Renal Denervation in Treatment Resistant Hypertension

• office BP [ Time Frame: baseline, 6 months ]
  change in office blood pressure from baseline to 6 months post-renal denervation
• 24-ABPM [ Time Frame: baseline, 6 months ]
  change in 24 hour ambulatory blood pressure (ABPM) from baseline to 6 months post-renal denervation
• Magnetic resonance imaging (MRI) [ Time Frame: baseline, 3 and 6 months ]
  • change in total sodium content measured by MRI from baseline to 6 months post-renal denervation
  • change in renal perfusion measured by MRI from baseline to 3 months post-renal denervation
• Albuminuria [ Time Frame: baseline, 6 months ]
  change in urinary albumin/creatinine ratio from baseline to 6 months post-renal denervation
• Systemic RAS activity [ Time Frame: baseline, 6 months ]
  • change in sodium, potassium and creatinine from baseline to 6 months post-renal denervation
  • change in aldosterone excretion from baseline to 6 months post-renal denervation
  • change in sodium/potassium ratio from baseline to 6 months post-renal denervation
  • change in plasma renin activity and angiotensin II concentration at least 30 minutes of rest in a supine position and immediately after standing from baseline to 6 months post-renal denervation
• Vascular structure and function of large and small arteries [ Time Frame: baseline, 6 months ]
  • change in flow-mediated vasodilation (FMD)from baseline to 6 months post-renal denervation
  • change in scanning laser Doppler flowmetry (SLDF) from baseline to 6 months post-renal denervation
  • change in funduscopy from baseline to 6 months post-renal denervation
  • change in pulse wave analysis (PWA) from baseline to 6 months post-renal denervation
  • change in pulse wave velocity (PWV) from baseline to 6 months post-renal denervation
  • change in urinary albumine/creatinine ratio (UACR) of the morning spot urine sample from baseline to 6 months post-renal denervation
• Local RAS activity [ Time Frame: baseline, 6 months ]
  change in urinary angiotensinogen concentration from the morning spot urine from baseline to 6 months post-renal denervation

• BP [ Time Frame: 3 and 12 months ]
  • change in office BP from baseline to 3 and 12 months post-renal denervation
  • change in 24 hour ABPM from baseline to 3 and 12 months post-renal denervation
• MRI [ Time Frame: 1 day and 12 months ]
  • change in total sodium content measured by MRI from baseline to 12 months post-renal denervation
  • change in renal perfusion measured by MRI spin labelling technique from baseline to 1 day post-renal denervation
• Local RAS activity [ Time Frame: 1 day, 3 and 12 months ]
  change urinary angiotensinogen concentration from the morning spot urine from baseline to 1 day, 3 and 12 months post-renal denervation
• Systemic RAS activity [ Time Frame: 1 day, 3 and 12 months ]
  • change in sodium potassium and creatinine from baseline to 1 day, 3 and 12 months post-renal denervation
  • change in aldosterone excretion from baseline to 1 day, 3 and 12 months post-renal denervation
  • change in sodium/potassium ratio from baseline to 1 day, 3 and 12 months post-renal denervation
  • change in plasma renin activity and angiotensin II concentration at least 30 minutes of rest in a supine position and immediately after standing from baseline to 1 day, 3 and 12 months post-renal denervation
• Albuminuria [ Time Frame: 3 and 12 months ]
  - change in albuminuria from baseline to 3 and 12 months post-renal denervation
• Vascular structure and function of large and small arteries [ Time Frame: 3 and 12 months ]
  • change in flow mediated vasodilation (FMD) from baseline to 12 months post-renal denervation
  • change in scanning laser Doppler flowmetry (SLDF) from baseline to 12 months post-renal denervation
  • change in funduscopy from baseline to 3 and 12 months post-renal denervation
  • change in pulse wave analysis (PWA) from baseline to 12 months post-renal denervation
  • change in pulse wave velocity (PWV) from baseline to 12 months post-renal denervation
  • change in urinary albumine/creatinine ratio of the morning spot urine sample from baseline to 3 and 12 months post-renal denervation

In patients with treatment resistant hypertension renal nerve ablation emerged as an effective interventional approach of treating hypertensive disease with a progressively increasing fall in blood pressure. Decreased activity of the sympathetic nervous system is one of the major underlying pathogenetic mechanism of the fall in blood pressure but the precise mechanisms that causes the fall in blood pressure in the short-term and, in particular, long-term remains elusive. The objective of the study is to understand the pathogenetic mechanisms of renal denervation beyond the reduced activity of the sympathetic nervous system. In 100 hypertensive patients most advanced technology will be applied, before and repeatedly after renal denervation, throughout the follow-up period of 1 year. Systemic activity of the renin angiotensin aldosterone system, renal perfusion (by MRI spin labeling technique), local activity of the renin angiotensin system in the kidney (urinary angiotensinogen concentrations), sodium excretion and total sodium content (23 Na-MRI technique) and vascular remodelling of small (retinal arterioles 50 - 150 µm) and large arteries (carotid - femoral pulse wave velocity and augmentation index, both measured over 24 hours) will be assessed. Identification of the pathogenetic mechanisms involved in the fall in blood pressure after renal denervation may help to identify those hypertensive patients that profit most from renal nerve ablation in terms of blood pressure reduction.

The investigators propose the following hypotheses why a progressive decrease in blood pressure happens, in addition to the decreased activity of the central nervous system, after renal nerve ablation:

Short term effects:

A)Preservation of renal function and perfusion B)Reduction of local RAS activity in the kidney C)Exaggerated sodium excretion immediately after renal nerve ablation

Long term effects:

D)Decrease of total sodium content after 6 and 12 months E)Improvement of vascular wall properties after 6 and 12 months

• Schmieder RE, Ott C, Schmid A, Friedrich S, Kistner I, Ditting T, Veelken R, Uder M, Toennes SW. Adherence to Antihypertensive Medication in Treatment-Resistant Hypertension Undergoing Renal Denervation. J Am Heart Assoc. 2016 Feb 12;5(2). pii: e002343. doi: 10.1161/JAHA.115.002343.
• Schmieder RE, Ott C, Veelken R, Schmid A, Uder M, Toennes SW. 7B.01: FINAL ANALYSIS ON ADHERENCE TO ANTIHYPERTENSIVE MEDICATION IN TREATMENT RESISTANT HYPERTENSION (TRH) UNDERGOING RENAL DENERVATION (RDN). J Hypertens. 2015 Jun;33 Suppl 1:e92. doi: 10.1097/01.hjh.0000467598.27100.ca.
• Ott C, Schmid A, Toennes SW, Ditting T, Veelken R, Uder M, Schmieder RE. Central pulse pressure predicts BP reduction after renal denervation in patients with treatment-resistant hypertension. EuroIntervention. 2015 May;11(1):110-6. doi: 10.4244/EIJV11I1A19.
• Ott C, Mahfoud F, Schmid A, Ditting T, Veelken R, Ewen S, Ukena C, Uder M, Böhm M, Schmieder RE. Improvement of albuminuria after renal denervation. Int J Cardiol. 2014 May 1;173(2):311-5. doi: 10.1016/j.ijcard.2014.03.017. Epub 2014 Mar 15.
• Ott C, Mahfoud F, Schmid A, Ditting T, Sobotka PA, Veelken R, Spies A, Ukena C, Laufs U, Uder M, Böhm M, Schmieder RE. Renal denervation in moderate treatment-resistant hypertension. J Am Coll Cardiol. 2013 Nov 12;62(20):1880-6. doi: 10.1016/j.jacc.2013.06.023. Epub 2013 Jul 10.

Inclusion Criteria:

• treatment resistant hypertension
• male of female aged over 18 years
• written informed consent
• agreement to attend all study visits as planned in the protocol

Exclusion Criteria:

• chronic kidney disease 3 - 5
• any contradictions for MRI
• claustrophobia
• strabismus
• severe ocular diseases
• history of epilepsia