1. Renal Nerve Ablation: Will It Become the treatment
Of Choice for Resistant Hypertension?
Jie Wang MD PhD
Mark Gelfand, MS
Howard Levin, MD
Disclosure: JW was a consultant and shareholder of Ardian; MG/HL were Co-founders of Ardian

2. Three Different Diseases,
One Common Pathway
Heart Failure, Hypertension and Chronic Renal Failure have many different initial causes
Irrespective of initial cause, all follow a common pathway on their progression to end-stage disease
Physiologic changes caused by the kidney are responsible for this progression including:
Abnormal hormone secretion (renin, aldosterone, Norepi)
Renal, systemic and pulmonary vasoconstriction
Salt and water retention
The Common Pathway: Renal Nerve Hyperactivity

3. Renal Sympathetic Efferent Nerve Activity: Kidney as Recipient of Sympathetic Signals
Renal Efferent
Nerves
Renal Ischemia
↑ Adenosine production
BNP resistance
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow

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

5. Previous Data Confirm Positive Effects of Renal Nerve Blocking
Renal injury/ dysfunction identified as mechanism of increased sympathetic nervous system activity leading to HTN (Campese, 2002)
Blocking of renal nerve activity controls HTN in animals with chronic renal insufficiency (Campese, 1995)
Surgical renal denervation done to eliminate intractable pain in patients with polycystic kidney disease also eliminates HTN (Valente, 2001)
Denervation (by nephrectomy) eliminates HTN in humans on dialysis with severe HTN refractory to multi-drug therapy (Converse,1992)
Blocking of renal nerve activity increases diuresis/ naturesis in rats with CHF (Dibona)
Blocking of renal nerve activity limits ventricular remodeling in rats post-MI (Tozawa, 2002)

6. Totally Novel Therapy, Original Plan
Intelligent, programmable fully implanted infusion pump with the catheter tip placed in the proximity of the renal nerve
Programmable battery operated electronic device similar in size and complexity to a pacemaker
Integrated electronic feedbacks to guide therapy
Percutaneous refilling of the reservoir once per month

7. How Does It Work?-Original Thought
Catheter is implanted in the periarterial space outside of the renal artery (Gerota’s fascia)
This technique is similar to percutaneous drainage of perinephric abscess
As needed, a bolus of a nerve blocking drug is infused and temporarily blocks renal nerve activity
Drug can be an approved drug such as Marcaine, local anesthetic commonly used for pain management

8. Our Animal Studies Confirmed The Clinical Utility Of This Concept
Obtained data from the 11 dogs with micro-embolization model of Acute HF
8 dogs had Renal Nerve Block (RNB) created by injecting 10 ml of Marcaine (bupivicaine) inside Gerota’s fascia
3 dogs served as controls
Urine output (Urine output/every 15 min) significantly increased compared to controls
Both naturesis and diuresis were observed confirming physiologic basis for effect
Same results found in other 6 dogs with micro- embolization model of chronic CHF

9. Acute Heart Failure : Urinary output (UOP) in the Treated Kidney (A) and in both Kidneys (Total)
(B) after Unilateral Renal Nerve Block (URNB) and Bilateral Renal Nerve Block (BRNB). A significant reduction
in UOP was seen after Acute Heart Failure, but UOP was increased significantly after URNB. No additional
increase in UOP was seen after BRNB (* p<0.05 vs. Baseline, † p<0.05 vs. AHF).

10. Congestive Heart Failure : Urinary Output (UOP) in the Treated Kidney and in both Kidneys
(Total) after Unilateral Renal Nerve Block (URNB) and Bilateral Renal Nerve Block (BRNB). A
significant increase in UOP was seen after URNB compared to the CHF state (* p<0.05 vs. CHF),
but BRNB failed to produce a significant increase in UOP compared to URNB alone.

11. Proposed Two Step Approach To Prove Clinical Utility in Humans
Acute study of renal nerve block using CT guided technique to demonstrate either:
Diuresis and neurohormonal effects in patients with HF and fluid overload
Lowering of blood pressure and neurohormonal effects in patients with hypertension

12. Acute Human Feasibility Study in 5-10 Patients
Class III-IV CHF patients refractory to diuretics or patients with BP > 140/90 on medication
Injection of drug to block RN using CT guided technique
Comparison of urine volume, urine and serum electrolytes, hemodynamic and neurohormonal effects from 6 hours pre- to 12 hours post- injection

13. Intervention Performed In 5 Patient
Successful test of RN blocking technique
Performed under CAT Scan Guidance
Needle placed at the hilum of the kidney
Single injection of Marcaine resulted as predicted in:
Nerve block for 12 hours
Reduction in blood pressure

14. Proposed Two Step Approach To Prove Clinical Utility in Humans
Chronic (1-3 month) study of renal nerve block using minimally invasively implanted port to demonstrate either:
Diuresis and neurohormonal effects in patients with HF and fluid overload
Lowering of blood pressure and neurohormonal effects in patients with hypertension

15. What the Therapy/Device Should be?
Device Based Therapy
Interventional/Trans-catheter
Similar to Current Medical Practice

16. Renal Nerve Anatomy Allows a Catheter-Based Approach
Standard interventional technique
4-6 two-minute treatments per artery
Proprietary RF Generator
Automated
Low-power
Built-in safety algorithms
In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use. 16 16

17. Symplicity Catheter System
Simple, 40-minute catheter-based procedure
Simultaneously ↓ the renal contribution to systemic sympathetic activation and the efferent effects of sympathetic activation of the kidney
Selectively disable the renal sympathetic afferent and efferent nerves without impairing sympathetic signaling to other organs
An anticipated durable clinical benefit
Ramped low power radiofrequency energy delivery (5-8W)
Blood flow minimizes surface/endothelial injury
Focal ablations spaced along vessel allows for rapid healing
CE Mark
In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use.

19. Multiple Discrete Treatments Maximize Nerve Coverage Without Applying Circumferential Energy in a Single Segment

20. Study Aims
Krum et al. Lancet. 2009;373(9671):

21. Inclusion/Exclusion Criteria
Key Inclusion Criteria
Office SBP ≥160 mmHg despite 3+ anti-hypertensive medications (including diuretic), or confirmed intolerance to medications
eGFR (MDRD formula) of ≥ 45 mL/min/1.73m2
Key Exclusion Criteria
Known secondary cause of hypertension
Type I diabetes mellitus
Currently taking clonidine, moxonidine, or rilmenidine
Renovascular abnormalities: significant renal artery stenosis, prior renal stenting or angioplasty, dual renal arteries
Krum et al. Lancet. 2009;373(9671):

22. Baseline Patient Characteristics
Treated Patients
(N=45)
Age (years)
58 ± 9
Gender (% female) 44
Race (% non-Caucasian) 4
Diabetes Mellitus II (%) 31
CAD (%) 22
Heart Rate (bpm)
72 ± 11
eGFR (mL/min/1.73m2)
81 ± 23
BP (mmHg)
177/101 ± 20/15
Krum et al. Lancet. 2009;373(9671):

23. Results: Procedure Characteristics & Safety
Procedure time: median 38 (IQR 34-48) minutes
Treatment delivered without complication in 43/45:
1 renal artery dissection during catheter delivery (before RF energy application)
1 femoral pseudoaneurysm, manually reduced without further sequelae

24. Vascular and Renal Safety
No chronic vascular complications
18 patients with angiograms at days post-procedure
38 of 38 patients with CTA/MRA 6 months post-procedure
No chronic renal (∆ eGFR) complications
3 Month: 0.4 mL/min/1.73m2 (95% CI: -4.2 to 4.9; N=31; p=0.87)
12 Month: -3.1 mL/min/1.73m2 (95% CI: -9.0 to 2.8; N=28; p=0.31)
No orthostatic or electrolyte disturbances

25. Change in Blood Pressure (mmHg)
Blood Pressure Response
Change in Blood Pressure (mmHg)
89% Responder Rate
Repeated measures ANOVA: P<0.001 for SBP & DBP
P< vs. baseline for each SBP & DBP

26. The Potential Market Developed Countries: Drug-Resistant Hypertension
China: Hypertension Patient, 160 millions
Optimized Drug Therapies: 6.1%, 3.23 millions

27. Conclusions

28. Staged Clinical Evaluation
First-in-Man 
Series of Pilot studies 
Symplicity HTN-2 
EU/AU Randomized Clinical Trial
Symplicity HTN-1
USA
Symplicity HTN-3
US Randomized Clinical Trial
(upcoming)
EU/AU
Other Areas of Research:
Insulin Resistance, HF/Cardiorenal,
Sleep Apnea, More 28 28