Temi caldi in Nefrologia

La denervazione dell’arteriarenale nel trattamento

dell’ipertensione arteriosa

Luigi Amoroso UOC Nefrologia e Dialisi

Ospedale “SS Annunziata”Chieti

I numeri dell’Ipertensione Arteriosa a livello mondiale

7,6 milioni di morti premature/anno (13,6% del totale) 92 milioni di anni di disabilità (6,0% del totale) 54% degli ictus, 47% delle cardiopatie ischemiche 70 miliardi di dollari all’anno per l’insufficiente controllo della

pressione ( 10% della spesa mondiale annua per la salute) 3600 miliardi di costi indiretti/anno

Lewington S.et al.; Lancet 2002

Lawes CM.; Lancet 2008

OMS : 20111

• Stroke 35-40%

• Miocardial Infarction 20-25%

• Heart Failure 50%

• Total CV Mortality 25%

Benefits of Lowering BP

He W. et al.; Am Heart J 1999Kannel WB. et al.; JAMA 1996Moser M. et al.; J Am Coll Cadiol 1996

Pathophysiological Mechanism of Hypertention

Oparil S. et al.; Ann Intern Med 2003

Grassi G. et al.; Exp Physiol 2009

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80 90 100 110 120

****

**

MS

NA

(b

urs

t p

er 1

00 h

eart

bea

ts)

MAP (mmHg)

Progressive increase in muscle sympathetic nerve activity in normotensive control subjects (light green square), mild-to-moderate (red square) and more severe essential hypertensive patients (dark green square)

** P < 0.01 between groups.

Muscle Sympathetic Nerve Activity

Renal Sympathetic DenervationBaroreflex Activation Therapy

(Rheos carotid sinus stimulator)

Device-based approaches to the treatment of Resistant Hypertension

• ↑ Contractility• ↑ Heart rate• Hypertrophy• Arrhythmia• Heart Failure

Renal Sympathetic Nerve Activity:Kidney as Origin & Recipient of Central Sympathetic Drive

Afferent Nerves

•Vasoconstriction•Atherosclerosis•Insulin resistance

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

EfferentNerves

BloodPressure

Vessel Lumen

Media

Adventitia

RenalNerves

Renal Nerve Ablation Devices

Radiofrequency Ablation- Medtronic Semplicity

- St. Jude EnligHTN

- Convidien One Shot system

- Vessix Vascular V2 system

Ultrasound- ReCor Medical Paradise

- Kona Medical

Chemical Ablation (Guanethedine,Ethanol, Botox B, Vincristine)- Mercator MedSystems

11

Symplicity Catheter System (Medtronic)

Steerable tip

Technique of treatment• From distal to proximal• 4-6 ablation spots

• 2 min for each spot• ≥ 5 mm of distance

What are the effects on BP?

ESC Expert Consensus:European Heart Journal 2013

Average BP reduction : -29/-11 mmHg

Reduction PAS ≥ 10 mmHg:

(Mean baseline BP: 178/97±18/16 mmHg)

Responders: 84%

Non-responders: 16%

Reduction PAS ≥ 10 mmHg:

(Mean baseline BP: 176/98±17/14 mmHg)

Responders: 92%

Non-responders: 8%

Symplicity HTN-1 Investigators: Hypertension 2011

Symplicity HTN-1: Reduction through 3 years

Krum H. : American College of Cardiology Annual Meeting 2012

-35

-30

-25

-20

-15

-10

-5

0

BP change(mmHg)

1 Mo 3 Mo 6 Mo 12 Mo 18 Mo 24 Mo 30 Mo 36 Mo (n=143) (n=148) (n=144) (n=130) (n=107) (n=59) (n=24) (n=24)

-19-21

-22

-26

-33

-9

-26

-33 -33

-10 -10

-13 -12-15 -14

-19

Systolic BP

Diastolic BP

P<0.01 for Δ from BLfor all time points

The Symplicity HTN-2 Trial:MEDICATION CHANGES

RDN Control P-value (n=49) (n=51)

Med Dose Decrease (%) 10 (20%) 3 (6%) 0.04

Med Dose Increase (%) 4 (8%) 6 (12%) 0.74

Symplicity HTN-2 Investigators: Lancet 2010

Does RDN reduce Sympathetic tone?

Schlaich MP et al.; NEJM 2009

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0102030405060708090

100 Left kidney Right kidney

Baseline 30 Days after Bilateral Denervation

Baseline 30 Days after Bilateral Denervation

A Kidney Spillover B Whole-Body Spillover

Nor

epin

eph

rin

e S

pill

over

(ng/

min

)

Nor

epin

eph

rin

e S

pill

over

(ng/

min

)

Mean Systolic/Diastolic Office BP

161/107 mmHg (baseline) 141/90 mmHg (30 days after RDN)

Direct Measurement of Reduced Sympathetic Nerve Activity

- 48%

- 75%

- 42%

What are the risks?

Semplicity HTN-1 Trial

Short-term safety outcomes

Renal artery dissection beforeenergy delivery (n 1)

Femoral artery pseudoaneurysm at access site (n 3)

Long-term safety outcomes

No renal vascular complication

Semplicity HTN-2 Trial

Short-term safety outcomes

Intraprocedural bradicardia (n 7)

Post procedural drop in BP (n 1)

Femoral artery pseudoaneurysm at access site (n 1)

Long-term safety outcomes

No renal vascular complication

After 5 months, due to recurrent hypertension, renal angiography wasperformed demonstrating an 80% ostial and 70% mid-segment rightmain renal artery stenosis and a mid 50% stenosis in the right upperpole accessory renal artery Kaltenbach B. et al.: JACC 2012

After six months increse of BP . Renal Angiographyshowed a 75% stenosis near the ostium of the rightrenal artery

Lancet 2012

-Local loss of the endotelial monolayer as acute phase-Acute edematous cellular swelling and connective tissue coagulation within the medial and adventitial layer-Subacute reduction in nerve fascicle quantity and size-Tickening of perinerium and reduced neurofilament of nerve J Hypertens 2012

Clin Res Cardiol 2011

Fibrosis of 10%-25% of total media andunderlying adventitia with mild disruptionof the external elastic lamina

Nerve fibrosis, replacement of nerve fascicleswith fibrous cennective tissue and thickeningof the perineurium

6 months

The Symplicity HTN-2 Trial:Renal Function Changes

Renal denervation group Control group Difference in mean change (95%Cl)

eGFR (mL/min per 1,73 m2)

Serum creatinine (μmol/L)

Cystatin C (mg/L)

eGFR= Calculated on the basis of MDRD

Patients (n°) Mean change (SD) Patients (n°) Mean change (SD)

p value

49 0.2 (11) 51 0.9 (12) -0.7 (-5.4 to 3.9) 0.76

49 0.2 (17.6) 51 -1.1 (10.3) 1.3 (-4.5 to 7.0) 0,67

37 0.1 (0.2) 40 0.0 (0.1) 0.0 (0.0 to 0.1) 0.31

Symplicity HTN-2 Investigators: Lancet 2010

The Symplicity HTN-1 Trial:RENAL FUNCTION

eGFR (mL/min per 1,73 m2)

months 1 3 6 12 24

n° pts

+ 0.1 - 1.6 - 0.1 - 2.9 - 16.0

112 102 87 64 10

Symplicity HTN-1 Investigators: Hypertension 2011

What are the eligibility criteria?

• Office-based SBP ≥160 mmHg (≥150 mmhg diabetes type 2)• ≥ 3 antihypertensive drugs in adequate dosage and combination (incl. diuretic)• Lifestyle modification• Exclusion of secondary hypertension• Exclusion of pseudo-resistance using ABPM• Eligible renal arteries: no polar or accessory arteries, no renal artery stenosis, main renal arteries of < 4 mm in diameter or < 20 mm in lenght, no prior revas- scularization (stenting/PTA)• Preserved renal function (eGFR ≥ 45 ml/min/1.73m2)•Pts should be referred to Hypertension Excellence Centers

Future applications of RDN

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Controls HT Obese CHF MS RF

bs/

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MSNA *

**

*

*

* *

* *

*

Behaviour of muscle (MSNA) and skin sympathetic nerve activity (SSNA) in healthy sunjects and in patients with hypertension (HT), obesity (OB), congestive hearth failure (CHF), methabolic syndrome (MS) or renal failure (RF)

Grassi G. et al.; Exp Physiol 2009

Mahfoud F. et al.; Circulation 2011

Mahfoud F. et al.: Circulation 2011

-17,5

-12,5

-7,5

-2,5

2,5

7,5

12,5

17,5Renal denervation (n=37)

Control (n=13)

Ch

ange

in f

asti

ng

glu

cise

(m

g/d

l)C

han

ge in

fas

tin

g C

-pep

tid

e (n

g/d

l)

A

B

C

D

-8,9

+3,9

-9,4

+0,9

Ch

ange

in f

asti

ng

insu

lin

(μ

IU/d

l)C

han

ge in

HO

MA

-IR

(n

g/d

l)

P=0.001

1 month 3 month

P=0.402

P=0.043 P=0.039

P=0.847

p for interaction (ANOVA)=0,043-15

-10

-5

0

5

10

15Renal denervation (n=37)

Control (n=13)

p for interaction (ANOVA)=0,016

+0,5+6,4

-8,7 -11,6

P=0.129

P=0.984

P=0.036 P=0.006

1 month 3 month

-4-3,5

-3-2,5

-2-1,5

-1-0,5

00,5

11,5

2Renal denervation (n=37)

Control (n=13)

p for interaction (ANOVA)=0,031

+0,2+0,2

P=0.699 P=0.776

P=0.006P=0.002

-2,0 -2,3

1 month 3 month1 month 3 month

-5-4-3-2-1012345

Renal denervation (n=37)

Control (n=13)

+0,3

-3,0 -3,5

+2,1

P=0.085

P=0.734

P=0.008p for interaction (ANOVA)=0,003

NDT 2012

JACC 2012

Curr Cardiol Rep 2012

J Am Soc Nephrol 2012

Limitations

• RDN does not cause universal BP lowering

• Only a small number of patients have been exposed to RDN and the

follow-up is short

• Lacking of randomized blinded studies

• Lacking of any procedural marker that might identify good

responders to RDN

• Lacking of standardized certification of RDN centers