RENAL ARTERY STENOSIS Grand Rounds 12/20/12

• 55 y.o Male with PMHx of hypertension, CKD stage III, PVD s/p bilateral common iliac artery stent 5 years ago, renal artery stenosis referred to vascular surgery from WBVA for stenting of renal artery

• He started feeling intermittent burning sensation in his feet and claudication after a walking a block Right>Left and decided to go to his family PCP.

• PCP did basic lab work that showed cr of 3.7 and K of 5.8 (8/1/12) Lisinopril was d/ced and patient was referred to a Nephrologist at the WBVA.

• Repeat lab work by the nephrologist showed cr of 1.9 after lisinopril was d/ced. U/S abdomen was also performed that revealed right renal artery stenosis, left occluded renal artery and left small kidney

Physical Exam • VS: BP 167/103 HR 64 T 98.4 SO2 100% on RA • Gen: Middle aged male, NAD • Resp: clear to auscultation b/l • CVS: RRR, normal S1S2 • Abd: soft, nt, nd, bs positive • LE: no edema,warm, non palpable DP/PT bilaterally

Meds: Plavix 75 mg Norvasc 5 mg qday Atenolol 100 mg qday Chlorthalidone 12.5 mg q day Allergies: NKDA Fhx: Mother with history of HTN and MI Shx: h/o smoking 1PPD for 10 years. Occasional Etoh. No IV drug abuse

Labs: BMP: Na 138 K 3.4 Cl 99 bicarb 32 BUN 27 Cr 1.8 Ca 10.1 phos 3.6 Mg 2.0 CBC: WBC 8.2 Hgb 16.5 plt 296 Lipid panel Chol 199 HDL 33 TG 231 LDL 119 UA Protein neg, blood neg

Imaging Renal Ultrasound: Right kidney 11.3 cm, right renal artery stenosis. Left kidney 9.6 cm. Left renal artery occluded MRA abdomen There is atherosclerotic vascular disease of the abdominal aorta. The origin of left renal artery is not demonstrated with signal void from the artifact in the expected region of the origin and proximal left renal artery which may represent a stent, suggest clinical correlation. There is severe focal stenosis in the right proximal renal artery

Introduction • Atherosclerotic renal artery stenosis is a common problem

that is present in roughly 1% to 5% of the 60 million Americans with hypertension and in a higher percentage of patients with peripheral or coronary artery disease

• Recent date suggests that at least 7% of patients >65 years may have ARAS

… • Vascular occlusive disease poses a threat to kidney

viability, but whether the events leading to injury and fibrosis actually entail reduced oxygenation and regional tissue ischemia is unknown

• Is there a method to assess tissue oxygenation in humans?

Use of Magnetic Resonance to Evaluate Tissue Oxygenation in Renal artery Stenosis • BOLD (blood oxygen level dependent MRI detects changes in tissue

deoxyhemoglobin during manueuvers that affect oxygen consumption

• BOLD MRI was used to image and analyze cortical and medullary segments of 50 kidneys in 25 subjects undergoing MRI angiography to diagnose RAS

• Magnetic rate of relaxation (R2*)positively correlates with deoxyhemoglobin levels and therefore used as a surrogate measure of tissue oxygenation

• Lasix was administered to examine the effect of inhibiting energy dependent electrolyte transport on tissue oxygenation

J Am Soc Nephrol 19:780-788, 2008

J Am Soc Nephrol 19:780-788, 2008

J Am Soc Nephrol 19:780-788, 2008

J Am Soc Nephrol 19:780-788, 2008

J Am Soc Nephrol 19:780-788, 2008

Revascularization with stenting vs Medical therapy ?

Stenting for atherosclerotic renal artery stenosis: DRASTIC TRIAL: Dutch renal artery Stenosis Intervention Cooperative trial • 106 patients with renal artery stenosis and hypertension(

diastolic blood pressure >95 mm Hg) despite treatment with 2 antihypertensive medications were randomly assigned to either renal angioplasty( n =56) or drug therapy ( n=50)

• Primary outcome measures were the systolic and diastolic blood pressure at 3 months and 12 months after randomization

• Secondary outcome measures were the numbers and defined daily doses of antihypertensive drugs, the serum creatinine, the creatinine clearance according to Cockcroft and Gault

N Engl J Med 2000:342:1007-1014

23 had at least 50% stenosis

5 had an increase in the stenosis (20%points or more) 16 had no change 4 had a regression of stenosis

Progressed to total occlusion in 4 patients

N Engl J Med 2000:342:1007-1014

DRASTIC PROBLEMS Sample size was insufficient Balloon angioplasty without stenting was used Renal artery stenosis was defined as greater than 50% stenosis 22 of the 50 patients randomized to medical therapy crossed over to the angioplasty group

STAR TRIAL- Stent Placement in patients with atherosclerotic Renal artery Stenosis and Impaired Renal function

• 140 patients with a creatinine clearance of less than 80ml/min/1.73m2, renal artery stenosis greater than 50%, and well controlled blood pressure were randomized to either renal artery stenting plus medical therapy(n=64) or medical therapy alone (n=76).

• The primary end point was worsening of renal function, defined as a 20% or greater decrease in creatinine clearance compared with baseline.

• Secondary end points were procedural complications, changes in blood pressure, incidence of refractory or malignant hypertension and pulmonary edema, cardiovascular morbidity and mortality , and total mortality

Ann Intern Med. 2009; 150(12):840-848

Ann Intern Med. 2009; 150(12):840-848

Primary end point was reached in both the groups at a mean of 10 months 5/10 patients in the stent group had repeated angiography before reaching the end point-3 had no stenosis 1 had restenosis treated with stenting, 1 had restenosis treated with balloon angioplasty. All had persistence of decline in renal function1 month after repeated angiography

Ann Intern Med. 2009; 150(12):840-848

Ann Intern Med. 2009; 150(12):840-848

Primary end point

Primary end point plus death

… • Complications: • 2 died of procedure related causes within 30 days after

stent placement • 11 patients had hematoma at the puncture site. • 2 had false aneurysm of the femoral artery • Injury to the kidney or renal artery occurred in 5 patients

Ann Intern Med. 2009; 150(12):840-848

FLAWS

• Mild renal artery stenosis: 33% of the patients in the study had mild stenosis(50 to 70%) and 12 (19%) of the 64 patients randomized to stenting actually had stenosis of less than 50%

• More than half of the patients had unilateral disease • Not all “stent” patients received stents- only 46 (72%) of the 64 patients

randomized to stenting actually received a stent, while 18 (28%) did not . There were 2 technical failures and 12 patients should not have been randomized because they had less than 50% stenosis on angiography and thus were not stented. Yet all 64 patients were analyzed(by intention to treat) in the stent group

• Like DRASTIC , this trial was underpowered

• High complication rates. The periprocedural complication and death rates were much higher than in many other reports on renal artery stenting

ASTRAL TRIAL- Angioplasty and stenting for Renal artery Lesions • 806 patients with the atherosclerotic renal artery stenosis

were randomized to either stent based revascularization combined with medical therapy or medical therapy alone

• The primary outcome measure was the change in renal function over time as assessed by the mean slope of the reciprocal of the serum creatinine

N Eng J Med 2009;361:1953-62

N Eng J Med 2009;361:1953-62

N Eng J Med 2009;361:1953-62

N Eng J Med 2009;361:1953-62

N Eng J Med 2009;361:1953-62

N Eng J Med 2009;361:1953-62

… Complications of revascularization • 38 periprocedural complications in 31 of 359 patients(9%) who

underwent revascularization • 19 of these events were considered to be serious complications • 1 Pulmonary edema • 1 Myocardial infarction • 5 Renal embolizations • 4 Renal artery occlusions • 4Renal artery perforations • 1 Femoral artery aneurysm • 3 Cholesterol embolism leading to peripheral gangrene and

amputations of toes or limbs • 20% had an adverse event between 24 hours and 1 month after the

procedure- deaths(2), groin hematoma/hemorrhage (4), AKI (5)

N Eng J Med 2009;361:1953-62

ASTRAL Author’s Conclusion “ We found substantial risks but no evidence of clinical benefit from revascularization in patients with atherosclerotic renovascular disease” Despite size, flaws remain • Selection bias. For patient to be enrolled, the treating physician had to

be undecided on whether the patient should undergo revascularization or medical management alone

• Normal renal function at baseline. 25% of patients had normal renal function. In addition significant number had unilateral disease and 41% had stenosis less than 70%

• There was no core laboratory to adjudicate the interpretation of the imaging studies. The reason this is so important is that visual assessment of the degree of stenosis on angiography is not accurate and almost always overestimates the degree of stenosis

• High adverse event rate. Major adverse event rate in the first 24 hours was 9% whereas the usual rate is 2% or less

CORAL TRIAL- Cardiovascular Outcomes in Renal Atherosclerotic Lesions Will CORAL give us the answer? • CORAL is a randomized clinical trial contrasting optimal medical

therapy alone to stenting with optimum medical therapy on a composite cardiovascular and renal end point

• The primary end point is survival free of cardiovascular and renal adverse events, defined as composite of cardiovascular or renal death, stroke, myocardial infarction, hospitalization for congestive heart failure, progressive renal insufficiency or need for permanent renal replacement therapy.

• The secondary end points evaluate the effectiveness of revascularization in important subgroups of patients and with respect to all cause mortality, kidney function, renal artery patency, microvascular renal function and blood pressure control

American Heart Journal volume 152, july 2006

Primary inclusion criteria are 1) An atherosclerotic renal stenosis of ≥60% with a 20mm

Hg systolic pressure gradient or ≥ 80% with no gradient necessary and 2) systolic HTN of ≥ 155mm Hg on ≥ 2 antihypertensive medications

Study design

Optimal Medical therapy

• The first line drug will be an AII type I receptor antagonist, candesartan, with an ACE inhibitor used as a substitute for candesartan in candesartan intolerant subjects

• If the ARB or ACE-I produce a significant increase in Cr, then an alternative antihypertensive agent will be used

• An algorithm for stepwise BP control will be used • There will be no limit on the number or class of additional

antihypertensive drugs that patients can receive in either treatment arm

• Consistent with JNC VII recommendations, the target BP in patients without comorbidities will be <135/85mm Hg:

• In patients with diabetes and/or proteinuria, a lower target BP of <130/85 will be used

American Heart Journal volume 152, july 2006

Indications for stenting American College of Cardiology/AHA guidelines on indications for renal artery stenosis : Percutaneous revascularization is reasonable for patients with hemodynamically significant renal artery stenosis and • Accelerated hypertension, resistant hypertension and

malignant hypertension

• progressive kidney disease

• recurrent Unexplained congestive heart failure or sudden unexplained pulmonary edema

Thank You!