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Experimental Studies |
1 From the Departments of Radiology (M.C., C.E.B., G.A.T., P.S.D.) and Urology (R.G., A.B.B.), Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115. Received August 26, 1998; revision requested September 23; final revision received November 23; accepted March 29, 1999. G.A.T. supported in part by Alliance Pharmaceutical, San Diego, Calif, and Acuson, Mountain View, Calif. Address reprint requests to G.A.T. (e-mail: taylor_g@a1.tch.harvard.edu).
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Abstract |
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MATERIALS AND METHODS: In 12 piglets, the distal ureter was obstructed for 60 minutes, followed by intravenous injection of furosemide. In six piglets, ureteral pressure was further elevated to mean arterial pressure, and in six other piglets ureteral obstruction was released. Contrast-enhanced harmonic imaging was performed, and interlobar resistive index (RI) and renal blood flow were determined at baseline and during each experimental condition. A bolus injection curve was constructed by plotting mean pixel intensity versus time, and the area under this normalized curve was compared with renal blood flow values.
RESULTS: Ureteral obstruction and high ureteral pressure reduced cortical renal blood flow to 88% and 66%, respectively, of baseline values. Administration of contrast agent resulted in marked homogeneous enhancement of the renal cortex. The area under the curve diminished during ureteral obstruction and correlated well with mean cortical blood flow. RI correlated well with renal perfusion pressure but poorly with changes in renal blood flow.
CONCLUSION: Contrast-enhanced harmonic US imaging depicts changes in renal blood flow during acute obstruction. Interlobar RI is a good predictor of renal perfusion pressure but not of changes in renal blood flow.
Index terms: Kidney, stenosis or obstruction, 81.145, 81.84 • Kidney, US, 81.12981, 81.12982, 81.12984, 81.12988 • Renal arteries, US, 963.12981, 963.12982, 963.12984, 963.12988, 963.762 • Ultrasound (US), Doppler studies, 963.12984 • Ultrasound (US), harmonic study • Ureter, stenosis or obstruction, 82.145, 82.84
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Introduction |
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Results from previous animal and human studies (4–6) have shown that occlusion of the ureter is associated with a reduction in global renal blood flow by up to 45%. Results of several studies (7–9) have suggested that this vasoconstrictive response could be identified by using the Doppler criteria of intrarenal resistive index (RI) of 0.70 or greater or an increased difference between the RI of the obstructed and contralateral kidney of 0.08–0.10 or greater. Intravenous administration of furosemide and a bolus of normal saline solution also has been reported to increase the differences in RI between the kidneys by causing the RI to increase in the obstructed kidney and decrease in the nonobstructed kidney (10–12). However, other authors (13–16) have shown a lack of sensitivity of renal Doppler US to acute obstruction. Because of this uncertainty, an alternative or complementary noninvasive method to detect early hemodynamic changes in the obstructed kidney might be desirable. The aims of this study were therefore to assess the feasibility of contrast-enhanced gray-scale harmonic US imaging and to compare it with Doppler hemodynamics for the evaluation of renal blood flow during acute ureteral obstruction.
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MATERIALS AND METHODS |
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A cystotomy was performed, and a 4-F balloon catheter (Cook, Bloomington, Ind) was placed in the orifice of the right ureter. The balloon was inflated with fluoroscopic guidance, and the catheter was connected to a pressure transducer. The positions of the cardiac and ureteral catheters were confirmed fluoroscopically. Arterial, left ventricular, and ureteral pressure and the core temperature were monitored continuously with a physiologic monitoring system (model 76; Hewlett-Packard, Andover, Mass). Arterial PO2, PCO2, pH, and hematocrit levels were measured intermittently throughout the experiment.
Imaging Protocol
The right kidney was imaged in situ by using a curved transducer (Sequoia Systems; Acuson, Mountain View, Calif) transmitting at 4.0 MHz and receiving at 8.0 MHz and held in place by an articulated mechanical holder during the entire experiment. Linear image pre- and postprocessing, or input-output conversion, curves were used. The mechanical index was set at 0.5 units, the gray-scale gain was set at 0 dB, and no persistence was used. These imaging parameters were held constant during the entire experiment.
The contrast agent, AF0150 (Imagent; Alliance Pharmaceutical, San Diego, Calif), was reconstituted according to the manufacturer's directions and yielded a dispersion of surfactant-coated perfluorohexane nitrogen-containing microbubbles with a volume-weighted median diameter of approximately 5 µm. Elimination from the blood is accomplished by evaporation through the lungs (17). The contrast agent was administered at a dose of 0.1 mL/kg. Each dose was injected intravenously over an interval of 1–2 seconds. At least 15 minutes elapsed between injections. The catheter and stopcock were flushed with saline solution by using three times the catheter volume after each dose to clear any residual contrast agent.
The transducer-to-kidney surface distance was 1.5–2.0 cm in each animal. Serial harmonic gray-scale images of the kidney were obtained in sagittal projection before, during, and after the injection of contrast agent. The renal pelvis diameter was measured in the anteroposterior dimension, and at least three interlobar arteries were interrogated with pulsed Doppler US at every experimental point. Waveforms lasting at least 3 seconds were selected, and an RI was measured electronically. The mean of these three values was used for analyses.
Image Processing
A continuous digital movie clip of the kidney was started at the onset of the intravenous injection of contrast agent. Images were captured electronically every 0.3 second for a total of 60 seconds by using a digital image processing unit (Sequoia Systems, Acuson) and were saved in an 8-bit tag image file format, or TIFF. Images were then transferred onto a computer (G3 MacIntosh; Apple Computer, Cupertino, Calif) and analyzed by using OPEN LAB (Improvision, Coventry, UK). Each digital movie clip was saved as a serial image stack.
Three separate regions of interest of similar size were drawn over the cortex and medulla in the upper, middle, and lower portions of the kidney (Fig 1). These regions of interest were identified on images obtained before the administration of contrast agent and electronically superimposed on subsequent anatomically registered images obtained after the administration of contrast agent. Thus, the same region of interest was used for the determination of mean pixel intensity in each area of the kidney so that differences in intensity reflected changes in mean pixel value and not variations in the size and location of the area measured. The number of pixels and mean pixel value were calculated for each region of interest by using the program's measurement and results functions. Mean pixel intensity was measured on a scale with equal increments from 0 for black to 255 for white and was expressed as the mean intensity per number of pixels in the region of interest.
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Regional Renal Blood Flow Determinations
Renal blood flow was determined for both kidneys in every animal by using the reference-sample radiolabeled-microsphere technique (18). We used microspheres of 16 µm ± 0.5 (SD) labeled with four separate isotopes: cerium 141, tin 113, ruthenium 103, and scandium 46 (Dupont-New England Nuclear Products, Boston, Mass). Each of these isotopes has a different photon energy and therefore can be measured independently. For each blood flow determination, a volume containing 1.5 x 106 microspheres labeled with one of these isotopes was injected into the left ventricle and flushed with 5 mL of saline solution for 20 seconds to distribute the spheres throughout the body according to regional blood flow. A reference blood sample was withdrawn from a femoral catheter at a rate of 2 mL/min beginning 30 seconds before microsphere injection and continued for 90 seconds after completion of the saline solution flush. Microsphere injection did not alter the mean arterial blood pressure.
At the end of each experiment, the animals were killed with an intravenous injection (2 mL/kg) of pentobarbital and potassium chloride. Both kidneys were resected and immediately sectioned to determine regional renal blood flow, or r-RBF, to the cortical regions identified on the US images. After sectioning, each tissue sample was weighed and placed in a 15-mL vial for analysis in an autogamma scintillation spectrometer (Cobra II Gamma Counter; Packard Instruments, Meriden, Conn). Blood flow was determined by comparing counts for each radiolabel in each tissue sample to counts in the reference blood samples. All counts were corrected for isotope decay. Cortical blood flow was expressed in milliliters per minute per gram of tissue by normalizing for tissue weight. The medullary vascular bed is unique in that venous outflow is consistently higher than arterial inflow. The radiolabeled microsphere method relies on the assessment of inflow and, as a result, it is likely to cause underestimation of medullary blood flow (19). Therefore, only cortical blood flows were used for analysis.
Experimental Protocol
Contrast-enhanced US images, interlobar arterial RIs, and renal blood flow determinations in the right kidney were obtained at baseline, 60 minutes after ureteral occlusion, and 10 minutes after the intravenous administration of 1 mg/kg furosemide (Lasix; American Regent Laboratories, Shirley, NY). In six animals, the ureteral obstruction was relieved by removing the balloon catheter. In the other six animals, a bag of saline solution was connected to the ureteral catheter, and its height was adjusted to increase ureteral pressure in increments of 10 mm Hg approximately to mean arterial pressure (65–80 mm Hg). US evaluation and microsphere injections were performed 10 minutes after the release of ureteral obstruction in the first six animals and at maximal ureteral pressure in the other six. An experimental timeline is shown in Figure 2.
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This study was approved by our institutional animal care and use committee and complied with the guidelines of the National Institutes of Health for the care and handling of animals.
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RESULTS |
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Distention of the renal pelvis was present almost immediately after the placement of the ureteral catheter and correlated strongly with changes in ureteral pressure (r = 0.63, P = .001; linear regression). The pelvis was largest at peak ureteral pressures and became smaller with release. Perinephric fluid collections 1–4 mm thick developed in six animals: after furosemide administration in two animals and during maximal ureteral pressure in four animals.
Before obstruction, administration of contrast agent resulted in marked homogeneous enhancement of the renal cortex (Fig 3). The mean cortical pixel intensity increased from 67.8 intensity units ± 5 before the injection of contrast agent to 138.6 intensity units ± 5 at the peak effect of the contrast agent (P < .001). The percentage of enhancement, expressed as the peak enhancement ratio, was significantly less in the upper pole of the kidney (85% ± 11) compared with the middle (153% ± 11) and lower-pole (150% ± 21) regions of the kidney (P < .04).
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Both peak cortical enhancement and measures of the area under the curve diminished during acute ureteral obstruction. They were further reduced by furosemide and high ureteral pressures (P < .001) (Table, Fig 4). The release of ureteral obstruction resulted in only a minimal increase in enhancement values. These differences did not reach statistical significance. There was a weak but significant correlation between the area under the curve during the administration of contrast agent and the mean cortical blood flow averaged from all three regions of the kidney (r = 0.43, P < .001; linear regression) (Fig 5). The area under the curve also correlated with ureteral pressure (r = 0.37, P < .001).
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Blood flow to the normal, nonobstructed kidney is characterized by large differences in flow to the cortex and medulla. Cortical blood flow is approximately 15- to 20-fold greater than blood flow to the medulla (21). Contrast-enhanced harmonic imaging of the normal kidney depicted these normal regional differences in blood flow. Enhancement was bright and homogeneous throughout the renal cortex and was proportionately lower in medullary pyramids. This differential enhancement is consistent with enhancement results obtained by other authors (22).
During occlusion of the ureter, a consistent reduction in ipsilateral renal blood flow and glomerular filtration rate has been shown in a variety of experimental animals (4,5). In animals with multipapillary kidneys, such as the pig or rat, this reduction occurs immediately after the onset of acute obstruction and appears to be effected primarily by prostaglandin mediators (5,20). The renal resistance to blood flow follows these changes and correlates strongly with intrarenal pressure (5). Blood flow to the contralateral kidney may or may not be elevated depending on how elevated intrarenal pressure is on the obstructed side (5,20).
In this study, alterations in renal hemodynamics during obstruction were evident on contrast-enhanced harmonic images. Compared with baseline values, the peak enhancement ratio and the area under the curve decreased during obstruction. Both measures were further reduced after furosemide administration and during high ureteral pressure. After release of ureteral obstruction, cortical enhancement did not return to baseline levels. We postulate that this was owing to mild residual obstruction related to ureteral edema after prolonged instrumentation. Although there was a highly significant correlation between cortical blood flow and the area under the curve, there was considerable variability about the regression line, and the relationship was relatively weak.
Contrast-enhanced power Doppler US images have shown markedly reduced enhancement of peripheral portions of cortex during hemorrhagic shock while enhancement of deeper cortical areas is preserved (23). We hypothesized that similar regional redistribution of blood flow might be seen during ureteral obstruction, particularly at higher pressure levels. As shown in Figure 3, there was homogeneous cortical enhancement throughout the entire thickness of the renal cortex during obstruction. Unlike the kidney imaged during shock, there was no visual evidence of diminished enhancement of the peripheral cortex.
Findings of the current study confirm that the RI increases in the setting of acute ureteral occlusion and that there is a strong correlation between RI and ureteral pressure in the obstructed kidney (24). Our data also show that RI is a poor predictor of changes in renal blood flow and only a weak predictor of renal vascular resistance. Administration of furosemide during obstruction did not increase RI or ureteral pressure significantly compared with obstruction without furosemide.
These data may help us understand the variability in clinical results reported for Doppler US in acute renal obstruction. According to Platt (25), marked elevations of pressure in the collecting system occur quickly with the onset of acute urinary occlusion, with the rate of increase dependent on the rate of urine flow at the onset of obstruction. With urinary occlusion, there may be a return of renal pelvic pressure to normal levels soon after the onset of obstruction (25,26). As shown in this study, the RI is strongly dependent on intrarenal pressure. Thus, if intrarenal pressure is not high, the RI may not be elevated at certain times during renal occlusion, despite the presence of diminished renal blood flow.
An additional factor that may dampen the intrarenal RI during occlusion is the development of small perforations of the upper urinary tract, probably at the fornix of a calix. These tears have been described in association with distal obstruction and may result in urinomas or ascites (27). In this study, we observed the development of similar perinephric fluid collections in six animals during obstruction and the administration of furosemide or under conditions of high ureteral pressure. Although these collections were associated with only small reductions in RI and ureteral pressure, it is likely that tears resulting in larger fluid collections may have larger reductions in intrarenal pressure and RI.
There are several technical problems that may limit the utility of contrast-enhanced harmonic imaging. First, peak enhancement of the upper-pole cortex was less than that observed in other regions of the kidney, without an associated reduction in the area under the curve or renal blood flow. This diminished enhancement may be due to differences in the destruction of contrast agent by US energy experienced by bubbles of contrast agent near the focal zone of the transducer or possibly due to relative shadowing by echogenic contrast agent in the liver overlying the upper renal pole.
Second, the correlation between the degree of cortical enhancement and renal blood flow was significant but not strong (P < .05). According to Ophir and Parker (28), when stable contrast agents are used, the peak time and mean transit time are related directly to the flow rate. However, the properties of the time-intensity curves may be affected substantially by the attenuation and instability of microbubble-based contrast agents within the vascular bed. Nonetheless, our data show that contrast-enhanced harmonic gray-scale US imaging shows potential for depicting changes in global renal blood flow in real time.
Practical application: Harmonic imaging techniques might be a useful adjunct for serial bedside evaluation of abnormalities in renal cortical perfusion without the use of radioactive agents. This would have important applications in children in whom respiratory and voluntary motion are more difficult to control and in large adults in whom Doppler and gray-scale signal intensity from renal parenchyma can be attenuated markedly by distance and fat. However, further work is needed before this technique is used for clinical assessment of renal blood flow.
The identification of urinary obstruction still remains a challenge, especially in young children in whom an intrarenal RI of 70 or more may be normal and in patients with obstruction without elevated intrarenal pressure.
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Acknowledgments |
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Footnotes |
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Abbreviations: ANOVA = analysis of variance RI = resistive index
Author contributions: Guarantor of integrity of entire study, G.A.T.; study concepts, M.C., G.A.T.; study design, M.C., C.E.B., G.A.T., P.S.D., R.G.; definition of intellectual content, M.C., G.A.T.; literature research, M.C., G.A.T.; experimental studies, all authors; data acquisition, all authors; data analysis, M.C., C.E.B., G.A.T.; statistical analysis, M.C., G.A.T.; manuscript preparation, M.C., G.A.T.; manuscript editing, M.C., C.E.B., G.A.T., P.S.D.; manuscript review, all authors
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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