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Temi caldi in Nefrologia

Temi caldi in Nefrologia. La denervazione dell’arteria renale nel trattamento dell’ipertensione arteriosa Luigi Amoroso UOC Nefrologia e Dialisi Ospedale “SS Annunziata” Chieti. I numeri dell’Ipertensione Arteriosa a livello mondiale.

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Temi caldi in Nefrologia

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  1. Temi caldi in Nefrologia La denervazione dell’arteria renale nel trattamento dell’ipertensione arteriosa Luigi Amoroso UOC Nefrologia e Dialisi Ospedale “SS Annunziata” Chieti

  2. 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 BenefitsofLowering BP • Stroke 35-40% • MiocardialInfarction 20-25% • HeartFailure 50% • Total CV Mortality 25% He W. et al.; Am Heart J 1999 Kannel WB. et al.; JAMA 1996 Moser M. et al.; J Am Coll Cadiol 1996

  3. Pathophysiological Mechanism of Hypertention Oparil S. et al.; AnnInternMed 2003

  4. Muscle Sympathetic Nerve Activity ** ** ** MSNA (burst per 100 heart beats) MAP (mmHg) Progressive increase in musclesympatheticnerveactivity in normotensive control subjects (light green square), mild-to-moderate (redsquare) and more severe essentialhypertensivepatients (dark green square) ** P < 0.01 betweengroups. Grassi G. et al.; ExpPhysiol 2009

  5. Device-based approaches to the treatment of Resistant Hypertension Baroreflex Activation Therapy (Rheos carotid sinus stimulator) Renal Sympathetic Denervation

  6. Renal Sympathetic Nerve Activity:Kidney as Origin & Recipient of Central Sympathetic Drive • ↑ Contractility • ↑ Heart rate • Hypertrophy • Arrhythmia • Heart Failure • Vasoconstriction • Atherosclerosis • Insulin resistance Afferent Nerves Efferent Nerves Blood Pressure ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow

  7. Vessel Lumen Media Adventitia RenalNerves

  8. 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

  9. Symplicity Catheter System (Medtronic) Steerable tip 11

  10. Technique of treatment • From distal to proximal • 4-6 ablation spots • 2 min for each spot • ≥ 5 mm of distance

  11. What are the effects on BP?

  12. Average BP reduction : -29/-11 mmHg ESC Expert Consensus:European Heart Journal 2013

  13. Symplicity HTN-1 Investigators: Hypertension 2011 Reduction PAS ≥ 10 mmHg: (Mean baseline BP: 176/98±17/14 mmHg) Responders: 92% Non-responders: 8% Reduction PAS ≥ 10 mmHg: (Mean baseline BP: 178/97±18/16 mmHg) Responders: 84% Non-responders: 16%

  14. Symplicity HTN-1: Reduction through 3 years -9 -10 -10 -12 -13 -14 -15 BP change (mmHg) -19 -19 -21 -22 -26 -26 Systolic BP Diastolic BP -33 -33 -33 P<0.01 for Δ from BL for all time points 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) Krum H. : American College of CardiologyAnnual Meeting 2012

  15. 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

  16. Does RDN reduce Sympathetic tone?

  17. Direct Measurement of Reduced Sympathetic Nerve Activity A Kidney Spillover B Whole-Body Spillover Norepinephrine Spillover (ng/min) Norepinephrine Spillover (ng/min) - 42% - 48% - 75% Baseline 30 Days after Bilateral Denervation Baseline 30 Days after Bilateral Denervation 161/107 mmHg (baseline) 141/90 mmHg (30 days after RDN) Mean Systolic/Diastolic Office BP Schlaich MP et al.; NEJM 2009

  18. What are the risks?

  19. Short-term safety outcomes Renal artery dissection before energy delivery (n 1) Femoral artery pseudoaneurysm at access site (n 3) Long-term safety outcomes No renal vascular complication 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 Semplicity HTN-2 Trial Semplicity HTN-1 Trial

  20. After 5 months, due to recurrent hypertension, renal angiography was performed demonstrating an 80% ostial and 70% mid-segment right main renal artery stenosis and a mid 50% stenosis in the right upper pole accessory renal artery Kaltenbach B. et al.: JACC 2012 After six months increse of BP . Renal Angiography showed a 75% stenosis near the ostium of the right renal artery Lancet 2012

  21. 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 6 months Nerve fibrosis, replacement of nerve fascicles with fibrous cennective tissue and thickening of the perineurium Fibrosis of 10%-25% of total media and underlying adventitia with mild disruption of the external elastic lamina Clin Res Cardiol 2011

  22. The Symplicity HTN-2 Trial:Renal Function Changes Renal denervation group Control group Difference in mean change (95%Cl) p value Patients (n°) Mean change (SD) Patients (n°) Mean change (SD) • 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 eGFR (mL/min per 1,73 m2) Serum creatinine (μmol/L) Cystatin C (mg/L) eGFR= Calculated on the basis of MDRD Symplicity HTN-2 Investigators: Lancet 2010

  23. The Symplicity HTN-1 Trial:RENAL FUNCTION months 1 6 12 3 24 eGFR (mL/min per 1,73 m2) + 0.1 - 1.6 - 0.1 - 2.9 - 16.0 n° pts 102 87 10 112 64 Symplicity HTN-1 Investigators: Hypertension 2011

  24. What are the eligibility criteria?

  25. 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

  26. Future applications of RDN

  27. MSNA * * * * * * * * ** bs/min Controls HT Obese CHF MS RF 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.; ExpPhysiol 2009

  28. Mahfoud F. et al.; Circulation 2011

  29. A B 1 month 3 month 1 month 3 month P=0.129 P=0.402 P=0.847 P=0.984 +3,9 +0,9 +6,4 +0,5 Change in fasting glucise (mg/dl) Change in fasting insulin (μIU/dl) -8,9 -9,4 -8,7 -11,6 C P=0.043 P=0.039 P=0.036 P=0.006 p for interaction (ANOVA)=0,043 p for interaction (ANOVA)=0,016 D 1 month 3 month 1 month 3 month P=0.085 P=0.699 P=0.776 Change in fasting C-peptide (ng/dl) Change in HOMA-IR (ng/dl) +0,2 +0,2 P=0.734 +2,1 +0,3 -2,0 -2,3 -3,0 -3,5 p for interaction (ANOVA)=0,031 p for interaction (ANOVA)=0,003 P=0.006 P=0.002 P=0.008 P=0.001 Mahfoud F. et al.: Circulation 2011

  30. NDT 2012 JACC 2012 CurrCardiol Rep 2012

  31. J Am Soc Nephrol 2012

  32. 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

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