Urol Radiol 14:79-84 (1992)

Urologic Radiology © Springer*VerlagNew York Inc. 1992

Diuretic Renography: Concepts and Controversies Salil D. Sarkar Department of Radiology, SUNY Health ScienceCenter at Brooklyn,Brooklyn,New York, USA

Abstract.

Diuretic renography has proved to be a reliable, noninvasive test for the diagnosis of upper urinary tract obstruction. False positive and false negative results may occur but can be minimized by careful attention to technique. The timing of diuretic administration, state of hydration, and furosemide dosage appear to be the key methodologic variables.

Key words: Diuretic renography -- Furosemide renography -- Tc-99m D T P A -

1-131 hippurate.

Diuretic renography, originally described by Rado et al. [ 1] and popularized by the pioneering works of O'Reilly and Koff [2-7], has become an invaluable noninvasive tool for evaluating upper urinary tract obstruction. Used most frequently in hydronephrotic young children to distinguish pelvicalyceal dilatation from ureteropelvic junction obstruction, this test has provided an alternative to the pressure-flow study of Whitaker, a more invasive and difficult procedure in this age group. The diuretic renogram is based on the premise that radiotracer accumulated in the dilated collecting system is cleared promptly by furosemide-induced increase in urine flow if obstruction is absent, but is not cleared if obstruction is present. Two techniques are available for assessing the diuretic response. With one, furosemide is given at a fixed interval, generally 20 min after (more recently, 15 rain before) the administration of radiotracer. With the other, furosemide is administered at a variable

Address offprint requests to: Salil D. Sarkar, M.D., Department of Nuclear Medicine, SUNY Health ScienceCenter at Brooklyn, 450 Clarkson Avenue, Brooklyn,NY 11203, USA

interval after radiotracer dose when the collecting system appears full. With either technique, a renal time-activity histogram ("renogram") is obtained and the renogram pattern and/or the clearance halftime (i.e., time to clear half of the collecting system activity) are evaluated. Criteria for a normal study have been proposed, although pitfalls in the traditional interpretive schemes, related in part to renographic methodology, have been found. These are discussed in detail below. This review is devoted to diuretic renography as it applies to obstructive upper urinary tract disease and does not address the use of diuretics with renography in other conditions. For instance, the captopril study for renovascular hypertension [812] may be modified to include the use of furosemide [ 13]. This topic is discussed elsewhere in the current issue of Urologic Radiology.

Methodology Timing of Furosemide Injection The diuretic renogram, as originally described by O'Reilly, involved the injection of furosemide at a fixed interval of 20 min after 1-131-hippurate administration ("F + 20" method) [2, 3]. Subsequently, Thrall described a technique using technetium (Tc)-99m-DTPA (diethylenetriamine pentaacetic acid) and a variable interval for diuretic administration [4-6]. Currently the method of choice in the United States, this technique involves the administration of furosemide only after most of the radiotracer has left the renal cortex and filled the pelvicalyceal system. The rationale behind this approach is obvious. Premature injection of furosemide before complete filling of the collecting sys-

80 tem may result in apparent delay in clearance as additional filling occurs. Therefore, a relatively long waiting period may be required before furosemide administration, particularly in impaired cortical function with delayed pelvicalyceal filling. For practical reasons, this waiting period generally does not exceed about 60 min. It is emphasized, however, that prolonging the interval between radiotracer administration and diuretic dose may not suffice if renal function is decreased to less than 20-25% of normal. The F + 20 method (furosemide administration 20 min after iodohippurate), used extensively in Europe, has been modified recently to improve the diagnostic accuracy [ 14]. The modification involves a change in the timing of the diuretic dose and is based on the observation that obstructive symptoms generally appear during periods of peak urine flow [ 14-16]. Since the diuretic effect of furosemide begins early at about 3 min and peaks at about 15-18 min, the early diuresis may wash away most of the radiotracer leaving very little at the time of peak flow. Therefore, an obstruction, if present at the time of the peak flow, may be missed. The modified method therefore calls for furosemide administration 15 min before radiohippurate injection ("F - 15" method) so that the peak diuretic effect occurs when maximum (or adequate) amounts of radiotracer are present in the collecting system. Observing the peak flow period should facilitate the evaluation o f kidneys with decreased function (and decreased flow rates). The modification also may represent an improvement over the F + 20 method for assessing the massively dilated unobstructed pelvis [ 17, 18]. In this condition, increased flow is required to demonstrate normal clearance because of mixing o f incoming urine with pelvic radiotracer without prompt distal flow. An important component of the furosemide renogram is the evaluation of renal cortical function, and it is cautioned that cortical uptake and washout may be altered if furosemide is administered before radiotracer injection. Specifically, it has been reported that the 2-min radiohippurate uptake is increased since furosemide increases renal flow, the time to peak cortical uptake is shortened, and the cortical washout is more rapid and complete by 20 min [19].

Furosemide Dose and Hydration A low rate o f urine flow may result in slower clearance of pelvic radiotracer activity despite the absence of obstruction. Therefore, adequate hydration

S.D. Sarkar: Diuretic Renography and adequate diuresis are essential for avoiding falsepositive studies, particularly in two situations. The first is impaired renal function with decrease in radiotracer uptake and diuretic response. The second is a massively dilated unobstructed pelvis which requires a relatively high flow to clear the radiotracer activity. Not surprisingly, the Whitaker test, where high flow rates are more easily attainable, may be normal in some of these cases. Insuring adequate urine flow may also decrease the potential for falsenegative studies in those instances where obstruction is believed to manifest only at high flow rates. The originally proposed furosemide dose of 0.30.5 mg/kg may well be too low for adequate diuresis in small children and therefore has been increased to 1 mg/kg at several institutions. The usual dose for adults is 40 mg. For optimum results, adequate hydration also is necessary and may be achieved with oral ingestion of water or juice prior to the test and intravenous infusion ofhypotonic saline during the test.

Drainage of Bladder A full bladder may slow emptying of the proximal collecting system or contribute counts to a low-lying kidney [6, 20]. Therefore, older children are asked to void before radiotracer administration and again before furosemide is given, while an indwelling catheter is preferred for infants and small children. The catheter also serves to measure urine output after diuretic administration, an output of at least 5 ml/ min (10 ml/min in older children) insuring adequate urine flow. Bladder catheterization is a must in the presence ofvesicoureteral reflux because of apparent prolongation of the clearance halftime due to contribution of counts from refluxed urine.

Patient Position A change in position occasionally may lead to normalization of an "obstructive" renogram [17]. Therefore, infants may be turned from the supine to the prone position and older children, from the supine to the sitting position, if needed.

Radiopharmaceutical Selection Selection of an appropriate radiopharmaceutical depends to some extent on the technique used. If furosemide is to be administered when the collecting system is filled, a radiopharmaceutical that permits adequate visualization of the collecting system should be used. The conventional agent, Tc99m

S.D. Sarkar: Diuretic Renography DTPA, with abundant counts from its Tc-99m label, is a logical choice. More recently, some institutions have used Tc99m-labeled MAG3, showing greater renal extraction than Tc-99m-DTPA [21]. Whether this radiopharmaceutical has any advantage over Tc-DTPA, particularly in patients with impaired renal function, remains to be seen. If furosemide is administered at a fixed time relative to the tracer dose, as with the F - 15 method, the collecting system need not be optimally visualized and high counts are not necessary. Therefore, a radiopharmaceutical with low photon yield, namely, radioiodine-labeled hippurate, may suffice.

Analysis of Diuretic Renal Study Although visual assessment of the scintiimages for pelvicalyceal clearance postfurosemide often suffices in unequivocal cases, it is generally agreed that a quantitative measure of clearance is necessary, both to increase the diagnostic accuracy of the initial study and to allow comparisons in foUow-up studies. Discussed below are important issues related to the assessment of the furosemide renal study.

Obtaining a Time-Activity Curve and Clearance Halftime A renal time-activity histogram is generated after carefully selecting a region of interest (ROI) to include the area in question, for example, the entire pelvis for a suspected ureteropelvic junction obstruction. Inadvertent exclusion of only a part of the pelvis may lead to erroneous results. Theoretically, limiting the ROI to the pelvicalyceal area is ideal but often may be difficult in young children, and a more commonly used alternative involves a single ROI to include the entire kidney with the pelvicalyceal system. The clearance halftime is measured from the renal time-activity curve. If the curve is sigmoidshaped, showing initial clearance in a steep straight line with subsequent flattening, the straight portion of the curve is used for the halftime measurement [22].

Evaluating the Time-Activity Curve O'Reilly classified the renal time-activity curves into four types: type I, a normal renogram before and during diuresis, indicating a normal-sized pelvis without obstruction; type II, an "obstructive" renogram pattern with no response to the diuretic (obstructed); type IIIa, an initially obstructive pattern

81 with prompt clearance after the diuretic (dilated pelvis, not obstructed); and type IIIb, an initially obstructive pattern with only slight response to furosemide (obstruction likely). As noted earlier, these curve patterns have been combined with measurements of clearance halftimes. Using Tc-99m DTPA and a variable interval for diuretic administration, a halftime of less than 15 min is considered normal, more than 20 min abnormal, and 15-20 rain equivocal (Figs. 1 and 2). It is now recognized that renogram patterns and clearance halftimes are occasionally misleading. An "obstructive" pattern in the nonobstructed massively dilated pelvis, particularly with inadequate urine flow, has been mentioned. False-positive renographic studies also may occur shortly after the relief of obstruction, with improvement in clearance halftimes in later studies [7, 23, 24]. False-negative renograms also have been reported and the timehonored assumption that a type IIIa curve pattern rules out obstruction has been questioned recently. Using an experimental pig model of ureteral obstruction, Harving has found a type lIIa furosemide renogram in several obstructed kidneys [25]. Since it is also possible to convert a type I pattern to a type IIIa pattern by mere dehydration, he concluded that a type IIIa pattern in the presence of adequate hydration suggested obstruction. It should be noted that Harving administered furosemide 15 min after radiohippurate administration, and it is unclear if the results would be identical if higher flows were achieved using the F - 15 method. Using the clearance halftime measurement, Kass found a false-negative diuretic renogram in one infant who had a follow-up study a year later which was positive [24]. The author suggested an initial phase in the obstructive process when adequate flow was maintained by increased intrapelvic pressure. Kekomaki, using an experimental model of hydronephrosis in rabbits, showed furosemide-induced tracer clearance from the pelves of some of the obstructed kidneys [26]. However, these kidneys developed subtle functional impairment in that the ability to retain water and to concentrate urine in the "thirst test" was lost. These findings again underscore the need for follow-up studies in patients with normal furosemide response.

Correlative Techniques Discrepancies between the furosemide renogram and the pressure-perfusion study of Whitaker have been reported in about 15% of studies [27]. Although the Whitaker test has been considered by some to be

82

S.D. Sarkar: Diuretic Renography

a

b

C 400.8

2go. e

e.e

,e

I

~?~

I

4.OJ ks*,~

the "'gold standard," it does not necessarily approximate n o r m a l renal physiology. Flow rates o f about l0 m l / m i n used for this procedure m a y trigger a positive test, but m a y n e v e r be reached under physiologic conditions. This could account for false-positive Whitaker tests, as reported by Kass et al. [24]. These investigators also found false-negative studies and theorized that although the infused rate is constant, the actual intrarenal flow rate m a y be low if the intrinsic renal flow is p o o r due to functional impairment. A n o t h e r variable relates to compliance and capacity o f the collecting system. Pelvic pressure m a y be n o r m a l i f pelvic capacity exceeds urine v o l u m e and vice versa [28, 29]. For instance, the pressure m a y be n o r m a l in a compliant and dilated pelvis despite obstruction. F u r t h e r m o r e , the pressure-volu m e relationships are not constant and m a y vary o v e r time. Nonetheless, despite potential pitfalls, the Whitaker test generally does correlate with the

Fig. 1. Sequential 2-min posterior images and time-activity curves using Te-99m-DTPA are shown in a patient with left ureteropelvic junction obstruction. Images from 0-30 min (a) show spontaneous clearance of radiotracer from the fight renal collecting system and stasis in the left pelvicalyceal system. Images from 30--60 min (b) show no clearance of left pelvic activity after furosemide administration (arrow). Renal time-activity curves (e) show progressive increase in left renal activity (L). Right renal (R) and bladder (B) curves are also shown.

degree o f obstruction [30] and m a y be used, i f feasible, in instances where renography is equivocal. A newer technique employing contrast-enhanced diuretic M R I has been proposed for the evaluation o f hydronephrosis [31]. In an experimental model o f ureteral obstruction in micropigs, the response o f cortical signal e n h a n c e m e n t to furosemide appears to differentiate obstructed f r o m n o n o b structed hydronephrosis. While this modality appears promising, additional studies are needed to establish its role in obstructive renal disease.

Conclusions and Protocol T h e value o f diuretic renography can be m a x i m i z e d by recognizing its limitations and pitfalls. First and foremost, careful attention should be given to methodology. T h e following protocol is suggested: 1.

Hydrate the patient with water or juice prior to the test and intravenous infusion o f

S.D. Sarkar: Diuretic Renography

83

a

b

C

/ ~tS/S~Ce:.-

3o8.ol// \-,.. 21~,

0

100.0

-

.;. ]

2.

3.

4.

5.

0.0

¢~%~ [

~

t .0

I

! ~.0

I

I

hypotonic saline (about 10 ml/min) during the test to help maintain an adequate urine flow. Catheterize the bladder, if feasible, since a full bladder may impede emptying of the ureters and if reflux is present, may contribute to proximal ureteral-pelvic counts. Older children may void before the test and again before furosemide administration. Position the patient supine with the camera detector underneath for posterior viewing and administer Tc-99m DTPA. Monitor renal area and administer furosemide, 1 mg/kg, when cortical washout is nearly complete and the collecting system is full (if the collecting system fails to visualize by about 60 min, furosemide is unlikely to be effective and the study may be terminated). Monitor for an additional 30 min after fu-

.

.

4,0 I

kS~c

Fig. 2. Sequential2-min posterior TcDTPA imagesand time-activitycurves are shown in a patient with left-sidedhydronephrosis. Imagesfrom 0-30 min (a) show spontaneousclearance of radiotracer from the fight renal collectingsystem and stasis in the left pelvicalycealsystem. Furosemide administrationis indicated by an a r r o w . Imagesfrom 30-60 min (5) show progressive clearanceof radiotracer from the left pelvis with the renal timeactivity curve (c) indicatinga clearance halftimeof approximately 11 min.

rosemide injection. If significant pelvicalyceal clearance has not occurred by 30 min, turn the patient over to the prone position and monitor the kidneys for an additional 20 rain. Older children may void and sit uptight for the additional acquisition. A change in position occasionally may allow emptying of the proximal collecting system. Generate time-activity curves making certain that the kidney and the entire area in question (e.g., pelvis) is included in the ROI. Calculate the clearance halftime using the initial (linear) portion of the clearance curve.

Increased urine flow resulting from hydration and an adequate and appropriately timed furosemide dose helps decrease false-positive studies, particularly if renal function is impaired or the pelvis is markedly dilated. Nevertheless, in the presence of these conditions, patients with positive diuretic

84 r e n o g r a m s m a y u n d e r g o t h e W h i t a k e r test, b e a r i n g in m i n d t h e l i m i t a t i o n s o f t h i s test. M a i n t e n a n c e o f a n a d e q u a t e u r i n e flow a l s o d e c r e a s e s t h e t h e o r e t i c a l p o s s i b i l i t y o f f a l s e - n e g a t i v e d i u r e t i c r e n o g r a m s in o b s t r u c t i o n s m a n i f e s t o n l y a t h i g h flows. D e s p i t e a d e q u a t e flow, h o w e v e r , o c c a s i o n a l a n d t r a n s i e n t f a l s e - n e g a t i v e f i n d i n g s m a y o c c u r . I t is t h e r e f o r e p r u d e n t t o r e p e a t n o r m a l s t u d i e s in a p p r o x i m a t e l y 6 months. In summary, diuretic renography has evolved over the years from a simple nonimaging "probe" t e c h n i q u e to p r e s e n t - d a y h i g h - r e s o l u t i o n q u a n t i t a tive scintiimaging. The utility of the test can be s i g n i f i c a n t l y e n h a n c e d b y c a r e f u l a t t e n t i o n to m e t h o d o l o g y . U r i n a r y t r a c t o b s t r u c t i o n , h o w e v e r , is a complex and dynamic process and despite our best efforts, f a l s e - p o s i t i v e a n d f a l s e - n e g a t i v e o u t c o m e s cannot be entirely eliminated. Therefore, selected cases may warrant further corroboration with the Whitaker test and/or a follow-up renogram.

References

1. Rado JP, Banos C, Tako J, Szende L: Renographic studies during furosemide diuresis in partial ureteral obstruction. Radiol Clin Bio138:132-146, 1969 2. O'Reilly PH, Testa H J, Lawson RS, Farrar DJ, Edwards EC: Diuresis renography in equivocal urinary tract obstruction. Br J Urol 50:76-80, 1978 3. O'Reilly PH, Lawson RS, Shields RA, Testa HJ: Idiopathic hydronephrosis--The diuresis renogram: A new non-invasive method of assessing equivocal pelvioureteral junction obstruction. J Urol 121:153-155, 1979 4. Koff SA, Thrall JH, Keyes JW: Diuretic radionuclide urography: A non-invasive method for evaluating nephroureteral dilatation. J Urol 122:451-454, 1979 5. KoffSA, Thrall JH, Keyes JW Jr: Assessment ofhydroureteronephrosis in children using diuretic radionuclide urography. J Urol 123:531-534, 1980 6. Thrall JH, Kotf SA, Keyes JW Jr: Diuretic radionuclide renography and scintigraphy in the differential diagnosis of hydroureteronephrosis. Semin Nucl Med 11:89-104, 1981 7. KoffSA, Thrall JH: Diagnosis ofobstruction in experimental hydroureteronephrosis. Urology 17:570-577, 1981 8. Geyskes GG, Oei HY, Puylaert CBAJ, Dorhout Mees EJ: Renovascular hypertension identified by captopril-induced changes in the renogram. Hypertension 9:451-458, 1987 9. Subramanian K, Sarkar SD, Mann SJ, Picketing TG, Rozenblit G, Becker DV, Sos TA, Laragh JH: Single dose captopril renography with Tc-99m-DTPA and I-13 l-hippuran in renovascular hypertension. J Nucl Med 28:735, 1987 10. Mann SJ, Picketing TG, Sos TA, Uzzo RG, Sarkar S, Friend K, Rackson ME, Laragh JH: Captoptil renography in the diagnosis of renal artery stenosis: Accuracy and limitations. Am J Med 90:30-40, 1991 l 1. Cuocolo A, Esposito S, Volpe M, Celentano L, Brunetti A, Salvatore M: Renal artery stenosis detection by combined Gates' technique and captoptil test in hypertensive patients. J Nucl Med 30:51-56, 1989 12. Fine EJ, Sarkar SD: Differential diagnosis and management

S.D. Sarkar: Diuretic Renography

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28. 29. 30.

31.

ofrenovascular hypertension through nuclear medicine techniques. Semin Nucl Med 19:101-115, 1989 Erbsloh-Moller B, Dumas A, Roth D, Sfakianakis GN, Bourgoignie J J: Furosemide- 13 l-I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension. Am J Med 90:23-29, 1991 English PJ, Testa H J, Lawson RS, Carroll RNP, Edwards EC: Modified method of diuresis renography for the assessment of equivocal pelviuretetic junction obstruction. Br J Urol 59:10-14, 1987 Davies P, Woods KA, Evans CM, Gray WM, Kulatilake AE: The value of provocative and acute urography in patients with intermittent loin pain. Br J Urol 50:227-232, 1978 Sukhai RN, Kooy PPM, Wolff ED, Scholtmeijer RJ, Van Der Heijden AJ: Evaluation of obstructive uropathy in children. 99mTc-DTPA renography studies under conditions of maximal diuresis. Br J Urol 57:124--129, 1985 Shore RM, Uehling DT, Bruskewitz R, Polcyn RE: Evaluation of obstructive uropathy with diuretic renography. Am J Dis Child 137:236-240, 1983 Ireton RC, Parker RM, Hayden P: Diuretic renography in evaluating dilated upper urinary tract in children. Urology 29:178-184, 1987 Upsdell SM, Testa H J, Lawson RS, Carroll RNP, Edwards EC: The uses and interpretation of modified diuresis renography. In Blaufox MD, Hollenberg NK, Raynaud C (eds): Radionuclides in Nephro-Urology, Basel: Karger, 1990, pp 103107 Berdon WE, Baker DH: The significance of a distended bladder in the interpretation of intravenous pyelograms on patients with "hydronephrosis." AJR 120:402--409, 1974 Hvid-Jacobsen K, Thomsen HS, Nielsen SL: Diuresis renography. A simultaneous comparison between 131-l-hippuran and 99mTc-MAG3. Acta Radio131:83-86, 1990 Kletter K, Nurnberger N, Dudczak R: Quantitative assessment of the diuresis renogram. Contr Nephrol 56:261-266, 1987 Lupton EW, Testa H J, Lawson RS, Edwards EC, Carroll RN, Barnard RJ: Diuresis renography and the results of pyeloplasty for idiopathic hydronephrosis. Br J Uro151:449-453, 1979 Kass EJ, Majd M, Belman AB: Comparison of the diuretic renogram and the pressure perfusion study in children. J Urol 134:92-96, 1985 Harving N, Christiansen P, Taagehoj-Jensen F, Frokjaer J, Djurhuus JC, Mortensen J: Experimental evaluation of furosemide renography in unobstructed and partially obstructed upper urinary tracts in pigs. Urology 27:590-594, 1991 Kekomaki M, Rikalainen H, Ruotsalainen P, Bertenyi C: Correlates of diuretic renography in experimental hydronephrosis. J Urol 141:391-394, 1989 Whitaker RH, Buxton-Thomas MS: A comparison of pressure flow studies and renography in equivocal upper urinary tract obstruction. J Urol 131:446-449, 1984 Koff SA: Determinants of progression and equilibrium in hydronephrosis. Invest Uro121:496-500, 1983 Djurhuus JC, Sakso P, Mortensen J: The pressure-volume relationship of the pig renal pelvis. J Uro1135:648-650, 1986 Ryan PC, Maher K, Hurley GD, Fitzpatrick JM: The Whitaker test: Experimental analysis in a canine model of partial ureteric obstruction. J Urol 141:387-390, 1989 Tzika AA, Thurnher S, Hricak H, Price DC, Arrive L, AboseifS, Engelstad BL, Rector FC Jr: Rapid, contrast-enhanced, diuretic magnetic resonance imaging of unilateral partial ureteral obstruction. An experimental study in micropigs. Invest Radiol 24:37-46, 1989