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Resistive Index in Rabbits with Experimentally Induced Hydronephrosis
Resistive Index in Rabbits with Experimentally Induced Hydronephrosis: Effect of Furosemide1 Hak Jong Lee, MD, Jeong Yeon Cho, MD, Seung Hyup Kim, MD
Rationale and Objectives. The purpose of this study in rabbits was to evaluate the effect of furosemide on resistive index (RI) in the diagnosis of partial hydronephrosis. Materials and Methods. In 14 rabbits the left ureter was ligated by being tied to an angiographic guide wire. Doppler sonography was performed before and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ureteral ligation. At each interval it was performed both before and after intravenous injection of saline and furosemide. RIs were compared (a) between obstructed and contralateral kidneys and (b) before and after furosemide administration, and the statistical significance of any differences was determined. Results. Obstructed kidneys had significantly higher RIs than the contralateral kidneys before furosemide administration at five of seven postligation measurements and after furosemide administration at all seven. The differences between obstructed and contralateral kidneys were significantly higher after furosemide administration (P ⬍ .05). The increase in RI after furosemide administration was significantly greater in obstructed than in contralateral kidneys (P ⬍ .05). Conclusion. The results in a rabbit model indicate that Doppler sonography with furosemide administration is a valuable method for evaluating hydronephrosis. The administration of furosemide accentuates the difference in RI between obstructed and nonobstructed kidneys. Key Words. Hydronephrosis; kidney, effects of drugs on; kidney, stenosis or obstruction; kidney, US.
Although renal obstruction is a common clinical problem, its diagnosis in the clinical setting can be elusive. Symptoms and results of laboratory and imaging examination vary with the degree of obstruction, preexisting renal conditions, and residual renal function. Intravenous pyelography and scintigraphic studies are usually helpful in determining the presence of obstruction, but poor renal func-
Acad Radiol 2001; 8:987–992 1
From the Department of Radiology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine, 1-19, Mookjung-Dong, Chung-Ku, Seoul 100-138, Korea (H.J.L., J.Y.C.), and the Department of Radiology and the Institute of Radiation Medicine, Seoul National University College of Medicine, and the Clinical Research Institute, Seoul National University Hospital, Seoul, Korea (S.H.K.). Received March 27, 2001; revision requested May 2; revision received and accepted May 9. Supported by the 1997 Medison Research Fund. Address correspondence to J.Y.C.
©
AUR, 2001
tion can render the results of these examinations equivocal. The combination of conventional and color Doppler ultrasonography (US) has proved to be a valuable complementary examination in patients with renal obstruction, by demonstrating the presence or absence of hydronephrosis (1). The use of Doppler US to measure the resistive index (RI) is a safe and effective means of differentiating obstruction from nonobstructive pyelocaliectasis. It has some limitations, however, especially in cases of chronic and mild obstruction (2). Some studies have found that the RI after furosemide administration was more accurate in the diagnosis of obstruction (3–7). According to another article, however, intravenous furosemide had variable effects on peak systolic and end-diastolic velocities and a statistically insignificant effect on RI but caused a constant and dramatic
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Table 1 Means and Standard Deviations of RI Values before and after Furosemide Administration Before Furosemide
After Furosemide
Interval after Ligation
Obstruction
No Obstruction
Obstruction
No Obstruction
Before ligation 1h 6h 1d 3d 1 wk 2 wk 4 wk
0.56 ⫾ 0.04 0.67 ⫾ 0.09 0.67 ⫾ 0.05 0.64 ⫾ 0.08 0.66 ⫾ 0.05 0.63 ⫾ 0.05 0.62 ⫾ 0.09 0.61 ⫾ 0.06
0.56 ⫾ 0.04 0.62 ⫾ 0.07 0.62 ⫾ 0.04 0.63 ⫾ 0.06 0.64 ⫾ 0.04 0.61 ⫾ 0.04 0.60 ⫾ 0.09 0.59 ⫾ 0.06
0.58 ⫾ 0.04 0.74 ⫾ 0.10 0.72 ⫾ 0.09 0.70 ⫾ 0.10 0.69 ⫾ 0.08 0.69 ⫾ 0.05 0.66 ⫾ 0.10 0.63 ⫾ 0.09
0.56 ⫾ 0.04 0.65 ⫾ 0.08 0.65 ⫾ 0.05 0.65 ⫾ 0.08 0.64 ⫾ 0.05 0.64 ⫾ 0.05 0.63 ⫾ 0.08 0.60 ⫾ 0.09
subjective increase in vascularity (8). The purpose of this study was to evaluate the effect of intravenous furosemide administration on RI in the diagnosis of partial obstructive uropathy in a rabbit model with experimentally induced partial hydronephrosis. MATERIALS AND METHODS Fourteen New Zealand white rabbits (weight, 2.0 –3.0 kg) underwent partial unilateral obstruction of the left proximal ureter. Anesthesia was induced with intramuscular injection of a mixture of 50 mg of ketamine hydrochloride (Ketalar; Yuhan, Seoul, Korea) and 20 mg of xylazine hydrochloride (Rompun; Bayer Korea, Seoul, Korea) before left ureteral ligation. After vertical incision parallel to the midline, the left ureter was exposed. Partial ureteral obstruction was induced by placing an angiographic guide wire (Cook; Bloomington, Ind) (outer diameter, 0.38 inch [0.97 mm]) next to the ureter and tying them together with a 3-0 silk suture. The guide wire was then removed to establish a partial ureteral obstruction. The rabbits were under the direct supervision of a veterinarian, and all procedures were performed according to the guidelines of the Institutional Animal Care and Use Committee. We performed intravenous urography to confirm partial obstruction of the ligated ureter 10 days after ligation. Although we could not evaluate its degree, we could confirm the partial obstruction. Gentamicin sulfate (Kukjae Veterinary; Seoul, Korea) and cefazolin sodium (Dong-A Pharmaceutical; Seoul, Korea) were injected intramuscularly to prevent infection. Conventional and Doppler US were performed before and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ureteral ligation. Doppler US
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was repeated 10 and 20 minutes after injection of 1 mg/kg furosemide (Handok Pharmaceutical; Seoul, Korea; license of Hoechst, Frankfurt [Main], Germany). Before injection of furosemide, 15 mL/kg normal saline was infused intravenously within 30 – 60 minutes. All examinations were performed with an Ultramark HDI3000 US scanner (Advanced Technology Laboratories, Bothell, Wash) and a 5–10-MHz linear-array transducer. Renal RI was calculated with this formula: RI ⫽ (peak systolic velocity ⫺ end-diastolic velocity)/peak systolic velocity. Serial changes in RI were evaluated before and after furosemide administration, before ureteral ligation, and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ligation. We determined the statistical significance of differences between obstructed and contralateral kidneys at each measurement interval, before and after furosemide administration (Wilcoxon signed rank test), and of differences in RI between before and after furosemide administration at each interval, obstructed and contralateral kidneys (Wilcoxon signed rank test). We also analyzed (a) differences in furosemide effect between obstructed and nonobstructed kidneys and (b) the effects of furosemide on the degree of difference in RI between obstructed and nonobstructed kidneys (paired t test). RESULTS Table 1 summarizes the RI findings in rabbits with partial ureteral obstruction. The mean RI (⫾ standard deviation) before ligation was 0.56 ⫾ 0.04 in both kidneys. After administration of normal saline and furosemide, the mean RIs increased to 0.58 ⫾ 0.04 (obstructed kidney) and 0.56 ⫾ 0.04 (contralateral kidney). The mean maximum RI of the obstructed kidneys before furosemide ad-
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Academic Radiology, Vol 8, No 9, September 2001
Table 2 Differences in RI between Obstructed and Nonobstructed Kidneys and between before and after Furosemide Administration Obstructed minus Nonobstructed
Increase after Furosemide
Interval after Ligation
Before Furosemide
After Furosemide
Obstructed Kidneys
Before ligation 1h 6h 1d 3d 1 wk 2 wk 4 wk
0.00 ⫾ 0.04 0.05 ⫾ 0.05 0.05 ⫾ 0.05 0.02 ⫾ 0.04 0.02 ⫾ 0.06 0.02 ⫾ 0.04 0.02 ⫾ 0.05 0.02 ⫾ 0.03
0.02 ⫾ 0.03 0.09 ⫾ 0.07 0.07 ⫾ 0.07 0.05 ⫾ 0.04 0.06 ⫾ 0.05 0.05 ⫾ 0.03 0.03 ⫾ 0.06 0.03 ⫾ 0.05
0.02 ⫾ 0.03 0.07 ⫾ 0.06 0.04 ⫾ 0.06 0.06 ⫾ 0.06 0.03 ⫾ 0.07 0.06 ⫾ 0.02 0.04 ⫾ 0.05 0.02 ⫾ 0.03
Nonobstructed Kidneys 0.00 ⫾ 0.04 0.03 ⫾ 0.05 0.02 ⫾ 0.04 0.03 ⫾ 0.03 0.00 ⫾ 0.04 0.03 ⫾ 0.02 0.03 ⫾ 0.05 0.01 ⫾ 0.03
Note.—Differences are given as means ⫾ standard deviations.
Figure 1. RIs before and after ureteral ligation. Compared with findings before ligation, RIs were elevated markedly in obstructed kidneys, especially at 1 and 6 hours after ligation. The difference induced by furosemide was greatest soon after ligation. f ⫽ obstruction, F ⫽ obstruction and furosemide, Œ ⫽ no obstruction, 䉬 ⫽ no obstruction but with furosemide.
ministration was 0.67 at 1 and 6 hours after ureteral ligation. The mean maximum RI of the obstructed kidneys after furosemide administration was 0.74 ⫾ 0.10 at 1 hour after ligation. In contralateral kidneys, the mean maximum RI before furosemide administration was 0.64 at 3 days after ligation, and the mean maximum after furosemide administration was 0.65 before ligation and 1 hour, 6 hours, and 1 day after ligation.
Before furosemide administration, the obstructed kidneys had significantly higher RIs than the nonobstructed kidneys in five of seven measurement points after ligation: at 1 hour (P ⫽ .006), 6 hours (P ⫽ .006), 1 day (P ⫽ .049), 1 week (P ⫽ .027), and 4 weeks (P ⫽ .005) after ligation. After furosemide administration, the obstructed kidneys had significantly higher RIs than nonobstructed kidneys for all postligation measurements: 1 hour (P ⫽ .001), 6 hours (P ⫽ .005), 1 day (P ⫽ .001), 3 days (P ⫽ .001), 1 week (P ⫽ .001), 2 weeks (P ⫽ .019), and 4 weeks (P ⫽ .022). In contralateral kidneys, the increase in RI after furosemide administration was significant at three intervals: 6 hours (P ⫽ .045), 1 day (P ⫽ .049), and 1 week (P ⫽ .009) after ureteral ligation. In obstructed kidneys, the increase in RI after furosemide administration was significant at five postligation measurement points: 1 hour (P ⫽ .003), 6 hours (P ⫽ .017), 1 day (P ⫽ .008), 1 week (P ⫽ .003), and 2 weeks (P ⫽ .021). Table 2 shows the differences in RI at each measurement point. Before furosemide administration, the maximum difference in RI between obstructed kidneys and contralateral kidneys was 0.05 at 1 and 6 hours after ligation. After furosemide administration, the differences were increased to 0.09 and 0.07 at 1 and 6 hours after ligation, respectively. The difference between obstructed and contralateral kidneys was significantly greater after furosemide administration than before it (P ⬍ .05, paired t test). In the obstructed kidneys, the maximum increase in RI after furosemide administration was 0.07, compared with 0.03 for contralateral kidneys (Table 2). The increase in RI after furosemide administration was significantly
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Figure 2. Duplex Doppler sonograms obtained 6 hours after ureteral ligation. (a) Before administration of saline and furosemide, RI was 0.71. (b) After administration of saline and furosemide, RI increased to 0.77 in the same rabbit.
greater in the obstructed kidneys than in the contralateral, nonobstructed kidneys (P ⬍ .05, paired t test). DISCUSSION Dilatation of the renal collecting system is commonly encountered in clinical imaging of the kidneys, and it is crucial to differentiate true renal obstruction from nonobstructive dilatation. The diagnosis of urinary tract obstruction is an important and difficult problem, because pelvic dilatation can have other causes. The current diagnostic modalities used in evaluating urinary tract dilatation are renal US, intravenous urography, furosemide renography, and the Whitaker test (9). Diuretic renal scintigraphy can be affected by many variables, including hydration, motion, dose and timing of
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the diuretic injection, and, in neonates, poor glomerular filtration rate and poor renal concentration ability (10). The Whitaker test, another conventional diagnostic test, is performed by placing a percutaneous nephrostomy tube into the collecting system of the dilated kidney, but the use of a single percutaneous nephrostomy tube for both instillation and pressure management is problematic. US is noninvasive, requires no sedation or radioactive materials, and is quicker than renal scintigraphy (11). US is commonly used as the initial imaging procedure in patients suspected of having renal obstruction, but pyelocaliectasis identified at US is certainly not synonymous with true obstruction. RI has recently received attention in the literature for its putative role as a barometer of intrarenal vascular resistance and thus as a possible predictor of decreased re-
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EFFECT OF FUROSEMIDE ON RESISTIVE INDEX
Figure 3. Duplex Doppler sonograms obtained 2 weeks after ureteral ligation. (a) Before administration of saline and furosemide, RI was 0.59. (b) After administration of saline and furosemide, RI increased to 0.64 in the same rabbit.
nal perfusion and obstructive nephropathy. Platt et al (12,13) reported the results of renal artery waveform analysis in a series of adults with dilated collecting systems in their kidneys; an RI of 0.7 emerged as the cutoff value between obstructive and nonobstructive dilatation. The basic premise underlying these clinical investigations is that a decrease in renal blood flow mediated by intrarenal vasoconstriction and increased vascular resistance affects diastolic flow velocities more than systolic flow velocities, leading to an increase in the ratio. Chen et al (14), however, stated that RIs are not significantly elevated in all cases of renal obstruction; they may be low or normal in cases of mild or chronic obstruction. This lack of response could be caused by a marked decrease in absolute blood flow in chronic highgrade obstruction, decreased filtration pressure produced
by a minimally functioning renal cortex, or elevated compliance in a capacious, dilated collection system. In our earlier findings (2) published in 1996, for an RI cutoff of 0.7, the overall sensitivity in the diagnosis of unilateral obstructive uropathy in adults was 19.3%. The RI was elevated only in cases of acute and severe obstruction. In rabbit models with unilateral renal obstruction, Kim et al (15) reported an elevated RI in the initial 3 days after partial ligation of the ureter, but the RI subsequently decreased 7 days after ligation. Coley et al (16) stated that although complete obstruction caused a significant increase in RI in their rabbit model, partial obstruction failed to do so and RI values proved to be insensitive predictors of obstruction. RI values after furosemide administration have also been reported to be significantly increased in children
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with hydronephrosis. Although a diuretic has no measurable effect on the renal vascular resistance of normal kidneys (8), obstructed kidneys apparently show a measurable increase in renal vascular resistance, provided the kidney is not too damaged to respond to the pharmacologic challenge (17,18). Palmer et al (17) and Keller et al (19) used Doppler sonography in children before and after intravenous administration of furosemide and found that furosemide caused RIs to increase above baseline in obstructed kidneys. Shokeir et al (5) showed that hyperhydration with normal saline and the administration of furosemide significantly increased the sensitivity, specificity, and overall accuracy of Doppler US in identifying obstruction in 27 children with unilateral or bilateral hydronephrosis. Significant differences in RIs were seen between kidneys with obstructive dilatation and those with nonobstructive dilatation, before and after diuresis. Our results in the present study of experimentally induced partial ureteral obstruction are consistent with those of other clinical investigators (Fig 1, Table 1). In obstructed kidneys in the rabbit model, RIs increased early after ureteral ligation but declined after 3 days. The effect of furosemide on RIs was especially pronounced early after ligation (Figs 2, 3). After furosemide administration, obstructed kidneys had significantly elevated RIs at more measurement points than contralateral kidneys. Animal and clinical studies have demonstrated that renal blood flow is affected by ureteric obstruction, mediated by a renal humoral response involving a complex interaction between changes in intrarenal pressure and prostaglandin release (20,21). Furosemide, a loop diuretic, precipitates renin release. Renin activity is evident 10 minutes after intravenous furosemide administration. Renin stimulates the formation of angiotensin, which then opposes the vasodilatory effect of the prostaglandins, and this interaction may explain the variable velocity changes observed in kidneys after administration of furosemide (8). In our results, the differences in RI between obstructed kidneys and contralateral, nonobstructed kidneys were accentuated after furosemide administration. The increases in RI caused by furosemide administration were significantly greater in obstructed than in contralateral kidneys. In conclusion, our results in rabbits with partial ureteral obstruction indicate that duplex Doppler sonography before and after furosemide administration is valuable in evaluating dilatation of the renal collecting system. Administration of furosemide accentuates the difference be-
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tween obstructed and nonobstructed kidneys, and especially early after obstruction, when RI is most elevated. REFERENCES 1. Cole TC, Brock JW III, Pope JC IV, et al. Evaluation of renal resistive index, maximum velocity, and mean arterial flow velocity in a hydronephrotic partially obstructed pig model. Invest Radiol 1996; 32:154 – 160. 2. Lee HJ, Kim SH, Jeong YK, et al. Doppler sonographic resistive index in obstructed kidneys. J Ultrasound Med 1996; 15:613– 618. 3. Shokeir AA, Provoost AP, El-Azab M, et al. Renal Doppler ultrasonography in children with equivocal obstructive uropathy: effect of intravenous normal saline fluid load and furosemide. Br J Urol 1997; 80:313– 318. 4. Mallek R, Bankier AA, Etele-Hainz A, et al. Distinction between obstructive and nonobstructive hydronephrosis: value of diuresis duplex Doppler sonography. AJR Am J Roentgenol 1996; 166:113–117. 5. Shokeir AA, Provoost AP, El-Azab M, et al. Renal Doppler ultrasound in children with obstructive uropathy: effect of intravenous normal saline fluid load and furosemide. J Urol 1996; 156:1455–1458. 6. Palmer JM, Disandro M. Diuretic enhanced duplex Doppler sonography in 33 children presenting with hydronephrosis: a study of test sensitivity, specificity and precision. J Urol 1995; 154:1885–1888. 7. Ordorica RC, Lindfors KK, Palmer JM. Diuretic Doppler sonography following successful repair of renal obstruction in children. J Urol 1993; 150:774 –777. 8. Renowden SA, Cochlin DL. The effect of intravenous furosemide on the Doppler waveform in normal kidneys. J Ultrasound Med 1992; 11: 65– 68. 9. Pope JC, Showalter PR, Milam DF, et al. Intrapelvic pressure monitoring in the partially obstructed porcine kidney. Urology 1994; 44:565– 571. 10. Lim GY, Jang HS, Lee EJ, et al. Utility of resistance index ratio in differentiating obstructive from nonobstructive hydronephrosis in children. J Clin Ultrasound 1999; 27:187–193. 11. Anderson KR, Weiss RM. Physiology and evaluation of ureteropelvic junction obstruction. J Endourol 1996; 10:87–91. 12. Platt JF, Rubin JM, Ellis JH, et al. Duplex Doppler US of the kidney: differentiation of obstructive from nonobstructive dilatation. Radiology 1989; 171:515. 13. Platt JF. Distinction between obstructive and nonobstructive pyelocaliectasis with duplex Doppler sonography. AJR Am J Roentgenol 1989; 153:997. 14. Chen JH, Pu YS, Liu SP, et al. Renal hemodynamics in patients with obstructive uropathy evaluated by duplex Doppler sonography. J Urol 1993; 150:18 –21. 15. Kim WS, Yeon KM, Kim SH, et al. Renal Doppler ultrasound findings of partial ureteral obstruction: experimental study in rabbits. J Korean Soc Med Ultrasound 1994; 13:19 –23. 16. Coley BD, Arellano RS, Talner LB, et al. Renal resistive index in experimental partial and complete ureteral obstruction. Acad Radiol 1995; 2:373–378. 17. Palmer JM, Lindfors KK, Ordorica RC, et al. Diuretic Doppler sonography in postnatal hydronephrosis. J Urol 1991; 146:605– 608. 18. Renowden SA, Cochlin DL. The potential use of diuresis Doppler sonography in PUJ obstruction. Clin Radiol 1992; 46:94 –96. 19. Keller MS, Krosvik HE, Weiss RM. Diuretic Doppler sonography in postnatal hydronephrosis. J Urol 1991; 146:605– 608. 20. Vaughan ED, Sorenson EJ, Gillenwater JW. The renal hemodynamic response to chronic unilateral complete ureteral occlusion. Invest Urol 1970; 9:78 – 83. 21. Nagle RB, Bulger RE, Cutter RI, et al. Unilateral obstructive uropathy in the rabbit. I. Early morphologic, physiologic and histochemical changes. Lab Invest 1976; 28:456 – 462.
Rationale and Objectives. The purpose of this study in rabbits was to evaluate the effect of furosemide on resistive index (RI) in the diagnosis of partial hydronephrosis. Materials and Methods. In 14 rabbits the left ureter was ligated by being tied to an angiographic guide wire. Doppler sonography was performed before and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ureteral ligation. At each interval it was performed both before and after intravenous injection of saline and furosemide. RIs were compared (a) between obstructed and contralateral kidneys and (b) before and after furosemide administration, and the statistical significance of any differences was determined. Results. Obstructed kidneys had significantly higher RIs than the contralateral kidneys before furosemide administration at five of seven postligation measurements and after furosemide administration at all seven. The differences between obstructed and contralateral kidneys were significantly higher after furosemide administration (P ⬍ .05). The increase in RI after furosemide administration was significantly greater in obstructed than in contralateral kidneys (P ⬍ .05). Conclusion. The results in a rabbit model indicate that Doppler sonography with furosemide administration is a valuable method for evaluating hydronephrosis. The administration of furosemide accentuates the difference in RI between obstructed and nonobstructed kidneys. Key Words. Hydronephrosis; kidney, effects of drugs on; kidney, stenosis or obstruction; kidney, US.
Although renal obstruction is a common clinical problem, its diagnosis in the clinical setting can be elusive. Symptoms and results of laboratory and imaging examination vary with the degree of obstruction, preexisting renal conditions, and residual renal function. Intravenous pyelography and scintigraphic studies are usually helpful in determining the presence of obstruction, but poor renal func-
Acad Radiol 2001; 8:987–992 1
From the Department of Radiology, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine, 1-19, Mookjung-Dong, Chung-Ku, Seoul 100-138, Korea (H.J.L., J.Y.C.), and the Department of Radiology and the Institute of Radiation Medicine, Seoul National University College of Medicine, and the Clinical Research Institute, Seoul National University Hospital, Seoul, Korea (S.H.K.). Received March 27, 2001; revision requested May 2; revision received and accepted May 9. Supported by the 1997 Medison Research Fund. Address correspondence to J.Y.C.
©
AUR, 2001
tion can render the results of these examinations equivocal. The combination of conventional and color Doppler ultrasonography (US) has proved to be a valuable complementary examination in patients with renal obstruction, by demonstrating the presence or absence of hydronephrosis (1). The use of Doppler US to measure the resistive index (RI) is a safe and effective means of differentiating obstruction from nonobstructive pyelocaliectasis. It has some limitations, however, especially in cases of chronic and mild obstruction (2). Some studies have found that the RI after furosemide administration was more accurate in the diagnosis of obstruction (3–7). According to another article, however, intravenous furosemide had variable effects on peak systolic and end-diastolic velocities and a statistically insignificant effect on RI but caused a constant and dramatic
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Academic Radiology, Vol 8, No 9, September 2001
Table 1 Means and Standard Deviations of RI Values before and after Furosemide Administration Before Furosemide
After Furosemide
Interval after Ligation
Obstruction
No Obstruction
Obstruction
No Obstruction
Before ligation 1h 6h 1d 3d 1 wk 2 wk 4 wk
0.56 ⫾ 0.04 0.67 ⫾ 0.09 0.67 ⫾ 0.05 0.64 ⫾ 0.08 0.66 ⫾ 0.05 0.63 ⫾ 0.05 0.62 ⫾ 0.09 0.61 ⫾ 0.06
0.56 ⫾ 0.04 0.62 ⫾ 0.07 0.62 ⫾ 0.04 0.63 ⫾ 0.06 0.64 ⫾ 0.04 0.61 ⫾ 0.04 0.60 ⫾ 0.09 0.59 ⫾ 0.06
0.58 ⫾ 0.04 0.74 ⫾ 0.10 0.72 ⫾ 0.09 0.70 ⫾ 0.10 0.69 ⫾ 0.08 0.69 ⫾ 0.05 0.66 ⫾ 0.10 0.63 ⫾ 0.09
0.56 ⫾ 0.04 0.65 ⫾ 0.08 0.65 ⫾ 0.05 0.65 ⫾ 0.08 0.64 ⫾ 0.05 0.64 ⫾ 0.05 0.63 ⫾ 0.08 0.60 ⫾ 0.09
subjective increase in vascularity (8). The purpose of this study was to evaluate the effect of intravenous furosemide administration on RI in the diagnosis of partial obstructive uropathy in a rabbit model with experimentally induced partial hydronephrosis. MATERIALS AND METHODS Fourteen New Zealand white rabbits (weight, 2.0 –3.0 kg) underwent partial unilateral obstruction of the left proximal ureter. Anesthesia was induced with intramuscular injection of a mixture of 50 mg of ketamine hydrochloride (Ketalar; Yuhan, Seoul, Korea) and 20 mg of xylazine hydrochloride (Rompun; Bayer Korea, Seoul, Korea) before left ureteral ligation. After vertical incision parallel to the midline, the left ureter was exposed. Partial ureteral obstruction was induced by placing an angiographic guide wire (Cook; Bloomington, Ind) (outer diameter, 0.38 inch [0.97 mm]) next to the ureter and tying them together with a 3-0 silk suture. The guide wire was then removed to establish a partial ureteral obstruction. The rabbits were under the direct supervision of a veterinarian, and all procedures were performed according to the guidelines of the Institutional Animal Care and Use Committee. We performed intravenous urography to confirm partial obstruction of the ligated ureter 10 days after ligation. Although we could not evaluate its degree, we could confirm the partial obstruction. Gentamicin sulfate (Kukjae Veterinary; Seoul, Korea) and cefazolin sodium (Dong-A Pharmaceutical; Seoul, Korea) were injected intramuscularly to prevent infection. Conventional and Doppler US were performed before and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ureteral ligation. Doppler US
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was repeated 10 and 20 minutes after injection of 1 mg/kg furosemide (Handok Pharmaceutical; Seoul, Korea; license of Hoechst, Frankfurt [Main], Germany). Before injection of furosemide, 15 mL/kg normal saline was infused intravenously within 30 – 60 minutes. All examinations were performed with an Ultramark HDI3000 US scanner (Advanced Technology Laboratories, Bothell, Wash) and a 5–10-MHz linear-array transducer. Renal RI was calculated with this formula: RI ⫽ (peak systolic velocity ⫺ end-diastolic velocity)/peak systolic velocity. Serial changes in RI were evaluated before and after furosemide administration, before ureteral ligation, and 1 and 6 hours, 1 and 3 days, and 1, 2, and 4 weeks after ligation. We determined the statistical significance of differences between obstructed and contralateral kidneys at each measurement interval, before and after furosemide administration (Wilcoxon signed rank test), and of differences in RI between before and after furosemide administration at each interval, obstructed and contralateral kidneys (Wilcoxon signed rank test). We also analyzed (a) differences in furosemide effect between obstructed and nonobstructed kidneys and (b) the effects of furosemide on the degree of difference in RI between obstructed and nonobstructed kidneys (paired t test). RESULTS Table 1 summarizes the RI findings in rabbits with partial ureteral obstruction. The mean RI (⫾ standard deviation) before ligation was 0.56 ⫾ 0.04 in both kidneys. After administration of normal saline and furosemide, the mean RIs increased to 0.58 ⫾ 0.04 (obstructed kidney) and 0.56 ⫾ 0.04 (contralateral kidney). The mean maximum RI of the obstructed kidneys before furosemide ad-
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Academic Radiology, Vol 8, No 9, September 2001
Table 2 Differences in RI between Obstructed and Nonobstructed Kidneys and between before and after Furosemide Administration Obstructed minus Nonobstructed
Increase after Furosemide
Interval after Ligation
Before Furosemide
After Furosemide
Obstructed Kidneys
Before ligation 1h 6h 1d 3d 1 wk 2 wk 4 wk
0.00 ⫾ 0.04 0.05 ⫾ 0.05 0.05 ⫾ 0.05 0.02 ⫾ 0.04 0.02 ⫾ 0.06 0.02 ⫾ 0.04 0.02 ⫾ 0.05 0.02 ⫾ 0.03
0.02 ⫾ 0.03 0.09 ⫾ 0.07 0.07 ⫾ 0.07 0.05 ⫾ 0.04 0.06 ⫾ 0.05 0.05 ⫾ 0.03 0.03 ⫾ 0.06 0.03 ⫾ 0.05
0.02 ⫾ 0.03 0.07 ⫾ 0.06 0.04 ⫾ 0.06 0.06 ⫾ 0.06 0.03 ⫾ 0.07 0.06 ⫾ 0.02 0.04 ⫾ 0.05 0.02 ⫾ 0.03
Nonobstructed Kidneys 0.00 ⫾ 0.04 0.03 ⫾ 0.05 0.02 ⫾ 0.04 0.03 ⫾ 0.03 0.00 ⫾ 0.04 0.03 ⫾ 0.02 0.03 ⫾ 0.05 0.01 ⫾ 0.03
Note.—Differences are given as means ⫾ standard deviations.
Figure 1. RIs before and after ureteral ligation. Compared with findings before ligation, RIs were elevated markedly in obstructed kidneys, especially at 1 and 6 hours after ligation. The difference induced by furosemide was greatest soon after ligation. f ⫽ obstruction, F ⫽ obstruction and furosemide, Œ ⫽ no obstruction, 䉬 ⫽ no obstruction but with furosemide.
ministration was 0.67 at 1 and 6 hours after ureteral ligation. The mean maximum RI of the obstructed kidneys after furosemide administration was 0.74 ⫾ 0.10 at 1 hour after ligation. In contralateral kidneys, the mean maximum RI before furosemide administration was 0.64 at 3 days after ligation, and the mean maximum after furosemide administration was 0.65 before ligation and 1 hour, 6 hours, and 1 day after ligation.
Before furosemide administration, the obstructed kidneys had significantly higher RIs than the nonobstructed kidneys in five of seven measurement points after ligation: at 1 hour (P ⫽ .006), 6 hours (P ⫽ .006), 1 day (P ⫽ .049), 1 week (P ⫽ .027), and 4 weeks (P ⫽ .005) after ligation. After furosemide administration, the obstructed kidneys had significantly higher RIs than nonobstructed kidneys for all postligation measurements: 1 hour (P ⫽ .001), 6 hours (P ⫽ .005), 1 day (P ⫽ .001), 3 days (P ⫽ .001), 1 week (P ⫽ .001), 2 weeks (P ⫽ .019), and 4 weeks (P ⫽ .022). In contralateral kidneys, the increase in RI after furosemide administration was significant at three intervals: 6 hours (P ⫽ .045), 1 day (P ⫽ .049), and 1 week (P ⫽ .009) after ureteral ligation. In obstructed kidneys, the increase in RI after furosemide administration was significant at five postligation measurement points: 1 hour (P ⫽ .003), 6 hours (P ⫽ .017), 1 day (P ⫽ .008), 1 week (P ⫽ .003), and 2 weeks (P ⫽ .021). Table 2 shows the differences in RI at each measurement point. Before furosemide administration, the maximum difference in RI between obstructed kidneys and contralateral kidneys was 0.05 at 1 and 6 hours after ligation. After furosemide administration, the differences were increased to 0.09 and 0.07 at 1 and 6 hours after ligation, respectively. The difference between obstructed and contralateral kidneys was significantly greater after furosemide administration than before it (P ⬍ .05, paired t test). In the obstructed kidneys, the maximum increase in RI after furosemide administration was 0.07, compared with 0.03 for contralateral kidneys (Table 2). The increase in RI after furosemide administration was significantly
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Figure 2. Duplex Doppler sonograms obtained 6 hours after ureteral ligation. (a) Before administration of saline and furosemide, RI was 0.71. (b) After administration of saline and furosemide, RI increased to 0.77 in the same rabbit.
greater in the obstructed kidneys than in the contralateral, nonobstructed kidneys (P ⬍ .05, paired t test). DISCUSSION Dilatation of the renal collecting system is commonly encountered in clinical imaging of the kidneys, and it is crucial to differentiate true renal obstruction from nonobstructive dilatation. The diagnosis of urinary tract obstruction is an important and difficult problem, because pelvic dilatation can have other causes. The current diagnostic modalities used in evaluating urinary tract dilatation are renal US, intravenous urography, furosemide renography, and the Whitaker test (9). Diuretic renal scintigraphy can be affected by many variables, including hydration, motion, dose and timing of
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the diuretic injection, and, in neonates, poor glomerular filtration rate and poor renal concentration ability (10). The Whitaker test, another conventional diagnostic test, is performed by placing a percutaneous nephrostomy tube into the collecting system of the dilated kidney, but the use of a single percutaneous nephrostomy tube for both instillation and pressure management is problematic. US is noninvasive, requires no sedation or radioactive materials, and is quicker than renal scintigraphy (11). US is commonly used as the initial imaging procedure in patients suspected of having renal obstruction, but pyelocaliectasis identified at US is certainly not synonymous with true obstruction. RI has recently received attention in the literature for its putative role as a barometer of intrarenal vascular resistance and thus as a possible predictor of decreased re-
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EFFECT OF FUROSEMIDE ON RESISTIVE INDEX
Figure 3. Duplex Doppler sonograms obtained 2 weeks after ureteral ligation. (a) Before administration of saline and furosemide, RI was 0.59. (b) After administration of saline and furosemide, RI increased to 0.64 in the same rabbit.
nal perfusion and obstructive nephropathy. Platt et al (12,13) reported the results of renal artery waveform analysis in a series of adults with dilated collecting systems in their kidneys; an RI of 0.7 emerged as the cutoff value between obstructive and nonobstructive dilatation. The basic premise underlying these clinical investigations is that a decrease in renal blood flow mediated by intrarenal vasoconstriction and increased vascular resistance affects diastolic flow velocities more than systolic flow velocities, leading to an increase in the ratio. Chen et al (14), however, stated that RIs are not significantly elevated in all cases of renal obstruction; they may be low or normal in cases of mild or chronic obstruction. This lack of response could be caused by a marked decrease in absolute blood flow in chronic highgrade obstruction, decreased filtration pressure produced
by a minimally functioning renal cortex, or elevated compliance in a capacious, dilated collection system. In our earlier findings (2) published in 1996, for an RI cutoff of 0.7, the overall sensitivity in the diagnosis of unilateral obstructive uropathy in adults was 19.3%. The RI was elevated only in cases of acute and severe obstruction. In rabbit models with unilateral renal obstruction, Kim et al (15) reported an elevated RI in the initial 3 days after partial ligation of the ureter, but the RI subsequently decreased 7 days after ligation. Coley et al (16) stated that although complete obstruction caused a significant increase in RI in their rabbit model, partial obstruction failed to do so and RI values proved to be insensitive predictors of obstruction. RI values after furosemide administration have also been reported to be significantly increased in children
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with hydronephrosis. Although a diuretic has no measurable effect on the renal vascular resistance of normal kidneys (8), obstructed kidneys apparently show a measurable increase in renal vascular resistance, provided the kidney is not too damaged to respond to the pharmacologic challenge (17,18). Palmer et al (17) and Keller et al (19) used Doppler sonography in children before and after intravenous administration of furosemide and found that furosemide caused RIs to increase above baseline in obstructed kidneys. Shokeir et al (5) showed that hyperhydration with normal saline and the administration of furosemide significantly increased the sensitivity, specificity, and overall accuracy of Doppler US in identifying obstruction in 27 children with unilateral or bilateral hydronephrosis. Significant differences in RIs were seen between kidneys with obstructive dilatation and those with nonobstructive dilatation, before and after diuresis. Our results in the present study of experimentally induced partial ureteral obstruction are consistent with those of other clinical investigators (Fig 1, Table 1). In obstructed kidneys in the rabbit model, RIs increased early after ureteral ligation but declined after 3 days. The effect of furosemide on RIs was especially pronounced early after ligation (Figs 2, 3). After furosemide administration, obstructed kidneys had significantly elevated RIs at more measurement points than contralateral kidneys. Animal and clinical studies have demonstrated that renal blood flow is affected by ureteric obstruction, mediated by a renal humoral response involving a complex interaction between changes in intrarenal pressure and prostaglandin release (20,21). Furosemide, a loop diuretic, precipitates renin release. Renin activity is evident 10 minutes after intravenous furosemide administration. Renin stimulates the formation of angiotensin, which then opposes the vasodilatory effect of the prostaglandins, and this interaction may explain the variable velocity changes observed in kidneys after administration of furosemide (8). In our results, the differences in RI between obstructed kidneys and contralateral, nonobstructed kidneys were accentuated after furosemide administration. The increases in RI caused by furosemide administration were significantly greater in obstructed than in contralateral kidneys. In conclusion, our results in rabbits with partial ureteral obstruction indicate that duplex Doppler sonography before and after furosemide administration is valuable in evaluating dilatation of the renal collecting system. Administration of furosemide accentuates the difference be-
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tween obstructed and nonobstructed kidneys, and especially early after obstruction, when RI is most elevated. REFERENCES 1. Cole TC, Brock JW III, Pope JC IV, et al. Evaluation of renal resistive index, maximum velocity, and mean arterial flow velocity in a hydronephrotic partially obstructed pig model. Invest Radiol 1996; 32:154 – 160. 2. Lee HJ, Kim SH, Jeong YK, et al. Doppler sonographic resistive index in obstructed kidneys. J Ultrasound Med 1996; 15:613– 618. 3. Shokeir AA, Provoost AP, El-Azab M, et al. Renal Doppler ultrasonography in children with equivocal obstructive uropathy: effect of intravenous normal saline fluid load and furosemide. Br J Urol 1997; 80:313– 318. 4. Mallek R, Bankier AA, Etele-Hainz A, et al. Distinction between obstructive and nonobstructive hydronephrosis: value of diuresis duplex Doppler sonography. AJR Am J Roentgenol 1996; 166:113–117. 5. Shokeir AA, Provoost AP, El-Azab M, et al. Renal Doppler ultrasound in children with obstructive uropathy: effect of intravenous normal saline fluid load and furosemide. J Urol 1996; 156:1455–1458. 6. Palmer JM, Disandro M. Diuretic enhanced duplex Doppler sonography in 33 children presenting with hydronephrosis: a study of test sensitivity, specificity and precision. J Urol 1995; 154:1885–1888. 7. Ordorica RC, Lindfors KK, Palmer JM. Diuretic Doppler sonography following successful repair of renal obstruction in children. J Urol 1993; 150:774 –777. 8. Renowden SA, Cochlin DL. The effect of intravenous furosemide on the Doppler waveform in normal kidneys. J Ultrasound Med 1992; 11: 65– 68. 9. Pope JC, Showalter PR, Milam DF, et al. Intrapelvic pressure monitoring in the partially obstructed porcine kidney. Urology 1994; 44:565– 571. 10. Lim GY, Jang HS, Lee EJ, et al. Utility of resistance index ratio in differentiating obstructive from nonobstructive hydronephrosis in children. J Clin Ultrasound 1999; 27:187–193. 11. Anderson KR, Weiss RM. Physiology and evaluation of ureteropelvic junction obstruction. J Endourol 1996; 10:87–91. 12. Platt JF, Rubin JM, Ellis JH, et al. Duplex Doppler US of the kidney: differentiation of obstructive from nonobstructive dilatation. Radiology 1989; 171:515. 13. Platt JF. Distinction between obstructive and nonobstructive pyelocaliectasis with duplex Doppler sonography. AJR Am J Roentgenol 1989; 153:997. 14. Chen JH, Pu YS, Liu SP, et al. Renal hemodynamics in patients with obstructive uropathy evaluated by duplex Doppler sonography. J Urol 1993; 150:18 –21. 15. Kim WS, Yeon KM, Kim SH, et al. Renal Doppler ultrasound findings of partial ureteral obstruction: experimental study in rabbits. J Korean Soc Med Ultrasound 1994; 13:19 –23. 16. Coley BD, Arellano RS, Talner LB, et al. Renal resistive index in experimental partial and complete ureteral obstruction. Acad Radiol 1995; 2:373–378. 17. Palmer JM, Lindfors KK, Ordorica RC, et al. Diuretic Doppler sonography in postnatal hydronephrosis. J Urol 1991; 146:605– 608. 18. Renowden SA, Cochlin DL. The potential use of diuresis Doppler sonography in PUJ obstruction. Clin Radiol 1992; 46:94 –96. 19. Keller MS, Krosvik HE, Weiss RM. Diuretic Doppler sonography in postnatal hydronephrosis. J Urol 1991; 146:605– 608. 20. Vaughan ED, Sorenson EJ, Gillenwater JW. The renal hemodynamic response to chronic unilateral complete ureteral occlusion. Invest Urol 1970; 9:78 – 83. 21. Nagle RB, Bulger RE, Cutter RI, et al. Unilateral obstructive uropathy in the rabbit. I. Early morphologic, physiologic and histochemical changes. Lab Invest 1976; 28:456 – 462.