RENAL SYMPATHETIC DENERVATION

Anxiolytic for nervous kidneys???

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.

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.

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.

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Renal Sympathetic Activation: Efferent NervesKidney as Recipient of Sympathetic Signals

Renal EfferentNerves

↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow

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HypertrophyArrhythmiaOxygen Consumption

VasoconstrictionAtherosclerosis

InsulinResistance

Renal Sympathetic Activation: Afferent NervesKidney as Origin of Central Sympathetic Drive

Renal AfferentNerves

↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow

Sleep Disturbances

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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

Nerves arise from T10-L2 Follow the renal artery to the kidney Primarily lie within the adventitia.

Renal Nerve Anatomy

Vessel Lumen

Media

AdventitiaRenal

Nerves

1111

Catheter-Based Approach

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• 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.

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

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Hypertension. 2011;57:911-917.

Lancet. 2010;376:1903-1909.

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.

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

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.

June 09 – jan 10

  RDN(n = 52)

Control(n = 54)

Baseline systolic BP (mmHg) 178 ± 18 178 ± 16

Baseline diastolic BP (mmHg) 97 ± 16 98 ± 17Number anti-HTN medications 5.2 ± 1.5 5.3 ± 1.8

Age 58 ± 12 58 ± 12

Gender (female) (%) 35% 50%

Race (Caucasian) (%) 98% 96%

BMI (kg/m2) 31 ± 5 31 ± 5

Type 2 diabetes 40% 28%

Coronary artery disease 19% 7%

Hypercholesterolemia 52% 52%

eGFR (MDRD, ml/min/1.73m2) 77 ± 19 86 ± 20

Serum creatinine (mg/dL) 1.0 ± 0.3 0.9 ± 0.2

Urine alb/creat ratio (mg/g)* 128 ± 363 109 ± 254

Cystatin C (mg/L)† 0.9 ± 0.2 0.8 ± 0.2

Heart rate (bpm) 75 ± 15 71 ± 15

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.

. 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

Adverse events• No significant change in renal function.• One renal artery dissection from injection of contrast into renal arterwall 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)

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.

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

Discussion