temi caldi in nefrologia la denervazione dell’arteria renale nel trattamento dell’ipertensione...
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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
Grassi G. et al.; Exp Physiol 2009
30
40
50
60
70
80
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
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
Technique of treatment• From distal to proximal• 4-6 ablation spots
• 2 min for each spot• ≥ 5 mm of distance
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
Schlaich MP et al.; NEJM 2009
0
100
200
300
400
500
600
700
800
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%
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
• 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
0
20
40
60
80
Controls HT Obese CHF MS RF
bs/
min
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
-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
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