Abstract P203: Insights To Lesion Formation For Percutaneous Renal Denervation: Human And Porcine Histological Analyses

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
David Kandzari ◽  
Stefan Tunev ◽  
Markus P Schlaich ◽  
David P LEE ◽  
Aloke Finn ◽  
...  
Keyword(s):  
Renal Denervation ◽  
Renal Arteries ◽  
Renal Nerves ◽  
Swine Model ◽  
Renal Nerve ◽  
Perivascular Adipose Tissue ◽  
Human Cadavers ◽  
Procedural Outcomes ◽  
Maximal Reduction ◽  
Conduction Properties

Background: The safety and efficacy of radiofrequency (RF) renal denervation (RDN) have been demonstrated in multiple randomized trials. We performed histological analyses in a swine model and human cadavers to investigate RF lesion geometry, morphology and location in the context of local anatomic structures and describe their impact on procedural outcomes. Methods: The Symplicity Spyral catheter was used to perform RDN in 164 renal arteries from healthy swine terminated at 7 days post-treatment. Lesion characteristics were determined by semi-quantitative histology. Renal nerve functionality was measured by quantitative immunohistochemistry and correlated to renal norepinephrine. In addition, we investigated the retroperitoneal space in 10 human cadavers to determine the relative location of extravascular tissues. Results: In the swine model, RF lesions developed exclusively in the perivascular adipose tissue which contains the renal nerves. Lesions were irregularly shaped due to inherent sparing of surrounding perfused structures, such as veins and lymph nodes. Maximum depth of the irregularly shaped RF lesions was 6.8±2.5 mm, and mean depth was 3.9±2.4 mm. Renal norepinephrine levels were lowest when >80% of renal nerves were ablated ( Figure ). Reendothelialization of the lesion area was >99% within 7 days. In humans, only 0.3% of renal nerves were localized on the opposite side of the renal veins. Conclusion: Patterns of RF RDN are uniquely influenced by electrical and thermal conduction properties of tissues surrounding the renal arteries. Maximal reduction of renal norepinephrine content requires ablation of at least 80% of the renal nerves.

scholarly journals Microdissection of the Human Renal Nervous System

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1240-1246 ◽  
Author(s):  
Arturo García-Touchard ◽  
Eva Maranillo ◽  
Blanca Mompeo ◽  
José Ramón Sañudo
Keyword(s):  
Nervous System ◽  
Renal Artery ◽  
Renal Denervation ◽  
Left Kidney ◽  
Renal Nerves ◽  
Renal Nerve ◽  
Main Renal Artery ◽  
Area Under Roc Curve ◽  
Human Cadavers ◽  
The Right

Despite the use of renal denervation to treat hypertension, the anatomy of the renal nervous system remains poorly understood. We performed a detailed quantitative analysis of the human renal nervous system anatomy with the goal of optimizing renal denervation procedural safety and efficacy. Sixty kidneys from 30 human cadavers were systematically microdissected to quantify anatomic variations in renal nerve patterns. Contrary to current clinical perception, not all renal innervation followed the main renal artery. A significant portion of the renal nerves (late arriving nerves) frequently reached the kidney (73% of the right kidney and 53% of the left kidney) bypassing the main renal artery. The ratio of the main renal artery length/aorta-renal hilar distance proved to be a useful variable to identify the presence/absence of these late arriving nerves (odds ratio, 0.001 (95% CI, 0.00002–0.0692; P : 0.001) with a cutoff of 0.75 (sensitivity: 0.68, specificity: 0.83, area under ROC curve at threshold: 0.76). When present, polar arteries were also highly associated with the presence of late arriving nerve. Finally, the perivascular space around the proximal main renal artery was frequently occupied by fused ganglia from the solar plexus (right kidney: 53%, left kidney: 83%) and/or by the lumbar sympathetic chain (right kidney: 63%, left kidney: 60%). Both carried innervation to the kidneys but importantly also to other abdominal and pelvic organs, which can be accidentally denervated if the proximal renal artery is targeted for ablation. These novel anatomic insights may help guide future procedural treatment recommendations to increase the likelihood of safely reaching and destroying targeted nerves during renal denervation procedures.

Abstract P195: No Functional Nerve Recovery To 6 Months Post Renal Denervation With Rf Energy In A Normotensive Pig Model

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Andrew Sharp ◽  
Stefan Tunev ◽  
Markus P Schlaich ◽  
David P LEE ◽  
Aloke Finn ◽  
...  
Keyword(s):  
Animal Studies ◽  
Renal Denervation ◽  
Blood Pressure Reduction ◽  
Immunohistochemical Analysis ◽  
Swine Model ◽  
Renal Nerve ◽  
Tissue Samples ◽  
Axon Density ◽  
Rf Energy

Background: The safety and efficacy of catheter-based radio frequency (RF) renal denervation (RDN) have been demonstrated in randomized, sham-controlled trials. Long-term durability of blood pressure reduction following RDN has also been demonstrated by all-comer registries, although published pre-clinical reports of functional renal nerve regrowth are not consistent. We quantified the processes that support RDN procedural durability utilizing animal models. Methods: Animal studies were conducted in accordance with published guidelines. RDN was performed (4 lesions in the main renal artery) in normotensive swine using the Symplicity Spyral™ RDN system (Medtronic, Santa Rosa, CA, USA). Two additional groups not undergoing RDN served as control. Serial histological tissue samples were obtained in separate groups at 7 (n=12/group) and 180 (N=16/group) days post-procedure in all animals followed by bioanalytical quantification of cortical norepinephrine (NE) levels and immunohistochemical analysis of renal cortical axon density in matched samples. Results: Renal cortical axon density and NE levels were significantly reduced at 7 days and persisted through 180 days following RDN compared with control ( Figure ). Nerve fibrosis and necrosis were observed in the region of ablation, while nerve body atrophy was apparent distal to ablation location at 180 days. Conclusions: Reductions in both NE and renal cortical axon density were sustained at 7 and 180 days post-RDN procedure using RF renal denervation in a normotensive swine model. These data confirm and extend other pre-clinical and clinical evidence of long-term durability of the RDN procedure using RF energy.

scholarly journals Early Morphologic Alterations in Renal Artery Wall and Renal Nerves in Response to Catheter-Based Renal Denervation Procedure in Sheep: Difference Between Single-Point and Multiple-Point Ablation Catheters

2017 ◽  
pp. 601-614 ◽  
Author(s):  
M. TÁBORSKÝ ◽  
D. RICHTER ◽  
Z. TONAR ◽  
T. KUBÍKOVÁ ◽  
A. HERMAN ◽  
...  
Keyword(s):  
Renal Artery ◽  
Resistant Hypertension ◽  
Renal Denervation ◽  
Single Point ◽  
Renal Tissue ◽  
Renal Nerves ◽  
Multiple Point ◽  
Renal Nerve ◽  
Jude Medical ◽  
Novel Strategy

Renal sympathetic hyperactivity is critically involved in hypertension pathophysiology; renal denervation (RDN) presents a novel strategy for treatment of resistant hypertension cases. This study assessed effects of two RDN systems to detect acute intravascular, vascular and peri-vascular changes in the renal artery, and renal nerve alterations, in the sheep. The procedures using a single-point or multi-point ablation catheters, Symplicity FlexTM, Medtronic versus EnligHTNTM, St. Jude Medical were compared; the intact contralateral kidneys served as controls. Histopathological and immunohistochemical assessments were performed 48 h after RDN procedures; the kidney and suprarenal gland morphology was also evaluated. Special staining methods were applied for histologic analysis, to adequately score the injury of renal artery and adjacent renal nerves. These were more pronounced in the animals treated with the multi-point compared with the single-point catheter. However, neither RDN procedure led to complete renal nerve ablation. Forty-eight hours after the procedure no significant changes in plasma and renal tissue catecholamines were detected. The morphologic changes elicited by application of both RDN systems appeared to be dependent on individual anatomical variability of renal nerves in the sheep. Similar variability in humans may limit the therapeutic effectiveness of RDN procedures used in patients with resistant hypertension.

Renal denervation: current implications and future perspectives

2013 ◽  
Vol 126 (1) ◽  
pp. 41-53 ◽  
Author(s):  
Jianzhong Xu ◽  
Dagmara Hering ◽  
Yusuke Sata ◽  
Antony Walton ◽  
Henry Krum ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Resistant Hypertension ◽  
Renal Denervation ◽  
Interventional Procedure ◽  
Strong Association ◽  
Blood Pressure Reduction ◽  
Pressure Control ◽  
Renal Nerves ◽  
Renal Nerve ◽  
Disease States

SNS (sympathetic nervous system) activation is a common feature of arterial hypertension and has been demonstrated to contribute to the development and progression of the hypertensive state. Persuasive evidence suggests a strong association between SNS overactivity and variety of disease states, including chronic renal failure, insulin resistance, congestive heart failure, sleep apnoea, ventricular arrhythmias and others. Although sympatholytic agents are available to target SNS overactivity pharmacologically, they are not widely used in clinical practice, leaving the SNS unopposed in many patients. The recent introduction of catheter-based renal denervation as an alternative approach to target the SNS therapeutically has been demonstrated to result in a clinically relevant blood pressure reduction in patients with resistant hypertension, presumably through its effects on both efferent and afferent renal nerve traffic. Available data on this interventional procedure demonstrate a favourable vascular and renal safety profile. Preliminary data obtained primarily from small and mostly uncontrolled studies in related disease states often characterized by overactivity of the SNS are promising, but require confirmation in appropriately designed clinical trials. In the present paper, we briefly review the physiology of the renal nerves and their role in hypertension and other relevant disease states, summarize the data currently available from clinical studies pertaining to the safety and efficacy of renal denervation in resistant hypertension, discuss potential future implications and the available data supporting such a role for renal denervation, and describe some of the newer devices currently under investigation to achieve improved blood pressure control via renal denervation.

scholarly journals Persistent Increase in Blood Pressure After Renal Nerve Stimulation in Accessory Renal Arteries After Sympathetic Renal Denervation

Hypertension ◽  
2016 ◽  
Vol 67 (6) ◽  
pp. 1211-1217 ◽  
Author(s):  
Mark R. de Jong ◽  
Annemiek F. Hoogerwaard ◽  
Pim Gal ◽  
Ahmet Adiyaman ◽  
Jaap Jan J. Smit ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nerve Stimulation ◽  
Renal Denervation ◽  
Renal Arteries ◽  
Renal Nerve ◽  
Renal Nerve Stimulation ◽  
Accessory Renal Arteries

The renal afferent nerves in the pathogenesis of hypertension

1987 ◽  
Vol 65 (8) ◽  
pp. 1548-1558 ◽  
Author(s):  
Suzanne Oparil ◽  
Wanida Sripairojthikoon ◽  
J. Michael Wyss
Keyword(s):  
Renal Denervation ◽  
Genetic Model ◽  
Spontaneously Hypertensive Rat ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Experimental Models ◽  
Renal Nerves ◽  
Renal Nerve ◽  
Afferent Nerves ◽  
Hypertensive Rat

The renal nerves play a role in the pathogenesis of hypertension in a number of experimental models. In the deoxycorticosterone acetate – salt (DOCA–NaCl) hypertensive rat and the spontaneously hypertensive rat (SHR) of the Okamoto strain, total peripheral renal denervation delays the development and blunts the severity of hypertension and causes an increase in urinary sodium excretion, suggesting a renal efferent mechanism. Further, selective lesioning of the renal afferent nerves by dorsal rhizotomy reduces hypothalamic norepinephrine stores without altering the development of hypertension in the SHR, indicating that the renal afferent nerves do not play a major role in the development of hypertension in this genetic model. In contrast, the renal afferent nerves appear to be important in one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertensive rats (1K, 1C and 2K, 1C, respectively) and in dogs with chronic coarctation hypertension. Total peripheral renal denervation attenuates the severity of hypertension in these models, mainly by interrupting renal afferent nerve activity, which by a direct feedback mechanism attenuates systemic sympathetic tone, thereby lowering blood pressure. Peripheral renal denervation has a peripheral sympatholytic effect and alters the level of activation of central noradrenergic pathways but does not alter sodium or water intake or excretion, plasma renin activity or creatinine clearance, suggesting that efferent renal nerve function does not play an important role in the maintenance of this form of hypertension. Selective lesioning of the renal afferent nerves attenuates the development of hypertension, thus giving direct evidence that the renal afferent nerves participate in the pathogenesis of renovascular hypertension.

Renal nerves and experimental hypertension: evidence and controversy

1987 ◽  
Vol 65 (8) ◽  
pp. 1540-1547 ◽  
Author(s):  
Robert L. Kline
Keyword(s):  
Renal Function ◽  
Arterial Pressure ◽  
Renal Denervation ◽  
Spontaneously Hypertensive Rat ◽  
Sodium Intake ◽  
Renal Nerves ◽  
Experimental Hypertension ◽  
Renal Nerve ◽  
Spontaneously Hypertensive ◽  
Hemodynamic Variables

Noradrenergic fibers innervate various parts of the nephron and can contribute to sodium and water homeostasis by influencing hemodynamic variables, tubular reabsorptive mechanisms, and renin release. As renal function is considered to be a primary determinant of arterial pressure, efferent renal nerves may be an important link between the central nervous system and the kidney in the development and maintenance of hypertension. Little is known about the relative importance of renal nerves and their interactions with other factors in influencing renal function chronically. There is disagreement about the evidence for enhanced noradrenergic drive to the kidney in hypertensive rats, as the renal nerve firing rate, neurotransmitter release and metabolism, and receptor properties are generally not studied in association with measurements of renal function. However, chronic renal denervation has been shown to significantly affect arterial pressure in diverse forms of experimental hypertension in rats, including genetic models, as well as renovascular, mineralocorticoid, neurogenic, and angiotensin II hypertension. The actual mechanisms responsible for this effect of renal denervation are not clear, but presumably reflect changes in the arterial pressure – urinary sodium output relationship. On the whole, there is reasonable correlation between neurophysiological, biochemical, and renal denervation studies in the spontaneously hypertensive rat, suggesting that renal nerves do play a role in the onset of hypertension in these animals. The effect of renal denervation in other models of hypertension seems less clear, with recent reports showing that renal denervation does not alter the hypertensive process in renovascular, mineralocorticoid, and salt-related hypertension. These contradictory findings are not easily explained, but there is some indication that elevated sodium intake may alter the response to renal denervation. Resolution of these controversies must await a better understanding of the influence of renal nerves on renal function and arterial pressure in normal and hypertensive animals.

Renal effects of volume expansion in the renal-denervated nonhuman primate

1984 ◽  
Vol 247 (6) ◽  
pp. H960-H966
Author(s):  
T. V. Peterson ◽  
N. L. Chase ◽  
D. K. Gray
Keyword(s):  
Nonhuman Primate ◽  
Volume Expansion ◽  
Renal Denervation ◽  
Recovery Period ◽  
Isotonic Saline ◽  
Free Water ◽  
Renal Nerves ◽  
Renal Nerve ◽  
Renal Nerve Activity ◽  
A Cell

Experiments were performed to determine the role of renal nerves in mediating the renal excretory effects of volume expansion in the nonhuman primate. Male Macaca fascicularis monkeys underwent chronic bilateral renal denervation or sham surgery. After a 1- to 2-wk recovery period, each animal was anesthetized with pentobarbital sodium and volume expanded 20% of estimated blood volume. Two types of volume expansion were used, a hemodilutional expansion using 6% dextran in isotonic saline and an isohemic expansion using each monkey's own blood that had previously been withdrawn in exchange for dextran. Renal denervation did not attenuate the excretory responses to volume expansion in that similar increases in urine flow, sodium excretion, filtered load of sodium excreted, osmolar and free water clearances occurred in both the renal-denervated and sham-operated groups. The onset of the responses was not delayed by renal denervation. Furthermore, the results were the same with both volume expansions. These results suggest that, in the monkey, decreases in renal nerve activity that occur with volume expansion are not necessary for eliciting the excretory responses to this hypervolemic stimulus or that other factors compensate if the kidneys are chronically denervated. In addition, the failure of renal denervation to attenuate the excretory effects of a cell-free volume expansion is not related to any dilutional characteristics of the expansion.

scholarly journals α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease

2020 ◽  
Vol 31 (4) ◽  
pp. 783-798 ◽  
Author(s):  
Lydia Hering ◽  
Masudur Rahman ◽  
Henning Hoch ◽  
Lajos Markó ◽  
Guang Yang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Knockout Mice ◽  
Renal Denervation ◽  
Renin Angiotensin System ◽  
Sympathetic Nerves ◽  
Protective Role ◽  
Renal Nerves ◽  
Wild Type ◽  
Renal Nerve

BackgroundIncreased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.MethodsWe investigated effects of α2A-adrenoceptor–regulated renal NE release on the development of angiotensin II–dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor–knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days.ResultsUrinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor–knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor–knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor–knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor–deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor–knockout mice after renal denervation.ConclusionsOur findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

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