach in clinical practice, the test still has a couple of important problems. Firstly, as before, variable pharmacokinetics – how the body moves the medication around and to what degree it is excreted – may contribute to false negative results. Some patients have polymorphisms in cytochrome P450 enzymes, which affect both metabolism and drug transportation. These polymorphisms modify the clearance rates and thus the amount that is excreted at a given moment. If the medication is not cleared normally, the amount in the tested biomatrix may be below the assays limit of detection. Studies are needed to establish pharmacokinetic models in hypertensive patients. Secondly, there is a debate on which biomatrix to collect for testing. Urine offers ease and is non-invasive to collect surplus amounts. Blood derivatives overcome issues where medications are not excreted by the renal route, though sampling is more invasive. Either may be used, however. Thirdly, the “tooth-brush” or “white coat adherence” effect may skew true findings and lack of information on the dosing history may limit the global interpretation of the data. Therefore, the context of the result should always be noted (for example, is the patient achieving BP targets?) and mea-

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surements might be repeated during the course of therapy. Further issues include the limited use of CAT in the US (as insurance may not cover the test), and in randomised controlled trials are needed to consolidate its usefulness. Teaching and training guidance will need to be provided to allow homogenous application of CAT.  There are other issues that mostly pertain to variances in detectable medication (e.g., sampling time). As the technology develops, the outstanding issues will most likely be ironed out. It is hoped that in near future these CAT may be able to give insight to dosing habits or they might be combined with other technologies. They may also be used outside of gauging adherence. For example, up-titrating antihypertensive dose given a lower than usual amount found in blood (i.e., therapeutic drug monitroing). With precision medicine rapidly evolving, these approaches are likely. Currently, 38% of ESH Excellence centres use CAT [37]. This number will likely increase given a soon-to-­be published manuscript (circa., Dec 2021) providing recommendations and guidance on adherence testing has been endorsed by the European Society of Hypertension (ESH) Working Group on Cardiovascular Pharmacotherapy and Adherence [38]. Finally, there is a need to educate health care professionals on the assessment of non-adherence and, more importantly, on how to discuss this with patients. There are some initiatives being undertaken by the ESH in this area. Acknowledgments None.

Sources of Funding  L is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East Midlands (ARC EM). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. Disclosures  None.

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235 32. Mahfoud F, Böhm M, Schmieder R, et al. Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-­ up from the Global SYMPLICITY registry. Eur Heart J. 2019;40(42):3474–82. 33. Persu A, Jin Y, Azizi M, et al. Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hypertens. 2014;28(3):150–6. 34. Azizi M, Schmieder RE, Mahfoud F, et  al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-­controlled trial. Lancet. 2018;391(10137):2335–45. 35. Kandzari DE, Böhm M, Mahfoud F, et  al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. 2018;391(10137):2346–55. 36. Azizi M, Sanghvi K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCEHTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. The Lancet. 2021;397(10293):2476–2486. 37. Burnier M, Prejbisz A, Weber T, et al. Hypertension healthcare professional beliefs and behaviour regarding patient medication adherence: a survey conducted among European Society of Hypertension Centres of Excellence. Blood Press. 2021;30(5):282–290. 38. Lane D, Lawson A, Burns A, et al. Nonadherence in hypertension: how to develop and implement chemical adherence testing. Hypertension. 2022;79(1):12–23. 39. Gupta P, Patel P, Tomaszewski M. Measurements of antihypertensive medications in blood and urine. 2018:29-41Oct 25, 2018.

Patient Preference for Therapies in Hypertension

24

Filip M. Szymanski and Anna E. Platek

The physician’s instrumental communication behavior, such preference is dependent on a milieu of factors and is not easas obtaining and providing information, accounts for 60% of ily measurable [4]. interactions with the patient, 23% of which are dedicated to Importantly, patient preference affects several aspects of patient questions [1]. Many patients believe that doctors treatment. It seems that it plays a crucial role in chronic disspend too little time informing the patient about the medical ease treatment, including hypertension. Lifelong effective condition and treatment options and patient preference is treatment of hypertension, especially non- or mildly sympoften not explored or taken into consideration. tomatic, requires a high level of determination and doctor-­ The approach to medical care has changed significantly patient cooperation. Therefore, patient preference regarding over the centuries. In the last decades doctors’ approaches to which antihypertensive strategy should be used is currently patients have changed. In previous centuries the main focus extensively studied. was the biomedical aspect of a disease with less attention to A primary component upon which adherence to a parthe impact of mental factors on health. A breakthrough that ticular treatment depends upon is patient preference. changed this concept was the new definition of health devel- Review of the literature shows that several factors play a oped by the World Health Organization in 1946. It defined crucial role in adherence: schedules, type and efficacy of health not only as the absence of disease but also as a full pharmacotherapy [5]. It was shown that, in general, physical, mental and social well-being. It promoted a return patients  prefer more effective over safer medications. to approaching health and illness in the Hippocratic fashion, Factors responsible for changes in long-term adherence to a and the patient was approached holistically again. Another therapy include dosing and costs. pivotal moment was introducing the term ‘patient-­ It has also been reported that, in patients taking cardiovascenteredness’ by Balint, who suggested that each patient cular medications, dosing schedule not corresponding with “has to be understood as a unique human being” [2]. Among patient preference negatively affects adherence [6]. One in many others, those moments laid a foundation for a human- four patients reported being inconvenienced by their drug istic approach to medical care and medicine we know today. dosing schedule, and these subjects were less adherent Much time had to pass before the patient became a subject (46.2% vs 16.7%) to their drug regimen than those who did rather than an object of the treatment. Patient-centeredness not report inconvenience. Taking into consideration preferwas defined as “providing care that is respectful of and ence regarding the preferred medication schedule could sigresponsive to individual patient preferences, needs, and val- nificantly improve adherence. ues” [3]. Patient preference became a concept in outcomes research, medical product development and has been incorporated into several clinical practice guidelines. Patients’ Preference in Hypertension Unfortunately, research on patient preference is still Treatment insufficient, and there is much heterogenicity in outcomes studies across the literature. This may be because patient A pivotal aspect that improves patients’ involvement in therapy is education. Even simple aspects such as medication list composition are relevant and may play a role in patients’ attiF. M. Szymanski (*) Cardinal Stefan Wyszynski University in Warsaw, Warsaw, Poland tude towards treatment. A study of patients taking eight or more medications, aimed to identify medication-list compoA. E. Platek Cardinal Stefan Wyszynski University in Warsaw, Warsaw, Poland nents preferred by patients [7]. It showed that patients prefer a more elaborate list, including dosing, timing, the onset of Medical University of Warsaw, Warsaw, Poland © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_24

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treatment and reason for the medication. More importantly, the survey showed that 22.7% of patients did not know the names of all the medications they were taking; 13.2% did not know the medical problems for which they were taking their medications and 30.2% did not know the dosages of the medications. Nevertheless, 96.2% felt that they took an active part in their medical care. It shows that patients feel a need for active participation despite problems in understanding provided information. One of the more important studies on patient preferences towards hypertension management was conducted in the United Kingdom as an unlabeled discrete choice experiment (DCE) [8]. In a DCE participants are presented with questions asking to choose between hypothetical alternatives. In the described study, participants were aged 50–86 years and 73% had been diagnosed with hypertension for >5  years. They were interviewed to help establish their preferences regarding hypertension management based on four factors: a model of care, frequency of blood pressure measurements, reduction in 5-year cardiovascular risk, and costs to the National Health Service. With respect to the model of care domain, patients preferred treatment guided by a doctor over pharmacist, telehealth or self–management. As for the frequency of blood pressure measurements, patients preferred more frequent measurements over those conducted twice or once a year. The most significant factor influencing patients’ preference towards treatment was the predicted reduction in 5-year cardiovascular risk. Scenario analysis showed that when the outcome changed from lowest to highest risk reduction category, the likelihood that participants would choose a model of care doubled. Patients preferred therapies with a higher risk reduction level and were willing to pay more for those kinds of treatment (annually £374.74, £398.98, and £673.45 for 10%, 15%, and 25% reduction in 5-year cardiovascular disease risk, respectively). In summary, the study showed that when offering new models of care, it is essential to discuss the outcomes in terms of risk and risk reduction, which may impact the ‘buy-in” among patients. In a survey assessing the impact of patient preference on the initiation of treatment, a group of 52 hypertensive participants was evaluated [9]. The study showed that 56% of patients informed about their condition preferred treatment with hypertensive medications rather than no treatment. Moreover, there was a substantial disagreement between the patient decision and the actual initiation of the pharmacotherapy. In another study conducted in Germany, classical pharmacotherapy methods were compared with catheter-based renal denervation (RDN) [10]. The study included patients with stage 1 or stage 2 hypertension treated in outpatient settings. A questionnaire-based cross-sectional survey collected information on demographics, duration of hypertension, antihypertensive medication duration, medication (how many pills and side effects), willingness to receive alterna-

F. M. Szymanski and A. E. Platek

tive treatment with catheter-based RDN, and determinants for the choice of their decision. A total of 1011 patients at a mean age of 66 years completed the survey. The mean duration of hypertension and time on hypotensive treatment was 10.8 and 10.2 years, respectively. In the previously untreated patients, 61.7% of survey participants would prefer tablets and 38.2% would opt for a one-time RDN procedure. Of the entire study population, between 36.3% and 39% opted for RDN, with patients