Pathophysiology: The Target for Renal Denervation



Fig. 1.1
Interaction between the brain and the kidney with the effect of increasing sympathetic nerve activities. Sympathetic activation is generated in the kidney, where it reaches the heart, the vessels and the kidney by efferent sympathetic nerves. Sympathetic activation activates functional and structural changes of end organs. Renal efference is activated by renal adrenergy, ischemia and impaired renal perfusion by mediation of adenosine, acidosis and others. The afferent feedback stimulation of the sympathetic nervous system further increases sympathetic activating tone. Rationale of renal denervation is to interrupt afferent and efferent nerves (depicted by red triangles) (Adapted by permission from Macmillan Publishers Ltd: Böhm et al. [49])





Renal Afferent Nerve Activity


Activation of renal sensory afferent fibers derives primarily from the renal pelvis [3, 4]. Chemosensitive receptors in the renal interstitium are sensitive to ion and osmolar concentration changes, ischemia and the metabolic products of ischemia, like adenosine [2, 3]. Consistently, adenosine infusion increases the blood pressure by stimulating afferent signaling initiated by adenosine receptors located in the pelvis [4]. On the contrary, application of 100 % oxygen reduces sympathetic nerve activity in patients with renal failure [5]. The concept of direct interaction between the central nervous system and the kidney is shown by the reduction of sympathetic activity after renal nephrectomy in patients with renal failure [6]. Furthermore, the BP rise seen in rats after 5/6 nephrectomy can be prevented by dorsal thizectomy [7]. Finally, it was demonstrated that bilateral nephrectomy following successful renal transplantation reduced sympathetic activity, whereas transplantation alone did not. These data provided clear evidence to suggest that not uremia, but the remaining non-functioning kidneys via afferent signaling were the source of sympathetic overstimulation [8].


Renal Efferent Sympathetic Activity


Efferent nerve fibers from sympathetic ganglia reach the kidney as they follow the renal arteries typically within the adventitial layer of the vessel. These nerves invade all segments of the renal cortex and terminate at the arterioles of the glomeruli [9, 10]. Furthermore, the glomerular renin containing juxtaglomerular cells are targeted by efferent sympathetic nerves [11]. α1b-adrenergic receptors mediate sodium and water retention and, therefore, antidiuretic effects in the proximal tubulus, while α1a-adrenergic receptors mediate vasoconstriction and reduce renal blood flow [3]. β1-adrenergic receptors stimulate renin secretion with subsequent activation of the renin-angiotensin-aldosterone system [12], again, contributing to sodium water retention and producing the right shift of the pressure natriuresis curve [2, 3, 12]. The concept is summarized in Fig. 1.1.


Interaction Between Right and Left Kidney


Interestingly, afferent stimulation of nerves in one kidney also increases norepinephrine and dopamine release from the contralateral kidney [13]. Besides these experiments in dogs [13], an increase of heart rate and blood pressure was observed by contralateral nerve stimulation in conscious rats [14]. However, the effect is highly variable in between species, because the distribution of excitatory and inhibitory renal nerves are differently distributed among the different species [15].


Renal Denervation



Experimental Studies


Stimulation of renal sympathetic nerves increases the urinary excretion of norepinephrine, which can be inhibited by experimental renal denervation [16, 17]. Renal denervation reduces blood pressure in genetic models of hypertension [18]. In two-kidney one clip rats blood pressure was reduced [19]. In an inherited model of polycystic kidney disease, renal denervation reduced blood pressure and restored renal blood flow [20].

In humans, the first experiences with interventional reduction of sympathetic activity were obtained by thoracolumbar splanchniectomy, which had significant effects on blood pressure in the majority but not all patients with severe hypertension and reduced cardiovascular end organ damage [2123]. Although mortality was remarkably reduced [23], this technique had serious adverse effects and a high perioprative morbidity and mortality and was abandoned once effective antihypertensive drugs had started to emerge. More recently and applying a similar conceptin patients with resistant hypertension, catheter-based radiofrequency ablation of renal nerves (as schematically illustrated in Fig. 1.2) resulted in significant blood pressure reduction in the Symplicity HTN-1 pilot study [24] and in the randomized controlled Symplicity HTN-2 trial, in which optimal medical therapy + RDN was compared to optimal medical therapy alone ([25], Fig. 1.3). Meanwhile, Symplicity HTN-1 and Symplicity HTN-2 studies provided data to indicate that blood pressure changes that occurred were sustained up to 3 years post-procedure [26, 27]. Data from experienced centers also provided ABPM measurements showing that systolic and diastolic night time, day time and average blood pressure were significantly reduced in resistant hypertensive patients, while in pseudoresistance only office but not ABPM values were diminished [28]. In patients with moderately elevated levels of blood pressure a reduction was also observed [29], albeit the effect was less pronounced. The intriguing finding that after renal denervation not only renal spillover but also a total body spillover is reduced, is strongly arguing in favor of a significant role of both, afferent and efferent denervation [30].

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Fig. 1.2
Upper left: schematic illustration of sympathetic renal nerves in the adventitia of the renal artery. The high frequency electrode is positioned through a guiding catheter. The administration of high frequency energy produces heat, which is cooled by high intraluminal bloodflow, blood is sticking at the adventitia, where it damages the sympathetic nerves (©2014 Medtronic, Inc. Printed with Permission). Lower left: Catheter is rotationally pulled back in order to provide energy to superior, posterior, anterior and inferior part of the vessel in an attempt to provide a circumferenterial complete denervation. Right: The view of the investigator in four different positions of renal denervation [14]


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Fig. 1.3
Changes in systolic and diastolic blood pressure at 1 month (1M), 3 months (3M) and 6 months (6M) in patients with renal denervation (upper part) and blood pressure changes in the control group (lower part) (Reprinted from Symplicity HTN-2 Investigators et al. [25] with permission from Elsevier)


Pathophysiology of Potential Adverse Effects of Renal Denervation



Exercise Tolerance and Heart Rate


Concerns were raised that renal denervation might producea limitation in exercise tolerance through interference with the sympathetic nervous system [31]. However, a systematic cardiorespiratory exercise testing revealed no evidence for chronotropic incompetence, while exercise tolerance was even slightly increased [32]. Furthermore, exercise blood pressure levels and heart rate responses and recovery were also reduced by renal denervation [32], which might explain the improved exercise tolerance. Furthermore, this finding might provide indirect evidence for potential clinical benefits, because these factors are related to cardiovascular complications including sudden cardiac death [33, 34]. Significant bradycardia was not observed [2427], probably because heart rate reductions were only reported at higher levels of resting heart rates at baseline with no significant effects on atrioventricular conduction [35]. Interestingly, heart rate reduction and blood pressure reduction showed a dependency on baseline levels, i.e. blood pressure and heart rate effects were most pronounced in those patients with the highest the baseline values (Fig. 1.4, [35]).

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Fig. 1.4
Change in blood pressure (left) and heart rate (right) after 3 and 6 months according to the systolic blood pressure (SBP) and heart rate (HR) and the results at baseline. Please note that the higher SBP or heart rate at baseline were the greater were the reduction at follow-up (Reprinted from Ukena et al. [35] with permission from Elsevier)


Orthostatic Dysfunction


Sympathetic nervous activity regulates the increase of heart rate in vasoconstriction to maintain sufficient blood pressure after orthostatic stress. Tilting causes the transfer of thoracic blood into the venous capacitance vessels and promoted fluid filtration into the interstitium resulting in up to 1,500 ml acute volume shifting [36], which has to be counterbalanced by activation of the sympathetic nervous system. Therefore, concerns have been raised on whether hypotensive reactions might limit the clinical benefits of renal denervation [37], which is evidenced by a drop in sympathetic activity and baroreceptor function just before collapse in syncope [3841]. However, systematic table tilt testing has not shown significant occurrence of syncope or blood pressure drops in patients after renal denervation, in particular no difference between responders and non-responders to blood pressure reduction after renal denervation [42].


Psychological Disturbances


Hypertension is often associated with anxiety [43] involving activation of the autonomic nervous system in this condition [44]. Depression is also associated with a dysregulation of the central nervous noradrenergic process [45], but depressed individuals often have an activation of the peripheral sympathetic nervous system [46]. However, renal denervation has been reported to increase quality of life [47] and was not associated with increased depressive symptoms, rather it was associated with reduced anxiety, depression, intensity of headaches and with improved stress tolerance in patients with resistant hypertension [48].


Perspectives


Renal denervation is a promising field to improve many disease conditions by a reduction of sympathetic activity beyond hypertension with a sound pathophysiological background [49]. It might proof to be effective in renal protection [50], atrial [51] and ventricular [52] arrhythmias, sleep apnea [53], hypertrophy reduction [54] and heart failure [55] as well as in metabolic syndrome [56]. In particular, in the latter conditions prospective trials with appropriate clinical endpoints have to be evaluated in order to proof the pathophysiological concept raised by the first experiences with renal sympathetic denervation.


References



1.

Ludwig C. De viribus physicis secretionem urinae adjuvantibus (Latin). Thesis, University of Marburg; 1842.


2.

Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum H. Sympatho-renal axis in chronic disease. Clin Res Cardiol. 2011;100:1049–57.PubMedCentralPubMedCrossRef


3.

Esler M. The 2009 Carl Ludwig lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol. 2010;108:227–37.PubMedCrossRef

Jun 20, 2017 | Posted by in NEPHROLOGY | Comments Off on Pathophysiology: The Target for Renal Denervation

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