1. RENAL SYMPATHETIC DENERVATION Anxiolytic for nervous kidneys???

3. HYPERTENSION  Is according to the WHO the most frequent cause of death worldwide.  In 2025, 50% of the adult population will be hypertensive.  20-30% of patients are considered to have resistant HTN despite availability of potent medications.

4. HYPERTENSION  20/10mmHg increase in blood pressure doubles cardiovascular mortality.  Reduction of systolic blood pressure by only 10 mmHg reduces the risk of stroke by 30%.  7.5 million deaths annually.

5. HYPERTENSION Only half of all treated hypertensives are controlled to established BP targets. High prevalence: Affects 1 in 3 adults. 1B people worldwide  1.6 B by 2025 35% Treated & Controlled 30% Untreated 35% Treated but Uncontrolled Chobanian et al. Hypertension. 2003;42(6):1206–1252. 5

6. Renal Sympathetic Activation: Efferent Nerves Kidney as Recipient of Sympathetic Signals Renal Efferent Nerves ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 6

7. Hypertrophy Arrhythmia Oxygen Consumption Vasoconstriction Atherosclerosis Insulin Resistance Renal Sympathetic Activation: Afferent Nerves Kidney as Origin of Central Sympathetic Drive Renal Afferent Nerves ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow Sleep Disturbances 7

10. Initial Cohort – Reported in the Lancet, 2009: -First-in-man, non-randomized -Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min) -12-month data

11. Nerves arise from T10-L2 Follow the renal artery to the kidney Primarily lie within the adventitia. Renal Nerve Anatomy Vessel Lumen Medi a Adventitia Renal Nerves 11

12. Catheter-Based Approach 12 Renal artery access via standard interventional technique Radiofrequency electrode tip 4-6 two-minute treatments per artery RF generator – Automated – Low power-max 8 Watts – Built-in safety mechanisms Spacing of e.g. 5 mm.

13. Expanded Cohort – This Report (Symplicity HTN-1): -Expanded cohort of patients (n=153) -36-month follow-up -90% response rate, >20/10mmHg reduction. 13 Hypertension. 2011;57:911-917.

14. Lancet. 2010;376:1903-1909.

15. The simplicity HTN-2 Trial Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension. Study design: Randomized, controlled clinical trial. Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control. Participating centres: 24 centers in Europe, Australia, & New Zealand.

16. The simplicity HTN-2 Trial Inclusion Criteria: -Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) -3+ more anti-HTN medications -Age 18-85 years Exclusion Criteria: -Significant renal artery abnormalities or prior renal artery intervention -eGFR < 45 mL/min/1.73m2 (MDRD formula) -Type 1 diabetes -Contraindication to MRI -Significant stenotic valvular heart disease -MI, unstable angina, or CVA in the preceding 6 months

17. The simplicity HTN-2 Trial Before randomisation and to assess eligibility: Screening process required patients to record daily bd automated BP measurements and to document drug compliance for 2/52. Renal artery anatomical screening, with renal duplex, CT, MRI or renal angiography to confirm anatomical eligibility. Baseline creatinine, Cystatin C, ACR. 24hr BP measurement.

18. June 09 – jan 10

19. RDN (n = 52) Control (n = 54) Baseline systolic BP (mmHg) 178 ± 18178 ± 16 Baseline diastolic BP (mmHg)97 ± 1698 ± 17 Number anti-HTN medications5.2 ± 1.55.3 ± 1.8 Age58 ± 12 Gender (female) (%)35%50% Race (Caucasian) (%)98%96% BMI (kg/m 2 )31 ± 5 Type 2 diabetes40%28% Coronary artery disease19%7% Hypercholesterolemia52% eGFR (MDRD, ml/min/1.73m 2 )77 ± 1986 ± 20 Serum creatinine (mg/dL)1.0 ± 0.30.9 ± 0.2 Urine alb/creat ratio (mg/g) * 128 ± 363109 ± 254 Cystatin C (mg/L) † 0.9 ± 0.20.8 ± 0.2 Heart rate (bpm)75 ± 1571 ± 15

21. Follow up At 1, 3 and 6 months, with rpt creat, Cystatin C, BP, ACR. Office and home BP readings, average of 3. Daily home BP and drug compliance diary 2/52 prior to the 6 month FU. At 6 months: 24hr BP monitor and renal imaging in the renal denervation group.

22. . 84% of RDN patients had ≥10 mmHg reduction in SBP. 10% of RDN patients had no reduction in SBP. p <0.001 for difference between RDN and Control

25. Adverse events No significant change in renal function. One renal artery dissection from injection of contrast into renal arter wall during dye angiography. The lesion was stented without further consequences. Minor adverse events (n=52) 1 femoral artery pseudoaneurysm  manual compression 1 post-procedural drop in BP resulting in a reduction in medication 1 urinary tract infection 1 prolonged hospitalization for evaluation of paraesthesias 1 back pain treated with pain medications & resolved after one month 6-month renal imaging (n=43) No vascular abnormality at any RF treatment site 1 MRA indicates possible progression of a pre-existing stenosis unrelated to RF treatment (no further therapy)

26. Conclusions Catheter-based renal denervation, done in a multicentre, randomised trial in patients with treatment-resistant essential hypertension, resulted in significant reductions in BP. The technique was applied without major complications. This therapeutic innovation, based on the described neural pathophysiology of essential hypertension, affirms the crucial relevance of renal nerves in the maintenance of BP in patients with hypertension. Catheter-based renal denervation may be beneficial for patients with treatment-resistant essential hypertension.

27. Limitations Non-blinded trial. ?long-term benefit, ?evidence of reinnervation Small number of patients. Was the population truly treatment resistant? Adjustments in medications, unclear effect on pill burden Effect in patients with more severe CKD. Simplicity HTN-3 trial on way

28. Discussion