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Furosemide-131I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension
Furosemide =J3%Hippuran Renography After Angiotensin-Converting Enzyme Inhibition for the Diagnosis of Renovascular Hypertension BRIGITTEERBSLGH-M~LLER,M.D.,ARGYRIOSDUMAS,M.D.,DAVIDROTH,M.D.,GEORGE~\~. SFAKIANAKIS,M.D.,JACQUESJ.BOURGOIGNIE,M.D., Miami, ,%rida
PURPOSE: We have previously demonstrated the greater sensitivity of 1311-hippuran renography than ggmTC-DTPA scintigraphy to diagnose renovascular hypertension (RVH). This study assesses the predictive diagnostic value of furosemide-1311-hippuran renography after angiotensin-converting enzyme (ACE) inhibition in patients with and without RVH. PATIENTSANDMETHODS: Allpatientswereinvestigated at the University of Miami/Jackson Memorial Medical Center. Twenty-eight patients had RVH and 22 did not. Twenty-eight patients had normal or minimally decreased renal function (serum creatinine level 1.5 mg/dL or less) and 22 had renal insufficiency (serum creatinine level 1.8 mg/dL or more). Renography was performed 60 minutes after oral administration of 50 mg captopril or 10 minutes after intravenous injection of 40 &kg enalaprilat. Forty milligrams of furosemide were administered intravenously 2 minutes after injection of 1311-hippuran. The residual cortical activity (RCA) of 1311-hippuran was measured at 20 minutes. RESULTS: RVH was unlikely when RCA after ACE inhibition was less than 30% of peak cortical activity. Conversely, RVH was present when 1311-hippuran cortical activity steadily increased throughout the test to reach 100% at 20 minutes. In azotemic patients with RCA between 31% and lOO%, RVH was differentiated from intrinsic renal disease by obtaining a baseline renogram without ACE inhibition and comparing RCA in that study and RCA after ACE inhibition. If RCA increased (indicating worsening renal function) after ACE inhibition, RVH was
From the Divisions of Nephrology and Nuclear Medicine, University of Miami/Jackson Memorial Medical Center, Miami, Florida, This work was supported by a grant from the National Kidney Foundation of South Florida. Requests for reprints should be addressed to Jacques J. Bourgoignie, M.D., Division of Nephrology(R-IX), University of Miami School of Medicine, P.O. BoxO16960, Miami, Florida 33101. Manuscript submitted July 19, 1990, and accepted in revised form October 1, 1990.
likely; whereas, intrinsic renal disease was more likely if RCA remained unchanged or decreased (indicating improved renal function) with ACE inhibition. The test had a specificity of 95% and a sensitivity of 96% in this population. There was a direct correlation between the results of angioplasty or surgery on high blood pressure and the changes in RCA before and after intervention (n = 20). CONCLUSION: Furosemide-1311-hippuran renography with ACE inhibition is highly predictive in identifying patients with RVH.
enal artery stenosis, often correctable by perR cutaneous transluminal renal angioplasty (PTRA) at the time of renal angiography, may be a cause of hypertension and/or renal insufficiency. Whereas renovascular hypertension (RVH) is rare in young adults, it can be identified in up to 10% of patients more than 60 years old [l]. Assessing the hemodynamic importance of renal artery stenosis as a cause of hypertension or as a complicating factor in patients with prior hypertension, however, remains controversial. A practical test is still needed to diagnose functionally important renovascular disease on an outpatient basis prior to hospital admission for further evaluation and treatment if indicated. Many screening and diagnostic procedures have been proposed. None, however, has been universally accepted because of lack of sensitivity and/or specificity, or lack of reproducibility. The introduction of angiotensin-I-converting enzyme (ACE) inhibition promises to greatly enhance the predictive value of several tests [2]. Measurements of peripheral plasma renin or renal vein renin activity have been used after ACE inhibition [3-51. The former, however, is variably sensitive, and variable conclusions regarding its utility have been reached in prospective evaluations [6-91; whereas, renal vein renin measurement remains an invasive procedure. Since ACE inhibition decreases glomerular filtration rate in the ipsilateral kidney with renal artery January
1991
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Volume
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23
ACE-INHIBITED
0
13%HIPPURAN
RENOGRAPHY
AND RENOVASCULAR
Peak
HYPERTENSION
20min
Figure 1. Measurement of residual cortical activity of 1311-hippuran (RCA). Cp = cortical peak activity; Cr = cortical activity remaining at 20 minutes.
stenosis, many studies have concentrated on using ggmTc-diethylenetriamine pentaacetic acid (DTPA) scintigraphy before and after captopril administration to assess the hemodynamic importance of renovascular disease [6,10-171. Results, however, have been variable in patients with bilateral renal artery stenoses or in patients with azotemia [l&19]. Renography using 1311-hippuran or a hippuran analogue has shown greater promise than ggmTCDTPA for diagnostic purposes [20-241. We present a quantitative assessment of 1311-hippuran renography after ACE inhibition with captopril or enalaprilat. The test can be completed on an outpatient basis with a sensitivity and a specificity greater than 90%.
PATIENTS AND METHODS FurosemideJ3WHippuran Renography Renography was performed following methods previously described using a computer-interfaced gamma camera and 1311-orthoiodohippurate (1311hippuran) [21,25]. Prior to the test, patients were hydrated orally (10 mL water/kg) and an intravenous infusion of isotonic sodium chloride solution was started. ACE inhibition was achieved using 50 mg captopril orally or 40 pg/kg enalaprilat given intravenously over 3 to 5 minutes. Administration of 1311-hippuran (300 PCi) was performed 60 minutes after administration of captopril or 10 minutes after completion of the enalaprilat injection. Within 3 minutes of injection of 1311-hippuran, 40 mg furosemide was administered intravenously to increase the sensitivity of the test [21,25]. Renography was performed with the patient supine or sitting in posterior projection. Renographic images were obtained every 2 minutes for 20 minutes with simultaneous computer acquisition of the data every 30 seconds. Blood pressure was measured every 10 minutes for the duration of the test. If systolic blood pressure decreased by more than 20%, the
24
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/ ERBSLOH-MijLLER
ET AL
rate of infusion of isotonic saline was accelerated. Furosemide-1311-hippuran renography after ACE inhibition was performed in all patients. Furosemide-1311-hippuran renography was also carried out under baseline conditions using the same procedure except that captopril or enalaprilat was not given in 10 patients without RVH and in all patients with RVH. Antihypertensive drugs were withdrawn overnight before ACE-inhibited scintigraphy. ACE inhibitors were discontinued 48 hours before baseline scintigraphy. Renograms were interpreted by visual inspection of the images and by quantitative analysis of the computer-derived graphs [21,25]. A single criterion was used for the assessment of possible RVH, namely, the amount of residual cortical activity (RCA) remaining 20 minutes after injection of 1311hippuran. Visual inspection of the images served to assess the technical adequacy of the test; it also provided a direct evaluation of overall kidney function, of abnormalities present within a kidney or the collecting system, and of differences existing between two kidneys; finally, it confirmed the cortical localization of 1311-hippuran retention and furnished an estimate of RCA. The computer-derived graphs provide a quantitative expression of lxlIhippuran activity in a carefully selected cortical area excluding the collecting system. RCA is expressed in percent as the ratio of cortical 1311-hippuran activity remaining at 20 minutes to the peak activity observed in the same cortical area of the same kidney (Figure 1). On the basis of previous experience, RCA should not exceed 30% in nonazotemic patients without RVH [21,25]. Patient Population ACE-inhibited renography was performed at the University of Miami/Jackson Memorial Medical Center in a selected population of patients with and without RVH. All patients underwent renal angiography. Since chronic renal insufficiency may be associated with cortical retention of hippuran, results were considered separately for patients with normal or minimally decreased renal function (serum creatinine 1.5 mg/dL or less) and for patients with chronic renal insufficiency (serum creatinine 1.8 mg/dL or more). PATIENTS WITHOUT RVH: Twenty-two patients, eight normotensive and 14 hypertensive, are included. Fourteen patients were male and 14 were white. Mean age was 39.7 years (range 20 to 70 years). The serum creatinine level for the group averaged 1.51 mg/dL. Fourteen patients had normal or minimally decreased renal function (serum creatinine 0.4 to 1.5 mg/dL); whereas serum creatinine in eight ranged from 1.8 to 5.3 mg/dL. Normotensive sub-
ACE-INHIBITED
‘311-HIPPURAN
RENOGRAPHY
AND RENOVASCULAR
S. creatinine
HYPERTENSION
~lSmg/dl
/ ERBSLOH-MijLLER
ET AL
S. creatinine
2 1.8mg/dl
.
T-* ,
W .
1
:
Figure 2. RCA after ACE inhibition in patients without and with RVH. Data for each kidney are shown for patients without RVH (Groups 1 and 3). Data for the ipsilateral kidney or the more affected kidney with arterial stenosis are shown for patients with RVH (Groups 2 and 4). One patient in Group 2 and one in Group 4 were tested twice.
0.
zj
t .
40 20 0L
P
I A 7
.
jects were evaluated for kidney donation and transplantation. All had normal renal function and normal renal angiograms. Hypertensive patients underwent renal angiography for evaluation of possible renovascular disease because of age, severe hypertension, or other clinical indication. All had angiographically normal renal arteries. PATIENTS WITH RVH: Twenty-eight patients are included. Eighteen patients were male and 26 were white. Mean age for the group was 53.4 years (range 15 to 70 years). The serum creatinine level averaged 1.86 mg/dL. Fourteen patients had serum creatinine in the range of 0.8 to 1.5 mg/dL; whereas 14 had renal insufficiency with a serum creatinine from 1.8 to 5.3 mg/dL. The renovascular disease was atherosclerotic in 25 patients. One patient had a single kidney and 12 had bilateral renovascular disease. In 17 patients, RVH was proven by cure (n = 6) or improvement (n = 11) of the hypertension after successful unilateral or bilateral PTRA (n = 16) or surgery (n = 1). Cure was defined by the maintenance of normotension without medication. Improvement was defined by the maintenance of normotension with one or two drugs less than were necessary prior to renal angioplasty. Sixteen patients had greater than 80% reduction in arterial lumen in at least one renal artery. In one patient, renal angiography disclosed only an apparent 50% stenosis of one renal artery. An additional 11 hypertensive patients were considered to have RVH on the basis of angiographically severe (greater than 90%) occlusion of at least one renal artery [4]. In these patients, PTRA was not performed (n = 4) or was technically unsuccessful or incomplete (n = 7). Statistical Analysis Data are means f SE. Statistical analysis was performed using Student’s t-test for unpaired data or for paired data, where appropriate.
. .
p
GROUP 1 n=28
GROUP 2 n=15
.
t P” :. p
GROUP 3 n=15
GROUP 4 n=15
RESULTS RCA values after ACE inhibition are shown in Figure 2 for individual kidneys of patients with normal renal function and no RVH (Group 1). RCA averaged 15.2 f 1.2% with a range of 4% to 30%. All patients but one had RCA values less than 25%. The exception was a patient with RCA values of 30% and 28% whose blood pressure fell to 85/65 mm Hg after enalaprilat. In contrast, in nonazotemic patients with RVH (Group 2), RCA after ACE inhibition averaged 70.6 f 7.3% with a range from 18% to 100% in the ipsilatera1 kidney for patients with unilateral renal artery stenosis or in the most affected kidney for patients with bilateral renovascular disease (Figure 1). The difference between Groups 1 and 2 was highly significant (p
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ACE-INHIBITED
13WHIPPURAN
1 loo-
RENOGRAPHY
Serum
I
AND RENOVASCULAR
Creatinine
HYPERTENSION
/ ERBSLOH-MijLLER
ET AL
mg/dl r1.8
51.5
80. d a ki
80. 40.
*O 1 #----+ 0'
L
I
I
I
I
BSL
ACEI
BSL
ACEI
To differentiate 1311-hippuran retention resulting from RVH versus intrinsic renal disease, a baseline renogram was obtained without ACE inhibition for comparison with renograms obtained with ACE inhibition (Figure 3). In nonazotemic as well as in azotemic patients without RVH, RCA remained unchanged or decreased nonsignificantly with ACE inhibition. In contrast, in patients with RVH, ACE inhibition significantly increased RCA from 43.1 f 7.7% to 67.5 f 8.0% in nonazotemic patients (p <0.005) and from 67.4 f 7.0% to 93.7 f 3.8% in azotemic patients (p <0.002). Changes in RCA after ACE inhibition observed 5 days to 1 year after intervention are presented in Figure 4 for individual kidneys subjected to PTRA or surgery. Hypertension was cured or improved after successful intervention in 10 of 11 kidneys (nine patients); in these patients, RCA improved and decreased from a pre-PTRA mean value of 64.5 f 9.5% (range 31% to 100%) to a mean post-PTRA value of 22.2 f 2.5% (range 8% to 37%) (p
COMMENTS The present study shows the value of 1311-hippuran renography after ACE inhibition in the diagnosis of RVH and refines the conditions for performing the test. Experimentally, in dogs with unilateral renal artery stenosis and RVH, an impressive increase in diagnostic accuracy was demonstrated when 1311-hippuran renography was performed during ACE inhibition. Test results that were normal under baseline conditions became 26
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Figure 3. Mean (i SE) RCA before (BSL) and after ACE inhibition (ACEI) in patients with (open symbols) and without (solid symbols) RVH.
readily abnormal and diagnostic after ACE inhibition with enalaprilat [26]. Similar observations are reported in patients with RVH using captopril as an ACE inhibitor before hippuran renography [20-221. ACE inhibition in RVH disrupts glomerular function and decreases glomerular filtration rate but not renal blood flow or effective renal plasma flow [26-301. Many scintigraphic studies, therefore, logically concentrated on using ggmTc-DTPA, a glomerular filtrate marker, to assess renovascular disease [6,10-171. The procedure requires comparing a baseline DTPA scintigram with one obtained during ACE inhibition. The presence of RVH is indicated by demonstration of a decrease in ggmT~DTPA excretion, reflecting a decrease in glomerular filtration rate after ACE inhibition. We previously showed the superiority of 1311-hippuran renography over gQmTc-DTPA scintigraphy for the diagnosis of RVH after ACE inhibition, particularly in patients with azotemia [19,21]. The present study confirms these earlier observations (data not shown). Although we did not identify instances of false-positive results of DTPA scintigraphy in patients without RVH, we did encounter numerous instances (about 30%) in which results of ggmT~DTPA scintigraphy were falsely negative after ACE inhibition in patients with RVH, particularly when azotemia existed. Finally, whereas ggmTc-DTPA scintigraphy requires two procedures (one baseline study without ACE inhibition and one after ACE inhibition), a single hippuran renogram after ACE inhibition is sufficient to rule out hemodynamically important renovascular disease in nonazotemic patients and in many azotemic patients. The mechanism underlying the greater sensitivity and specificity of 1311-hippuran renography over ggmTc-DTPA scintigraphy is readily explained by the different renal handling of the two radiophar-
ACE.INHIBITED
=ll-HIPPURAN
RENOGRAPHY
1
Figure 4. Changes in RCA in individual kidneys with renal artery stenosis after successful versus unsuccessful PTRA.
,Pie
AND RENOVASCULAR
HYPERTENSION
Successful n=ll
PTRA
maceutical agents. DTPA is excreted purely by glomerular filtration; whereas, hippuran undergoes glomerular filtration, proximal tubular uptake from peritubular capillaries into proximal tubular cells, and secretion from proximal tubular cells into tubular fluid. ACE inhibition in RVH decreases filtration fraction by decreasing glomerular filtration but not renal blood flow [26-301. Thus, proximal tubular uptake of hippuran from peritubular capillaries continues after ACE inhibition even though glomerular filtration may eventually have been completely obliterated. Accumulation of r311-hippuran continues in proximal tubular cells, but tubular secretion and washout of hippuran from tubular cells into proximal tubular fluid are delayed as a result of decreased single-nephron glomerular filtration and decreased proximal tubular fluid flow rate, resulting in increased RCA of the isotope. Whereas ACE inhibition affects glomerular filtration, the radiohippuran renographic images in RVH are intensified from the combination of decreased singlenephron glomerular filtration, continued proximal tubular uptake of 1311-hippuran from peritubular capillary blood, and delayed washout in proximal tubular fluid [25]. The cortical retention of 1311hippuran likely occurs inside the proximal tubular cells rather than inside the proximal tubular lumen. Indeed, radiohippuran retention is most striking when ACE inhibition completely obliterates the glomerular filtration rate and, thus, the proximal tubular fluid flow rate. The use of furosemide during r311-hippuran ,renography is important. Furosemide, by eliminating the calyceal and pelvic accumulation of urine, facilitates the accurate assessment of cortical retention of 1311-hippuran on the late renographic images and prevents false-positive readings that may occur when furosemide is not given [21]. Furosemide, a
/ ERBSLOH-M6LLER
ET AL
Unsuccessful n=9
Pdst ,
,Pie
PTRA
P&t
,
“distal” diuretic, has no effect on the renal cortical accumulation and washout of 1311-hippuran in RVH [21,29,31]. In contrast, agents that increase the proximal tubular flow rate, such as mannitol, accelerate the washout of hippuran from the renal cortex and may invalidate J311-hippuran renography in patients with proven RVH [22]. Captopril and enalaprilat are equivalent for the purpose of inhibiting ACE. Inhibition of ACE is readily achieved 60 minutes after oral captopril and 10 minutes after intravenous enalaprilat [4]. By eliminating the uncertainties of gastrointestinal absorption and decreasing the time necessary for ACE inhibition, intravenous enalaprilat reduces the duration of the test to less than 1 hour. Hypotension may potentially develop with either drug, particularly if furosemide induces a diuresis. Blood pressure, therefore, should be carefully monitored and patients should not be released after the test unless blood pressure is stable. In the present study, systolic and diastolic blood pressures decreased by means of 27/10.5 mm Hg in patients without RVH, and 39.5/12 mm Hg in patients with RVH. Because of this potential hazard, and unless otherwise contraindicated, liberal amounts of intravenous isotonic sodium chloride should be administered during the procedure. An algorithm is presented in Figure 5 that summarizes our experience with 13rI-hippuran renography in the diagnostic work-up of patients suspected of having RVH. Such patients include those with a suggestive history, an abdominal bruit, evidence of atherosclerosis in the other vascular beds, or an unusual response to ACE inhibitors such as a profound reduction in blood pressure or decrease in renal function. Renography with 1311-hippuran is initially performed after ACE inhibition with intravenous enaJanuary
1991
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ACE-INHIBITED 1311-HIPPURANRENOGRAPHY AND RENOVASCULAR HYPERTENSION / ERBSLijH46LLER
ET AL
ACE inhibited Hippuran Renogram RCA NH
2 3DqoA&)@?,ob
3’-‘00%20 min. PeakRCAbefore
unl’ke’y/
peG~t
I~F’“’
sy;J
creilnlne
F;;dl
Anglography /
RvH-EJi+
Anglography RCA
decreased
RCA unchanged or increased
RVH likely
Renal
Dlsease
/ Anglography
tic work-up pected RVH.
laprilat or oral captopril. If RCA is less than 30%, whatever the level of renal function, RVH is unlikely and no angiographic work-up is advised. If RCA equals lOO%, with peak cortical activity at 20 minutes, showing on the renogram as a slowly rising curve with progressive accumulation of the isotope throughout the duration of the test, whatever the level of renal function again, RVH is likely and we proceed to angiography. If RCA after ACE inhibition ranges from 31% to 100% with maximal activity observed before 20 minutes, the level of renal function must be considered. In patients with a normal or modest decrease in renal function (serum creatinine level up to 1.5 mg/dL), RVH is likely and renal angiography is scheduled. In patients with renal insufficiency, 1311-hippuran uptake is decreased and RCA may exceed 30%. Intrinsic renal disease and RVH can be differentiated in this population by comparing a baseline hippuran renogram obtained without ACE inhibition with a study obtained after ACE inhibition. If RCA remains unchanged or decreases with ACE inhibition (indicating improved renal function), intrinsic renal disease is likely. In contrast, if RCA increases by more than 10% with ACE inhibition (indicating decreased renal function), hemodynamically important renovascular disease is likely and renal angiography is scheduled. For poorly functioning kidneys with RCA of lOO%, renovascular and intrinsic renal disease can also be differentiated by the shape of the computerderived graphs. In kidneys with hemodynamically important renovascular disease, l3lI-hippuran accumulation is low but slowly progressive, peaking at 20 minutes on the renogram; in contrast, in kidneys with intrinsic disease, 1311-hippuran accumulation 28
January 1991
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Figure 5. Algorithm
of Medicine
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90
of
for the disgnospatients with sus-
may be equally low but reaches a maximum before 20 minutes and plateaus thereafter without directional change [21]. Using the approach outlined in Figure 5, furosemideJ311-hippuran renography would have correctly led to angiography in 27 of 28 patients, for a sensitivity of 96%. Moreover, this approach would have had a specificity of 95%, as only one of 22 hypertensive patients without renovascular disease would have been unnecessarily subjected to angiography.
ACKNOWLEDGMENT We are indebted to Ms. Kim Schauers tion of the manuscript.
for secretarial
assistance
in the prepara-
REFERENCES l.Anderson hypertension. 1: 301-4.
GH Jr, Blakeman N, Streeten DHP. Prediction of renovascular Comparison of clinical diagnostic indices. Am J Hypertens 1988;
2. Nally JV. The captopril tests: a new concept in detecting renovascular hypertension. Cleve Clin J Med 1989; 56: 395-4.01. 3. Muller FB, Sealey JE, Case DB, eta/. The captopril test for identifying renovascular disease in hypertensive patients. Am J Med 1986; 80: 633-44. 4. Tunny TJ, Klemm SA, Hamlet SM, Gordon RD. Diagnosis of unilateral renovascular hypertension: comparative effect of intravenous enalaprilat and oral captopril. J Urol 1988; 140: 713-5. 5. Kutkuhn B, Szabio 2, Torsello G, Grabensee B. Endocrine and nuclear medicine diagnosis of renovascular hypertension. Dtsch Med Wochenschr 1989: 114: 1828-32. 6. Svetkey LP, Himmelstein SI. Dunnick NR, et al. Prospective analysis of strategiesfor diagnosing renovascular hypertension. Hypertension 1989; 14: 247-57. 7. McCarthy JE. Weder AB. The captopril test and renovascular hypertension: a cautionary tale. Arch Intern Med 1990; 150: 493-5. 8. Frederickson ED, Wilcox CS, Bucci CM, et al. A prospective evaluation of a simplified captopiil test for the detection of renovascular hypertension. Arch Intern fvled 1990; 150: 569-72. 9. Postma CT, van der Steen PHM, Hoefnagels WHC. de Boo T, Thien T. The captopril test in the detection of lenovascular disease in hypertensive patients. Arch Intern Med 1990; 150: 625-8. 10. Lamki L, Spence JD. MacDonald AC, Roulston M. Differential glomerular
ACE-INHIBITED filtration
rate in the diagnosis
of renovascular
1311-HIPPURAN hypertension
RENOGRAPHY
and follow-up
of
balloon angioplasty. Clin Nucl Med 1986; 11: 188-93. 11. Jackson B, McGrath BP, Matthews PG. Wong C. Johnston Cl. Differential renal function during angiotensin converting enzyme inhibition in renovascular hypertension. Hypertension 1986; 8: 650-4. 12. Fommei E, Ghione S, Palla L, eta/. Renal scintigraphic captopril test in the diagnosis of renovascular hypertension. Hypertension 1987; 10: 212-20. 13. Sallai G, Fornet B. A new examination method for detecting renovascular hypertension: functional DTPA renal scintigraphy sensitized by captopril. Acta Physiol Hung 1988; 72: 15-22. 14. Wilcox CS, Smith TB. Frederickson ED, Wingo CD, Phillips MI, Williams CM. The captopril glomerular filtration rate renogram in renovascular hypertension. Clin Nucl Med 1989; 14: 1-7. 15. Chaignon M. Coutant V, Akerman M, Tainturier C, Lucsko M, Guedon J. Renal effects of captopril in hypertension with renal artery stenosis. Comparison between Tc-99m-DTPA scintigraphy and clearance method. Arch Mal Coeur 1989; 82: 1205-Q. 16. Dondi M. Franchi R, Levorato M, eta/. Evaluation of hypertensive patients by means of captopril enhanced renal scintigraphy with technetium-99m DTPA. J Nucl Med 1989; 30: 615-21. 17. Cuocolo A, Esposito S, Volpe M, Celentano L, Brunetti A, Salvatore M. Renal artery stenosis detection by combined Gates’ technique and captopril test in hypertensive patients. J Nucl Med 1989; 30: 51-6. 18. ltoh K, Shinohara M, Togashi M, KoyanagiT. Captopril renal scintigraphy in a patient with bilateral renal artery stenosis. J Nucl Med 1989; 30: 2042-5. 19. Sfakianakis GN, Jaffe DJ, Bourgoignie JJ. Captopril scintigraphy in the diagnosis of renovascular hypertension. Kidney Int 1988; 34: 5142-4. 20. Geyskes GG, Oei HY, Puylaert CB, Mees EJ. Renovascular hypertension identified by captopril-induced changes in the renogram. Hypertension 1987; 9: 451-8. 21. Sfakianakis GN. Bourgoignie JJ, Jaffe D, Kyriakides G, Perez-Stable E, Duncan RC. Single-dose captopril scintigraphy in the diagnosis of renovascular hy-
AND RENOVASCULAR pertension.
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22. Kremer-Hovinga TK. de Jong PE, Piers DA, Beekhuis H, van der Hem GK. de Zeeuw D. Diagnostic use of angiotensin converting enzyme inhibitors in radioisotope evaluation of unilateral renal artery stenosis. J Nucl Med 1989; 30: 605-14. 23. Thorstad BL, Russell CD, Dubovsky EV, Keller FS, Luke RG. Abnormal captopril renogram with a technetium-99m-labeled hippuran analog. J Nucl Med 1988; 29: 1730-7. 24. Kletter K. Neue Aspekte der nuklearmedizinischen Nierenfunktionsdiagnostik: verbesserte Aussagekraft durch pharmakologische lntervenbon und quantitative Analyseverfahren. Wien Klin Wochenschr 1988; 177: l-34. 25. Sfakianakis GN, Sfakianaki E, Bourgoignie J. Renal scintigraphy following angiotensin-converting enzyme inhibition in the diagnosis of renovascular hypertension (captopril scintigraphy). Nuci Med Annu 1988; 125-70. 26. Jonker GJ, de Zeeuw D, Huisman RM, Piers DB, Beekhuis H, van der Hem GK. Angiotensin converting enzyme inhibition improves diagnostic procedures for renovascular hypertension In dogs. Hypertension 1988; 12: 411-9. 27. Jonker GJ. de Zeeuv D, Huisman RM, van der Hem GK. Angiotensin converting enzyme inhibrtion induces alterations to hippuran renography despite unchanged ipsilateral renal blood flow in conscious two-kidney, one-clip Goldblatt hypertensive dog. J Hypertens 1988; 6: 5455-7. 28. Geyskes GG, Oei HY, Puylaert CB, Doorhout Mees EJ. Renography with captopril. Changes in a patient wrth hypertension and unilateral renal artery stenosis. Arch Intern Med 1986; 146: 1705-8. 29. Kopecky RT, Thomas FD, McAfee JG. Furosemide augments the effects of captopril on nuclear studies in renovascular stenosis. Hypertensron 1987; 10: 181-8. 30. Mourad G, Ribstein J, Argiles A, Mimran A. Mion C. Contrasting effects of acute angiotensin converting enzyme inhibitors and calcium antagonists In transplant renal artery stenosis. Nephrol Dial Transplant 1989; 4: 66-70. 31. lshibashi M, Morita S, Umezaki N, Ohtake H. Evaluation of renal first pass blood flow with a funcbonal image technique in hypertensive patients. Eur J Nucl Med 1988; 14: 25-7.
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PURPOSE: We have previously demonstrated the greater sensitivity of 1311-hippuran renography than ggmTC-DTPA scintigraphy to diagnose renovascular hypertension (RVH). This study assesses the predictive diagnostic value of furosemide-1311-hippuran renography after angiotensin-converting enzyme (ACE) inhibition in patients with and without RVH. PATIENTSANDMETHODS: Allpatientswereinvestigated at the University of Miami/Jackson Memorial Medical Center. Twenty-eight patients had RVH and 22 did not. Twenty-eight patients had normal or minimally decreased renal function (serum creatinine level 1.5 mg/dL or less) and 22 had renal insufficiency (serum creatinine level 1.8 mg/dL or more). Renography was performed 60 minutes after oral administration of 50 mg captopril or 10 minutes after intravenous injection of 40 &kg enalaprilat. Forty milligrams of furosemide were administered intravenously 2 minutes after injection of 1311-hippuran. The residual cortical activity (RCA) of 1311-hippuran was measured at 20 minutes. RESULTS: RVH was unlikely when RCA after ACE inhibition was less than 30% of peak cortical activity. Conversely, RVH was present when 1311-hippuran cortical activity steadily increased throughout the test to reach 100% at 20 minutes. In azotemic patients with RCA between 31% and lOO%, RVH was differentiated from intrinsic renal disease by obtaining a baseline renogram without ACE inhibition and comparing RCA in that study and RCA after ACE inhibition. If RCA increased (indicating worsening renal function) after ACE inhibition, RVH was
From the Divisions of Nephrology and Nuclear Medicine, University of Miami/Jackson Memorial Medical Center, Miami, Florida, This work was supported by a grant from the National Kidney Foundation of South Florida. Requests for reprints should be addressed to Jacques J. Bourgoignie, M.D., Division of Nephrology(R-IX), University of Miami School of Medicine, P.O. BoxO16960, Miami, Florida 33101. Manuscript submitted July 19, 1990, and accepted in revised form October 1, 1990.
likely; whereas, intrinsic renal disease was more likely if RCA remained unchanged or decreased (indicating improved renal function) with ACE inhibition. The test had a specificity of 95% and a sensitivity of 96% in this population. There was a direct correlation between the results of angioplasty or surgery on high blood pressure and the changes in RCA before and after intervention (n = 20). CONCLUSION: Furosemide-1311-hippuran renography with ACE inhibition is highly predictive in identifying patients with RVH.
enal artery stenosis, often correctable by perR cutaneous transluminal renal angioplasty (PTRA) at the time of renal angiography, may be a cause of hypertension and/or renal insufficiency. Whereas renovascular hypertension (RVH) is rare in young adults, it can be identified in up to 10% of patients more than 60 years old [l]. Assessing the hemodynamic importance of renal artery stenosis as a cause of hypertension or as a complicating factor in patients with prior hypertension, however, remains controversial. A practical test is still needed to diagnose functionally important renovascular disease on an outpatient basis prior to hospital admission for further evaluation and treatment if indicated. Many screening and diagnostic procedures have been proposed. None, however, has been universally accepted because of lack of sensitivity and/or specificity, or lack of reproducibility. The introduction of angiotensin-I-converting enzyme (ACE) inhibition promises to greatly enhance the predictive value of several tests [2]. Measurements of peripheral plasma renin or renal vein renin activity have been used after ACE inhibition [3-51. The former, however, is variably sensitive, and variable conclusions regarding its utility have been reached in prospective evaluations [6-91; whereas, renal vein renin measurement remains an invasive procedure. Since ACE inhibition decreases glomerular filtration rate in the ipsilateral kidney with renal artery January
1991
The American
Journal
of Medicine
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23
ACE-INHIBITED
0
13%HIPPURAN
RENOGRAPHY
AND RENOVASCULAR
Peak
HYPERTENSION
20min
Figure 1. Measurement of residual cortical activity of 1311-hippuran (RCA). Cp = cortical peak activity; Cr = cortical activity remaining at 20 minutes.
stenosis, many studies have concentrated on using ggmTc-diethylenetriamine pentaacetic acid (DTPA) scintigraphy before and after captopril administration to assess the hemodynamic importance of renovascular disease [6,10-171. Results, however, have been variable in patients with bilateral renal artery stenoses or in patients with azotemia [l&19]. Renography using 1311-hippuran or a hippuran analogue has shown greater promise than ggmTCDTPA for diagnostic purposes [20-241. We present a quantitative assessment of 1311-hippuran renography after ACE inhibition with captopril or enalaprilat. The test can be completed on an outpatient basis with a sensitivity and a specificity greater than 90%.
PATIENTS AND METHODS FurosemideJ3WHippuran Renography Renography was performed following methods previously described using a computer-interfaced gamma camera and 1311-orthoiodohippurate (1311hippuran) [21,25]. Prior to the test, patients were hydrated orally (10 mL water/kg) and an intravenous infusion of isotonic sodium chloride solution was started. ACE inhibition was achieved using 50 mg captopril orally or 40 pg/kg enalaprilat given intravenously over 3 to 5 minutes. Administration of 1311-hippuran (300 PCi) was performed 60 minutes after administration of captopril or 10 minutes after completion of the enalaprilat injection. Within 3 minutes of injection of 1311-hippuran, 40 mg furosemide was administered intravenously to increase the sensitivity of the test [21,25]. Renography was performed with the patient supine or sitting in posterior projection. Renographic images were obtained every 2 minutes for 20 minutes with simultaneous computer acquisition of the data every 30 seconds. Blood pressure was measured every 10 minutes for the duration of the test. If systolic blood pressure decreased by more than 20%, the
24
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/ ERBSLOH-MijLLER
ET AL
rate of infusion of isotonic saline was accelerated. Furosemide-1311-hippuran renography after ACE inhibition was performed in all patients. Furosemide-1311-hippuran renography was also carried out under baseline conditions using the same procedure except that captopril or enalaprilat was not given in 10 patients without RVH and in all patients with RVH. Antihypertensive drugs were withdrawn overnight before ACE-inhibited scintigraphy. ACE inhibitors were discontinued 48 hours before baseline scintigraphy. Renograms were interpreted by visual inspection of the images and by quantitative analysis of the computer-derived graphs [21,25]. A single criterion was used for the assessment of possible RVH, namely, the amount of residual cortical activity (RCA) remaining 20 minutes after injection of 1311hippuran. Visual inspection of the images served to assess the technical adequacy of the test; it also provided a direct evaluation of overall kidney function, of abnormalities present within a kidney or the collecting system, and of differences existing between two kidneys; finally, it confirmed the cortical localization of 1311-hippuran retention and furnished an estimate of RCA. The computer-derived graphs provide a quantitative expression of lxlIhippuran activity in a carefully selected cortical area excluding the collecting system. RCA is expressed in percent as the ratio of cortical 1311-hippuran activity remaining at 20 minutes to the peak activity observed in the same cortical area of the same kidney (Figure 1). On the basis of previous experience, RCA should not exceed 30% in nonazotemic patients without RVH [21,25]. Patient Population ACE-inhibited renography was performed at the University of Miami/Jackson Memorial Medical Center in a selected population of patients with and without RVH. All patients underwent renal angiography. Since chronic renal insufficiency may be associated with cortical retention of hippuran, results were considered separately for patients with normal or minimally decreased renal function (serum creatinine 1.5 mg/dL or less) and for patients with chronic renal insufficiency (serum creatinine 1.8 mg/dL or more). PATIENTS WITHOUT RVH: Twenty-two patients, eight normotensive and 14 hypertensive, are included. Fourteen patients were male and 14 were white. Mean age was 39.7 years (range 20 to 70 years). The serum creatinine level for the group averaged 1.51 mg/dL. Fourteen patients had normal or minimally decreased renal function (serum creatinine 0.4 to 1.5 mg/dL); whereas serum creatinine in eight ranged from 1.8 to 5.3 mg/dL. Normotensive sub-
ACE-INHIBITED
‘311-HIPPURAN
RENOGRAPHY
AND RENOVASCULAR
S. creatinine
HYPERTENSION
~lSmg/dl
/ ERBSLOH-MijLLER
ET AL
S. creatinine
2 1.8mg/dl
.
T-* ,
W .
1
:
Figure 2. RCA after ACE inhibition in patients without and with RVH. Data for each kidney are shown for patients without RVH (Groups 1 and 3). Data for the ipsilateral kidney or the more affected kidney with arterial stenosis are shown for patients with RVH (Groups 2 and 4). One patient in Group 2 and one in Group 4 were tested twice.
0.
zj
t .
40 20 0L
P
I A 7
.
jects were evaluated for kidney donation and transplantation. All had normal renal function and normal renal angiograms. Hypertensive patients underwent renal angiography for evaluation of possible renovascular disease because of age, severe hypertension, or other clinical indication. All had angiographically normal renal arteries. PATIENTS WITH RVH: Twenty-eight patients are included. Eighteen patients were male and 26 were white. Mean age for the group was 53.4 years (range 15 to 70 years). The serum creatinine level averaged 1.86 mg/dL. Fourteen patients had serum creatinine in the range of 0.8 to 1.5 mg/dL; whereas 14 had renal insufficiency with a serum creatinine from 1.8 to 5.3 mg/dL. The renovascular disease was atherosclerotic in 25 patients. One patient had a single kidney and 12 had bilateral renovascular disease. In 17 patients, RVH was proven by cure (n = 6) or improvement (n = 11) of the hypertension after successful unilateral or bilateral PTRA (n = 16) or surgery (n = 1). Cure was defined by the maintenance of normotension without medication. Improvement was defined by the maintenance of normotension with one or two drugs less than were necessary prior to renal angioplasty. Sixteen patients had greater than 80% reduction in arterial lumen in at least one renal artery. In one patient, renal angiography disclosed only an apparent 50% stenosis of one renal artery. An additional 11 hypertensive patients were considered to have RVH on the basis of angiographically severe (greater than 90%) occlusion of at least one renal artery [4]. In these patients, PTRA was not performed (n = 4) or was technically unsuccessful or incomplete (n = 7). Statistical Analysis Data are means f SE. Statistical analysis was performed using Student’s t-test for unpaired data or for paired data, where appropriate.
. .
p
GROUP 1 n=28
GROUP 2 n=15
.
t P” :. p
GROUP 3 n=15
GROUP 4 n=15
RESULTS RCA values after ACE inhibition are shown in Figure 2 for individual kidneys of patients with normal renal function and no RVH (Group 1). RCA averaged 15.2 f 1.2% with a range of 4% to 30%. All patients but one had RCA values less than 25%. The exception was a patient with RCA values of 30% and 28% whose blood pressure fell to 85/65 mm Hg after enalaprilat. In contrast, in nonazotemic patients with RVH (Group 2), RCA after ACE inhibition averaged 70.6 f 7.3% with a range from 18% to 100% in the ipsilatera1 kidney for patients with unilateral renal artery stenosis or in the most affected kidney for patients with bilateral renovascular disease (Figure 1). The difference between Groups 1 and 2 was highly significant (p
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1991
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25
ACE-INHIBITED
13WHIPPURAN
1 loo-
RENOGRAPHY
Serum
I
AND RENOVASCULAR
Creatinine
HYPERTENSION
/ ERBSLOH-MijLLER
ET AL
mg/dl r1.8
51.5
80. d a ki
80. 40.
*O 1 #----+ 0'
L
I
I
I
I
BSL
ACEI
BSL
ACEI
To differentiate 1311-hippuran retention resulting from RVH versus intrinsic renal disease, a baseline renogram was obtained without ACE inhibition for comparison with renograms obtained with ACE inhibition (Figure 3). In nonazotemic as well as in azotemic patients without RVH, RCA remained unchanged or decreased nonsignificantly with ACE inhibition. In contrast, in patients with RVH, ACE inhibition significantly increased RCA from 43.1 f 7.7% to 67.5 f 8.0% in nonazotemic patients (p <0.005) and from 67.4 f 7.0% to 93.7 f 3.8% in azotemic patients (p <0.002). Changes in RCA after ACE inhibition observed 5 days to 1 year after intervention are presented in Figure 4 for individual kidneys subjected to PTRA or surgery. Hypertension was cured or improved after successful intervention in 10 of 11 kidneys (nine patients); in these patients, RCA improved and decreased from a pre-PTRA mean value of 64.5 f 9.5% (range 31% to 100%) to a mean post-PTRA value of 22.2 f 2.5% (range 8% to 37%) (p
COMMENTS The present study shows the value of 1311-hippuran renography after ACE inhibition in the diagnosis of RVH and refines the conditions for performing the test. Experimentally, in dogs with unilateral renal artery stenosis and RVH, an impressive increase in diagnostic accuracy was demonstrated when 1311-hippuran renography was performed during ACE inhibition. Test results that were normal under baseline conditions became 26
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Figure 3. Mean (i SE) RCA before (BSL) and after ACE inhibition (ACEI) in patients with (open symbols) and without (solid symbols) RVH.
readily abnormal and diagnostic after ACE inhibition with enalaprilat [26]. Similar observations are reported in patients with RVH using captopril as an ACE inhibitor before hippuran renography [20-221. ACE inhibition in RVH disrupts glomerular function and decreases glomerular filtration rate but not renal blood flow or effective renal plasma flow [26-301. Many scintigraphic studies, therefore, logically concentrated on using ggmTc-DTPA, a glomerular filtrate marker, to assess renovascular disease [6,10-171. The procedure requires comparing a baseline DTPA scintigram with one obtained during ACE inhibition. The presence of RVH is indicated by demonstration of a decrease in ggmT~DTPA excretion, reflecting a decrease in glomerular filtration rate after ACE inhibition. We previously showed the superiority of 1311-hippuran renography over gQmTc-DTPA scintigraphy for the diagnosis of RVH after ACE inhibition, particularly in patients with azotemia [19,21]. The present study confirms these earlier observations (data not shown). Although we did not identify instances of false-positive results of DTPA scintigraphy in patients without RVH, we did encounter numerous instances (about 30%) in which results of ggmT~DTPA scintigraphy were falsely negative after ACE inhibition in patients with RVH, particularly when azotemia existed. Finally, whereas ggmTc-DTPA scintigraphy requires two procedures (one baseline study without ACE inhibition and one after ACE inhibition), a single hippuran renogram after ACE inhibition is sufficient to rule out hemodynamically important renovascular disease in nonazotemic patients and in many azotemic patients. The mechanism underlying the greater sensitivity and specificity of 1311-hippuran renography over ggmTc-DTPA scintigraphy is readily explained by the different renal handling of the two radiophar-
ACE.INHIBITED
=ll-HIPPURAN
RENOGRAPHY
1
Figure 4. Changes in RCA in individual kidneys with renal artery stenosis after successful versus unsuccessful PTRA.
,Pie
AND RENOVASCULAR
HYPERTENSION
Successful n=ll
PTRA
maceutical agents. DTPA is excreted purely by glomerular filtration; whereas, hippuran undergoes glomerular filtration, proximal tubular uptake from peritubular capillaries into proximal tubular cells, and secretion from proximal tubular cells into tubular fluid. ACE inhibition in RVH decreases filtration fraction by decreasing glomerular filtration but not renal blood flow [26-301. Thus, proximal tubular uptake of hippuran from peritubular capillaries continues after ACE inhibition even though glomerular filtration may eventually have been completely obliterated. Accumulation of r311-hippuran continues in proximal tubular cells, but tubular secretion and washout of hippuran from tubular cells into proximal tubular fluid are delayed as a result of decreased single-nephron glomerular filtration and decreased proximal tubular fluid flow rate, resulting in increased RCA of the isotope. Whereas ACE inhibition affects glomerular filtration, the radiohippuran renographic images in RVH are intensified from the combination of decreased singlenephron glomerular filtration, continued proximal tubular uptake of 1311-hippuran from peritubular capillary blood, and delayed washout in proximal tubular fluid [25]. The cortical retention of 1311hippuran likely occurs inside the proximal tubular cells rather than inside the proximal tubular lumen. Indeed, radiohippuran retention is most striking when ACE inhibition completely obliterates the glomerular filtration rate and, thus, the proximal tubular fluid flow rate. The use of furosemide during r311-hippuran ,renography is important. Furosemide, by eliminating the calyceal and pelvic accumulation of urine, facilitates the accurate assessment of cortical retention of 1311-hippuran on the late renographic images and prevents false-positive readings that may occur when furosemide is not given [21]. Furosemide, a
/ ERBSLOH-M6LLER
ET AL
Unsuccessful n=9
Pdst ,
,Pie
PTRA
P&t
,
“distal” diuretic, has no effect on the renal cortical accumulation and washout of 1311-hippuran in RVH [21,29,31]. In contrast, agents that increase the proximal tubular flow rate, such as mannitol, accelerate the washout of hippuran from the renal cortex and may invalidate J311-hippuran renography in patients with proven RVH [22]. Captopril and enalaprilat are equivalent for the purpose of inhibiting ACE. Inhibition of ACE is readily achieved 60 minutes after oral captopril and 10 minutes after intravenous enalaprilat [4]. By eliminating the uncertainties of gastrointestinal absorption and decreasing the time necessary for ACE inhibition, intravenous enalaprilat reduces the duration of the test to less than 1 hour. Hypotension may potentially develop with either drug, particularly if furosemide induces a diuresis. Blood pressure, therefore, should be carefully monitored and patients should not be released after the test unless blood pressure is stable. In the present study, systolic and diastolic blood pressures decreased by means of 27/10.5 mm Hg in patients without RVH, and 39.5/12 mm Hg in patients with RVH. Because of this potential hazard, and unless otherwise contraindicated, liberal amounts of intravenous isotonic sodium chloride should be administered during the procedure. An algorithm is presented in Figure 5 that summarizes our experience with 13rI-hippuran renography in the diagnostic work-up of patients suspected of having RVH. Such patients include those with a suggestive history, an abdominal bruit, evidence of atherosclerosis in the other vascular beds, or an unusual response to ACE inhibitors such as a profound reduction in blood pressure or decrease in renal function. Renography with 1311-hippuran is initially performed after ACE inhibition with intravenous enaJanuary
1991
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ACE-INHIBITED 1311-HIPPURANRENOGRAPHY AND RENOVASCULAR HYPERTENSION / ERBSLijH46LLER
ET AL
ACE inhibited Hippuran Renogram RCA NH
2 3DqoA&)@?,ob
3’-‘00%20 min. PeakRCAbefore
unl’ke’y/
peG~t
I~F’“’
sy;J
creilnlne
F;;dl
Anglography /
RvH-EJi+
Anglography RCA
decreased
RCA unchanged or increased
RVH likely
Renal
Dlsease
/ Anglography
tic work-up pected RVH.
laprilat or oral captopril. If RCA is less than 30%, whatever the level of renal function, RVH is unlikely and no angiographic work-up is advised. If RCA equals lOO%, with peak cortical activity at 20 minutes, showing on the renogram as a slowly rising curve with progressive accumulation of the isotope throughout the duration of the test, whatever the level of renal function again, RVH is likely and we proceed to angiography. If RCA after ACE inhibition ranges from 31% to 100% with maximal activity observed before 20 minutes, the level of renal function must be considered. In patients with a normal or modest decrease in renal function (serum creatinine level up to 1.5 mg/dL), RVH is likely and renal angiography is scheduled. In patients with renal insufficiency, 1311-hippuran uptake is decreased and RCA may exceed 30%. Intrinsic renal disease and RVH can be differentiated in this population by comparing a baseline hippuran renogram obtained without ACE inhibition with a study obtained after ACE inhibition. If RCA remains unchanged or decreases with ACE inhibition (indicating improved renal function), intrinsic renal disease is likely. In contrast, if RCA increases by more than 10% with ACE inhibition (indicating decreased renal function), hemodynamically important renovascular disease is likely and renal angiography is scheduled. For poorly functioning kidneys with RCA of lOO%, renovascular and intrinsic renal disease can also be differentiated by the shape of the computerderived graphs. In kidneys with hemodynamically important renovascular disease, l3lI-hippuran accumulation is low but slowly progressive, peaking at 20 minutes on the renogram; in contrast, in kidneys with intrinsic disease, 1311-hippuran accumulation 28
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Figure 5. Algorithm
of Medicine
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90
of
for the disgnospatients with sus-
may be equally low but reaches a maximum before 20 minutes and plateaus thereafter without directional change [21]. Using the approach outlined in Figure 5, furosemideJ311-hippuran renography would have correctly led to angiography in 27 of 28 patients, for a sensitivity of 96%. Moreover, this approach would have had a specificity of 95%, as only one of 22 hypertensive patients without renovascular disease would have been unnecessarily subjected to angiography.
ACKNOWLEDGMENT We are indebted to Ms. Kim Schauers tion of the manuscript.
for secretarial
assistance
in the prepara-
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2. Nally JV. The captopril tests: a new concept in detecting renovascular hypertension. Cleve Clin J Med 1989; 56: 395-4.01. 3. Muller FB, Sealey JE, Case DB, eta/. The captopril test for identifying renovascular disease in hypertensive patients. Am J Med 1986; 80: 633-44. 4. Tunny TJ, Klemm SA, Hamlet SM, Gordon RD. Diagnosis of unilateral renovascular hypertension: comparative effect of intravenous enalaprilat and oral captopril. J Urol 1988; 140: 713-5. 5. Kutkuhn B, Szabio 2, Torsello G, Grabensee B. Endocrine and nuclear medicine diagnosis of renovascular hypertension. Dtsch Med Wochenschr 1989: 114: 1828-32. 6. Svetkey LP, Himmelstein SI. Dunnick NR, et al. Prospective analysis of strategiesfor diagnosing renovascular hypertension. Hypertension 1989; 14: 247-57. 7. McCarthy JE. Weder AB. The captopril test and renovascular hypertension: a cautionary tale. Arch Intern Med 1990; 150: 493-5. 8. Frederickson ED, Wilcox CS, Bucci CM, et al. A prospective evaluation of a simplified captopiil test for the detection of renovascular hypertension. Arch Intern fvled 1990; 150: 569-72. 9. Postma CT, van der Steen PHM, Hoefnagels WHC. de Boo T, Thien T. The captopril test in the detection of lenovascular disease in hypertensive patients. Arch Intern Med 1990; 150: 625-8. 10. Lamki L, Spence JD. MacDonald AC, Roulston M. Differential glomerular
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balloon angioplasty. Clin Nucl Med 1986; 11: 188-93. 11. Jackson B, McGrath BP, Matthews PG. Wong C. Johnston Cl. Differential renal function during angiotensin converting enzyme inhibition in renovascular hypertension. Hypertension 1986; 8: 650-4. 12. Fommei E, Ghione S, Palla L, eta/. Renal scintigraphic captopril test in the diagnosis of renovascular hypertension. Hypertension 1987; 10: 212-20. 13. Sallai G, Fornet B. A new examination method for detecting renovascular hypertension: functional DTPA renal scintigraphy sensitized by captopril. Acta Physiol Hung 1988; 72: 15-22. 14. Wilcox CS, Smith TB. Frederickson ED, Wingo CD, Phillips MI, Williams CM. The captopril glomerular filtration rate renogram in renovascular hypertension. Clin Nucl Med 1989; 14: 1-7. 15. Chaignon M. Coutant V, Akerman M, Tainturier C, Lucsko M, Guedon J. Renal effects of captopril in hypertension with renal artery stenosis. Comparison between Tc-99m-DTPA scintigraphy and clearance method. Arch Mal Coeur 1989; 82: 1205-Q. 16. Dondi M. Franchi R, Levorato M, eta/. Evaluation of hypertensive patients by means of captopril enhanced renal scintigraphy with technetium-99m DTPA. J Nucl Med 1989; 30: 615-21. 17. Cuocolo A, Esposito S, Volpe M, Celentano L, Brunetti A, Salvatore M. Renal artery stenosis detection by combined Gates’ technique and captopril test in hypertensive patients. J Nucl Med 1989; 30: 51-6. 18. ltoh K, Shinohara M, Togashi M, KoyanagiT. Captopril renal scintigraphy in a patient with bilateral renal artery stenosis. J Nucl Med 1989; 30: 2042-5. 19. Sfakianakis GN, Jaffe DJ, Bourgoignie JJ. Captopril scintigraphy in the diagnosis of renovascular hypertension. Kidney Int 1988; 34: 5142-4. 20. Geyskes GG, Oei HY, Puylaert CB, Mees EJ. Renovascular hypertension identified by captopril-induced changes in the renogram. Hypertension 1987; 9: 451-8. 21. Sfakianakis GN. Bourgoignie JJ, Jaffe D, Kyriakides G, Perez-Stable E, Duncan RC. Single-dose captopril scintigraphy in the diagnosis of renovascular hy-
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22. Kremer-Hovinga TK. de Jong PE, Piers DA, Beekhuis H, van der Hem GK. de Zeeuw D. Diagnostic use of angiotensin converting enzyme inhibitors in radioisotope evaluation of unilateral renal artery stenosis. J Nucl Med 1989; 30: 605-14. 23. Thorstad BL, Russell CD, Dubovsky EV, Keller FS, Luke RG. Abnormal captopril renogram with a technetium-99m-labeled hippuran analog. J Nucl Med 1988; 29: 1730-7. 24. Kletter K. Neue Aspekte der nuklearmedizinischen Nierenfunktionsdiagnostik: verbesserte Aussagekraft durch pharmakologische lntervenbon und quantitative Analyseverfahren. Wien Klin Wochenschr 1988; 177: l-34. 25. Sfakianakis GN, Sfakianaki E, Bourgoignie J. Renal scintigraphy following angiotensin-converting enzyme inhibition in the diagnosis of renovascular hypertension (captopril scintigraphy). Nuci Med Annu 1988; 125-70. 26. Jonker GJ, de Zeeuw D, Huisman RM, Piers DB, Beekhuis H, van der Hem GK. Angiotensin converting enzyme inhibition improves diagnostic procedures for renovascular hypertension In dogs. Hypertension 1988; 12: 411-9. 27. Jonker GJ. de Zeeuv D, Huisman RM, van der Hem GK. Angiotensin converting enzyme inhibrtion induces alterations to hippuran renography despite unchanged ipsilateral renal blood flow in conscious two-kidney, one-clip Goldblatt hypertensive dog. J Hypertens 1988; 6: 5455-7. 28. Geyskes GG, Oei HY, Puylaert CB, Doorhout Mees EJ. Renography with captopril. Changes in a patient wrth hypertension and unilateral renal artery stenosis. Arch Intern Med 1986; 146: 1705-8. 29. Kopecky RT, Thomas FD, McAfee JG. Furosemide augments the effects of captopril on nuclear studies in renovascular stenosis. Hypertensron 1987; 10: 181-8. 30. Mourad G, Ribstein J, Argiles A, Mimran A. Mion C. Contrasting effects of acute angiotensin converting enzyme inhibitors and calcium antagonists In transplant renal artery stenosis. Nephrol Dial Transplant 1989; 4: 66-70. 31. lshibashi M, Morita S, Umezaki N, Ohtake H. Evaluation of renal first pass blood flow with a funcbonal image technique in hypertensive patients. Eur J Nucl Med 1988; 14: 25-7.
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