is with the Department of Radiology at Emory University Hospital,
enovascular disease can be divided into three categories: 1) renal
artery stenosis, 2) ischemic nephropathy, and 3) renovascular
hypertension. Renal artery stenosis is common in non-hypertensive
elderly persons and is an associated, but non-etiologic, finding in
a number of hypertensive patients.
Ischemic nephropathy refers to a loss of renal function due to
progressive severe occlusive disease of the extraparenchymal renal
artery. Renovascular hypertension (RVH) describes an elevated blood
pressure due to anatomic stenosis of the renal artery, a reduction
of perfusion pressure distal to the stenosis, and activation of the
renin-angiotensin system. RVH is estimated to affect <1% to 3%
of the unselected hypertension population and up to 15% to 30% of
patients referred to a subspecialty center because of refractory
The strength of ACE (angiotensin converting enzyme) inhibition
renography is that it is the only widely available imaging
procedure that directly tests for the presence of renovascular
hypertension; other imaging procedures examine only for the
presence of renal artery stenosis.
Who is at risk for renovascular hypertension?
Clinical features associated with a moderate or high risk of
renovascular hypertension include abrupt onset of hypertension in
patients under age 30 or over age 55, grade 3 or 4 hypertensive
retinopathy, severe hypertension resistant to medical therapy in a
compliant patient, bruits in the abdomen or flank, occlusive
disease in other vascular beds, and unexplained azotemia or
worsening renal function during ACE inhibitor therapy. In patients
with a very low likelihood of RVH, diagnostic imaging tests to
detect renovascular hypertension are not indicated; the prevalence
of the disease is simply too low for any test to be cost
Guideline development for ACE inhibition
A review of ACE inhibition renography literature over the past
10 years revealed that the protocols for the performance of ACE
inhibition renography and the criteria for findings indicative of
renovascular hypertension varied from center to center. The lack of
standardization, coupled with the fact that many studies used
stenosis of the renal artery rather than blood pressure response to
revascularization (i.e., true renovascular hypertension) as the end
point, often made it difficult to draw definitive conclusions. In
an attempt to address these issues, an international consensus
committee on ACE inhibitor renography was established by the Ninth
International Symposium of Radionuclides in Nephrourology. Their
consensus report was published in 1996.
Members of the original consensus committee, with the addition of
Alain Prigent, MD, recently updated the Society of Nuclear Medicine
(SNM) Guideline on ACE inhibitor renography.
This guideline can now be downloaded from the Society of Nuclear
Medicine website at SNM.org. The 1996 Consensus Report,
the 1999 SNM ACE inhibition guideline for the detection of
renovascular hypertension, and a recent article in
Seminars of Nuclear Medicine
form the basis of the following discussion and recommendations.
Pathophysiology of renovascular hypertension and ACE
Renovascular hypertension depends on secretion of renin from the
juxta-glomerular apparatus of the underperfused, stenotic kidney.
ACE inhibition interrupts the renin-angiotensin system by
preventing the conversion of angio-
tensin I to angiotensin II, such that the vasoconstrictor and
aldosterone-stimulating effects of angiotensin II are blocked.
Within the stenotic kidney, inhibition of the enzyme reduces the
angiotensin II-dependent constriction of the postglomerular
arteriole, thereby lowering the transcapillary forces that maintain
glomerular filtration. This decrease in individual kidney
glomerular filtration can be assessed noninvasively by radionuclide
Alternative diagnostic tests
Conventional angiography and digital subtraction angiography
the gold standards for the diagnosis of renal artery stenosis (not
necessarily renovascular hypertension), but they are invasive and
relatively expensive, and subject the kidney to a contrast load.
Thus, they are less useful as screening exams, especially in
patients with poor renal function. CT angiography is noninvasive
but also subjects the kidney to a contrast load. The 1996 American
College of Radiology Appropriateness Criteria lists ACE inhibition
renography or Duplex sonography as the most appropriate initial
exams in patients with compromised renal function. Duplex
sonography is noninvasive but the test can be quite time consuming
to perform and it has achieved reliability only at certain
dedicated centers due to difficulties inherent in performing and
interpreting the exam. MR angiography is gaining wider appeal due
to its noninvasive nature and lack of iodinated contrast, but MR
angiography does not appear to be sensitive for segmental or distal
renal artery stenosis. It may be more useful in older patients who
are most likely to have proximal renal artery stenosis.
Other tests (such as renal vein renin sampling, hypertensive
IVU, and intravenous digital subtraction angiography) are not
appropriate as screening procedures, although renal vein renin
assays and ACE inhibitor renography can be used to evaluate the
significance of a renal artery stenosis. The captopril test
(stimulated plasma renin following captopril administration) has a
low sensitivity of approximately 60% for RVH and its accuracy
decreases as the prevalence of RVH increases in the patient
Which radiopharmaceutical should be used for ACE
In patients with azotemia, tubular agents such as MAG3 or I-123
OIH are considered to be the agents of choice.
In patients with normal renal function, MAG3 and DTPA give
Should patients be hydrated?
Dehydration can prolong the excretory phase of the renogram
curve and reduce the specificity of the study. Patients should be
instructed to arrive well hydrated. Many centers also have the
patient drink 5 to 10 mL/kg of water on arrival in the department,
preferably 30 to 60 minutes before the study. Finally, if a
two-stage ACE inhibition examination is scheduled, it is important
to continue hydration between the studies.
Which medications interfere with ACE inhibition
--Chronic ACE inhibition may reduce the sensitivity of the test.
ACE inhibitors should be withheld for 3 to 7 days before the study,
depending on the half-life of the radiopharmaceutical to be used.
In addition to ACE inhibitors, patients should also be questioned
about new combination antihypertensive drugs, such as Teczem, which
include both an ACE inhibitor (enalapril) and a calcium channel
--A patient on chronic diuretics has an increased likelihood of
volume depletion, which may reduce the specificity of the test; in
addition, volume depletion increases the risk of a hypotensive
response. Because of these concerns, it is advisable to stop
diuretics for several days prior to the study.
Angiotensin II receptor antagonists
--Angiotensin II receptor antagonists block type I angiotensin II
receptors and have been used in place of ACE inhibitors to detect
Currently available angiotensin receptor blockers include losartan
(Cozaar), irbesartan (Avapro), valsartan (Diovan), and candesartan
(Atacand). The effect of chronic angiotensin II receptor blockade
on the sensitivity and specificity of ACE inhibitor scintigraphy is
not known. A baseline study cannot be performed if the patient is
taking angiotensin II receptor antagonists. At present, it is
appropriate to discontinue these drugs prior to ACE inhibition
renography until further data become available.
Calcium channel blocker
s--A recent report suggests that calcium channel blockers may
result in a bilaterally symmetrical abnormal renogram curves in the
absence of renal artery stenosis,
although we have not found calcium channel blockers to be a
significant problem in our practice.
Which ACE inhibitor and what dose?
Captopril (25 to 50 mg crushed and administered orally with 250
mL of water) is the most widely used ACE inhibitor. A 25-mg tablet
is sufficient unless the patient has delayed gastric emptying or
poor absorption from the gastrointestinal tract. Food can interfere
with the absorption of captopril, and patients should not eat
before captopril scintigraphy. Since the peak activity of captopril
does not occur until approximately 60 minutes after ingestion, the
radiopharmaceutical should be given 1 hour after captopril.
A second approach is to inject enalaprilat (Vasotec, 40 µg/kg IV
over 3 to 5 minutes, with a maximum dose of 2.5 mg), wait at least
15 minutes, and then inject the radiopharmaceutical.
An advantage of enalaprilat is that the patient can be placed under
constant observation for hypotension after enalaprilat injection as
the technologist prepares for and then performs the study.
Intravenous injection of enalaprilat also avoids the possibility of
a false negative test due to poor absorption of captopril in a
patient who has recently eaten or has delayed gastric emptying due
to diabetes. A potential disadvantage of enalaprilat is that the
patient may be at greater risk of a significant hypo tensive
Monitoring blood pressure
Blood pressure must be monitored throughout the procedure.
Volume depletion or asymptornatic hypotension secondary to ACE
inhibition can result in bilateral symmetrical abnormalities in the
renogram curves (figure 1). This phenomenon is uncommon, but may
occur in as many as 3% of patients referred for ACE inhibition
renography; it appears to be most likely to occur in patients who
are volume- or salt-depleted.
One- versus a two-day protocol?
Some centers begin with captopril or enalaprilat renography
because normal findings on ACE inhibitor renography obviate a
baseline study. If the results are abnormal, the specificity can be
improved by obtaining a baseline renogram; however, because of the
administration of the ACE inhibitor, the patient will have to
return for the baseline study on another day. In some centers, an
abnormal ACE inhibition study in a patient with high clinical
probability of renovascular hypertension is justification for
A second approach is to use a 1 to 2 mCi dose of MAG3 (Tc-99m
mercaptoacetyltriglycine) or DTPA (Tc-99m
diethylenetriaminepentaacetic acid) for the baseline study,
administer the ACE inhibitor, and then obtain a second renogram
with a significantly higher 8 to 10 mCi dose. This protocol
consists of two studies on the same day and requires the patient to
spend a longer time in the department, but the complete study is
finished in a single day. The first approach is less costly if the
time required for the patient to return on a second day for a
baseline test is not factored into the calculation.
We routinely measure a camera-based MAG3 clearance, post-void
residual and several quantitative indices using the QuantEM
software program which was initially developed at Emory for a GE
; a more expanded version based on the multicenter trial was later
developed for Elscint.
Camera-based clearances are not as accurate as clearances based on
plasma samples, but they appear to be highly reproducible in
patients with stable renal function.
In addition to measurement of a MAG3 clearance, the latest software
version includes semi-automated assignment of kidney regions of
automated assignment of background regions of interest, automated
assignment of cortical regions of interest, and generation of the
following quantitative indices which are useful in the diagnosis of
The relative renal uptake of each radiopharmaceutical provides a
measure of relative function and is an important parameter in the
interpretation of most studies. The measurement is usually made
during the 1 to 2, 1 to 2.5, or 2 to 3 minute period postinjection
for MAG3, OIH, and DTPA. Background subtraction using a C-shaped,
elliptical, or perirenal region of interest appears to be superior
to no background or inferior background regions of interest
and an automated background subtraction probably improves
Time to peak height--
The time to the peak height on the renogram curve is a useful
measurement in the evaluation of patients with suspected
renovascular hypertension. In general, the peak should occur by 5
minutes after injection, but retention of the radiopharmaceutical
in the renal calices or pelvis can alter the shape of the renogram
and affect this measurement.
The latest version of the QuantEM
software automatically places cortical regions of interest and we
routinely measure the time to peak and the 20 minute/maximum
(min/max) ratios using cortical ROIs to minimize the effect of
radiopharmaceutical retention in the calices or renal pelvis.
The 20 or 30 minute/maximum ratios--
As renal function deteriorates, there is often a pronounced
prolongation of the excretory phase of the renogram. The degree of
abnormality can be quantitated by a measurement of residual
cortical activity using the ratio of the counts at 20 or 30 minutes
to the maximum (peak) counts. The 20 or 30 min/max ratio is also a
useful index in the detection of renovascular hypertension. In a
series of potential renal donors studied with MAG3, the 20 min/max
ratio for background subtracted parenchymal regions of interest
(activity within the collecting system was excluded from the ROI)
was 0.18 ± 0.06.
If the patient is not dehydrated and the 20 min/max ratio for the
cortical ROI exceeds 0.36 (three standard deviations above the
mean), the kidney is likely to be abnormal.
If part of the dose is infiltrated, the excretory phase of the
renogram curve may be prolonged
; an increase in the grade of the renogram curve from 0 to 2 or 1
to 2 grades (figure 1) can lead to an erroneous interpretation of
an ACE inhibition renogram. A 30-second injection site image at the
conclusion of imaging is routine in our institution; the QuantEM
software estimates what percent, if any, of the injected dose was
infiltrated. Infiltration can also be evaluated qualitatively by
viewing an image of the injection site.
MAG3 and OIH--
With MAG3 and OIH, the most specific diagnostic criterion for
renovascular hypertension is a ACE inhibition induced change in the
renogram (figure 2). A change in the relative uptake of MAG3 or OIH
by 10 percentage points (50/50 to 40/60) is uncommon even in a
patient with RVH, but it is highly significant when it occurs. For
MAG3 and OIH, the most important criterion is parenchymal retention
in the affected kidney(s).
Parenchymal retention is secondary to the decrease in the
glomerular filtration rate (GFR) induced by ACE inhibition; with
the decrease in GFR, there is decreased flow in the renal tubules
and delayed washout of the radionuclide from the tubules and
We prefer renograms derived from the cortical ROIs because they
help avoid the diagnostic difficulty that can be introduced by
retention of the tracer in the collecting system. Parenchymal
retention may be evaluated qualitatively by changes in the shape of
the renogram curve (figure 3) or it may be evaluated quantitatively
by a prolongation of the 20 or 30 min/max ratio and/or a
prolongation of the time to peak. An increase in the 20 min/max
ratio of 0.15 or greater for parenchymal ROIs represents the 90%
confidence limit for a significant change.
A prolongation of the time to peak of 120 seconds for a cortical
ROI is significant at the 90% to 95% confidence limit. It is
important to note, however, that a change from 5 to 7 minutes is
more meaningful than a change from 15 to 17 minutes.
The principal diagnostic criterion for the purely glomerular agent
DTPA is a decrease in uptake by the affected kidney(s) resulting in
a change in the relative uptake in patients with unilateral disease
or asymmetrical bilateral disease. The decrease in DTPA uptake
following ACE inhibition is due to a decrease in glomerular
filtration of the affected kidney.
A reduction in the relative uptake greater than 10 percentage
points (50/50 to 60/40) is a highly significant change and 5 to 9
percentage points is considered to be a intermediate response,
although a recent study performed under carefully controlled
conditions suggests that smaller changes in relative uptake may be
Parenchymal retention with a change in the shape of the renogram
curve following ACE inhibition is also an important diagnostic
finding. As with MAG3 and OIH, parenchymal retention can be
quantitated by a delay in the time to peak or an increase in the 20
to 30 min/max ratios although, in general, changes have to be much
more pronounced than with MAG3 and OIH to be significant.
Reporting the test results
The Consensus Panel has recommended that the test results be
reported as high, intermediate, or low probability for RVH. Most
studies have reported sensitivities and specificities in the range
of 80% to 90%, although the gold standard has often been the
detection of renal artery stenosis in a hypertensive patient, not
the blood pressure response to revascularization. Almost uniformly,
better results are obtained when the end point is normalization or
reduction in blood pressure following revascularization.
In communicating with the referring physician, it is important to
distinguish between the hypertensive patient with normal renal
function and the hypertensive patient with ischemic nephropathy.
The utility of the test differs substantially in these two patient
ACE inhibition renography in patients with normal
ACE inhibitor renography is highly accurate in patients with
normal renal function (normal creatinine and the absence of a
small, poorly functioning kidney); the sensitivity and specificity
of ACE inhibitor renography for renovascular hypertension in this
patient population approach 90%.
ACE inhibitor renography in patients with ischemic
A positive ACE inhibition test result indicates that
hypertension is very likely to improve following revascularization;
however, it is important to recognize that patients with azotemia
or a small, poorly functioning kidney often have an intermediate
probability test result (abnormal baseline study which does not
change following ACE inhibition). In the appropriate clinical
setting, an intermediate test result may be sufficient to refer a
patient for angiography. When there is a high index of suspicion,
azotemic patients may be referred directly for angiography. MR
angiography may play an increasing role in this patient
Patients with ischemic nephropathy may or may not have
co-existing renovascular hypertension; however, revascularization
is sometimes performed in these patients in an attempt to improve
or stabilize renal function. Revascularization can result in an
amelioration or stabilization of azotemia, but a reduction in
complications or an improvement in survival compared to currently
available medical therapy has not yet been demonstrated and the
long-term utility of this approach is still being debated.
If a patient has a moderate to high likelihood of RVH and normal
renal function, ACE inhibition renography provides a logical,
noninvasive, and cost-effective approach to patient management. A
normal ACE inhibition renogram obviates the need for further
work-up; an abnormal study should lead to referral for angiography
and revascularization. If a small, poorly functioning kidney is
identified, angiography or Duplex sonography, depending on local
experience and expertise, is a reasonable next step.
The evaluation of a patient with azotemia is more problematic. A
positive test result should lead to angiography and
revascularization if technically feasible, but these patients have
a high percentage of intermediate probability test results. A large
percentage of intermediate test results is not necessarily a
problem if the referring physician understands the likelihood of
this outcome when referring such a patient for ACE inhibition
renography. An intermediate test result in the appropriate clinical
setting may be sufficient to refer a patient for angiography. False
negative results are uncommon but when they occur, they appear to
be more likely in azotemic patients with bilateral disease,
probably due to pressure natriuresis with suppression of the renin
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