René van der Bel

Discussion | 119 | Chapter 7 Discussion Although not yet fully understood at the time, the conceptual framework introduced at the beginning of this thesis served as the pathophysiological basis for the development of cath- eter based renal sympathetic denervation (RDN) in the first decade of the two thousands  1,2 . This technique aimed to interrupt the kidneys’ sympathetic innervation by severing the sym- pathetic nerves located along the vascular wall of the renal arteries using radiofrequency ablation, thereby taking away the sympathetic signal arising from the kidneys. Resulting in a decreased sympathetic tone, reduced renin/angiotensin activity, lowered blood pres- sure and potentially improved kidney oxygenation. This made RDN ideally suited for the treatment of therapy resistant hypertension, rapidly generating interest from clinicians who previously had been without adequate further treatment options such patients. However, after initial enthusiasm aroused by two open label trials that indicated therapeutic benefit, the sham controlled Symplicity HTN-3 trial failed to show treatment efficacy of RDN on the blood pressure goals  3,4 . Now much controversy surrounds the use of the technique and the basis on which it was founded  5-7 . Proposed reasons for the failure of RDN are much varied, from technique failure, the large Hawthorne effects, increased drug adherence and patient selection, to a flawed pathophysiologic rationale  6-11 . This thesis investigates several mechanisms related to (nephrogenic) hypertension. Some of their results question the pathophysiological rationale for RDN in humans, starting with a study into the relations between the sympatho-vagal balance and cardiovascular risk in the general population and an expanded repeat of one of the studies that founded the rationale for RDN  12 . The sympathetic nervous system is not uniquely affected in CKD The study by Hering et al. suggested an altered renal chemoreflex response in CKD patients during oxygen supplementation, attenuating sympathetic activity and blood pressure during systemic hyperoxia. With this in mind, one would expect increased sympatho-vagal impair- ment with renal function decline compared to other cardio-metabolic risk factors. However, we found no such relation in baroreflex sensitivity analysis among almost 6,000 participants of the HELIUS study described in Chapter 2 . Furthermore, we were unable to repeat the results of these experiments in a group of 19 CKD patients in Chapter 3 . In our hands, oxygen supplementation causes a dose-dependent blood pressure increase in these patients, which was caused by an increase in systemic vascular resistance, likely as the result of hyperoxic vasoconstriction independent of baroreflex function in patients with an insufficient nitric oxide mediated vasodilatory response. Although, oxygen supplementation may alleviate pe- ripheral sympathetic activity  12 , it presents a major cardiovascular stressor to CKD patients. The central hemodynamic effects overshadows any beneficial renal effect, if at all present. Whether sympathetic dysregulation in patients is cause or consequence of cardio-metabolic