René van der Bel

Summary | 131 | Appendices Summary Chronic kidney disease (CKD) is characterized by a progressive decrease of the kidney’s filtra- tion capacity. It is an increasing public health issue, with an estimated worldwide prevalence of 8 to 16% back in 2013. Hypertension and diabetes mellitus are the leading causes of CKD and ultimately end-stage renal failure. However, cardiovascular disease is the most common cause of death among CKD patients. In fact hypertension is not only a causal factor in CKD it is a consequents as well and blood pressure management is often difficult in these patients. Hypertension is a hallmark of CKD and substantial evidence indicates that nephrogenic hypertension can be attributed to increased sympathetic nerve activity (SNA) in these pa- tients, founded the concept that the trigger of the enhanced central sympathetic outflow resides in the affected kidneys themselves. Deterioration of renal oxygenation by altered renal perfusion and increased metabolic demand has been postulated as a common factor in the progression of CKD and nephrogenic sympathetic hyperactivity and hypertension. This concept served as the pathophysiological basis for the development of catheter based renal sympathetic denervation (RDN) the first decade of the two thousands. Interrupting the kidneys’ sympathetic innervation would take away the sympathetic signal arising from the kidneys. Hopefully, resulting in a decreased sympathetic tone, reduced renin/angiotensin activity, lowered blood pressure and potentially improved kidney oxygenation. This made it ideally suited for the treatment of therapy resistant hypertension. However, the mechanisms underlying increased SNA in CKD are not completely understood and with the failure of the sham controlled Symplicity HTN-3 trial to show treatment efficacy of RDN on the blood pressure goals, now much controversy surrounds its use and the basis on which is was founded. Proposed reasons for its failure are much varied, from technique failure, the large Hawthorne effects, increased drug adherence and patient selection, to a flawed pathophysiologic rationale. This thesis puts several aspects of the pathophysiologic rationale for RDN in humans under pressure. Namely: one, the uniqueness of the sympathetic dysregulation in CKD patients ( Chapter 2 ); two, the effect of hyperoxia on blood pressure in CKD patients ( Chapter 3 ); three, the use of functional MRI to assess kidney oxygenation and the extend of the effects of angiotensin II ( Chapters 4 & 6 ) and four, the link between SNA and kidney hypoxia in humans ( Chapter 5 ). Sympatho-vagal balance and cardio-metabolic impairment Sympathetic hyperactivity is not merely present in CKD, it is common in many cardio-meta- bolic diseases. Therefore, before we dove into its role in kidney disease we need to explore its epidemiology. Baroreflex sensitivity has been established as an important determinant of the sympatho-vagal balance of the cardiovascular system. Baroreflex dysfunction is com-