Renal Artery Stenosis

1
Renal Artery Stenosis The Good, The Bad and The
Different

• Rick Stouffer MD
• University of North Carolina

2
Disclosure

• I will discuss off-label uses
• No financial conflicts of interest

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The classic patient for renal artery
revascularization

• 55 year old male
• HTN, known CAD (prior PCI)
• Admitted with CP/SOB, BP 194/124 mm Hg
• BP Rx ACEI, beta blocker, nitrate
• Creatinine 1.6 mg/dl, HCT 41.8
• Referred for cardiac catheterization

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Renal angiography hemodynamic assessment
Aorta
Right renal artery
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Renal artery revascularization

• Accelerated HTN
• Mild elevation in creatinine
• Symptoms

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Did We Benefit This Patient?
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Outline

• Types of RAS
• Atherosclerotic RAS
• Natural history of the patient with RAS
• Treatment of RAS

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Renal Artery Stenosis

• Atherosclerotic (90)
• Fibromuscular dysplasia (10)
• Medial fibroplasia (90)
• classic "string of beads" appearance
• middle-to-distal portion of the artery
• Perimedial fibroplasia
• focal stenoses
• Intimal/Medial fibroplasia
• a focal, concentric stenosis
• Aortorenal dissection
• Vasculitis involving the renal artery (i.e. PAN)
• AVMs involving the renal artery
• Irradiation of the renal artery
• Scleroderma

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FMD Anatomy and Pathophysiology
70 year old female with chest pain and 4-drug
hypertension.
Circulation. 2005112e278-9.
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Before balloon angioplasty
After balloon angioplasty
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A Cautionary Tale

• 37-year-old male admitted with headache of six
  months duration that had worsened in the last
  week and was accompanied by blurry vision,
  dyspnea on exertion and weakness in his legs.
• No significant PMH, was not taking any
  medications and had never been diagnosed with
  hypertension. No history of alcohol or drug use.
• FH - mother with hypertension and a sister with
  migraine headaches.
• Brachial BP was 252/160 mm Hg with no significant
  difference between arms.

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A Cautionary Tale

• BP 252/160 mm Hg
• Ophthamology consultant - Grade IV retinopathy
  including marked AV nicking and venous
  dilatation, cotton wool spots, large areas of
  choroidal ischemia, delayed vascular filling,
  blind spots and papilledema in both eyes.
• MRI of the brain - No evidence of intracerebral
  mass but increased signal abnormality within the
  pons, consistent with hypertensive
  encephalopathy.
• MRI/MRA of the abdomen showed normal kidney size,
  no renal or adrenal masses and No evidence of
  renal artery stenosis.

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FMD not visualized on MRI/MRA
Balloon angioplasty with resolution of pressure
gradient
J Invasive Cardiol. 200719E31-3.
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5 years later - He has run marathons and climbed
Mount Kilimanjaro. Home systolic BPs of 130 mm Hg
on HCTZ 20 mg daily, enalapril 10 mg daily and
Norvasc 10 mg twice daily.
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Outline

• Types of RAS
• Atherosclerotic RAS
• Natural history of the patient with RAS
• Treatment of RAS

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Atherosclerotic RAS

• Usually ostial
• Associated with diseased aorta
• Can be unilateral or bilateral

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Prevalence of Atherosclerotic RAS

• 6.8 in healthy adults gt 65 years old
• Evaluation with renal artery duplex of 834
  patients consecutive patients who were
  participants in the Forsyth county cohort of the
  Cardiovascular Health Study (J Vasc Surg.
  20023644351).

• Unselected autopsies 4-27
• Hypertensives 1-4
• Aged 65 years and older 6.8
• Diabetics 8

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RAS is common in patients with vascular disease

• Prevalence of RAS
• Proven MI 12
• Undergoing cardiac catheterization 6-19
• Lower extremity PVD 22-59
• Predictors of RAS in patients undergoing cardiac
  catheterization
• CAD Age PVD serum creatinine hypertension

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Traditional Paradigm of Renal Artery Stenosis
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The Changing Paradigm of Renal Artery Stenosis
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Outline

• Types of RAS
• Atherosclerotic RAS - Prevalence and 'Risk
  factors'
• Natural history of the patient with RAS
• Treatment of RAS

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A tale of two patients
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RAS is a marker of a poor prognosis
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Dismal Prognosis Associated with RAS

• 3 year mortality
• 26 in patients treated with stents (Circulation
  199898642-647)
• 28 in patients managed medically (Mayo Clin Proc
  200075437)
• 4 year mortality
• 43 in patients with RAS discovered incidentally
  at cardiac catheterization (Kidney International
  2001601490-1497)
• 35 in patients with RAS discovered incidentally
  at cardiac catheterization (JASN 19989252-256)
• 26 in a multi-center study of patients
  undergoing percutaneous renal revascularization
  (Circulation 199898642-647)
• 5 year mortality
• 33 in a single-center study of patients
  undergoing percutaneous renal artery
  revascularization (Catheter Cardiovasc Interv.
  2007691037)

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Effect of RAS on Prognosis Relative Five year
Survival
Ries LAG et al. SEER Cancer Statistics Review,
1973-1998. National Cancer Institute. September
2000.
26
Clinical Events in Patients With RAS
Claims data from a 5 random sample of the United
States Medicare population were used to select
patients without atherosclerotic renovascular
disease in the 2 years preceding December 31,
1999 (N 1,085,250), followed until December 31,
2001.
J Am Coll Cardiol Intv 20092175-182
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The 64000 Question

• Is RAS a marker of severe atherosclerosis and
  thus portends a poor prognosis?
• or
• Does RAS contribute to progression of vascular
  disease - thus implying that effective treatment
  may improve clinical outcomes?

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Outline

• Types of RAS
• Atherosclerotic RAS
• Natural history of the patient with RAS
• Treatment of RAS

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Optimal Medical Treatment

• ARB diuretic to get BP to target
• lt140/90 mm Hg
• lt130/80 mm Hg with DM
• LDL to goal
• Currently lt100 (or 70) mg/dl
• Diabetes Management
• HbA1c to target (lt7)
• Smoking Cessation
• Anti-platelet therapy (aspirin /-
  clopidogrel/prasugrel)

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What role does revascularization play?
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Percutaneous Treatment of RAS

• 1978 - Gruentzig and colleagues report first
  balloon angioplasty of renal artery stenosis
• Gruentzig A, Kuhlmann U, Vetter W. Treatment of
  renovascular hypertension with percutaneous
  transluminal dilatation of a renal artery
  stenosis. Lancet 1978 1801-802.
• Fall 1978 - first renal artery angioplasty in US
  at UVa. - Patient referred by Carlos Ayers to
  Charles Tegtmeyer who obtained angioplasty
  balloon from Gruentzig in exchange for fishing
  equipment.
• Tegtmeyer CJ, Dyer R, Teates CD, Ayers CR, Carey
  RM, Wellons HA Jr, Stanton LW. Percutaneous
  transluminal dilatation of the renal arteries
  techniques and results. Radiology 1980
  135(3)589-599

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Treatment of RAS
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Evidence-based Medicine
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Evidence-based Medicine

• Reviewed 55 studies
• Almost two thirds of the studies that we
  reviewed were of poor methodologic quality none
  was deemed to be of good quality.
• More than half of the studies had limited
  applicability to patients commonly seen in
  practice or to modern management strategies.
• No study directly compared angioplasty with
  stent placement and "aggressive" medical
  treatment with currently available
  antihypertensive, antiplatelet, and
  lipid-lowering agents.

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Effect of RA Revascularization on HTN

• Study Device N Cure Improved
• Klinge stent 134 10 68
• Lossino stent 153 12 51
• DRASTIC balloon 106 7 68
• Rocha stent 150 6 50
• Dorros stent 145 1 52

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Effects of RA Revascularization on Ischemic
Nephropathy
Prog Cardiovasc Dis 200750136
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Angioplasty and STent for Renal Artery Lesions
NEJM 20093611953-1962
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ASTRAL Trial
Substantial atherosclerotic RAS Suitable for
endovascular revascularization
Patient's doctor was uncertain that the patient
would benefit from revascularization
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PATIENT CHARACTERISTICS
Revasc. Medical P-value
Mean age (range) 70 (42 86) 71 (43 88) 0.7
Male 63 63 0.9
Current smoker 20 22 0.5
Diabetes 31 29 0.5
CHD 49 48 0.2
PVD 41 40 0.7
GFR (ml/min) 40.3 (5.4 124.5) 39.8 (7.1 121.7) 0.7
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Blood Pressure, Cholesterol, Stenosis
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Procedural Complications

• 38 periprocedural complications in 31 of the 359
  patients (9) who underwent revascularization
  (including 1 of the 24 patients in the
  medical-therapy group who crossed over to
  revascularization)
• Nineteen of these events (in 17 patients) were
  considered to be serious complications
• Pulmonary edema (1) and Myocardial infarction (1)
• Renal embolizations (5), Renal arterial
  occlusions (4) and Renal-artery perforations (4)
• Femoral-artery aneurysm (1)
• Cholesterol embolism leading to peripheral
  gangrene and amputation of toes or limbs (3)

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Medications at One Year
Revasc. Medical P-value
Any Anti-hypertensives 97 99 0.03
Diuretic 64 69
Ca2 antagonist 63 71
Beta-blocker 46 55 0.02
ACE-I, A-II antagonist 50 43 0.05
Alpha-blocker 39 38

Mean no. anti-hypertensives 2.77 (1 - 6) 2.99 (1 - 6) 0.03
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Blood Pressure
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Serum Creatinine
45
Clinical Events
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Survival
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• An important limitation of our trial concerns
  the population that we studied. As noted,
  patients were enrolled in the trial only if their
  own physician was uncertain as to whether
  revascularization would provide a worthwhile
  clinical benefit.
• Patient selection (single center)
• 508 patients with atherosclerotic renovascular
  disease
• Of these, 283 patients had renal-artery stenosis
  of more than 60
• 71 underwent randomization
• 24 underwent revascularization outside the trial
• poorly controlled hypertension
• rapidly declining renal function,
• 188 received medical treatment only.

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RAS and stenting has the question been answered?
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Criticisms of ASTRAL

• 1. Selection bias and inexperienced operators
• On average, 2 patients per center per year
  underwent randomization, which indicates serious
  selection bias or inexperienced staff at centers
  with very low intervention rates. This concern is
  supported by a low rate of technical success (317
  of 403 patients 79 in the revascularization
  group) and a high rate of serious complication in
  23 of 280 patients (8) as compared with reports
  in the literature of 98 and 2, respectively.

NEJM 2010362762
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Criticisms of ASTRAL

• 2. There was a reduction in the number of
  antihypertensive drugs in stent treated patients
• The study design implies that optimal medical
  therapy was used to achieve normalized blood
  pressure in both groups. Thus, not only the blood
  pressure values but also the number of
  antihypertensive drugs used to achieve this goal
  should be taken into account. The significantly
  lower number of antihypertensive drugs
  administered in the revascularization group
  (P0.03) preclude the definitive conclusion that
  renal-artery revascularization provides no
  clinical benefit.

NEJM 2010362762
51
Criticisms of ASTRAL

• 3. Patients with severe RAS were not enrolled
• The results of the ASTRAL investigation should
  be read and interpreted critically. As with the
  COURAGE (Clinical Outcomes Utilizing
  Revascularization and Aggressive Drug Evaluation)
  trial, the take-home message should be that for
  patients with a moderate degree of renal-artery
  stenosis, medical management is as effective as
  revascularization over a 5-year follow-up period.
  Patients seen as requiring anatomical correction
  were not enrolled only those deemed suitable for
  randomization to stenting or medical therapy were
  included. Thus, the patients most likely to
  benefit from stenting (those with subocclusive
  lesions or with very severe disease in one or
  both kidneys) were not part of this study.

NEJM 2010362762
52
Criticisms of ASTRAL

• 4. More concern about high complication rate
• Another concern is the prohibitively high rate
  of amputation and embolization in this study.
  This calls into question the appropriateness and
  safety of the techniques currently used to
  perform the procedure. In more than 200
  consecutive cases in which the technique known as
  "no touch"1 was used (with a guidewire in the
  aorta preventing the guide catheter from
  dislodging aortic plaque), I have not seen
  amputation, limb ischemia, or any evident
  embolization.

NEJM 2010362762
53
Criticisms of ASTRAL

• 5. Were the right patients enrolled?
• The primary outcome was the change in renal
  function, inferred from the reciprocal of the
  serum level of creatinine. However, serum
  creatinine is only a rough indicator of the
  glomerular filtration rate. Furthermore, patients
  with major indications for revascularization were
  excluded from the study, whereas patients with
  either insignificant vascular lesions or advanced
  renal disease (kidneys 6 cm in length), for whom
  no benefit from revascularization could be
  expected, were enrolled. Moreover,
  intraparenchymal resistance, a relevant predictor
  of the success of revascularization, was not
  evaluated.

NEJM 2010362762
54
Criticisms of ASTRAL

• 6. Were the patients on the right drugs?
• only about 40 to 50 of the patients were
  treated with drugs that block the pathway of the
  reninangiotensinaldosterone system the use of
  such drugs is currently recommended in any
  patient with atherosclerotic renal-artery
  stenosis.

NEJM 2010362762
55
Criticisms of ASTRAL

• 7. Severe RAS was not confirmed prior to entry
  into the study
• A major limitation of the ASTRAL trial was its
  inclusion of patients whose diagnosis of renal
  artery stenosis was made on the basis of
  noninvasive imaging alone. No attempt was made to
  confirm the severity of stenosis with digital
  subtraction angiography or to assess its
  functional significance before randomization.

NEJM 2010362762
56
Criticisms of ASTRAL

• 8. Not all patients in the intervention group had
  stenting
• Furthermore, 17 of the patients in the
  revascularization group did not proceed to
  revascularization after invasive angiography.

NEJM 2010362762
57
be actuated by that perfect impartiality, which
has ever been considered most favorable to
correct decisions. Abraham Lincoln
Circulation 2007115271-276
Circulation 2007115263-270
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• NIH Funded Trial
• Prospective, multi-center, two armed,
  randomized, unblinded survival (time to event)
  clinical trial
• To test the hypothesis that optimal medical
  therapy stenting reduces the incidence of
  cardiovascular and renal events compared to
  optimal medical therapy alone in patients with
  systolic hypertension
• gt100 centers participating
• 1080 patients

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• Documented history of systolic hypertension
  (gt155 mm Hg) on 2 or more antihypertensive
  medications
• One or more renal artery stenosis (gt 60
  stenosis)
• All patients receive OMT - Randomization to
  stent vs no stent

• Large and with long term follow-up
• Clinically important outcomes
• Cardiovascular or Renal Death
• Stroke
• Myocardial Infarction
• Hospitalization from CHF
• Progressive Renal Insufficiency
• Renal Replacement Therapy
• All patients receive optimal medical therapy

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Where do we stand now?

• In the absence of trials showing benefit from
  revascularisation over conventional therapy and
  the significant risk of complications it seems
  reasonable to restrict procedures to patients who
  fail medical therapy with
• resistant or poorly-controlled hypertension
• recurrent flash pulmonary edema
• dialysis-dependent kidney failure resulting from
  renal artery stenosis
• chronic renal insufficiency and bilateral renal
  artery stenosis
• renal artery stenosis to a solitary functioning
  kidney.

Agency for Healthcare Research and Quality (AHRQ)
Available at www.guideline.gov
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Where do we stand now?

• In the absence of significant differences in
  long-term outcome measures, given the rates of
  restenosis following simple balloon angioplasty
  and the complications and costs of surgical
  intervention, it would seem reasonable to
  consider angioplasty with stenting as the
  revascularisation procedure of choice for
  medically recalcitrant renal artery stenosis.
  (Level IV evidence)
• The above clinical guidelines refer to patients
  with significant de novo renal artery stenosis
  (generally more than 5080 reduction in luminal
  diameter). There have been no studies in patients
  identified with lesser degrees of stenosis. It
  seems reasonable to offer medical therapy in
  these individuals, given the natural history of
  progressive stenosis in atherosclerotic renal
  disease.

Agency for Healthcare Research and Quality (AHRQ)
Available at www.guideline.gov
62
Are we asking the wrong question?

• Does RAS contribute to progression of vascular
  disease?
• Are there different phases of RAS with
  potentially different treatments?
• Will optimal treatment differ based on patient
  characteristics?
• What constitutes optimal medical therapy?
• What outcomes should we measure?
• Is the disease more than just BP and Ang II?

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Data from Animal Model of Renal Artery Stenosis
Time
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Summary

• RAS is an unusual cause of hypertension but a
  common finding in patients with vascular disease
• RAS identifies patients with very poor prognosis
  and a high risk of cardiovascular events
• Revascularization will benefit select patients
  with RAS but convincing evidence of improved
  cardiovascular outcomes in most patients is
  lacking
• A better understanding of the pathophysiology of
  RAS is needed in order to design more effective
  therapies

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RAS Still much to learn!
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