Renal Denervation, Hope or Hype?: Studies on patient selection and mechanisms

Abstract

The general objective of this thesis was to determine which patients are most likely to benefit most from treatment with RDN and to study the effects of renal denervation (RDN). This thesis is subdivided into three parts. Part I focused on pathophysiologic studies on renal oxygenation and the sympathetic nervous system (SNS). Firstly, we investigated the role of the kidney as source and target of sympathetic hyperactivity in rats. In conclusion, acute renal neurogenic hypertension leads to renal vasoconstriction and increased renal HIF-1a. Increasing HIF-1a by CoCl2 preconditioning ameliorates intrarenal phenol-induced renal neurogenic hypertension and renal vasoconstriction. In a second pathophysiologic study we investigated the relations between kidney function as well as direct and indirect variables of the renin angiotensin aldosterone system (RAAS) and SNS and renal oxygenation as determined using blood oxygen level dependent MRI (BOLD-MRI). In conclusion, in patients with hypertension,kidney function as well as direct and indirect variables of the RAAS and SNS relate to renal R2*-values, which can be interpreted as a measure of renal oxygenation. Part II of my thesis focused on the selection of patients for treatment with RDN. Firstly, we showed that implementation of a standardized screening program for patients referred for RDN leads to a high percentage of patients excluded from treatment. Secondly, we investigated whether the blood pressure (BP)-lowering effect of RDN would be inversely related to kidney function and addressed the question whether direct and indirect variables of the RAAS and SNS would be related as well. In conclusion, we found an inverse relation between the BP-lowering effect of RDN and eGFR. Secondly, we found some suggestion that kidney ischemia might be the mechanism behind this relation. The data complement current concepts on pathophysiology of sympathetic hyperactivity and hypertension and may give some insight in the wide range of the effect of RDN. In the final chapter of this part of the thesis, we showed that a relative percentage of patients referred for RDN, has multiple arteries. The BP-reduction in patients with multiple arteries which were all treated was comparable to patients with solitary arteries. However patients with multiple which were not all treated showed a trend towards a less pronounced but still relevant effect of RDN. Based on this, it seems reasonable not to exclude patients with multiple renal arteries from RDN. Part III of my thesis described the effects of RDN. In summary: treatment with RDN did not result in a change in MSNA (a measure for sympathetic activity). Changes in BP did not correlate with changes in MSNA.RDN did not affect renal oxygenation as determined by BOLD-MRI. RDN did not result in a measurable effect on end organ damage. Finally: a histopathological evaluation of the effects of RDN on perivascular nerves of the renal arteries in a human patient suggests that variable efficacy of RDN might at least in part relate to incomplete interruption of critical nerves along the renal arteries, especially in patients with increased vessel wall thickness.