Controversies in renal arterial interventions. ACHILLES CHATZIIOANNOU, MD Assoc. Professor of Radiology American Board of Radiology

60-year old male. Hypertension (180/100) 3 anti-HTN medications Cr: 2,1 mg/dl 60-year old male. Hypertension (180/100) 3 anti-HTN medications Cr: 2,1 mg/dl

Herculink 6X18-mm Normotensive with one medication.Normotensive with one medication. Cr=1.1mg/dlCr=1.1mg/dl

Renovascular Hypertension (RVH) Classic studies by Goldblatt (1930): RAS is the cause of RVH. Classic studies by Goldblatt (1930): RAS is the cause of RVH. RAS causing RVH: prevalence 3-5% of the hypertensive patients. RAS causing RVH: prevalence 3-5% of the hypertensive patients. Atherosclerosis: 70-90% of RHV. FMD: 10-30% of RVH. Atherosclerosis: 70-90% of RHV. FMD: 10-30% of RVH. Classic studies by Goldblatt (1930): RAS is the cause of RVH. Classic studies by Goldblatt (1930): RAS is the cause of RVH. RAS causing RVH: prevalence 3-5% of the hypertensive patients. RAS causing RVH: prevalence 3-5% of the hypertensive patients. Atherosclerosis: 70-90% of RHV. FMD: 10-30% of RVH. Atherosclerosis: 70-90% of RHV. FMD: 10-30% of RVH.

Atherosclerotic disease The prevalence of RAS is increasing because of population aging, and increased survival. The prevalence of RAS is increasing because of population aging, and increased survival. >60% RAS in 6.8% of individuals > 65y. >60% RAS in 6.8% of individuals > 65y. RAS in pts undergoing coronary DSA: 18%- 20%. RAS in pts undergoing coronary DSA: 18%- 20%. RAS in pts undergoing peripheral DSA: 35%- 50%. RAS in pts undergoing peripheral DSA: 35%- 50%. The prevalence of RAS is increasing because of population aging, and increased survival. The prevalence of RAS is increasing because of population aging, and increased survival. >60% RAS in 6.8% of individuals > 65y. >60% RAS in 6.8% of individuals > 65y. RAS in pts undergoing coronary DSA: 18%- 20%. RAS in pts undergoing coronary DSA: 18%- 20%. RAS in pts undergoing peripheral DSA: 35%- 50%. RAS in pts undergoing peripheral DSA: 35%- 50%.

Fibromuscular Dysplasia (FMD) Young patients –more commonly females. Medial fibroplasia (80%). Location: distal main renal artery, 25% into 1 st order branches. >50% of patients have bilateral disease. Commonly asymptomatic (3%-6% in Transplant donors). Young patients –more commonly females. Medial fibroplasia (80%). Location: distal main renal artery, 25% into 1 st order branches. >50% of patients have bilateral disease. Commonly asymptomatic (3%-6% in Transplant donors).

Atherosclerotic disease Patient 6 th decade or older. More often male. The majority of the lesions are incidental findings. Ostial lesions: within 1-cm from aorta. Truncal lesions (less than 10%): more than 1-cm. 50% have bilateral disease. 12%-20% of stenoses>75% will progress to total occlusion within one year (?) Patient 6 th decade or older. More often male. The majority of the lesions are incidental findings. Ostial lesions: within 1-cm from aorta. Truncal lesions (less than 10%): more than 1-cm. 50% have bilateral disease. 12%-20% of stenoses>75% will progress to total occlusion within one year (?)

Manifestations of Renovascular Disease (Textor SC, 2004) Renal Artery Stenosis Incidental RAS Renovascular Hypertension Ischemic Nephropathy Accelerated CV Disease CHF Stroke

Endovascular treatment (PTA-stents) is always indicated in RAS? 7660 interventions in interventions in interventions in interventions in fold increase by interventional cardiologists (“drive-by”). 2.8-fold increase by interventional cardiologists (“drive-by”) interventions in interventions in interventions in interventions in fold increase by interventional cardiologists (“drive-by”). 2.8-fold increase by interventional cardiologists (“drive-by”). Medicare data

Δεκαετία του μη ελεγχόμενες μελέτες Αγγειοπλαστική ή χρήση ενδοαυλικού νάρθηκα Σημαντική μείωση της Α.Π. 8,9 Σταθεροποίηση την χρόνιας νεφρικής ανεπάρκειας 10,11 8. Blum U et al. N Engl J Med Burket MW et al. Am Heart J Harden PN et al. Lancet Watson PS et al. Circulation Murphy TP et al. AJR Am J Roentgenol % 12

Treat RAS whenever found (easier when early, avoid progression to occlusion). Treat RAS whenever found (easier when early, avoid progression to occlusion). 1.Progressive nature of ARVD, progressing at the rate of 10% per year (45%-60% progression rate in 4- 7 year f-u) 2.Pre-occlusive lesions (70-90%): risk of occlusion 40%.. 1.Progressive nature of ARVD, progressing at the rate of 10% per year (45%-60% progression rate in 4- 7 year f-u) 2.Pre-occlusive lesions (70-90%): risk of occlusion 40%.. JVIR 2002

Ischemic nephropathy Progressive disease –Lesion progression 20% per year. –Renal atrophy 10% per year. –Artery occlusion 5% per year. RAS is a marker of increased cardiovascular mortality, predictors: –Older age –Impaired renal function –Bilateral RAS Progressive disease –Lesion progression 20% per year. –Renal atrophy 10% per year. –Artery occlusion 5% per year. RAS is a marker of increased cardiovascular mortality, predictors: –Older age –Impaired renal function –Bilateral RAS

Acute renal failure in patients with RAS 1-14 days after the initiation of treatment with ACE inhibitors days after the initiation of treatment with ACE inhibitors. After the use of diuterics or other antihypertensive drugs. After the use of diuterics or other antihypertensive drugs. After major surgery. After major surgery. After the spontaneous progression of RAS to total occlusion. After the spontaneous progression of RAS to total occlusion days after the initiation of treatment with ACE inhibitors days after the initiation of treatment with ACE inhibitors. After the use of diuterics or other antihypertensive drugs. After the use of diuterics or other antihypertensive drugs. After major surgery. After major surgery. After the spontaneous progression of RAS to total occlusion. After the spontaneous progression of RAS to total occlusion.

Results of revascularization for ischemic nephropathy 32 patients with unexplained renal impairment and RAS were treated with renal artery stent. In 70% of the patients the renal function improved or stabilized (p<0.007). 32 patients with unexplained renal impairment and RAS were treated with renal artery stent. In 70% of the patients the renal function improved or stabilized (p<0.007). Harden et al, Lancet 1997 Harden et al, Lancet 1997

Results of revascularization for ischemic nephropathy 33 patients with bilateral RAS or RAS in solitary kidney. 33 patients with bilateral RAS or RAS in solitary kidney. Follow up: 20±11 months. Follow up: 20±11 months. Significant improvement in 72%; mild improvement in 28%. Significant improvement in 72%; mild improvement in 28%. Preservation of renal size in all patients. Preservation of renal size in all patients. 33 patients with bilateral RAS or RAS in solitary kidney. 33 patients with bilateral RAS or RAS in solitary kidney. Follow up: 20±11 months. Follow up: 20±11 months. Significant improvement in 72%; mild improvement in 28%. Significant improvement in 72%; mild improvement in 28%. Preservation of renal size in all patients. Preservation of renal size in all patients. Watson et al. Circulation 2000

Signs that a patient with ischemic nephropathy will benefit from revascularization 1. Normal distal arterioles. 2. Bilateral disease. 3. Recent onset of renal insufficiency. 4. Resistive Index (Doppler sonography) <80 5. Extremely limited renal function (cr>2,5 mg/dl or 220 μmol/l)* 1. Normal distal arterioles. 2. Bilateral disease. 3. Recent onset of renal insufficiency. 4. Resistive Index (Doppler sonography) <80 5. Extremely limited renal function (cr>2,5 mg/dl or 220 μmol/l)* *Uder M, Huke U CVIR 2005 *Uder M, Huke U CVIR 2005

Percutaneous revascularization Technical success:98-100% Technical success:98-100% Long term patency rate 85%-98% Long term patency rate 85%-98% Complications: Complications: –Mortality 1-3% –Major complications: 3-5% –Minor complications 10-20% Technical success:98-100% Technical success:98-100% Long term patency rate 85%-98% Long term patency rate 85%-98% Complications: Complications: –Mortality 1-3% –Major complications: 3-5% –Minor complications 10-20%

An analysis of the pooled results of studies of conventional balloon angioplasty in 1118 patients Hospital death 0.5% Nephrectomy 0.3% Renal surgery 2% Occlusion of a side branch of the renal artery 2.2% Cholesterol embolization 1.1% Injury at the site of vascular access 2.3% Hospital death 0.5% Nephrectomy 0.3% Renal surgery 2% Occlusion of a side branch of the renal artery 2.2% Cholesterol embolization 1.1% Injury at the site of vascular access 2.3% The indications and results of PTA and stenting in renal artery stenosis. SeminVasc Surg 1996;9:

13. Van Jaarsveld BC et al. N Eng J Med Plouin PF et al. Hypertension Webster J et al. J Hum Hypertens The ASTRAL investigators. N Eng J Med Bax L et al. Ann Intern Med Cooper CJ. N Eng J Med έχουν πραγματοποιηθεί μέχρι τώρα.... και οι 6 απέτυχαν να δείξουν όφελος από την ενδαγγειακή θεραπεία της στένωσης της νεφρικής αρτηρίας Εν συνεχεία... Ελεγχόμενες τυχαιοποιημένες μελέτες 13, 14, 15, 16, 17, 18

EvidenceEvidence 3 randomized controlled trials compared medical treatment to percutaneous renal revascularization: DRASTIC: Dutch Renal Artery Stenosis Intervention Cooperative Study Group EMMA: Essai Multicentrique Medicaments vs Angioplastie Study Group SNRASCG: Scottish and Newcastle Renal Artery Stenosis Collaborative Group 3 randomized controlled trials compared medical treatment to percutaneous renal revascularization: DRASTIC: Dutch Renal Artery Stenosis Intervention Cooperative Study Group EMMA: Essai Multicentrique Medicaments vs Angioplastie Study Group SNRASCG: Scottish and Newcastle Renal Artery Stenosis Collaborative Group

Conclusions 1. In patients whose blood pressure could be controlled with medical therapy alone, no trial was able to demonstrate a statistically significant difference in blood pressure between balloon angioplasty and medical therapy. 2. In patients with refractory hypertension to medical therapy, the results of the DRASTIC trial demonstrated that balloon angioplasty was better than medical therapy in respect of more efficient blood pressure control. 1. In patients whose blood pressure could be controlled with medical therapy alone, no trial was able to demonstrate a statistically significant difference in blood pressure between balloon angioplasty and medical therapy. 2. In patients with refractory hypertension to medical therapy, the results of the DRASTIC trial demonstrated that balloon angioplasty was better than medical therapy in respect of more efficient blood pressure control.

Renal function No significant difference in serum creatinine or creatinine clearance between the two groups in any of the trials. Nordman. Cochrane Library of Systematic Reviews. 2004:;vol 2

“The majority of patients with significant RAS and hypertension or renal function loss can be treated medically without the risk of mortality or progression to end- stage disease”. Exceptions: Bilateral RAS; RAS in solitary kidney. 2X mortality risk; 1.5X risk of renal failure. Care if renal mass loss OR loss of renal function when ACE inhibitor is used! Exceptions: Bilateral RAS; RAS in solitary kidney. 2X mortality risk; 1.5X risk of renal failure. Care if renal mass loss OR loss of renal function when ACE inhibitor is used!

Angioplasty and Stent for Renal Arterial Lesions Multicenter Randomized clinical trial. Multicenter Randomized clinical trial. Approx 1000 pts will be randomized to optimal medical therapy or to stenting with optimal medical therapy Approx 1000 pts will be randomized to optimal medical therapy or to stenting with optimal medical therapy Multicenter Randomized clinical trial. Multicenter Randomized clinical trial. Approx 1000 pts will be randomized to optimal medical therapy or to stenting with optimal medical therapy Approx 1000 pts will be randomized to optimal medical therapy or to stenting with optimal medical therapy

Revascularization versus Medical Therapy for Renal-Artery Stenosis The ASTRAL Investigators Background Percutaneous revascularization of the renal arteries improves patency in atherosclerotic renovascular disease, yet evidence of a clinical benefit is limited. Methods In a randomized, unblinded trial, we assigned 806 patients with atherosclerotic renovascular disease either to undergo revascularization in addition to receiving medical therapy or to receive medical therapy alone. The primary outcome was renal function, as measured by the reciprocal of the serum creatinine level (a measure that has a linear relationship with creatinine clearance). Secondary outcomes were blood pressure, the time to renal and major cardiovascular events, and mortality. The median follow-up was 34 months. Results During a 5-year period, the rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was –0.07x10–3 liters per micromole per year in the revascularization group, as compared with –0.13x10–3 liters per micromole per year in the medical-therapy group, a difference favoring revascularization of 0.06x10–3 liters per micromole per year (95% confidence interval [CI], –0.002 to 0.13; P=0.06). Over the same time, the mean serum creatinine level was 1.6 µmol per liter (95% CI, –8.4 to 5.2 [0.02 mg per deciliter; 95% CI, –0.10 to 0.06]) lower in the revascularization group than in the medical- therapy group. There was no significant between-group difference in systolic blood pressure; the decrease in diastolic blood pressure was smaller in the revascularization group than in the medical-therapy group. The two study groups had similar rates of renal events (hazard ratio in the revascularization group, 0.97; 95% CI, 0.67 to 1.40; P=0.88), major cardiovascular events (hazard ratio, 0.94; 95% CI, 0.75 to 1.19; P=0.61), and death (hazard ratio, 0.90; 95% CI, 0.69 to 1.18; P=0.46). Serious complications associated with revascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs. Conclusions We found substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease. Revascularization versus Medical Therapy for Renal-Artery Stenosis The ASTRAL Investigators Background Percutaneous revascularization of the renal arteries improves patency in atherosclerotic renovascular disease, yet evidence of a clinical benefit is limited. Methods In a randomized, unblinded trial, we assigned 806 patients with atherosclerotic renovascular disease either to undergo revascularization in addition to receiving medical therapy or to receive medical therapy alone. The primary outcome was renal function, as measured by the reciprocal of the serum creatinine level (a measure that has a linear relationship with creatinine clearance). Secondary outcomes were blood pressure, the time to renal and major cardiovascular events, and mortality. The median follow-up was 34 months. Results During a 5-year period, the rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was –0.07x10–3 liters per micromole per year in the revascularization group, as compared with –0.13x10–3 liters per micromole per year in the medical-therapy group, a difference favoring revascularization of 0.06x10–3 liters per micromole per year (95% confidence interval [CI], –0.002 to 0.13; P=0.06). Over the same time, the mean serum creatinine level was 1.6 µmol per liter (95% CI, –8.4 to 5.2 [0.02 mg per deciliter; 95% CI, –0.10 to 0.06]) lower in the revascularization group than in the medical- therapy group. There was no significant between-group difference in systolic blood pressure; the decrease in diastolic blood pressure was smaller in the revascularization group than in the medical-therapy group. The two study groups had similar rates of renal events (hazard ratio in the revascularization group, 0.97; 95% CI, 0.67 to 1.40; P=0.88), major cardiovascular events (hazard ratio, 0.94; 95% CI, 0.75 to 1.19; P=0.61), and death (hazard ratio, 0.90; 95% CI, 0.69 to 1.18; P=0.46). Serious complications associated with revascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs. Conclusions We found substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease. Volume 361: November 2009

The ASTRAL Investigators. N Engl J Med 2009;361: Renal Function in Patients with Renal-Artery Stenosis Treated with Revascularization or Medical Therapy Alone

The ASTRAL Investigators. N Engl J Med 2009;361: Kaplan-Meier Curves for the Time to the First Renal and Cardiovascular Events

The ASTRAL Investigators. N Engl J Med 2009;361: Kaplan-Meier Curves for Overall Survival

The ASTRAL Investigators. N Engl J Med 2009;361: Systolic and Diastolic Blood Pressure

25% των ασθενών με φυσιολογική νεφρική λειτουργία 15% των ασθενών με οριακά φυσιολογική νεφρική λειτουργία “uncertainty principle” όσον αφορά την τυχαιοποίηση... Νεφρική λειτουργία Μέσος όρος αντιϋπερτασικών φαρμάκων 2.8% Αόριστο ‘best medical treatment” Υπέρταση 41% των ασθενών ≤ 70% Εκτίμηση της στένωσης «με το μάτι» και όχι από πιστοποιημένο εργαστήριο Στένωση ΝΑ 65% των κέντρων τυχαιοποίησαν < 1 ασθενή / έτος 9% επιπλοκές από το stenting vs 2% άλλων μελετών Εμπειρία επεμβατιστών ACC/AHA οδηγίες Ανθεκτική υπέρταση: ≥ 3 αντιϋπερτασικά

Συντηρητική θεραπεία μόνο Συντηρητική θεραπεία + stenting νεφρικής αρτηρίας Στένωση ΝΑ ≥ 60% Α.Π. ≥ 155 mmHg + ≥ 2 αντιϋπερτασικά φάρμακα και/ή GFR ≤ 60 ml/1.73 m 2

19. Arendhorst WJ, Navar LG. Diseases of kidney and urinary tract, 7 th ed. Vol 1, Lippincott W&W Imanishi M et al. Angiology 1992 Stenting μετρίου βαθμού στένωσης της νεφρικής αρτηρίας δεν οδηγεί σε κλινική βελτίωση του ασθενούς λόγω της μεγάλης νεφρικής εφεδρίας σε αιμάτωση και οξυγόνωση 19 Πειραματικά μοντέλα 20 δείχνουν αύξηση της Α.Π. σε στενώσεις > 75% και επιδείνωση νεφρικής λειτουργίας > 80%

Ενδείξεις επαναιμάτωσης νεφρικής αρτηρίας RI (DUS) < 0.8 DTPA Εκλεκτική αγγειογραφία της νεφρικής αρτηρίας Στένωση >75-80%

Συμπερασματικά... Δυστυχώς, οι ενδείξεις για επαναιμάτωση του νεφρού δεν είναι ακόμη ξεκάθαρες (evidence- based). Στηριζόμενοι στις σημερινές κατευθυντήριες οδηγίες οδηγίες (guidelines), πιθανόν να υποβληθούν ασθενείς σε αγγειοπλαστική, χωρίς να το έχουν πραγματικά ανάγκη. Ο συνδυασμός των κλινικών οδηγιών με επεμβατικές και μη μεθόδους ελέγχου της νεφροπάθειας αυξάνει την πιθανότητα να βρούμε την υποκατηγορία των ασθενών με στένωση νεφρικής αρτηρίας που θα ωφεληθούν.