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D. Hering et al.

Eects ofRenal Denervation onSympathetic Activity inPreclinical Models

Bilateral RDN has been found to prevent the development or attenuate the magnitude of BP in a large number of various animal models of experimental hypertension including genetic, salt-sensitive, and obesity hypertension [14].

Eects ofRenal Denervation onRenal NE andNerve Histology

In experimental studies, renal tissue NE concentration was measured to assess the effectiveness of nerve ablation. In addition to BP reduction, there were signicant decreases in renal tissue NE and histological disruption to the renal nerves bundle, and plasma renin activity in spontaneously hypertensive rats 3 months following the radiofrequency RDN procedure [15]. The impact of radiofrequency-induced RDN on renal function, BP, renal NE, and histology of nerves along the renal artery was tested in obese hypertensive dogs, an experimental model that closely mimics cardiorenal and metabolic changes in obese hypertensive humans [16]. In this study, at 8 weeks of follow-up catheter-based RDN reduced BP and renal cortex NE levels by 42% overall compared with control dogs. Sections of the examined renal artery found that approximately 46% of renal nerves exhibited injury after RDN.Renal nerve injury was most prevalent from 0.28–3.5mm from the renal artery lumen, with 90% of the injured nerves being found in this range. An interesting observation derives from this study is that signs of injury to the renal nerves assessed as perineural brosis, necrosis, and neuron loss, occurred in 49% of the nerves observed near the bifurcation, 38% of the nerves in the main renal artery, and 63% of the nerves near the ostium [16].

Eects ofRenal Denervation onRenal Aerent andEerent Nerves

A further study examined the effectiveness of RDN on both afferent sensory and efferent sympathetic renal nerves and the subsequent degree of possible functional and anatomic reinnervation at 5.5 and 11 months in normotensive 6 sheep after catheter-based RDN [17]. Immediately after RDN, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. Renal sympathetic nerve activity and the responses to electric stimulation were at normal levels at 11 months RDN.Immunohistochemical staining for renal efferent (TH) and renal afferent nerves (CGRP) and renal NE levels were normal 11 months after RDN.While RDN effectively ablated the renal afferent and efferent nerves in normotensive sheep, the functional affer-

ent and efferent responses to electric stimulation were normalized, accompanying normal anatomic distribution of afferent and efferent renal nerves, suggesting reinnervation at 11 months after RDN [17].

Renal Nerve Anatomy Based onHuman Autopsy Studies

The level of RDN needed to reduce BP remains unknown. Variable clinical BP response to RDN as a result of insufcient or suboptimal renal nerve ablation remains unknown as there are no procedural efcacy measures during the procedure. Human autopsy studies have broadened our knowledge of renal nerve anatomy and their localization to the renal artery lumen, likely explaining variability in BP response rates to RDN.Ablation of more distal parts of the main renal artery where efferent nerves are in proximity to the arterial lumen combined with ablation of renal artery branches seemed to be more efcient in reducing renal NE levels [18]. Nerve bers do not fully converge on the renal artery until beyond the main bifurcation [19]. Considerable individual variability of kidney innervation may affect the level of effectiveness of kidney denervation. This hypothesis has led to the initiation of a series of studies in preclinical models and human hypertension.

Eect ofRenal Denervation onNE Content Depending onRenal Artery Anatomy

The impact of different patterns of lesion placements on the efcacy and consistency of catheter-based radiofrequency RDN has been examined in pigs [20]. In this study, increasing the number of RF lesions (4, 8, and 12) in the main renal artery signicantly decreased cortical NE concentrations (−71± 27%) but had no clear impact on the dose-response relationship between NE content and axon density. On the contrary, targeted treatment of the renal artery branches resulted in a greater reduction in NE (−83± 21%). Singlecycle treatment in the main renal artery combined with renal artery branches was associated with the greatest reduction in NE (−92 ± 9%) and least variability. Treatment with twocycle RF ablation in the main renal artery and branches signicantly improved the renal NE reduction compared to the main artery treatment alone but not to single-cycle combination treatment (−91±11%). A signicant reduction in axon density in the renal cortex was observed in all treatment groups compared with the corresponding native kidneys.

Further support for the relevance of using renal NE as a biomarker to gauge RDN effectiveness comes from a healthy porcine model [21]. This study found a sufcient nerve injury as documented by a decrease in NE by −78.3% fol-

2 Animal andHuman Experience inQuantifying theEects ofRenal Denervation onSympathetic Nervous System Activity

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lowing one treatment per artery and by −88.1% after full artery-length treatment in the treated compared to the untreated contralateral kidney at 7 days post-procedure. However, at 28 days of follow-up, a reduction in NE was less pronounced accounting for 40% following single RF treatment per artery and −59% after full artery-length treatment. While the exact cause of the renal NE increase over time is unknown and can suggest reinnervation, it is likely due to the subsidence of the initial inammatory response and possible healing of the degenerative nerve bundles [21].

Histological analysis of nerve bers revealed that at 7 days morphologic changes in susceptible nerves included degenerative, necrotic, or chronic changes, whereas only chronic changes were identied at 28 days. More nerves (29%) were unaffected following one treatment, whereas only 15% of nerves were unaffected following full arterylength treatment [21]. This study suggests a sufcient renal nerve injury as demonstrated by changes in renal NE and TH immunostaining proportionally to electrode length and longitudinal treatment along the renal artery compared to untreated controls, providing the rationale for further investigation of an optimized RDN approach to reduce treatment variability.

The effectiveness of RDN in different regions of the renal artery assessed with NE levels was also performed in 14 pigs [22]. RDN reduced renal NE by 12% at the ostium, 45% near the bifurcation in the main renal artery, and 74% when RD was performed in extrarenal artery branches 2 weeks postprocedure. The number of renal nerves was greatest in extrarenal branches and the main artery compared to the ostium and the average distance from the lumen was greatest for nerves at the ostium and least at the branches. RDN decreases renal NE more signicantly when performed in branches of the renal artery closer to the kidney suggesting that increased efcacy of RDN in extrarenal arterial branches may be associated with a greater number of nerves near the artery lumen in the branches.

Changes inRenal Artery Treated withRenal Denervation

To get a better understanding of mechanisms underlying sustained BP reduction, chronological changes in the treated artery and associated tissue following RDN over the longer term were examined in a swine model [23]. In this study, renal nerve injury was the greatest in the subacute phase (7 days) compared to 30, 60 days, with peak functional nerve damage at 30 days, and least at 180 days. Changes in renal nerve injury paralleled injury caused to the renal artery, which was the greatest in the subacute phase (7 days), and least in the chronic phase (180 days), suggesting complete healing of the arterial wall and soft tissue. The level of TH

was signicantly lower after 7 and 30 days compared with 60 and 180 days. Focal nerve regeneration at the sites of ablation was observed in 17% of renal arteries at 60 days and 71% at 180 days. These ndings indicate gradual recovery of the renal arterial wall and surrounding tissue.

Does Renal Reinnervation Happen After RDN?

While there are no human studies documenting histological evidence of regrowth of renal nerves post arterial RDN in humans, data from the transplanted human kidney documented that supersensitivity to circulating NE and an inadequate response to lower body negative pressure were present 27 months post-procedure, suggesting functional denervation of the human transplanted kidney [24].

More studies in pre-clinical hypertension models at various time points are needed to better understand whether reinnervation if any, occurs post arterial RDN and affects BP levels. Clinically meaningful and durable long-term BP reduction up to 36 months following radiofrequency catheter- based RDN, independently of concomitant antihypertensive medication in patients with hypertension compared to the sham-controlled procedure [25] seems to be not affected by functional and relevant regrowth of the renal nerves, supporting the hypothesis of lack of renal sensory reinnervation and removal of excitatory reexes originating in the kidney.

Eects ofKidney Removal onMuscle Sympathetic Nerve Activity

Human studies support the concept of afferent signals arising in the native failing kidney to mediate central sympathetic activation and enhance sympathetic outow into the periphery [26], even in the presence of the diseased native kidneys in renal transplant recipients, and the absence of uremia. [27]. However, bilateral native kidney nephrectomy performed in renal transplant patients has been shown to reduce or even normalize MSNA, conrming the contribution of renal afferents from the diseased kidney to central integrative structures in the brain that cause both an increase in sympathetic nerve discharge and hypertension. Consistent with this hypothesis, bilateral nephrectomy has been shown to improve BP control in hemodialysis patients with refractory hypertension, suggesting the best treatment option for this patient cohort [28]. These clinical observations supported animal studies and provided proof-in-principle evidence that the interruption of efferent and afferent renal pathways may reduce both renal sympathetic outow and arterial BP in patients with hypertension and chronic kidney disease.

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D. Hering et al.

Acute Testing ofProcedural Ecacy inHuman

Observations from mechanistic studies in patients with resistant hypertension may throw some light on mechanisms involved in the BP reduction achieved with arterial RDN.Evidence from experimental studies indicates a potential role for renal afferent sensory nerves to modulate sympathetic outow to the kidney and other highly innervated organs involved in cardiovascular BP regulation. Ablation of efferent and afferent nerves is likely to directly contribute to BP reduction and/or modulate other mechanisms (i.e. renal chemo-, mechanoreceptors), not entirely understood, involved in long-term BP regulation. While afferent sensory nerve activity cannot be measured directly in humans, adenosine increases sympathetic tone, as assessed directly with MSNA recordings, via activating afferents nerves including chemoreceptors. Previous observational studies including our study on RDN have attempted to test afferent nerves via infusion of adenosine and measure invasive arterial beat-tobeat BP before and after RDN. This test is challenging to validate in humans, not only due to the very short half-life (in seconds) of adenosine but also sedatives and analgesics’ impact on BP and sympathetic response during the procedure. The second method for testing human afferent sensory nerves to assess the completeness of RDN and potential prediction of BP to RDN is high-frequency renal nerve stimulation. Several studies have demonstrated a signicantly blunted increase in BP in response to nerve stimulation after RDN [29] but not in the non-denervated renal accessory renal arteries [30]. While electric renal nerve stimulation and subsequent BP response can help to position RDN catheter to perform effective nerve ablation, possibly only in main renal arteries, this approach, taking into account experience in our laboratory, has some limitations, due to unbearable pain patients require general anesthesia which affects the impact of sedatives on sympathetic BP response.

Eects ofCatheter-Based Renal Denervation onNoradrenaline Spillover

First-in-man-RDN trial applied radiotracer dilution methodologies to assess the overow of neurotransmitter release from the kidney into the circulation before and after RDN [1]. This study revealed a substantial reduction in a mean renal NE spillover by 47% (95% CI 28–65%) 1 month after bilateral RDN, accompanying a decrease in renin secretion and increased renal blood ow, conrming disruption of efferent renal nerves [2].

However, RDN efcacy assessed with NE spillover was found to be incomplete and nonuniform among treated patients, indicating that achieving renal nerves ablation is not technically easy [31].

Eects ofCatheter-Based Renal Denervation onMuscle Sympathetic Nerve Activity

Sympathetic activation is a hallmark of resistant hypertension documented with postganglionic efferent multiunit MSNA [3] and single-unit MSNA [4], comparable to the high MSNA levels in patients with chronic kidney disease and heart failure despite antihypertensive multi-drug regimens that oppose efferent sympathetic outow. Given the relevance for sympathetic activation in arterial hypertension, RDN can be offered to patients with several conditions associated with chronic sympathetic activation. Bilateral catheterbased RDN reduced postganglionic efferent multi-unit MSNA beyond lowering ambulatory BP in resistant hypertension compared to the control group out to 1-year postprocedure [3, 4, 32, 33]. Moreover, RDN results in a rapid and substantial reduction in all properties of single active vasoconstrictors neurons (Fig. 2.3) including ring rate (Fig.2.3a), ring probability (Fig.2.3b), and the incidence of multiple spikes within a cardiac cycle (Fig.2.3c) which may have important clinical implications for sympathetic inhibition and BP control [3].

A further interesting observation comes from a large patient cohort of 91 resistant patients with multiple renal arteries who underwent RDN. This study included 65 patients with single renal arteries bilaterally, 16 patients with dual renal arteries on either one or both sides, and 10 patients with other anatomical constellations or structural abnormalities. Major ndings from this study were that RDN can be performed safely irrespective of the underlying renal anatomy. The presence of single renal arteries with or without structural abnormalities was associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with resistant hypertension. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was a trend towards a greater BP reduction. Insufcient renal sympathetic nerve ablation may account for these differences. This study corroborates similar observations from the pre-clinical model, suggesting that renal artery anatomy affects BP and sympathetic responses to the RDN procedure.

Further ndings which strengthen the relevance of sympathetic nervous activity in resistant hypertension were conrmed in another study [34]. Bilateral RDN was accompanied by a marked reduction in MSNA and ambulatory BP from baseline to 6 months post-procedure. Time-integrated changes in MSNA and BP showed a robust association between proportional changes in MSNA over time and simultaneous changes in systolic and diastolic BP, suggesting a close link between the sympathetic activity and BP responses to this procedure.

However, not all studies have demonstrated a reduced MSNA in patients with treatment-resistant hypertension after RDN [35, 36]. In a small study of 10 patients MSNA was

2 Animal andHuman Experience inQuantifying theEects ofRenal Denervation onSympathetic Nervous System Activity

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Fig. 2.3 Reduction in ring rate of single-unit muscle sympathetic nerve activity (MSNA) expressed as spikes per 100 heartbeats and spikes per minute (a), ring probability expressed as a percentage of heartbeats and percentage of bursts (b), and incidence of multiple ring

performed before and 6 months after RDN, and found that treatment with RDN did not result in MSNA changes. A lack of MSNA changes after RDN is likely to be related to a small study cohort and medications changes which included the measurements of MSNA in 5 patients during a medicationfree interval, 4 patients who used different drugs, and only 1

expressed as a percentage of heartbeat, burst and percentage of ring bursts (c) at 3 months (M) follow-up (FU) after renal denervation (based on results from original research from [3])

patient who used the same medication [35]. Importantly, in this study baseline levels of MSNA 37±4 bursts per minute indicate moderate neural activity, which commonly characterizes essential but not resistant hypertension.

Changes in MSNA after RDN were not conrmed in another small study in which patients were examined before,

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D. Hering et al.

and some of them at 6 (n=11), and 12 months (n=8) postprocedure [36]. Mean burst frequency at baseline was 34±3 bursts per minute and did not signicantly change at 6 months after renal nerve ablation. Surprisingly, BP decreased only in 3 of 11 patients [36]. While this study had not conrmed a sympathetic inhibition in treated patients, it is worth noting, that a lack of BP reduction is likely related to incomplete RDN given the nonresponsiveness to the RDN procedure. Furthermore, patients selected for this study [36] substantially differ from previously described resistant hypertension patients whose baseline levels of MSNA remain high with burst activity (50±2 bursts/minute, 79±3 bursts/100 heartbeats) synchronized with HR [3], a common feature of resistant hypertension compared to essential hypertension with average MSNA levels of 32±2 burst per minute [13].

Eects onRenal Denervation onHeart Rate

The effect of RDN on HR in patients with hypertension had been investigated in numerous studies. However, the results are conicting and not completely understood. A subanalysis of the SPYRAL HTN-OFF MED study found that patients free of any antihypertensive medications with baseline ofce HR ≥70 beats/min had a greater reduction in 24-h systolic BP (−6.2mm Hg) compared to the sham-controlled group, and patients with ofce HR <70 beats/min (−0.1mm Hg) [37]. In this study, comparable results were observed for ofce, daytime, and night-time systolic BP after RDN.While these ndings may have important implications for patient selection for the procedure, a systematic review and metaanalysis examining the efcacy of RDN on HR control found that the reduction of HR is highly related to the decrease of systolic BP and modied by achieving BP control [38]. This meta-analysis showed that RDN does not affect night-time HR.However, major limitations of studies included in this meta-analysis were small sample size, a lack of data on the beta-blocker use, and intra- and inter-study heterogeneity. The use of beta-blockers is very important in quantifying sympathetic nerve activity and the effects on HR and MSNA depend on their cardioselectivity and age [39]. Finally, an elevated HR is indicative of sympathetic activation in the heart and does not identify renal sympathetic activation [9] which is a target for renal nerve ablation.

Perspectives

Sympathetic activation is the leading contributor to the development of hypertension and its cardiovascular and renal complications. Targeting the neuroendocrine abnormalities is a major goal of hypertension management result-

ing in more effective prevention of cardiovascular events. Therapy with renin-angiotensin-aldosterone system blockage and anti-adrenergic drugs lowers BP in a substantial proportion of hypertensive patients and continues to be an important therapeutic strategy for hypertension management. A continuous problem with the pharmacological treatment of hypertension, however, is the poor patient adherence to the prescribed medication. Approximate 30–50% of patient have defaulted from therapy (partial or complete drug discontinuation) at the end of 12 months. This lack of compliance phenomenon does indirectly illustrate the potential value of a one-off device treatment, with ongoing and perhaps permanent BP lowering benet.

The positive results from randomized-controlled with the long-term safety prole and durable BP reduction indicate that catheter-based RDN provides an alternative or superior adjunctive to antihypertensive medication treatment modality for patients with uncontrolled hypertension. At this stage, testing the completeness of RDN in human studies is challenging and limited to a few laboratories with available devices for testing human sympathetic nerve activity and NE spillover methodology. Nevertheless, several aspects including comprehensive patient assessment and selection, exclusion of pseudo-resistance, and renal artery anatomy need to be appropriately addressed before RDN therapy.

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Preclinical Model andHistopathology

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Translational Medicine andRenal Denervation

YuSato, KenichiSakakura, MariaE.Romero, FrankD.Kolodgie, RenuVirmani, andAlokeV.Finn

Key points

1. The swine model is the most frequently used for the preclinical study, since the anatomy of the renovascular system is similar to that of humans.

2. A semi-quantitative ordinal grading system is useful for the evaluation of the histopathologic changes induced by renal denervation.

3. Appropriate time points (acute, sub-acute, or chronic) must be selected before conducting preclinical studies.

Main Text

Arterial hypertension is a major health concern in the developed and developing world. More than a quarter of the world’s adult population was affected by hypertension in 2000, and this proportion is expected to increase by 2025 to 29% [1]. Hypertension is associated with an increase in the risk of myocardial infarction, heart failure, stroke, and kidney disease [2]. Each incremental increase in BP by 20mm Hg in systolic or 10mmHg in diastolic blood pressure doubles the risk of death from stroke or ischemic heart disease for individuals aged 40 to 69 years [3]. Although antihypertensive medications are the rst-line of treatment for blood pressure control in hypertensive patients, uncontrolled hypertension rates have a high prevalence especially in older Americans, non-Hispanic blacks, diabetic individuals, and patients with chronic kidney disease [4]. Furthermore, the prevalence of resistant hypertension, which is dened as failure to achieve control of blood pressure (BP) (<150/90in ages > 60 years; <140/90in ages <60 years) [5] despite treat-

ment with optimal doses of 3 or more antihypertensive medications (including diuretics), is as high as 12–15% in all hypertensive patients [6–8].

Renal sympathetic denervation (RDN) is a novel treatment option for patients with hypertension. Catheter-based RDN demonstrated its efcacy and safety in initial randomized non-sham-controlled trials [9–11]. The results of these studies encouraged the further development in bringing this technology to clinical use [12–15]. However, contrary to expectations, the SYMPLICITY-HTN3 trial failed to meet its primary efcacy endpoint [16]. The SYMPLICITYHTN3 trial was a pivotal study designed as a prospective, randomized, masked procedure, sham-controlled, singleblind trial evaluating the safety and effectiveness of catheterbased bilateral RDN for the treatment of uncontrolled hypertension despite compliance with at least three antihypertensive medications of different classes at maximal tolerable doses [16]. Following the disappointing results, much of the enthusiasm for this technology decreased and most of the device manufacturers dropped out of the development. However, post hoc analysis of the SYMPLICITY HTN3 trial revealed the limitations of this trial. Newer generation randomized sham-controlled trials designed to ocercome these limitations showed promising results [17–19]. Although many unanswered questions remain, for the present and future, preclinical studies using different animal models will help researchers and clinicians to further rene this technology, improving both its safety and efcacy.

Anatomy ofPeri-arterial Nerves inPreclinical Animal Models andHumans

Y. Sato · M. E. Romero · F. D. Kolodgie · R. Virmani (*) · A. V. Finn CVPath Institute, Inc., Gaithersburg, MD, USA e-mail: rvirmani@cvpath.org; ann@cvpath.org

K. Sakakura Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan

Studies carried out in small rodents have assessed the effect of renal sympathetic denervation [20–22], however, small animal models may not be an ideal model for testing the current percutaneous procedure. Larger animals such as pigs, dogs, or sheep can be used for the performance of percutaneous renal sympathectomy in preclinical studies and may use

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Y. Sato et al.

devices similar to those used in humans. The swine preclinical model is the most frequently employed since the anatomy of renal vasculature and sympathetic nerve distribution closely mimics that of man [23, 24]. In 2013, Tellez etal. have reported the renal artery sympathetic nerve distribution in the porcine model [25]. They investigated a total of ve domestic Yorkshire swine, and showed that the nerve counts were greatest in the proximal region (45.62%) with a gradual decrease distally (mid: 24.58%; distal: 29.79%) [25]. Also, 52% of all nerves were located within 2.5mm of the arterial wall [25]. It is most important to determine differences in nerve anatomy, between swine and human as the former is used to predict safety outcomes in man. Atherton et al. reported the nerve distribution in nine renal arteries collected from ve human cases [26]. They summarized that 90.5% of all nerves existed within 2.0mm of the renal artery lumen, and the number of nerves tended to increase along the length of the artery from proximal to distal segments (proximal=216; middle 323; distal = 417) [26]. However, there were many methodological problems. The most important weakness of the study is that they measured nerves only within 2.5 mm axially from the lumen. Nerves beyond

2.5mm were not included or mentioned. Also, the number of samples was too few and no perfusion xation procedures were used to determine the variability in sampling and xa-

tion artifacts introduced from collapse and shrinkage. In 2014, we reported a larger and more detailed human autopsy study to evaluate human sympathetic nerve distribution [27]. A total of 40 renal arteries and surrounding tissues, which were perfusion xed under physiological pressure, were included. The number of nerves in the proximal and middle segments was similar (39.6±16.7 and 39.9±13.9 per section), whereas the distal segment showed fewer nerves (33.6±13.1 per section) (p=0.01). The distance from lumen to nerve was signicantly greatest in the proximal segments (3.40±0.78mm), followed by middle (3.10±0.69mm), and least in distal segments (2.60± 0.77 mm) (p < 0.001). The 50th, 75th, and 90th percentile of the distance from lumen to nerve were 2.44, 4.28, and 6.39mm, respectively (Fig.3.1). The results were different from the previous human study [26]. One possible reason was that the previous studies missed nerves in the proximal segments because these studies only observed nerves within 2.5 mm from the arterial lumen despite the fact that the distance from lumen to nerve is furthest in the proximal segments. We also reported anatomic distribution of peri-arterial nerves in human renal accessory arteries [28], which showed similar results in human main renal arteries and relationship between arterial diameter and number of peri-arterial nerves (i.e, the larger arteries have greater number of nerves).

Fig. 3.1 Cumulative distribution of nerves at distance from lumen. The cumulative distribution of nerves at distance from lumen is calculated from 8030 nerves before the arterial bifurcation. The 50th percentile in the distance from the lumen to nerves was

2.44mm, whereas 75th and 90th percentile in that were

4.28mm and 6.39mm, respectively. Reproduced with permission from Sakakura K etal. J Am Coll Cardiol 2014;64:635–643 [27]

3 Preclinical Model andHistopathology Translational Medicine andRenal Denervation

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Histopathologic Evaluation Methods inPreclinical Models

Histologic assessment of nerve injury that is induced during percutaneous ablation in animal models must be graded systematically and the distance from the lumen of the artery to the presence of nerves circumferentially must be determined. Similarly, the extent of renal artery damage must also be graded by a well-developed and reproducible method. We proposed standardized methods for the preclinical evaluation of catheter-based renal denervation [29]. First and foremost all renal arteries must be perfusion pressure xed at 80 to 100mmHg. However, the renal artery length must be determined invivo upon removal of tissue from the body, especially arteries which undergo shrinkage artifacts. It has been shown that the aorta undergoes marked shrinkage when removed from the body and is estimated to undergo as much

as 30 to 40% shrinkage but this is dependent on the age of the patient, with younger individuals showing greater shrinkage than older individuals because of loss of elasticity with age. Similarly, it has been estimated that 20% shrinkage occurs just because of xation and dehydration used prior to sectioning in parafn [30].

Semi-quantitative ordinal grading schemes are useful, when changes in the nerve, renal artery, and peri-arterial soft tissue are evaluated following denervation [29]. When evaluating nerve damage, it is important to mention that tissue damage may affect the peri-neuronal and/or endoneuronal portions of the renal nerves. The assessment of peri-neuronal injury should include inammation and brosis. Although acute-phase nerve injury may not necessarily be accompanied by peri-neuronal inammation or brosis, chronicphase nerve injury usually exhibits peri-neuronal brosis (Fig.3.2). Vacuolization and digestion chambers are unique

Fig. 3.2 Semi-quantitative grading scheme for nerve changes. Upper panels show representative images of nerves by increasing grade of injury. Middle panels show high power images of injured nerves (red boxed area in upper panels) in each grade. Lower panels show represen-

tative images of vacuolization, pyknotic nuclei, digestion chambers, and perineurial brosis. All image panels are stained with Hematoxylin and Eosin (H&E). Reproduced with permission from Sakakura K etal. JACC Cardiovasc Interv 2014;7:1184–93 [29]

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Fig. 3.3 Semi-quantitative grading scheme for renal artery damage. Upper panels represent depth of medial wall injury by the grade of damage, whereas lower panels represent circumferential grade of damage of the medial wall. Note, media thinning can only occur with grade 4

ndings of endoneuronal damage (Fig.3.2). Vacuolization is characterized by the presence of vacuolated areas, containing loose connective tissue with rare areas of homogenous eosinophilic staining of cell cytoplasm along with pyknotic nuclei [31]. Digestion chambers are identied by variable amounts of aggregated myelin (eosinophilic hyaline globules) and vacuolated spaces with occasional cells interspersed [31]. Since minimal or mild injury can be seen even in untreated animals from artifacts, moderate and severe injury, typically digestion chambers, frequent vacuolization, and necrosis, are considered as denite injury caused by renal denervation therapy [29]. Renovascular damage including endothelial cell loss and medial damage also can be assessed using a semi-quantitative ordinal grading system (Fig. 3.3). When evaluating medial damage, Movat pentachrome stain is useful because proteoglycan deposition can be easily appreciated [18].

depth of injury and should be distinguished. All images are stained with Movat pentachrome. Reproduced with permission from Sakakura K etal. JACC Cardiovasc Interv 2014;7:1184–93 [38]

Immunohistochemical stains can be used to distinguish the morphological or functional presence of neuronal markers relevant to renal sympathetic activity. However, most markers applied to date are not specic for sympathetic nerves. For example, immunoreactivity against S-100 protein, a marker for Schwann and glial cells, can be observed in all myelinated nerves [32], while neurolament protein (NFP) as an intermediate lament serves as a marker for neurons and ganglion cells. Glial brillary acidic protein (GFAP) is a marker for glial cells and can be used for the recognition of nerve fascicles [33]. On the other hand, immunohistochemistry against tyrosine hydroxylase (TH), which is the enzyme needed for converting tyrosine to DOPA (dihydroxyphenylalanine), is the most frequent marker used for efferent nerve recognition [34], and is graded as absence, very weak, moderate, and strong staining [29]. Therefore, the combination of any one axonal marker (S-100, NFP, or

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