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RENOVASCULAR

HYPERTENSION
Dr. Villaflor
February 5, 2016

BLOCK

19

MODULE 04
LECTURE 05

m When confronted with a patient with renal hypertension,


we have to rule out if there is really artery stenosis.
Is the stenosis causing the hypertension?
If we get the stenosis or dilate it, will the
hypertension actually be relieved?
There are instances where because of the prolonged
RAS, even if we relieve the artery stenosis there is
now a complicating renal ischemic parenchymal
damage that will cause the hypertension (because
you know that artery stenosis and parenchymal
destruction will cause hypertension)
m RAS as a secondary hypertension can actually be
reversed. It is important that when you identify patients
that are still in the reversibility period, make sure that
you do so because you want to make the patient pill
free for the rest of his life that the patient wont drink
antihypertensive medications.

Etiology
Atherosclerosis (ARAS) 70%-90% of cases
Usually involves the ostium and/or proximal third of
the main renal artery, with non-ostial lesions
comprising only 15-20% of cases
Fibromuscular dysplasia (FMD) 10-20%
Renal thromboembolic disease
Renal atheroembolic disease
Autorenal dissection
Vasculitis involving the renal artery (i.e. PAN)
AVMs involving the renal artery
Nephroangiosclerosis (hypertensive injury)
Trauma
Irradiation of the renal artery
Scleroderma
m Remember ARAS and FMD because they are the most
important.

*Based on another source the etiologies of RVH are:
1. Renal artery stenonsis*
2. Fibromuscular dysplasia (FMD)*
3. Nutcracker syndrome*
4. Renal vein thrombosis*
5. Aneurysm and pseudo-aneurysm
6. Arterio-venous communications
7. Renal Mass
8. Miscellaneous indications
*95% of cases

SUMMARY/OUTLINE
I.

Etiology
IV. Diagnosis
a. Renal Artery Stenosis
a. Captopril Renography
b. Fibromuscular Dysplasia
b. Functional Studies
c. Nutcracker Syndrome
c. Anatomic Studies
II. Pathophysiology
V. Treatment
a. Unilateral RAS
VI. Conclusions
b. Bilateral RAS
c. Ischemic Renal Disease
III. Clinical Features
th
LEGEND: Lecture Audio &/Box Harrisons 19 Ed Prev yr notes (SGD)

RENOVASCULAR HYPERTENSION
Defined as:
The presence of systemic hypertension due to a stenotic
or obstructive lesion within the renal artery
The mechanism of hypertension is generally related to
activation of the renin-angiotensin system.
Two patients are at risk for this disorder:
o Older arteriosclerotic patients
o Patients with fibromuscular dysplasia
Form of secondary hypertension, accounting for an
estimated 0.5% to 4% of cases in unselected
hypertensive patients
The simultaneous presence of renal artery stenosis (RAS)
and systemic hypertension should not lead to the
conclusion that the patient has RVH;
Strictly speaking, the definitive diagnosis of RVH can only
be made retrospectively when hypertension improves
upon correction of the stenosis
In practice, obtaining complete reversal of
hypertension is rarely possible
Important to recognize that renovascular disease
o Often accelerates preexisting hypertension,
o Can ultimately threaten the viability of the poststenotic kidney and
o Impair sodium excretion in subjects with
congestive heart failure
When to suspect RVH:
o Severe or refractory HPN
o Recent loss of hypertension control
o Recent onset of moderately severe HPN
o Unexplained deterioration of renal function
o Deterioration of renal function associated
with ACE inhibitor
If BP is adequately controlled with a simple antihypertensive
regimen and renal function remains stable, there may be little
impetus to pursue an evaluation for renal artery stenosis
m When we speak of renovascular hypertension, it should
be remembered that if you have RAS (renoarterial
stenosis) you will eventually have renal hypertension.

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Renal Artery Stenosis


Stenosis of the renal artery is due to atrerosclerotic
disease in the vast majority of patients, or to
fibromuscular dysplasia of the arterial wall in the
younger, generally female patient. RAS may cause
hypertension and may eventually cause renal failure. It is
frequently bilateral, and is responsible for up to 15% of
patients who require long-term dialysis. It is associated
with aortic aneurysm, neurofibromatosis or can be
traumatic in origin
It is estimated that ~5% of cases of hypertension are
caused by renal artery stenosis (RAS).
Autopsy studies in patients dying of stroke revealed that
at least 1 renal artery is >75% stenosed in 10% of the
patients studied.
The common cause in the middle-aged and elderly is an
atheromatous plaque at the origin of the renal artery.
Bilateral involvement is present in half of the affected
cases.
Renal hypotrophy is detectable in 20% of
affected kidneys.
In younger women (1550 years), stenosis is due to
intrinsic structural abnormalities of the arterial wall
caused by fibromuscular dysplasia.
In addition to stimulation of renin release, renovascular
disease is associated with increased sympathetic neural
activity, resulting in frequently described flushing, loss of
nocturnal blood pressure (BP) decrease, autonomic
instability, and rapid BP swings.
Glomerular filtration rate (GFR) is <60 mL/min, with 85%
having stage 35 chronic kidney disease.
Diagnosis is through Doppler ultrasonography, intrarenal
resistance index (RI), Gadolinium-enhanced
three-dimensional magnetic resonance angiography
(MRA).
Definitive diagnostic procedure is contrast enhanced
arteriography.
When blood pressure is controlled and renal function is
preserved, expectant therapy and careful follow-up form
the best approach for managing RAS
Angiotensin antagonists (ACE inhibitors or
angiotensin receptor blockers) and diuretics are required
in most patients.
Revascularization therapy (angioplasty with stent
placement) may improve the chances of attaining goal
BP, but should be considered only after optimal medical
therapy has failed to achieve goal BP, or resulted in a
>30% increase in serum creatinine.

Post stenotic
dilatation

main RA Branching
points

artery
Others (carotids)

Rare

Frequent

Fibromuscular dysplasia (FMD)


A condition in which at least one of your arteries has
abnormal cluster of cells growing in the artery wall. This
cluster causes artery to narrow, which can cause damage
to the organs that receive blood through that narrowed
artery. It can cause number of complications such as high
blood pressure and a bulging area of the artery. It
appears most commonly in the arteries leading to the
kidneys.
10% of cases of RVH are due to FMD
Mainly in younger women
Strong predilection for young Caucasian women (M:F =
8:1)
Medial fibroplasia most common variant (2/3 of
patients)
Bilateral renal artery involvement with extension into the
distal portion of the artery and its branches is common
Smoking is a prominent risk factor
Fibromuscular dysplasia may occur at any age, it has a
strong predilection for young women. The prevalence in
females is eightfold that in males
There are several histologic variants of fibromuscular
dysplasia, including medial fibroplasia, perimedial
fibroplasia, medial hyperplasia, and intimal fibroplasia.
Medial fibroplasia is the most common variant and
accounts for approximately two-thirds of patients.
The lesions of fibromuscular dysplasia are frequently
bilateral, and in contrast to atherosclerotic renovascular
disease, tend to affect more distal portions of the renal
artery.


** Important: Please take note of this chart.
Atherosclerosis
FMD

>90%
<20 %
Age
After age 50
Young
More common in
More common in
Gender
males
females
Location
Proximal 1 cm of
Middle of renal


Nutcracker syndrome
A vascular compression disorder and refers to the
compression of the left renal vein between the superior
mesenteric artery (SMA) and aorta. This can lead to renal
Page 2 of 9

venous hypertension, resulting in rupture of thin-walled


veins into the collecting system with resultant hematuria.

Renal Vein
Compression

Hypertension due to obstruction of a renal artery,


renovascular hypertension, is a potentially curable form
of hypertension.
The mechanism of hypertension is generally related to
activation of the renin-angiotensin system.
Patients are at risk for this disorder: (a) older
arteriosclerotic patients who have a plaque obstructing
the renal artery, frequently at its origin; (b) patients with
fibromuscular dysplasia.


Pathophysiology
Overview

(See last page for diagram of Pathophysiology)


The pathogenesis of arterial atherosclerosis is well


understood and rat studies have shown ARAS follows a
similar pattern
However, it is important to review the mechanisms by
which renovascular hypertension and Ischemic Renal
Disease (IRD) develop
Intraglomerular pressure remains constant during wide
swings in systemic blood by alterations in afferent and
efferent glomerular vascular resistance secondary to
renal autoregulation
Renal autoregulation fails to maintain GFR when renal
perfusion pressure dips below 70-85% mmHg. Generally
correlating with a greater that 70% renal artery stenosis
It has been hypothesized that this critical reduction in
perfusion pressure is required in order to set off the
cascade of events that lead to renovascular hypertension
and/or ischemic renal disease


Unilateral RAS
There seems to be three phases of hypertension in
patients with unilateral RAS:
1. High renin, low volume
2. High/normal renin, elevated plasma volume
3. Irreversible parenchymal HTN
m There is burden on the contralateral kidney

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Irreversible parenchymal HTN:
Prolonged exposure to high BP and high levels of ATII
causes widespread arteriolar damage and
glomerulosclerosis in the contralateral kidney
This is likely why RVH secondary to ARAS does not
resolve after revascularization
Hughes et al. showed that corrective surgery for
unilateral RVH was successful in 78% of those with HTN
of less than 5 years duration but in only 25% of those
with HTN of a longer duration

Ischemic Renal Disease


Several reversible, adaptive changes occur in response
to chronic renal ischemia:
Structural renal atrophy
Diminished conical blood flow
Reduction in GFR in order to decrease oxygen
demand
Hypertrophy of the contralateral kidney
Hyperfiltration occurs in the functional nephrons of the
non-effective kidney, which leads to glomerulosclerosis
It is very difficult to reliably delineate to what degree
renal insufficiency is due to adaptive changes vs.
irreversible parenchymal disease


Bilateral RAS
Much less is known about the mechanisms of RVH in
bilateral RAS
The overall picture is a mixed one with both renin and
volume factors playing a role
Evidence suggests there is an increase in effective
circulating blood volume owed to elevated aldosterone
levels and a blunted pressure natriuresis effect



Clinical Features
These patients do not exhibit specific clinical findings and
it is therefore particularly important to identity high-risk
groups in which suspicion of this condition should be
heightened
There are two important ischemic renal syndromes to
consider
1. ARF after the institution of an ACEI
m In a patient with CKD (e.g. those who have a
creatinine (Cr) of 1.2 or CKD 3-4), when you
give ACE inhibitors, it is a must that we
monitor the Cr about 5 days or 1 week after
institution because when there is elevation
of Cr, you have a sign that there is AKI -- you
might be dealing with an ARF or an ischemic
kidney.
This is your worry if you give ACEI/ARBs in
patients with CKD:
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m ACE inhibitors, although nami siya sa


kidneys, can decrease the intraglome-rular
pressure. But at times in CKD when your
angiotensin II (ATII) plays a role in the
maintenance of the function of your GFR,
when you block that, the function will
decrease.
m The effect of ARBs on an ATII-dependent
kidney function is that when you block the
ATII (constricts the efferent), somehow, the
constriction will increase your filtration of
GFR. When you dilate that, you released the
pressure, filtration will drop.
m This is what you should look at. Maybe my
function is ATII-dependent for now, and I
will give ACE, I will have to monitor the level
of creatinine.
2. Unexplained chronic and/or progressive
azotemia in the elderly with evidence of other
vascular disease.
Most of these patients have bland urine
sediments with minimal or no proteinuria
and atrophic kidneys on US.
m The elderly have atheromatous formation.
Atheromatous: most likely your kidneys or
your renal arteries will most likely be
affected.
The following clinical features should raise the suspicion
of renovascular disease:
- Young hypertensive pts with no family history or new
onset HTN in pts >50 y/o
- Abrupt onset of HTN
- Severe or Resistant HTN
- Deteriorating BP control in long standing, compliant
hypertensive patients
- Deterioration in renal function with ACEI
- Evidence of secondary hyperaldosteronism (low
plasma potassium, high renin)
- Recurrent flash pulmonary edema and hypertensive
urgency (more common with bilateral RAS)
m Sometimes your patient is so stable and suddenly
he will have pulmonary edema and there are
episodes of hypertensive urgency.
- Elderly patients with PVD (peripheral vascular dse)
- Abdominal bruit (OR 11.5)
m It is important to auscultate the major vessels in
the abdomen.
- Unexplained renal azotemia
- >1.5 cm difference in kidney size on US (70% of
atrophic kidneys in the elderly are associated with
ARAS)
m When you do diagnostic procedures, you will be
able to appreciate the difference in size of the
kidneys. You may wonder, why does one kidney
have a different size from the other? Maybe it
might be stenotic.

It is important to search for evidence of underlying


irreversible parenchymal renal disease, as this subgroup
will not likely benefit from therapy:
- Moderate to severe proteinuria
- Severe renal atrophy distal to obstruction
- Unilateral RAS with renal insufficiency
m Hambalon mo, ano pa ni ang humuon ko? Kay
lain na ni gali. Abi mo RVH. Iya sang RVH
macorrect but the parenchymal disease is still
there.
m You should suspect that because if it is pure RVH,
our urine is bland. But if you have some degree of
proteinuria, your kidneys have shrunk, and then
unilateral RAS, and you have renal insufficiency.
Most likely there is now a concomitant ischemic
renal damage.
&

Clinical findings associated with RVH:






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**highlighted = mentioned / emphasized by doc in the audio.


Nice to know: Iloilo has CT angiography. J

Functional Studies

Diagnostic Study
Pros
Cons
Renal Vein Renin
Useful in
Poor sensitivity
Measurements
confirming the

functional
Non lateralization
significance of a
not predictive of
lesion
the failure of HTN
demonstrated by
to improve with
anatomical studies therapy
particularly if
bilateral disease if
present
Nuclear imaging
Allows calculation Difficult to
99
with Tc -MAG or of single kidney
differentiate
99
Tc -DTPA to
GFR and/or RBF
reversible from
estimate fractional
intrinsic disease
flow to each
kidney
Conventional
Useful as both a
Lower sens/spec
Renography
screening test and compared to ACEI
functional study
renography
ACEI Renography
Test of choice for
Reduce sens/spec
the diagnosis of
in patients with
RVH in many
renal insufficiency
centers
(PCr>2.0)

Operator
dependent

Anatomic Studies

If youre searching for a lesion, look at the vessel.
Diagnostic Study
Pros
Cons
Renal
Gold standard
Direct contrast
Arteriography

load to kidneys
Can visualize

accessory vessels
Sometimes
and intrarenal
difficult to
branches well
distinguish
between critical
and non-critical
lesions
Doppler
Non invasive
Extremely
Ultrasonography
Inexpensive,
operator
widely available
dependent

Does not evaluate
accessory vessels
well

Bowel gas
patterns/Obesity
interfere

Diagnosis
There are two groups of diagnostic studies used to evaluate
RAS.

Anatomic studies:
Renal angiography gold standard
m This is the gold standard because you want to
look and are looking at the vessels. We
delineate the vessels the renal artery- as it
supplies the kidneys.
Doppler ultrasonography
Spiral CT angiography
MR angiography

Functional studies:
Renal-vein-renin measurement
m Because your arteries are constricted, you
expect that your renin is high. There is actually
measurement of your renal vein renin but it is
invasive.
125
Nuclear imaging with I iothalamate or DTPA to
determine GFR
Conventional renography
ACEI renography

Captopril Renography
Captopril renography is a nuclear study which takes
advantage of the fact ACEI can abruptly reduce function in
an ischemic kidney.
Patients are given radio-labeled agents that are
99
exclusively filtered (Tc -DTPA) thus estimating GFR
99
or agents that are filtered and secreted (Tc -MAG)
131
or I -hippurate) thus estimating RBF
A baseline study is done on day 1 and 50 mg of
captopril is given 1 hr prior to the second study on
day 2
The difference between the left and right kidney
with regard to uptake, excretion, kidney size and
asymmetry can be determined by this study.
99
Either a slowing of the excretion of Tc -DTPA or a
99
reduction of the uptake of the Tc -MAG can be used
to identity the effect of the ACEI in removing the
protective action of high levels of ATII on the
autoregulation of GFR and on maintenance of renal
blood flow.

Diagnostic Study
Sens.
Spec.
PPV
NPV
Renal Vein Renins
62%
70-80%


Doppler
80-98%
98%
99% 88-97%
Ultrasonography
Conventional
75%
85%
33%

Renography
ACEI Renography
75-90%
94%
92%
88%
CT angiography
92%
98%
87%
99%
MRA
100%
93%
90%
100%

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CT angiography

MRA


Antihypertensive Drug Therapy
Blockade of the Renin Angiotensin System
o ACE Inhibitors
o Angiotensin Receptor Blockers
o Direct Renin Inhibitors (Aliskiren) [efficacy
questionable]
Calcium Channel Blocking Agents
Diuretics
Mineralocorticoid Receptor Blockade
Additional classes: Beta-blockade, alpha-receptor
blockade, sympatholytic agents, vasodilators

Cardiovascular Risk Reduction
Removal of tobacco use
Treatment of Dyslipidemia: Statins, Fibrates, Others
Treatment of Obesity: Obstructive Sleep Apnea
Management of Glucose Intolerance/ Diabetes

Renal Revascularization
Endovascular revascularization:
o PTRA: Primary Fibromuscular Dysplasia
o PTRA with Stenting: Atherosclerotic Disease
most commonly used treatment for renovascular
HPN
Surgical:
o Renal Artery Bypass/Endarterectomy (reserved
for complex aorto-renal disease, aneurismal
disease, failed endovascular stent procedures,
etc.)
Nephrectomy
Open or Laparoscopic removal of pressor kidney;
usually non-functional


Management for RVH caused by ARAS
No general consensus among physicians on the ideal
therapy for this condition
o Numerous randomized prospective studies have
found no evidence of improvement in BP control in
patients undergoing angioplasty over medical therapy
alone
One of the largest trials,
o The Angioplasty and Stenting for Renal Artery Lesions
(ASTRAL) study,
806 renal failure patients (mean serum creatinine
approximately 2 mg/dL) with atherosclerotic
renal vascular disease included
Randomized to receive either revascularization
and medical therapy or medical therapy alone
On average, patients had 75% RAS
At 1-year follow-up there were no differences in
the change in serum creatinine level (it rose by
0.2 mg/dL in both groups) or in rates of renal
events, including acute renal failure
Currently, at least three major studies are under way to

Excellent
High-contrast
visualization of the requirement
vessels in 3D

Less reliable for
visualizing distal
segments and
small accessory
arteries
Noninvasive
Expensive


Provides excellent Prior stents
images
produce artifacts


Non-nephrotoxic, Blood flow
thus useful in
turbulence can
patients with renal exaggerate
insufficiency
measured stenosis


m If you localize the anatomic lesion, the renal
arteriography is the gold standard because you actually
visualize the artery plus the accessory vessels.
You may see that your main renal artery stenosed
and because your main renal artery is stenosed, you
will develop collaterals because your collaterals will
supply the rest. You have accessory vessels and some
have intrarenal branches. This procedure entails the
use of contrast.

Treatment
To date, there has been no large randomized clinical
controlled trial comparing medical therapy to newer
stenting procedures or surgery
m When you say stent, you place a tube so that you
will be able to dilate the stenosed area. If it is
surgical and you repair it, you cut and you
anastomose.
m For medical therapy, you just control the BP.
In addition, most of the reported date as to therapy have
been non-experimental reports
As result, no improvements in survival, freedom from
dialysis or protection from adverse cardiovascular
disease events have been demonstrated relative to an
equivalent non-interventional comparison group

RENOVASCULAR HYPERTENSION (RVH): MANAGEMENT


Treatment options include
1. Pharmacological
therapy
with
various
antihypertensive medications,
2. Percutaneous angioplasty with or without stent
placement, and
3. Surgical revision of RAS

Availability of potent antihypertensive drugs and the
advances in endovascular techniques, as well as stents, has
made surgical treatment rarely necessary

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help decipher optimum treatment for patients with ARAS


o STAR
o RAS-CAD
o CORAL
STAR study
o The STent placement and blood pressure and lipidlowering for the prevention of progression of renal
dysfunction caused by Atherosclerotic ostial stenosis
of the Renal artery (STAR) study aims to compare
The effects of renal artery stent placement
together with medication versus medication
alone on renal function in 140 ARAS patients
Medication consists of statins, antihypertensive
drugs, and antiplatelet therapy
RAS-CAD
o A trial looking at cardiac endpoints, the stenting of
Renal Artery Stenosis in Coronary Artery Disease
(RAS-CAD),
Randomized study aiming to recruit 168 patients
Designed to study the effect of medical therapy
alone versus medical therapy plus renal artery
stenting on
left ventricular hypertrophy progression
(primary endpoint), and
cardiovascular morbidity and mortality
(secondary endpoints), in patients affected by
ischemic heart disease and RAS
CORAL
o The Cardiovascular Outcomes with Renal
Atherosclerotic Lesions (CORAL) study is a National
Institutes of Healthfunded multicenter trial testing
the hypothesis that
Stenting atherosclerotic RAS in patients with
systolic hypertension reduces the incidence of
cardiovascular and renal events
The CORAL study has completed enrollment with
over 900 patients, but results will not be available
for some time
At this time, there is no clear benefit of revascularization
for ARAS,
o Especially in patients for whom BP can be controlled
easily and who have no evidence of ischemic
nephropathy
o The risks of the procedure may outweigh any
potential benefits
Angioplasty with or without stenting may be of benefit in
o Patients with HT that is difficult to control in the
setting of decreased renal perfusion, because
uncontrolled hypertension is a major cardiovascular
risk factor
Accordingly, aggressive treatment of hypertension with
medications is recommended
Antihypertensive treatment may also include
o ACE inhibitors and ARBs provided that
Renal function is stable and that close follow-up
is available
o Medical therapy should also include

Statins to prevent further progression of


atherosclerotic plaques in the renal arteries and
Cardiac prophylaxis with lowdose aspirin
Smoking should be strongly discouraged

Management for RVH caused by FMD


Percutaneous angioplasty is the treatment of choice,
o Often resulting in relief of the stenosis and
marked improvement (or cure) of the
hypertension
Stents may be used
o In patients with suboptimal results with
angioplasty alone
Surgery is considered to be the last option, particularly
o For patients for whom endovascular procedures
have failed

Conclusions
Natural History and Pathophysiology
ARAS is clearly a progressive disease
The initial degree of stenosis/burden of vascular
disease is most predictive of IRD progression
m So if it is atherosclerotic, since the formation takes a
long time, most likely there is ischemic renal disease.
Once patients with IRD are dialysis dependent, their
prognosis is extremely poor.
The pathogenesis of IRD is multifactorial and predicting
the degree of reversible vs irreversible disease in a
particular patient is challenging.
High RI, slow progression of IRD, significant
proteinuria and advanced age seem to be predictors
of irreversible disease
Normal RI, minimal proteinuria and fast progression
of renal insufficiency seem to be predictors of
reversible disease
m Multifactorial because there is renin, volume,
cardiovascular events that will make the patient
prone to this complication.

Diagnosis and Therapy


The diagnosis of IRD secondary to ARAS should be
based on anatomical studies.
Functional studies such as ACEI renography and
renal-vein-renin sampling are insensitive in detecting
significant stenosis in patients with renal
insufficiency.
Functional studies do not reliably predict who will
respond to therapy
Given the paucity of controlled, randomized data, it is
difficult to make any level I recommendations for the
treatment of RVH or IRD due to ARAS:
However, the following statements are reasons based on
the above data:
1. PTRA/S is not the initial treatment of choice in
patients with RVH secondary to ARAS.
Page 8 of 9

2.

Surgery appears to be more efficacious that PTRA/S


for both RVH and IRD but is also associated with a
much higher morbidity/mortality rate.
3. Surgery appears to be appropriate for patients with
a high burden of disease (bilateral or effective
bilateral ARAS) who have minimal preoperative
risks factors for preoperative death.
4. Rate of renal decline and underlying parenchymal
damage affect the likelihood of renal improvement
with therapy.
m We have successes in surgery especially if the condition is
diagnosed early. Medical therapy is still the mainstay.
m This is good actually with minimal perioperative risk
factors for perioperative death.


Juntado, R. | Lacson | Lagon | Lucero, S.


Pathophysiology of Renovascular Hypertension:

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