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Experimental Studies |
1 From the Departments of Radiology (M.E.T., F.N.T.) and Pharmacology (M.E.M.), Albany Medical College, 43 New Scotland Ave, Albany, NY 12208. From the 1998 RSNA scientific assembly. Received October 1, 1998; revision requested November 10; revision received December 17; accepted February 17, 1999. M.E.T. supported in part by a 1996 RSNA Seed Grant. M.E.M. supported in part by a grant-in-aid from the American Heart Association. Address reprint requests to M.E.T. (e-mail: tublin@rad.amc.edu).
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Abstract |
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MATERIALS AND METHODS: Rabbit kidneys were perfused by using a pulsatile perfusion system in which RVR, systolic and diastolic pulse pressures, and pulse kinetics were controlled and monitored while simultaneously measuring the RI.
RESULTS: When RVR was increased fivefold with phenylephrine hydrochloride, the RI increased only slightly (from 0.45 at baseline up to 0.50). There was a virtually linear relationship between the RI and the pulse pressure index ([systolic pressure - diastolic pressure]/systolic pressure) in the range of 0.30–0.80. The RI was not affected by the pulse rate or fraction of time that systolic pressure was applied during the pulse cycle.
CONCLUSION: Contrary to conventional teaching, which is based on theoretic considerations, the RI is not readily affected by acute changes in RVR. This indicates a need to reconsider the conventional explanations used to explain increases in RI that are frequently found in patients with renal disease or ureteral obstruction.
Index terms: Kidney, US, 81.1298, 81.12981, 81.12983, 81.12984 • Renal arteries, stenosis or obstruction, 961.723 • Renal arteries, US, 961.12983, 961.12984 • Ureter, stenosis or obstruction, 82.84
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Introduction |
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The introduction of Doppler US promised to improve the clinical utility of US in patients with renal dysfunction. Changes in intrarenal arterial Doppler spectra have been shown to occur with renal vascular disease, intrinsic renal disorders, and ureteral obstruction (1–9). In spite of opinions and data to the contrary (10–16), there is substantial evidence that Doppler US may aid in the differential diagnosis and treatment of patients with renal parenchymal disease and urinary obstruction (2,3,5–9,17–21). In general, these studies have used the Doppler resistive index (RI) (RI = [peak systolic velocity - end diastolic velocity]/peak systolic velocity) to quantify changes in intrarenal arterial Doppler US waveforms.
Underlying all this work is the assumption that the RI accurately reflects the subtle changes in renal vascular resistance (RVR) that occur with renal disease. Indeed, in many publications the terms "resistive index" and "renal vascular resistance" are used interchangeably. It is surprising that, although the correlation between the RI and RVR forms the theoretic basis for all Doppler US studies of renal disease, to our knowledge the relationship between these two parameters has not been studied systematically. While it is possible that the RI is directly affected by changes in RVR, another possibility is that changes in the RI seen with renal disease are due to other humoral and physical factors that only secondarily cause parallel changes in RVR.
The purpose of this study was to determine the relationships between the RI, RVR, pulse pressure, and pulse rate by using an isolated perfused rabbit kidney model in which these parameters could be independently controlled and measured and in which other humoral or physical factors were equalized or eliminated.
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MATERIALS AND METHODS |
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The kidney was initially perfused via the left renal artery with a physiologic saline solution with the following composition: 118 mmol/L NaCl, 4.7 mmol/L KCl, 1.20 mmol/L KH2PO4, 1.18 mmol/L MgSO4, 25 mmol/L NaHCO3, 0.023 mmol/L NaEDTA, 1.60 mmol/L CaCl2, 11.0 mmol/L glucose, 20.0 mL/L BME (basic minimal essential) amino acid solution, and 50 g/L dextran (mean molecular weight = 7,000). The solution was aerated with a mixture of 95% O2 and 5% CO2 and adjusted to a pH of 7.4. All reagents were obtained from Sigma Chemical (St Louis, Mo). The viscosity of the physiologic saline solution was similar to that of the original blood mixed with heparin, as measured by using a Connon-Fenske–type viscometer tube at 37°C.
After renal artery cannulation, the kidney continued to be perfused with physiologic saline solution for approximately 30 minutes. During this time, red blood cells were isolated from the whole blood obtained at exsanguination with three rounds of washing and centrifugation in physiologic saline solution containing 10 U/mL heparin. Washed red blood cells (packed volume, approximately 25 mL) were then added to 2 L of physiologic saline solution, and the kidney was perfused with this mixture for the remainder of the study. Preliminary trials suggested that this suspension of red blood cells provided sufficient acoustic scatterers for the Doppler US portion of the experiment.
An adjustable pulsatile perfusion system was constructed as shown in Figure 1. The perfusate was maintained in a large stirred reservoir aerated with a 95% O2 and 5% CO2 mixture and was pumped into the perfusion system by using an adjustable roller pump (model 505S; Watson-Marlow, Wilmington, Mass). The perfusate was pumped into a glass chamber that included a heat-exchange coil (Chemglass, Vineland, NJ). The water jacket was connected to a heating circulator set to maintain the kidney temperature between 36° and 38°C. The perfusate exited the chamber through tubing connected to the renal artery cannula. The chamber was also connected to a solenoid valve, which allowed the perfusate to freely pass into either of two open reservoirs with heights above the kidney that could be independently adjusted between 35 and 170 cm. The solenoid valve was driven by an adjustable square-wave-function generator (model 8002; Goldstar, Los Angeles, Calif), such that the chamber was cyclically connected first to one elevated bottle and then to the other, which created a pulsatile pressure cycle within the perfusion system. Characteristics of the pulse wave—the pulse pressure, pulse rate, and relative duration of "systole"—were controlled by changing the square-wave-function profile and reservoir heights. A constant perfusate pump rate of 18 mL/min that approximated normal in vivo rabbit renal blood flow was maintained throughout the experiment.
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Color duplex US of the perfused kidney was performed with a commercially available US unit (model 128XP-10; Acuson, Mountain View, Calif) equipped with a sector probe operating at 7 MHz for both gray-scale and color Doppler US. Six to 10 arterial spectra were typically obtained from segmental arteries during each phase of the experiment (Fig 2a). Waveforms were maximized on the display by using the lowest possible pulse repetition frequency without aliasing and the highest possible gain without visible background noise. A 2–4-mm Doppler gate was used.
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Typically, approximately 3,000 instantaneous pressure readings representing 200 solenoid cycles were recorded for each perfusion condition. Each data point was mapped to its position within the cycle and expressed as a fraction of the time through the cycle. A running mean of 20 pressure readings was calculated and plotted against its position in the cycle (Fig 2b). The minimal, maximal, and mean pressures were estimated from this plot. The differential between the higher (systolic) and lower (diastolic) pressures was reported as a pulse pressure index that was calculated in a manner similar to that of the RI ([systolic pressure - diastolic pressure]/systolic pressure).
RVR under the baseline condition and during perfusion with phenylephrine hydrochloride or sodium nitroprusside was estimated by closing off the solenoid valve and adjusting the pump speed in steps to deliver flow rates ranging from 3 to 21 mL/min. The pump was calibrated by measuring timed flow into a graduated cylinder before the experiment. Pressure values were plotted against the corresponding flow values and analyzed by using linear regression. The calculated slope described total resistance in units of millimeters of mercury times minutes per milliliter. The resistance of the renal artery cannula was determined independently, and the true RVR was calculated by subtracting the resistance of the cannula from the total resistance. In control studies (not shown), we verified this method of calculating RVR by measuring flow rates with an in-line US flowmeter (model T106; Transonic Systems, Ithaca, NY) during the actual pulsatile perfusion periods. In cases where RVR was estimated during both nonpulsatile and pulsatile periods, the mean RVR values were essentially identical.
Statistical Analysis
Several statistical tests were performed to determine whether changes in the RI were significant. First, in those experiments involving RVR (Fig 3), a two-way analysis of variance with subsequent post hoc analysis based on the Fischer PLSD (protected least significant difference) test (STATVIEW; SAS Institute, Cary, NC) was conducted, with assignment of the type of vasoactive agent and the date of the experiment as the two independent variables and the RI as the dependent variable.
Second, linear regression analysis (PRISM; GraphPad Software, San Diego, Calif) was used to determine whether RVR (Fig 3), pulse pressure index (Fig 4), or pulse rate (Fig 5) was significantly correlated to RI values, with assignment of the RVR, pulse pressure index, and pulse rate as continuous independent variables and the RI as the dependent variable. This analysis determined the square of the correlation coefficient R2, the slope of the correlation, the probability that the correlation was significant, and the probability that the slope was significantly different from 0 or 1.
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Because baseline values for the RI and RVR differed between kidneys, both parameters were normalized prior to linear regression. RI values were normalized by first calculating the mean RI under baseline conditions (which were tested for two or three separate periods during each experiment) and subtracting this single overall mean from each individual RI value. RVR values were normalized by first logarithmically transforming each RVR value, calculating the mean transformed RVR under baseline conditions, and subtracting this mean from each individual transformed RVR value.
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RESULTS |
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Because the baseline RI differed among the five kidneys (overall mean, 0.45 ± 0.02), multivariate analysis of variance, which factors out these differences, was used to analyze the changes in the RI. In each kidney, the mean RI increased only slightly as the RVR was elevated with phenylephrine hydrochloride (Fig 3a). The RI at the higher RVR levels increased by a mean of 0.047 units (±0.008 [SD]); this difference was significant (P < .05). The relationship between the RI and RVR was further analyzed by using linear regression (Fig 3b), in which the relative increase in the RI was plotted against the relative increase in RVR (with normalization of both parameters to the baseline values for each individual kidney). The slope was significantly different from zero and indicated that the RI increased 0.063 units for a 10-fold increase in RVR.
Figure 4 shows the relationship between the RI and the pulse pressure differential under various conditions in five separate experiments. Regression analysis demonstrated a significant linear correlation between the RI and the pulse pressure index. Furthermore, this regression did not differ significantly from the line of unity; that is, the RI was essentially identical to the pulse pressure index at all values between 0.3 and 0.8. In contrast, adjusting either the percentage of time that systolic pressure was applied (Fig 5b) or the pulse rate (Fig 5a) did not influence the RI at all.
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DISCUSSION |
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Underlying this diagnostic approach is the assumption that the RI accurately reflects changes in RVR. Indeed, initial work by Norris and Barnes (24) suggests a direct relationship between the RI and the RVR. In that study, RVR in an in vivo canine model was calculated by dividing the mean renal arteriovenous pressure gradient by the renal venous flow rate; RVR was then incrementally increased by embolizing renal arterioles with gel microspheres. Although they found a linear relationship between the RI and the RVR, they failed to measure or control for changes in renal arterial systolic to diastolic pressure ratios or pulse rates. In addition, they performed Doppler US on the main renal artery rather than on intrarenal vessels. Finally, their use of gel microspheres for mechanical arteriolar occlusion rather than reversible pharmacologic vasoconstriction was a nonphysiologic method of modulating renal hemodynamics.
Several recent clinical studies (25–29) also show a correlation between the RVR and the RI. However, these studies (25–29) were limited by difficulties in controlling for changes in pulse pressure and pulse rate, use of indirect measurements of RVR, and diverse patient populations.
For example, in a study by Terry et al (28), the pooled data from serial Doppler US examinations of nine patients with hypertension receiving a course of the vasodilator drug minoxidil showed no relationship between the RI and vascular resistance. However, when the RI was adjusted for differences in renal volume and pulse pressures, a significant correlation was found. Although these authors advocate use of this adjusted RI for the noninvasive evaluation of renal hemodynamics, to our knowledge, theoretic justifications for incorporating renal volume and pulse pressures into Doppler US measurements were not forthcoming from them. Moreover, baseline renal function varied widely in their study (28) (serum creatinine levels ranged from 0.9 to 3.3 mg/dL [80–292 µmol/L]). No change in RVR (indirectly evaluated by using brachial blood pressure and clearance-technique–derived renal blood flow measurements) was seen with antihypertensive therapy.
The relationship between the Doppler pulsatility index (a variant of the RI) and RVR was investigated in volunteers with normal blood pressure or hypertension in two recent studies by Jensen, Bardelli, and colleagues (25,27). These authors correlated intrarenal Doppler spectra with changes in RVR induced by angiotensin and angiotensin blockade. RVR was estimated by dividing mean brachial arterial blood pressure by renal plasma flow rate (assessed with PAH [para-aminohippurate] clearance technique). No relationship was seen between absolute pulsatility index values and RVR in subjects with normal blood pressure (25). These authors attempted to correct for differences in the Doppler pulsatility index potentially induced by differences in pulse pressure by dividing the pulsatility index by the "blood pressure" index ([systolic pressure-diastolic pressure]/mean arterial pressure). Changes in this derived "velocity" blood pressure index correlated with changes in RVR (although the changes in the Doppler pulsatility index were only slightly greater than the variability in pulsatility index measurements in individual subjects). Results in volunteers with hypertension were discrepant from those in subjects with normal blood pressure (27). In the study by Jensen et al (27), no correlation between the "velocity blood pressure index" and RVR was identified in individuals with hypertension, even though absolute pulsatility index values did correlate with RVR. Jensen, Bardelli, and their colleagues concluded that Doppler US is useful in identifying changes in RVR in both patient populations. However, we believe their unexplained, widely discrepant results, as well as the use of systemic (rather than renal arterial) pressure measurements for RVR calculation, limit the relevance of both studies (25,27).
While our study findings demonstrated a linear relationship between the RI and RVR, the RI increased only with marked—and likely nonphysiologic—increases in RVR. Moreover, the observed increases in the RI were only marginally greater than the inherent variability of RI measurements (graphically depicted by SEM bars in Fig 3b). Overall, the failure of large increases in RVR to cause corresponding dramatic increases in the RI weakens the long-standing theoretic assumption that RVR is the predominant factor controlling the RI.
In contrast, our results showed that the pressure differential between systole and diastole was more important than RVR in influencing the RI. Our ex vivo model allowed the selective adjustment and measurement of pulse pressures. By expressing the pulse pressure differential as a pulse pressure index (derived by use of an equation analogous to that for the RI), we found a direct one-to-one relationship between the two indices. This may be considered intuitively obvious (given that flow is proportional to pressure). To our knowledge, however, ours may be the first study to directly document the effect of proximal arterial pulsatility on intrarenal arterial Doppler spectra.
No relationship was seen between the RI and pulse rate or the duration of systole. The lack of correlation between the RI and pulse rate was in agreement with findings of several studies (30,31) but not with findings in a recent series published by Mostbeck et al (17). In that study of eight patients who underwent artificial pacing of the heart during electrophysiologic studies, the RI was shown to decrease with increasing heart rate (RI = 0.7 at a rate of 70 beats per minute, RI = 0.57 at a rate of 120 beats per minute). We believe that the changes in RI seen in the series by Mostbeck et al are actually a reflection of altered pulse pressures rather than of pulse rate per se. Although cardiac output did not change with external pacing, there was a marked decrease in stroke volume index and pulse pressure at higher heart rates.
To our knowledge, the ex vivo model used in our study has not been used previously, and it allowed us to control for changes in pulse pressure, pulse rate, and duration of systole. We obtained simultaneous direct measurements of RVR and RI during pharmacologic vasoconstriction and vasodilatation. The isolated perfused rabbit model that we used certainly does not reflect all aspects of renal circulation; there was no influence of neuronal or hormonal factors, nor were there any changes in venous or ureteral pressures. The absence of these factors in our experiments allowed us to specifically assess the influence of RVR and pulse pressure on the RI but may also limit the confidence with which our conclusions may be extrapolated to renal hemodynamics in vivo. Some assurance may be drawn, however, from the fact that our ex vivo model displayed the expected reversible responses to vasoconstrictors and vasodilators and that the mean baseline RI (0.45 ± 0.02) in our study was identical to previously reported RI values for normal rabbit kidneys in vivo (16).
It is important to note that our findings did not refute the results of multiple prior studies that demonstrate altered Doppler spectra with renal disease. However, the theoretic framework used to explain these results will need to be reconsidered if these data are to be used for research or clinical management.
Findings of preliminary work in our laboratory have suggested a direct relationship between ureteral and pelvic pressures and the RI. On the basis of these results, we suspect that the RI is more dependent on tissue compliance than it is on RVR. This concept might help to explain the elevation in the RI that may be seen with aging (32). Although it has been claimed that the age-related increase in the RI may be a manifestation of subclinical renal disease, it seems more likely that the altered Doppler spectra seen in this population are due to decreased vascular compliance and increased pulse pressures. Similarly, the elevated RI seen in patients with intrinsic renal disease and ureteral obstruction may be due to the effects of tissue fibrosis and edema on vascular compliance, but this concept will need to be explored with appropriately designed experimental models.
Practical applications: Our results may weaken the current theoretic understanding that RVR is the major factor controlling the RI. The correlation between an elevated RI and renal dysfunction is likely based on other parameters that still need to be elucidated.
Our results add experimental support to the clinical work of Jensen, Bardelli, and colleagues (25,27), who assert that an individual's pulse pressure should be considered when interpreting RI values. Although an RI value greater than 0.70 has been considered indicative of renal dysfunction, that threshold should be considered flexible. For example, individuals with elevated pulse pressures might be expected to have above-normal RI values even in the absence of nephropathy. Greater understanding of the multiple factors that may influence the RI of both normal and diseased kidneys may increase the clinical relevance of intrarenal Doppler US analysis.
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Footnotes |
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Author contributions: Guarantors of integrity of entire study, M.E.T., M.E.M.; study concepts and design, M.E.T., M.E.M.; definition of intellectual content, M.E.T., M.E.M.; literature research, M.E.T., M.E.M.; experimental studies, M.E.M., M.E.T.; data acquisition, M.E.M., M.E.T.; data analysis, M.E.M.; statistical analysis, M.E.M.; manuscript preparation, M.E.T., M.E.M., F.N.T.; manuscript editing, M.E.T., F.N.T.; manuscript review, F.N.T.
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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vs 
), the length of the pulse cycle was adjusted from 1 to 3 seconds. Linear regression analysis was used to generate best-fit lines for each experiment, the slopes of which were not significantly different from zero. (b) The cycle pattern of the solenoid valve was adjusted to apply the higher pressure to the perfusion system for 10%-50% of the overall cycle period (1.589 seconds in this experiment). Linear regression analysis was used to generate a best-fit line, the slope of which was not significantly different from zero.
