Renal Artery Stenosis

1
Renal Artery Stenosis

• Residents conference
• Presented by Gagandeep K Heer, MD
• (PGY-2)

2
Background

• Renal artery stenosis (RAS) is the major cause of
  renovascular hypertension and it accounts for
  about 1-10 of the 50 million people in the
  United States who have hypertension. The
  incidence is less than 1 of cases of mild to
  moderate HTN. However, it rises to 10 to 45 in
  patients with acute (or superimposed upon a
  preexisting elevation in blood pressure), severe,
  or refractory hypertension.
• Renovascular hypertension (RVHT) denotes
  nonessential hypertension in which a causal
  relationship exists between anatomically evident
  arterial occlusive disease and elevated blood
  pressure. RVHT is the clinical consequence of
  renin-angiotensin-aldosterone activation as a
  result of renal ischemia.
• RAS is also being increasingly recognized as an
  important cause of chronic renal insufficiency
  and end-stage renal disease. Studies suggest that
  ischemic nephropathy from RAS may be responsible
  for 5-22 of advanced renal disease in all
  patients older than 50 years in US.

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Causes of RAS

• Major causes of the renal arterial lesions are
• Atherosclerosis It is the cause of RAS in gt2/3rd
  of the cases. This primarily affects men over the
  age of 45 and usually involves the aortic orifice
  or the proximal main renal artery. This disorder
  is particularly common in patients with diffuse
  atherosclerosis, but can occur as a relatively
  isolated renal lesion.
• Fibromuscular dysplasia In comparison to
  atherosclerosis, fibromuscular dysplasia most
  often affects younger women and typically
  involves the distal main renal artery or the
  intrarenal branches.
• Other less common causes of RAS include
• Vasculitis (Takayasus arteritis)
• Dissection of the renal artery.
• Thromboembolic disease
• Renal artery aneurysm
• Renal artery coarctation
• Extrinsic compression
• Radiation injury

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Pathophysiology

• Atherosclerotic RAS
• The initiator of endothelial injury is not clear
  however, dyslipidemia, hypertension, cigarette
  smoking, diabetes mellitus, viral infection,
  immune injury, and increased homocysteine levels
  may contribute to endothelial injury.
• In the atherosclerotic lesion site, endothelium
  permeability to plasma macromolecules (e.g. LDL)
  increases, turnover of endothelial cells and
  smooth muscle cells and intimal macrophages also
  increases. When atherogenic lipoproteins exceed
  certain critical levels, the mechanical forces
  may enhance lipoprotein insudation in these
  regions, leading to early atheromatous lesions.
  The sites where the initial atherosclerotic
  lesions developed are more prone to physiological
  adaptation to mechanical stress secondary to
  variations in flow and wall tension (e.g. renal
  artery site).

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Pathophysiology

• Fibromuscular dysplasia
• Fibromuscular dysplasias are uncommon
  angiopathies associated with heterogeneous
  histologic changes that may affect the carotid
  circulation as well as the visceral and
  peripheral arteries.
• String of beads is the classic radiographic
  finding seen in FMD.
• FMD, as a cause of RAS usually affects young to
  middle-aged adults, mostly women, but it can also
  affect children.

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Pathophysiology

• Renal blood flow is 3 to 5 fold greater than the
  perfusion to other organs because it drives
  glomerular capillary filtration. Both glomerular
  capillary hydrostatic pressure and renal blood
  flow are important determinants of the glomerular
  filtration rate (GFR).
• In patients with RAS, the GFR is dependent on
  angiotensin II and other modulators that maintain
  the autoregulation system between the afferent
  and efferent arteries and can fail to maintain
  the GFR when renal perfusion pressure drops below
  70-85 mm Hg. Significant functional impairment of
  autoregulation, leading to a decrease in the GFR,
  is not likely to be observed until arterial
  luminal narrowing exceeds 50.
• RVHT develops as a result of increased renin and
  angiotensin II levels causing vasoconstriction as
  well as salt and water retention (volume
  expansion) due to increased aldosterone level.

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Pathophysiology

• Increased secretion of renin accelerates the
  conversion of angiotensin I to angiotensin II
  which enhances the adrenal release of
  aldosterone.
• Angiotensin II causes vasoconstriction of both
  afferent and efferent arterioles, with a
  preferential affect on the efferent side. Under
  physiologic conditions, efferent tone is
  essential to maintain intraglomerular pressure.
• In a kidney rendered ischemic by RAS with a
  reduced afferent blood flow, the intraglomerular
  pressure and glomerular filtration are maintained
  by angiotensin IImediated efferent
  vasoconstriction. Removal of the efferent
  vasoconstriction effect by using angiotensin
  blockade (e.g. by using ACEI) may reduce GFR by
  causing decrease in intraglumerular pressure.
• In patients with RAS, the chronic ischemia
  produces adaptive changes in the kidney that are
  more pronounced in the tubular tissue. These
  changes include atrophy with decreased tubular
  cell size, patchy inflammation and fibrosis,
  tubulosclerosis, atrophy of the glomerular
  capillary tuft, thickening and duplication of the
  Bowman capsule, and intrarenal arterial medial
  thickening.

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Demographics

• Race RVD is less common in African American
  patients. The incidence rate in 2 studies of
  patients with severe hypertension was 27-45 in
  whites compared to 8-19 in African Americans.
• Sex While the incidence of atherosclerotic RVD
  is independent of sex, Crowley et al showed that
  female sex (as well as older age, elevated serum
  creatinine level, coronary artery disease,
  peripheral vascular disease, hypertension, and
  cerebrovascular disease) is an independent
  predictor of RVD progression.
• Age The incidence of RAS increases with
  increasing age.
• In 1964, Holley et al reported
  data from 295 consecutive autopsies performed in
  their institution during a 10-month period. The
  mean age at death was 61 years. In the whole
  group, the prevalence rate of RAS was 27 of 256
  cases identified as having history of
  hypertension. 56 of these showed significant
  stenosis (gt50 luminal narrowing). Among
  normotensive patients, the incidence of severe
  RAS was 17. Among those older than 70 years, 62
  had severe RAS.
• Another study reported similar
  results, showing 18 incidence of severe RAS for
  patients aged 65-74 years and 42 for patients
  older than 75 years.

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Clinical Findings

• Difficult-to-control hypertension despite
  adequate medical treatment
• Hypertension with renal failure or progressive
  renal insufficiency
• Accelerated or malignant hypertension
• Severe hypertension (diastolic blood pressure
  gt120 mm Hg) or resistant hypertension
• Hypertension with an asymmetric kidney
• Paradoxical worsening of hypertension with
  diuretic therapy
• Onset of hypertension occurring in patients
  younger than 30 years or older than 50 years
• Symptoms of atherosclerotic disease elsewhere

10
Clinical Findings

• Negative family history of hypertension
• Cigarette smoking or use of other tobacco
  products
• Renal failure with ACE inhibition. An increase in
  serum creatinine of more than 15 is strongly
  associated with a high incidence of RVD
• Recurrent pulmonary edema (flash edema)
• Advanced fundoscopic changes
• Systolic-diastolic abdominal bruits (In
  combination with hypertension, these are
  suggestive of RVHT)
• Unexplained renal insufficiency in elderly
  patients
• Congestive heart failure with poor control of
  hypertension and renal insufficiency in the
  absence of a significant decrease in ejection
  fraction

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Risk factors associated with ischemic renal
disease

• Carotid artery disease
• Coronary artery disease
• Diabetes mellitus
• Hypertension
• Obesity
• Old age
• Peripheral vascular disease (vascular disease in
  the extremities, e.g. the legs)
• Smoking
• Familial history of AD or RAS

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Differential diagnosis

• Acute renal failure
• Chronic glomerulonephritis
• Malignant HTN causing renal failure
• Hypersensitivity nephropathy
• Nephrosclerosis
• Essential and other causes of hypertension with
  renal insufficiency

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Mortality/Morbidity

• In patients with hypertension, atherosclerotic
  renal artery disease is a strong predictor of
  increased mortality relative to the general
  population. In the setting of renal dysfunction,
  RVHT is associated with the greatest mortality
  rate.
• Major complications of RVHT include end-organ
  damage due to chronically uncontrolled
  hypertension (CAD, stroke, etc.) and progressive
  renal insufficiency, which is an important sequel
  of chronic renal ischemia.
• HTN may be particularly difficult to control or
  may require multiple antihypertensive agents
  (with increased adverse effects and drug
  interactions).
• In addition, atherosclerotic RVD frequently
  occurs in the setting of generalized vascular
  disease (i.e. cerebral, cardiac, peripheral),
  with the consequences associated with disease in
  those vascular beds.

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Work-up

• Laboratory Studies
• Serum creatinine and creatinine clearance.
• 24-hour urine protein Vascular renal disease is
  associated with minimal-to-moderate degrees of
  proteinuria, which are rarely in the nephrotic
  range.
• Urinalysis shows absence of red blood cells or
  red blood cell casts (a hallmark of
  glomerulonephritis).
• Serologic tests for SLE or vasculitis should be
  performed if these conditions are suggested (e.g.
  antinuclear antibodies, C3, C4, antinuclear
  cytoplasmic antibodies).
• Measurement of plasma renin activity The
  baseline plasma renin activity is elevated in
  50-80 of patients with RVHT.
• Captopril test Measuring the increase in the
  baseline plasma renin activity 1 hour after the
  administration of 25-50 mg of the ACE inhibitor
  (captopril) can increase the predictive value of
  baseline plasma renin activity. Patients with RAS
  have an exaggerated increase in baseline plasma
  renin activity, perhaps due to the removal of the
  normal suppressive effect of high angiotensin II
  levels on renin secretion in the ischemic kidney.
  
• Renal vein renin ratio 1.5 between
  stenotic/contralateral kidney are of considerable
  value in determining functionally important
  lesions and predicting cure or improvement of HTN
  with PTA or surgical intervention (although PTA
  or surgery will also benefit one-third to half
  the patients without lateralizing renal vein
  renin ratios).

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Imaging Studies

• Ultrasound/Duplex ultrasound Renal US may show
  significant asymmetry of kidney size (i.e. size
  discrepancy of gt1.5 cm). Additionally, US may be
  useful to determine the presence of a solitary
  kidney. Duplex ultrasound scanning is a
  noninvasive diagnostic technique that combines a
  B-mode ultrasound image with a pulse Doppler unit
  to obtain flow velocity data. It is noninvasive,
  relatively inexpensive, and can be used in
  patients with any level of renal function.
• Captopril renography Radionuclide renal imaging
  can be done using Tc99m DTPA, Tc99m MAG3 or OIH (
  orthoiodohippuran). It is a safe and noninvasive
  way to evaluate renal blood flow and excretory
  function. When captopril is administered
  (especially in unilateral RAS), the GFR of
  stenotic kidney falls by about 30 and the normal
  kidney exhibits an increase in the GFR.
  Sensitivity of this test is about 85-90 and
  specificity of 93-98. Significant azotemia and
  bilateral RAS adversely affect this accuracy,
  making it unsuitable for these situations.
• CT angiography (Spiral CT) This technique
  involves the use of IV iodinated contrast
  material and allows 3-dimensional reconstruction
  images of the renal arteries. Spiral CT is a
  useful technique that avoids arterial
  catheterization and produces accurate images of
  renal artery anatomy.

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Imaging Studies

• Magnetic resonance angiography Magnetic
  resonance angiography (MRA) is a very good
  noninvasive technique capable of demonstrating
  the renal vascular anatomy and direct
  visualization of renal artery lesions without
  iodinated contrast material.
• The limitations of MRA are its expense and its
  contraindication in patients with metallic clips,
  pacemakers, intraocular metallic devices, or
  other implants.
• The sensitivity of MRA gt 90 for proximal RAS,
  82 for main RAS, and very low ( 0) for
  segmental stenosis.

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Dynamic gadolinium-enhanced magnetic resonance
angiogram (MRA) shows normal renal arteries.
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Imaging

• Renal arteriography This technique remains the
  gold standard for the confirmation and
  identification of renal artery occlusion in
  persons with IRD. Specialists can perform renal
  arteriography by conventional aortography,
  intravenous subtraction angiography,
  intra-arterial digital subtraction angiography
  (DSA), or carbon dioxide angiography.
• Conventional aortography produces excellent
  radiographic images of the renal artery.
• It is, however, an invasive procedure that
  requires an arterial puncture, carries the risk
  of cholesterol emboli, and uses a moderate amount
  of contrast material with the risk of
  contrast-induced acute tubular necrosis (ATN).
• Low osmolar contrast material can limit the risk
  of CEN.

19
Digital subtraction flush aortogram in a
77-year-old normotensive man shows marked left
renal artery stenosis and diffuse aortic
atheroma. The patient presented with lower-limb
claudication.
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• Digital subtraction flush aortogram in an
  83-year-old mildly hypertensive man shows
  complete occlusion of the left renal artery only
  a stub of the artery is visualized. Note the
  diffuse aortic atheroma. The patient presented
  with lower-limb claudication.

21

• Aortogram of a 4-year-old child with renovascular
  hypertension caused by stenosis of the left renal
  artery.

22
Flush aortogram in a 32-year-old man with
familial hypercholesterolemia and
difficult-to-control hypertension. Radiograph
shows a complete occlusion of the right renal
artery and marked stenosis of the left renal
artery.
23

• Left Flush aortogram in a 63-year-old man with
  hypertension shows marked stenosis of the right
  renal artery and complete occlusion of the left
  renal artery. Note the extensive atheroma in the
  aorta and iliac arteries.
• Right nephrogram-phase image shows a
  significantly smaller left kidney with a faint
  nephrogram.

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Selection of diagnostic tests

• Once patients are identified as being at higher
  risk of RAS, the choice of the best test for
  diagnosis is controversial.
• Accurate identification of patients with
  correctable renovascular hypertension can be
  difficult with use of standard noninvasive
  techniques (e.g. sonography, CT angio, MRA)
  because they provide only indirect evidence of
  the presence of renal artery lesions.
• On the other hand, invasive techniques with more
  accurate diagnostic potential can produce a
  worsening of renal function because of contrast
  toxicity and complications related to the
  procedures themselves (e.g. arterial puncture,
  catheter-induced atheroembolism).

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Selection of diagnostic tests

• When the history is highly suggestive and no risk
  for radiocontrast-mediated renal injury is
  present, an intraarterial DSA or conventional
  angiogram is the appropriate initial test. In
  patients at risk, a carbon dioxide angiogram can
  determine the presence of a stenosis, and the
  risk of radiocontrast angiogram is imposed only
  on those individuals are most likely to benefit.
• Perform a spiral CT scan, MRA, or duplex
  ultrasonography (depending on availability and
  local experience) when moderate suspicion of
  renovascular disease exists. A negative test
  result indicates that an RAS is highly unlikely,
  while a positive test result can be followed by
  renal arteriography.

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Selection of Diagnostic Tests

• Gilfeather et al performed a study evaluating
  conventional angiography versus
  gadolinium-enhanced MRA in 54 patients and 107
  kidneys. The study showed that in 70 kidneys
  (65), the average degree of stenosis reported by
  readers of both modalities differed by 10 or
  less. In 22 cases (21), MRA overestimated the
  degree of stenosis by more than 10 relative to
  the results of conventional angiography in 15
  cases (14), MRA underestimated the stenosis by
  more than 10.

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Selection of Diagnostic Tests

• The obvious advantages of conventional
  angiography are its ability to accurately
  determine the extent of the lesion and suggesting
  its clinical importance (by demonstrating
  post-stenotic dilation) and the ability to
  concurrently perform endovascular therapy.
• However, specialists should weigh these
  advantages against the higher cost and greater
  morbidity of conventional angiography.
• All these tests should be done if the pt is a
  reasonable candidate for revascularization
  procedure.

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Prognosis

• Images from sequential abdominal aortographs or
  duplex ultrasound scans in patients with
  documented renal artery lesions who have been
  treated medically have shown that progressive
  arterial obstruction occurs in 42-53 of patients
  with atherosclerotic RAS, often within the first
  2 years of radiographic follow-up.
• The incidence rate of progression to complete
  renal artery occlusion in these studies ranges
  from 9-16 this often occurs in patients with a
  high-degree stenosis. In a study of 85 patients
  at the Cleveland Clinic who were followed for
  3-172 months, patients with mild-to-moderate
  stenosis remained unchanged upon follow-up, and
  39 of patients with greater than 75 lesions
  progressed to total occlusion.
• The prognosis of patients with RVHT is difficult
  to ascertain and varies with the extent of the
  occlusive phenomena, the sensitivity of the
  individual to antihypertensive therapy, and the
  efficacy of surgical repair and/or angioplasty.
• RVHT in the setting of chronic renal ischemia and
  consequent renal dysfunction has been linked to
  worse outcomes.

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Treatment

• It is crucial to remember that not all HTN in the
  presence of anatomic RAS is renovascular HTN.
• Many normotensive patients and those with
  essential HTN can also have some degree of RAS
  and do not need revascularization.

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Treatment

• Interventions appropriate for patients with
  RAS/RVHT may include
• Medical therapy
• Percutaneous transluminal angioplasty (PTA) with
  or without vascular stent placement
• Surgical revascularization
• Intravascular ultrasonography-guided atherectomy

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Medical therapy

• Treatment with antihypertensive drugs is
  indicated and optimal blood pressure control is
  essential. ACE inhibitors should be avoided. CCB,
  beta blockers and many other classes of drugs can
  be safely used. In many patients, blood pressure
  can be well controlled with medical therapy.
• Other risk factors that should be addressed
  include atherosclerosis, smoking, and
  hyperlipidemia.
• Definitive therapy for the RAS should always be
  considered not only for better control of HTN but
  also to prevent the development of ischemic
  nephropathy.
• In patients with diffuse atherosclerosis, the
  complication rate with both surgery and
  angioplasty is relatively high. Medical therapy
  may be preferred to other treatments many cases
  after carefully weighing risks and benefits of
  the invasive intervention.

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Percutaneous transluminal angioplasty (PTA)

• PTA has become the procedure of choice for
  treatment of symptomatic stenoses. Patency rates
  after PTA are strongly dependent on the size of
  the vessel treated and the quality of inflow and
  outflow through the vessel. Because of the
  excellent results obtained with renal
  angioplasty, it is the most commonly performed
  procedure in symptomatic RAS.
• Previously, a solitary or transplanted kidney was
  considered a contraindication for PTA. This is no
  longer the case and, angioplasty is now
  considered the procedure of choice for treatment
  of RAS in these patients.

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PTA

• Technical success is achieved in more than 90 of
  patients, and patency rates are 90-95 at 2 years
  for FMD and 80-85 for atherosclerosis.
• Restenosis requiring repeat angioplasty has been
  reported in fewer than 10 of patients with FMD
  and in 8-30 with atherosclerotic stenosis.
• Improvement in blood pressure control with fewer
  antihypertensive medications is achieved in
  30-35 of fibromuscular lesions and in 50-60 of
  atherosclerotic lesions.
• A success rate of 83 has been reported with PTA
  in RAS associated with renal transplantation.

35
Left A balloon angioplasty catheter is seen in
situ across the left renal artery stenosis.
Right After angioplasty, an excellent anatomic
(and functional) result was achieved.
36

• Left renal artery stenosis
  After PTA

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Vascular stent placement

• Vascular stenting is considered complementary to
  PTA.
• Many vascular stents are now available, which can
  be either self-expanding or balloon expandable.
  Drug-eluting stents are also available.
• Intravascular stents placed during angioplasty
  may be helpful in the prevention of restenosis.
• Early results suggest that stenting may prove
  useful in patients with ostial disease, in those
  in whom restenosis occurs after PTA, or in those
  with complications (e.g. renal artery dissection)
  resulting from PTA.
• Primary renal artery stenting in patients with
  atherosclerotic RAS has a high technical success
  rate and a low complication rate.

39
Intravascular ultrasonography-guided atherectomy

• In a single reported case, hypertension secondary
  to AD was successfully diagnosed with
  intravascular sonography, and intravascular
  sonography-guided renal atherectomy was curative.

40
Surgical revascularization

• Currently, surgical revascularization is reserved
  for patients in whom the main renal artery
  appears completely occluded and in whom the
  surviving renal parenchyma is vascularized by
  collaterals.
• Surgical revascularization might also be used
  when an ostial stenosis is present with a
  buttressing atheroma on either side of the
  ostium.

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Surgery

• Several surgical options are available.
• The stenotic segment may be excised and the
  artery resutured directly onto either the aorta
  or surviving stump.
• A vein graft may be transplanted or the kidney
  resected and reimplanted in the iliac fossa with
  the renal artery anastomosed to the iliac artery.
  
• Another novel method involves a splenectomy and
  anastomoses of the splenic artery to the renal
  artery when RAS involves the left kidney. The
  underlying diagnosis determines the results of
  this surgery.
• With advanced diffuse atherosclerosis, surgery
  may become less feasible because the certainty
  that the RAS is the cause of the hypertension is
  less and the prognosis may be determined by
  comorbidities.

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Surgery

• A potential complication of surgery is the
  release of cholesterol emboli during the surgery
  which can cause renal failure however, 80-90 of
  patients undergoing operation for atherosclerotic
  RAS benefit with cure or improvement. The
  perioperative mortality rate is less than 5.
• In patients with FMD, the cure rate is as high as
  80, and morbidity rates are low. However, these
  results are not significantly better than what
  can be achieved with renal angioplasty, at less
  morbidity, mortality, cost, and inconvenience.
• In patients with diffuse atherosclerosis, the
  complication rate with both surgery and
  angioplasty is relatively high.

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Criteria for Revascularization

• All patients with bilateral stenosis and stenosis
  in a solitary functioning kidney are candidates
  for revascularization, regardless of whether they
  have renal insufficiency.
• When renal insufficiency is present, patients
  with unilateral stenosis are also possible
  candidates for revascularization

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Criteria for Revascularization

• When renal function is normal or nearly normal,
  specialists recommend revascularization if the
  patient meets the following criteria
• The degree of stenosis is more than 80-85.
• The degree of stenosis is 50-80, and
  captopril-enhanced scintigraphy findings
  demonstrate an activation of intrarenal renin
  angiotensin system.
• Conversely, physicians can choose observation
  instead of revascularization (serial imaging
  every 6 mo with duplex scanning, accurate
  correction of dyslipidemia, use of drugs that
  block platelet aggregation) when the patient
  meets the following criteria
• Stenosis is 50-80, and scintigraphy findings are
  negative.
• The degree of stenosis is less than 50.

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Criteria for Revascularization

• When renal insufficiency is present and the
  objective is recovery of renal function together
  with prevention of further renal function
  impairment, the prerequisites for
  revascularization are as follows
• The serum creatinine level is lower than 4 mg/dL.
  
• The serum creatinine level is higher than 4 mg/dL
  but with a possible recent renal artery
  thrombosis.
• When these conditions are satisfied,
  revascularization can be done if the following
  apply
• The degree of stenosis is more than 80.
• The serum creatinine level is increased after
  administration of ACE inhibitors.
• The degree of stenosis is 50-80, and the
  scintigraphy findings are positive.

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When to chose conservative therapy

• Restrict conservative treatment in patients with
  an established diagnosis of IRD only to those
  with absolute contraindications to surgery or
  angioplasty or to patients who are likely to
  succumb due to other comorbid conditions before
  advancing to end-stage renal disease because of
  IRD.
• In these cases, the clinicians have to rely on
  pharmacologic agents (e.g. combination of calcium
  channels blockers to control blood pressure and
  optimize renal perfusion), accepting the high
  probability of deterioration in renal function.