Divisions of 1 Hypertension and 4 Cardiovascular Diseases, Department of Internal Medicine, 2 Department of Physiology and Biophysics, and 3 Biomathematics Resource, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
To assess the reliability of electron beam computed tomography (EBCT), measurements of single-kidney renal blood flow (RBF), glomerular filtration rate (GFR), and intratubular contrast medium concentration (ITC) of radiographic contrast media were quantified in anesthetized pigs before and after acetylcholine-induced vasodilation and diuresis. EBCT measurements were compared with those obtained with intravascular Doppler and inulin clearance. The capability of EBCT to detect chronic changes in single-kidney function was evaluated in pigs with unilateral renal artery stenosis, and their long-term reproducibility in normal pigs was studied repeatedly at 1-mo intervals. EBCT-RBF (ml/min) correlated with Doppler-RBF as RBFEBCT = 45 + 1.07 * RBFDoppler, r = 0.81. EBCT-GFR (ml/min) correlated with inulin clearance as GFREBCT = 11.7 + 1.02 * GFRinulin, r = 0.80. During vasodilation, RBF and GFR increased, whereas ITC decreased along the nephron. In renal artery stenosis, single-kidney GFR decreased linearly with the degree of stenosis, and ITC increased along the nephron, indicating increased fluid reabsorption. EBCT-RBF, GFR, and ITC were similar among repeated measurements. This approach might be invaluable for simultaneous quantification of regional hemodynamics and function in the intact kidneys, in a manner potentially applicable to humans.
renal blood flow; glomerular filtration rate; electron beam computed tomography
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
THE KIDNEY PLAYS A MAJOR ROLE in a variety of physiological and pathophysiological situations, which may be associated with redistribution of intrarenal blood flow, changes in glomerular filtration rate (GFR), or alterations in the renal tubular reabsorption process. The ability to accurately quantify intrarenal blood flow and tubular function would contribute substantially to our understanding of a variety of renal disease mechanisms, as well as potentially increasing the accuracy of diagnosis and directing appropriate therapy. Moreover, in diseases in which these alterations may present unilaterally, such as renal artery stenosis or ureteral obstruction, determination of single-kidney renal blood flow (RBF), GFR, or tubular dynamics may contribute to assessment of renal viability or success of therapy. Nevertheless, these measurements are difficult to obtain noninvasively or in a manner applicable to humans.
Electron beam computed tomography (EBCT) provides reliable measurements of regional renal volume and blood flow (30). Measurements of RBF with EBCT are obtained by recording changes in renal tissue image densities (i.e., radioopacity), which are consequent to transit of a bolus of X-ray contrast media in the renal vascular compartment (17). However, similar to inulin, urographic contrast media undergo glomerular filtration and are not secreted or reabsorbed in the kidney (17). This enables external detection of contrast media flow along the renal tubules, subsequent to their transit in the vascular compartment (18, 29). However, the resultant renal time-density curves (TDC) partially overlap because of the spatially intermingled vascular and tubular compartments, and assessment of intratubular contrast fluid concentration (ITC) and transit times therefore requires appropriate mathematical stripping (18).
We have developed a model that allows separate delineation of renal vascular and tubular fluid flow in individual nephron segments and thus faithful measurements of RBF and tubular dynamics in the intact kidney in vivo. Moreover, this approach enables simultaneous measurement of the accumulation rate of contrast media in the proximal tubule and thereby calculations of single-kidney GFR, using a single bolus injection of filterable contrast media. The aim of this study was to define whether this approach provides reliable measurements of single-kidney RBF, GFR, and tubular dynamics with EBCT across a wide range of acute and chronic physiological conditions.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This study was performed according to institutional guidelines for the care and use of laboratory animals. Domestic female pigs (body wt 30-70 kg) were used in this study.
Group 1 (n = 10) was used to compare the consistency of EBCT quantifications of RBF with those obtained using an intravascular Doppler wire, whereas group 2 (n = 5) was used to compare EBCT quantifications of GFR with simultaneous measurements of inulin clearance. To examine the reliability of EBCT measurements during increments of RBF and GFR, EBCT studies in group 2 and in six pigs from group 1 were repeated during renal vasodilation obtained with a suprarenal intra-aortic infusion of the renal vasodilator and diuretic acetylcholine.
To examine the capability of EBCT to detect chronic decrements in renal hemodynamics and function, group 3 (n = 6) was studied before and again 2 mo after induction of unilateral renal artery stenosis using an intra-vascular local-irritant stent device, as previously described (19). Values of RBF, GFR, and ITC obtained in these pigs were compared with those measured in group 4 (n = 4), which included sham-operated, body-size-matched normal pigs.
To test the reproducibility of our EBCT measurements of RBF, ITC, and GFR, group 4 pigs were studied with EBCT three consecutive times at 1-mo intervals. The quantifications obtained under basal conditions, and the degrees of response to suprarenal acetylcholine (percent change from baseline), were hence compared among the three different experimental periods.
Experimental Protocol
Animal preparation.
The night before the EBCT study, each animal was fasted but allowed ad
libitum access to water. On the day of the study, each animal was
anesthetized with 0.5 g intramuscular ketamine, intubated, and
mechanically ventilated with a mixture of room air and 50% O2. Anesthesia was maintained with a mixture of ketamine
(0.2 mg · kg1 · min
1) and
xylazine (0.03 mg · kg
1 · min
1) in normal
saline administered via an ear vein cannula at a rate of 3 ml · kg
1 · min
1. Under
sterile conditions an 8-F arterial guide was then advanced through a
left carotid arterial sheath, positioned under fluoroscopic guidance in
the upper abdominal aorta, and served for on-line monitoring of mean
arterial pressure (MAP). A tracker catheter was advanced through the
arterial guide to the upper abdominal aorta and placed above the level
of both renal arteries for infusion of saline (1.5-2 ml/min) or
acetylcholine (4.5 µg · kg
1 · min
1), and, in
groups 1 and 3, also for performance of Doppler
flowmetry or selective renal angiography. A "pigtail" catheter
advanced through a vascular sheath in the left jugular vein was placed in the superior vena cava or right cardiac atrium for subsequent contrast media injections. In group 2, a 40-ml primer bolus
of a 2% inulin solution was also administered into a side arm of the
venous sheath, followed by a constant infusion of 1.0 ml/min. Last, an
additional suprapubic pigtail catheter was placed in the urinary
bladder for collection of urine. Ureteral catheterization was not
performed to minimize invasiveness of the study.
EBCT studies. After placement of intravascular catheters, the animals were allowed a 1-h recovery period, during which they were positioned in the EBCT (C-150, Imatron, South San Francisco, CA) scanning gantry. All EBCT studies were performed during respiratory suspension at end-expiration. With the use of localization scans, all tomographic levels containing both kidneys were identified (for subsequent renal volume studies), whereas two adjacent midhilar tomographic levels demonstrating both kidneys were selected for performance of flow studies. Urine was collected from the urinary bladder catheter during a 10-min control period before each EBCT flow study, and a blood sample was collected in the middle of this period and placed on ice.
RENAL HEMODYNAMICS AND TUBULAR DYNAMICS. For the study of renal perfusion and tubular flow, the kidneys were scanned in the standard resolution (50 ms/image), multislice flow mode, resulting in two contiguous 8-mm-thick tomographic sections through the hilar regions of both kidneys. The field of view used was 26 cm with a matrix of 360 × 360 pixels, resulting in pixel size of 0.72 mm2 and voxel size of 5.8 mm3. Forty consecutive scans were obtained over the preselected levels 3 s after a bolus injection (0.5 ml/kg over 1-2 s) of iopamidol into the central venous catheter. The first 20 scans were performed at the rate of 1 scan/0.6-2.5 s to sample rapid intravascular density changes, whereas the last 20 images were acquired at 6- to 8-s intervals to follow intratubular density changes (18). Total scanning time was 3 min, and each animal received assisted ventilation in between scans during the last 20 scans. Fifteen minutes after the baseline flow study, a 20-min infusion of acetylcholine (4.5 µg · kgData Analysis
Blood and urine samples from group 2 were analyzed for concentration of inulin (using a spectrophotometer), and urinary flow rate (with a graduated cylinder) and sodium excretion were measured (using a flame photometer). Inulin clearance for both kidneys was calculated as UV/P, where U is urinary inulin concentration, V is urinary flow rate, and P is inulin plasma concentration. To estimate inulin clearance per kidney, total inulin clearance was multiplied by fractional renal volume (right or left renal volume divided by the sum of right and left renal volumes), assuming that in normal subjects the relative contribution of each kidney would be approximately proportional to its size.Renal arterial luminal diameter at the position of the Doppler flow
wire was measured off-line (19) from the fluoroscopy images obtained in group 1 under basal conditions and during
acetylcholine infusion. RBF was then determined from the corresponding
Doppler average peak velocity (APV) measurements as (5,
12) 60 * (APV/2) × × (renal arterial
radius)2.
Image Analysis
EBCT images were reconstructed using a standard tomography reconstruction algorithm and displayed on a Sun system workstation using the software package ANALYZE (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN).Renal perfusion and tubular dynamics. Regions of interest were selected in the cross-sectional images from the aorta and right and left renal cortex, medulla, and papilla (18, 29). The average image density of each sampled region in each of the 40 images was then calculated and recorded by the software, and the data were transferred to a personal computer to generate a TDC for each region describing the sequential change in tissue density. Our model, which is an extension of the standard gamma-variate curve fitting algorithm (see the APPENDIX), was custom implemented in a data-analysis/graphics computer program (KaleidaGraph, Synergy Software, Reading, PA) and sequentially applied to each raw data set according to the region of interest from which the data was obtained.
The renal cortical TDC typically exhibited three sequential peaks (Fig. 1A), which corresponded to transit of the contrast bolus in the cortical vascular compartment, proximal tubule, and distal tubule, respectively (18). The time-density data obtained from the cortex were therefore fitted with a curve-fitting algorithm, which assumes a tricompartmental (vascular, proximal tubular, and distal tubular) distribution of the indicator (see the APPENDIX)
![]() |
(1) |
|
![]() |
(2) |
![]() |
![]() |
Renal volume. After identification of the renal cortex and medulla on each tomographic level obtained in the volume study, volumes were calculated using a statistical point-counting volume estimation program implemented with ANALYZE (15). Papillary volume was not independently determined, because the papilla could be distinguished from the medulla at the vascular phase, during which a volume scan was performed.
RBF. RBF (ml/min) was subsequently calculated as the sum of cortical and medullary blood flows (14) obtained from each cortex and medulla as the product of its perfusion and volume.
GFR.
GFR (normalized; ml · min1 · ml
tissue
1) was calculated from the right and left cortical
TDC as
![]() |
Statistical Analysis
Results of the quantitative traits are expressed as means ± SE. In normal pigs the values of all kidneys were compiled. Statistical comparisons between experimental periods within groups (e.g., baseline vs. acetylcholine) were performed using a paired Student's t-test and among groups using ANOVA and an unpaired Student's t-test. Comparisons among repeated measures in group 4 utilized ANOVA. Regressions were calculated by the least-squares method. Statistical significance for all tests was judged at P ![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Infusion of acetylcholine into the suprarenal aorta was followed by a transient decrease in MAP, which returned to baseline levels within 2 min (8), whereas heart rate was unchanged.
EBCT vs. Doppler RBF
Cortical and medullary vascular volume fractions (0.38 ± 0.02 and 0.26 ± 0.02 ml/ml issue, respectively) did not change significantly during acetylcholine infusion. However, a significant decrease in their vascular MTT resulted in a significant increase in both cortical and medullary perfusion and, consequently, RBF. In group 1, a significant acetylcholine-induced increase in RBF was detected by both the Doppler (from 227.5 ± 27.2 to 375.6 ± 85.6 ml/min, P = 0.016) and EBCT (from 257.1 ± 24.9 to 415.3 ± 56.5 ml/min, P = 0.0003) techniques. RBF measurements obtained by the two methods were significantly correlated (Fig. 2A), and the relationship between them was not statistically different from the identity line at 90% confidence intervals.
|
EBCT-GFR vs. Inulin Clearance
In group 2, a significant acetylcholine-induced increase in GFR was detected by both inulin clearance (from 40.1 ± 2.2 to 58.8 ± 2.7 ml/min, P = 0.029) and EBCT (from 49.5 ± 2.2 to 69.0 ± 3.1 ml/min, P = 0.006). Inulin clearances were lower than EBCT-GFR (P = 0.02), but the measurements obtained by the two methods correlated well (Fig. 2B).EBCT Measurements of Tubular Dynamics
In group 2, acetylcholine induced a significant intratubular dilution (decrease in ITC) in all tubular segments (P < 0.0001), especially in the collecting duct (
|
EBCT Measurements of RBF, ITC, and GFR in Stenotic Kidneys
In group 3, 2 mo after implantation of the stent, severe renal artery stenosis (79 ± 5% decrease in luminal area by quantitative renal angiography) was accompanied by a significant increase in MAP (from 111 ± 6 to 150 ± 13 mmHg, P = 0.002). The stenotic kidney was significantly smaller than the normal kidneys of group 4 in the 2-mo study (70.1 ± 14.1 vs. 111.6 ± 5.1 ml, respectively, P = 0.005). EBCT-RBF of the stenotic kidney was lower than in group 4 (324.7 ± 99.4 vs. 509.3 ± 51.6 ml/min, respectively, P = 0.05) as was EBCT-GFR (18.4 ± 5.1 vs. 31.9 ± 4.4 ml/min, respectively, P = 0.03). EBCT-derived GFR in group 3 correlated well with the decreased volume and RBF of the stenotic kidney (r = 0.94 and 0.93, respectively, P < 0.001) as well as with the degree of renal artery stenosis (Fig. 3A, r =
|
In addition, a significantly higher ITC in group 3 compared
with group 4 was observed in all tubular segments (Fig.
3B, P 0.01 for each segment). Compared
with the initial increase observed in the proximal tubule, the only
more distal nephron segment that tended to show a further increase in
ITC relative to group 4 was the collecting duct
(P = 0.06). The changes in ITC were accompanied by a
significant prolongation of tubular transit times in the nephron
segments from the loop of Henle and distally (P
0.02).
Reproducibility of EBCT Measurements
In group 4, normalized (indexed to renal size) EBCT measurements of perfusion, GFR, and ITC studied at 1-mo intervals were generally similar to each other. Baseline cortical perfusion was lower than both the 1- and 2-mo measurements (2.5 ± 0.2, 4.6 ± 0.3, and 3.8 ± 0.4 ml · min ![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This study described an approach that enables obtaining simultaneous and minimally invasive indices of single-kidney RBF, GFR, and renal tubular function. Modeling EBCT-derived TDC as a series of gamma functions resulted in good detection of anticipated changes (both increments and decrements) in renal hemodynamics and function, which were also comparable to those obtained with other reference methods. Importantly, intrarenal measurements obtained distal to renal artery stenosis in pigs disclosed segmental tubular alterations in fluid reabsorption and a decrease in GFR proportional to the severity of stenosis. Therefore, this study demonstrates that EBCT can be used to obtain noninvasive and reliable simultaneous measurements of renal hemodynamics and function in the intact kidney in vivo.
A variety of techniques have been used for measurement of RBF or regional renal perfusion, but no single technique has reliably quantified both across a wide range of physiological conditions. Moreover, some of the methods are invasive and not readily applicable in humans (1). Imaging techniques like magnetic resonance imaging (2), positron emission tomography (24), or X-ray computed tomography (17), especially using intravenously injected indicators, may potentially have useful clinical applications. EBCT provides reliable measurements of renal volume and blood flow in humans (9, 16, 21) and may potentially be used for measurement of renal function.
In the present study, we compared EBCT quantifications of RBF with those obtained using an intravascular Doppler wire. The latter provides percutaneous single-kidney measurements of blood velocity (25), whereas synchronous documentation of renal arterial diameter enables calculation of RBF (7). We found that measurements of RBF obtained with EBCT and intravascular Doppler were linearly correlated over a wide range of RBF values, with the slope of this regression approaching identity.
The relationship between EBCT and Doppler measurements indicated a small, consistent discrepancy between the two techniques, which was likely related to methodological aspects. The intravascular Doppler technique provides accurate measurements of APV in small, straight tubes with diameters up to 4.76 mm (5). However, in larger or more tortuous tubes, as well as in flow rates above 200 ml/min, it significantly underestimates electromagnetic flow measurements, probably due to suboptimal positioning and instability of the wire or deformed flow profiles (5). Many pigs included in the present study had renal artery diameters >5 mm and RBFs >200 ml/min. Therefore, in the renal circulation the limitations of this technique may become consequential and underestimate RBF. In addition, flow in collateral circulation and accessory renal arteries, which are found in 20-30% of normal individuals (6), would be detectable in the renal parenchyma by EBCT but may be missed by Doppler measurements obtained within the main renal artery. Inaccuracies in determination of renal artery diameter for calculation of Doppler-RBF cannot be excluded either. Alternatively, it is possible that despite accounting for filtered contrast during calculation of RBF with EBCT, or because of an unknown Doppler or EBCT calibration factor, EBCT consistently overestimates RBF. Because EBCT and Doppler measurements were not obtained simultaneously, temporal variations in RBF could have also played a role in the difference between the two. Nevertheless, there was generally excellent agreement between the two methods regarding the relative magnitude and changes in RBF. Moreover, EBCT-RBF was reproducible, and its physiological meaningfulness was underscored by its good correlation with the degree of renal artery stenosis, which evidently decreased renal perfusion pressure below the lower limit of RBF autoregulation. The lower cortical perfusion observed in group 4 at baseline was likely related to the younger age of the animals during that study (3-5 mo), because the developing piglet exhibits lower RBF and higher renal vascular resistance than its adult counterpart (34). Nevertheless, its renal functional responses are intact (35), as was also observed in the present study.
GFR is the standard measure of renal function and is critical for the diagnosis and management of renal diseases. Rigorous assessment of GFR requires renal clearance of an exogenous marker like inulin, which constitutes the most accurate method of measuring GFR but is unsuitable for routine clinical practice (11). Many techniques using alternative filtration markers (10, 26) are limited by the need for urine collection (11) or repeated blood sampling and for ureteral catheterization to quantify single-kidney GFR. Renal scintigraphy, which compares relative GFR between the kidneys, cannot be used to reliably quantify a bilateral decrease in GFR or for longitudinal comparisons and can be skewed by renal depth (13). On the other hand, extraction of paramagnetic (28) or X-ray (3) contrast agents in individual kidneys can be externally quantified in tomographic images and thus has potential usefulness for noninvasive measurement of single-kidney GFR. Furthermore, cross-sectional capability eliminates superimposition and may thus allow assessment of intra-renal GFR in different cortical regions.
In the present study we compared EBCT-derived GFR to its reference standard, inulin clearance (11), and observed that these correlated well, with the slope of this relationship approaching unity. This suggests that our model provided faithful depiction of the accumulation of contrast media in the proximal tubule and demonstrates the plausibility of using its rate to calculate GFR. There may have been several reasons for the positive y-intercept, indicating overestimation of GFR by EBCT. Inulin clearance measurement was integrated over a 10-min period, whereas EBCT-GFR was measured during a 15- to 20-s long pass of the contrast bolus. Because GFR is a dynamic parameter (26), small temporal fluctuations in GFR (33) are possibly less reflected in inulin clearance than in EBCT measurements. Variability in inulin concentration and EBCT measurements, or inaccuracy due to incomplete urine collection (11), may also contribute to this difference. Last, the EBCT-measured increase in cortical density may be affected by filtrate reabsorption in the proximal tubule and likely also reflects contrast diffusion into the interstitial space. Although the magnitude of this diffusion is probably small compared with glomerular filtration, it may still lead to some overestimation of GFR by EBCT. A transient effect of the contrast medium per se during its first pass cannot be excluded either. Nonetheless, the relationship between EBCT and inulin clearance, and the reproducibility of EBCT measurements, demonstrated that this methodology provided a reliable index of GFR. Furthermore, its excellent correlation with the degree of renal artery stenosis further supports the potential value of these measurements for monitoring renal disease progression.
Evaluation of renal function can be further enhanced by measurements of tubular dynamics, reflecting in vivo the degree of fluid reabsorption along the nephron (18). EBCT-measured loop of Henle and distal tubular transit times (Table 1) agreed closely with those previously measured in dogs using micropuncture and intra-arterial injections of lisamine green (36, 41). Our proximal tubular transit time was longer than previously reported (16-22 s), probably due to different administration routes of indicator (intravenous vs. intra-arterial injections) as well as species differences (22). Indeed, using intra-aortic contrast injections in dogs, we have previously measured proximal tubular transit times of 18-23 s with EBCT (18). In addition, compared with other tubular segments, transit time in the proximal tubule is particularly sensitive to variable experimental conditions such as hydration status and blood pressure (36).
Administration of acetylcholine led to dilution of intratubular fluid throughout the nephron, most markedly in the collecting duct, and shortening of tubular transit times through the proximal and distal nephron segments. These EBCT findings were supported by diuresis and natriuresis observed in this group and agreed with the anticipated tubular effects of acetylcholine (38). Like RBF and GFR, ITC measurements were also found to be reproducible.
The EBCT methodology enabled exploration of tubular dynamics distal to renal artery stenosis, whereby we observed a notable increase in ITC in all tubular segments. Although the decrease in contrast delivery and filtered load decreases its tubular content (19), correction for concurrent RBF and GFR revealed increasingly augmented reabsorption along the nephron. The proximal tubular filtrate of the stenotic kidneys was twice as concentrated as that of control kidneys, likely due to the action of angiotensin II. During transit in the loop of Henle and the distal tubule, the filtrate maintained a concentration profile similar to that in control kidneys, suggesting that the main reabsorptive drive had been achieved in the proximal tubule. Nonetheless, filtrate flow along the nephron became progressively slower, probably due to a decrease in the driving intratubular pressure. By the time it reached the collecting duct, urine concentration was fivefold that of controls, suggesting distal fluid reabsorption. These observations extend previous micropuncture studies in superficial cortical nephrons during acute decrements of renal perfusion pressure (27, 36). Our observations demonstrate these alterations in the intact stenotic kidney during chronic reduction of renal perfusion pressure.
Other mathematical models may possibly be utilized to depict renal vascular and tubular flow. Furthermore, although the first moment of tissue TDC has been widely used for estimation of MTT (31, 32), within the framework of indicator-dilution theory (4, 39) appropriate modeling of the input and output functions is preferable; however, imaging a substantial portion of the renal vein is technically difficult. Our values of MTT were physiologically acceptable, and our measurements agreed with reference standards and with previous observations, suggesting that our approach provided adequate indices of RBF, GFR, and ITC. Other limitations of this technique are mainly related to the contrast load and radiation exposure. Although the dose of contrast media needed for these studies (0.5 ml/kg) is small relative to procedures such as renal angiography, it may present a limitation in patients with greatly compromised renal function. The radiation exposure also needs to be considered, as the effective dose equivalent involved in these renal studies (~900 mR for men and women) is about twice that of a conventional chest computed tomography examination. However, this exposure amounts to only about half of the effective dose equivalent incurred during clinically common radiological examinations such as radionuclide thalium myocardial perfusion or coronary angiography, and the breadth and sensitivity of the information acquired in our studies may be beneficial and useful in providing comprehensive quantitative assessment of single-kidney hemodynamics and function.
In summary, the high spatial and temporal resolution of EBCT, and the linear relationship between computed tomographic image density and iodine concentration, allow illustration of contrast transit in the renal vascular and tubular compartments and thus simultaneous and reproducible measurements of regional renal perfusion, tubular dynamics, and GFR in intact bilateral kidneys. This technique can be useful for quantification of concurrent regional hemodynamics and function in intact kidneys in a manner potentially applicable to humans.
![]() |
APPENDIX |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In accordance with the classic indicator-dilution theory
(31), EBCT-derived TDC are conventionally fitted with a
standard gamma-variate curve-fitting algorithm (37), which
describes the change in contrast concentration as
![]() |
(A1) |
![]() |
(A2) |
A similar approach can be used to describe the renal cortical TDC,
where the bicompartmental distribution of the contrast medium involves
its initial transit in the cortical blood vessels, followed by
glomerular filtration and subsequently proximal tubular retention. The
curve-fitting parameters a, b, and c
hence describe the vascular transit of the bolus, and d and
h describe accumulation and transit in the proximal tubule,
respectively. However, the cortical TDC demonstrates a third peak (Fig.
1A), corresponding to the transient return of intratubular
contrast to the cortical distal tubule (18). Because the
arrival of tubular fluid in the distal tubule is delayed relative to
the vascular or proximal tubular compartments, it is represented by an
additional independent gamma function. The final model that depicts the
transit of contrast in the three cortical compartments (vascular,
proximal, and distal tubular) therefore has three components
![]() |
(A3) |
The medullary TDC, on the other hand, exhibits two peaks (Fig.
1B), which correspond to the transit of the contrast medium in the vascular compartment, followed by its arrival from the cortex by
means of the tubular system into the medullary loop of Henle
(18). The filtrate (and contrast content) arriving in the
loop of Henle originates from the cortex, rather than being extracted
from the medullary vascular system. The vascular and Henle medullary
curves are hence fitted by a different modification of the standard
gamma-variate fit, assuming the raw data to be a mathematical sum of
two separate, independent gamma functions
![]() |
(A4) |
The papillary TDC is similar in appearance to the medullary TDC, except that its second peak derives from transit of contrast in the collecting duct and is fitted with Eq. A4.
Once each TDC is "stripped" and the various regional compartments are individually modeled, the characteristics of each curve can be obtained separately for use in the conventional calculations. The area under the vascular curve will portray only intravascular flow, excluding filtered contrast, providing more a faithful representation of regional perfusion and blood flow. Furthermore, the area under each tubular curve, which represents the degree of ITC (18, 29), can also be individually depicted and used to more reliably quantify the dynamics of tubular flow in the different nephron segments.
Notably, although ITC may be somewhat analogous to inulin TF/P, the two measures are not fully comparable. As opposed to inulin concentration, ITC does not rise monotonically along the nephron but seemingly decreases during transit from the loop of Henle to the distal tubule (Fig. 3). One of the reasons for this phenomenon may be that ITC is measured from average regional tissue density whereas inulin TF/P can be sampled within single tubules. Average regional tissue radiodensity is also affected by the number of contrast molecules in the region of interest and, consequently, regional geometry (or tubular volume fraction). When contrast-media molecules arrive at the cortical distal tubule from the anatomically smaller medullary region, average ITC decreases because of distribution of the contrast-filled tubular fluid over a smaller tubular volume fraction relative to the medullary region in which it had been condensed. Nevertheless, on the assumption that interindividual differences or experimental changes in regional geometry are smaller than those in tubular fluid reabsorption, ITC can serve as a valid index of the reabsorption process.
![]() |
ACKNOWLEDGEMENTS |
---|
The authors are grateful to the EBCT staff for technical assistance with performance of experiments.
![]() |
FOOTNOTES |
---|
This study was supported in part by National Heart, Lung, and Blood Institute Grants HL-03621 and HL-63282 and by the Mayo Foundation. Part of this work has been published in the proceedings of the American Society of Nephrology (J Am Soc Nephrol 10: 382A, 1999) and the International Society for Optical Engineering (SPIE Proc 3978: 539-546, 2000).
Address for reprint requests and other correspondence: L. O. Lerman, Division of Hypertension, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (E-mail: Lerman.Lilach{at}Mayo.Edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 16 February 2001; accepted in final form 18 May 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Aukland, K.
Intrarenal distribution of blood flow. Are reliable methods available for measurements in man?
Scand J Clin Lab Invest
35:
481-486,
1975[ISI][Medline].
2.
Bennett, HF,
and
Li D.
MR imaging of renal function.
Magn Reson Imag Clin N Am
5:
107-126,
1997.
3.
Blomley, MJ,
and
Dawson P.
The quantification of renal function with enhanced computed tomography.
Br J Radiol
69:
989-995,
1996[Abstract].
4.
Clough, AV,
al-Tinawi A,
Linehan JH,
and
Dawson CA.
Regional transit time estimation from image residue curves.
Ann Biomed Eng
22:
128-143,
1994[ISI][Medline].
5.
Doucette, JW,
Corl PD,
Payne HM,
Flynn AE,
Goto M,
Nassi M,
and
Segal J.
Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity.
Circulation
85:
1899-1911,
1992[Abstract].
6.
Dworkin, LD,
and
Brenner BM.
The renal circulations.
In: The Kidney (5th ed.), edited by Brenner BM,
and Rector FC.. Philadelphia, PA: Saunders, 1996, p. 247-285.
7.
Elkayam, U,
Mehra A,
Cohen G,
Tummala PP,
Karaalp IS,
Wani OR,
and
Canetti M.
Renal circulatory effects of adenosine in patients with chronic heart failure.
J Am Coll Cardiol
32:
211-215,
1998[ISI][Medline].
8.
Feldstein, A,
Krier JD,
Hershman Sarafov M,
Lerman A,
Best PJM,
Wilson SH,
and
Lerman LO.
In vivo renal vascular and tubular function in experimental hypercholesterolemia.
Hypertension
34:
859-864,
1999
9.
Flickinger, AL,
Lerman LO,
Sheedy PF,
and
Turner ST.
The relationship between renal cortical volume and predisposition to hypertension.
Am J Hypertens
9:
779-786,
1996[ISI][Medline].
10.
Gaspari, F,
Perico N,
and
Remuzzi G.
Application of newer clearance techniques for the determination of glomerular filtration rate.
Curr Opin Nephrol Hypertens
7:
675-680,
1998[ISI][Medline].
11.
Gaspari, F,
Perico N,
and
Remuzzi G.
Measurement of glomerular filtration rate.
Kidney Int
63:
S151-S154,
1997.
12.
Hasdai, D,
Gibbons RJ,
Holmes DR, Jr,
Higano ST,
and
Lerman A.
Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects.
Circulation
96:
3390-3395,
1997
13.
Inoue, Y,
Yoshikawa K,
Suzuki T,
Katayama N,
Yokoyama I,
Kohsaka T,
Tsukune Y,
and
Ohtomo K.
Attenuation correction in evaluating renal function in children and adults by a camera-based method.
J Nucl Med
41:
823-829,
2000[Abstract].
14.
Lerman, LO,
Bell MR,
Lahera V,
Rumberger JA,
Sheedy PF,
Sanchez Fueyo A,
and
Romero JC.
Quantification of global and regional renal blood flow with electron beam computed tomography.
Am J Hypertens
7:
829-837,
1994[ISI][Medline].
15.
Lerman, LO,
Bentley MD,
Bell MR,
Rumberger JA,
and
Romero JC.
Quantitation of the in vivo kidney volume with cine computed tomography.
Invest Radiol
25:
1206-1211,
1990[ISI][Medline].
16.
Lerman, LO,
Flickinger AL,
Sheedy PF,
and
Turner ST.
Reproducibility of human kidney perfusion and volume determinations with electron beam computed tomography.
Invest Radiol
31:
204-210,
1996[ISI][Medline].
17.
Lerman, LO,
Rodriguez-Porcel M,
and
Romero JC.
The development of X-ray imaging to study renal function.
Kidney Int
55:
400-416,
1999[ISI][Medline].
18.
Lerman, LO,
Rodriguez-Porcel M,
Sheedy PF,
and
Romero JC.
Renal tubular dynamics in the intact canine kidney.
Kidney Int
50:
1358-1362,
1996[ISI][Medline].
19.
Lerman, LO,
Schwartz RS,
Grande JP,
Sheedy PF,
and
Romero JC.
Noninvasive evaluation of a novel swine model of renal artery stenosis.
J Am Soc Nephrol
10:
1455-1465,
1999
20.
Lerman, LO,
Siripornpitak S,
Luna Muffei N,
Sheedy PF, II,
and
Ritman EL.
Measurement of in vivo myocardial microcirculatory function with electron beam CT.
J Comput Assist Tomogr
23:
390-398,
1999[ISI][Medline].
21.
Lerman, LO,
Taler SJ,
Textor S,
Sheedy PF,
Stanson AW,
and
Romero JC.
CT-derived intra-renal blood flow in renovascular and essential hypertension.
Kidney Int
49:
846-854,
1996[ISI][Medline].
22.
Macfarlane, WV.
Water and electrolytes in domestic animals.
In: Veterinary Physiology, edited by Phillis JW.. Philadelphia, PA: Saunders, 1976, p. 461-539.
23.
Mashiach, E,
Sela S,
Winaver J,
Shasha SM,
and
Kristal B.
Renal ischemia-reperfusion injury: contribution of nitric oxide and renal blood flow.
Nephron
80:
458-467,
1998[ISI][Medline].
24.
Middlekauff, HR,
Nitzsche EU,
Nguyen AH,
Hoh CK,
and
Gibbs GG.
Modulation of renal cortical blood flow during static exercise in humans.
Circ Res
80:
62-68,
1997
25.
Miller, DD,
Donohue TJ,
Wolford TL,
Kern MJ,
and
Bergmann SR.
Assessment of blood flow distal to coronary artery stenoses. Correlations between myocardial positron emission tomography and poststenotic intracoronary Doppler flow reserve.
Circulation
94:
2447-2454,
1996
26.
Morton, KA,
Pisani DE,
Whiting JH, Jr,
Cheung AK,
Arias JM,
and
Valdivia S.
Determination of glomerular filtration rate using technetium-99m-DTPA with differing degrees of renal function.
J Nucl Med Technol
25:
110-114,
1997[Abstract].
27.
Navar, LG,
Bell PD,
and
Burke TJ.
Autoregulatory responses of superficial nephrons and their association with sodium excretion during arterial pressure alterations in the dog.
Circ Res
41:
487-496,
1977[ISI][Medline].
28.
Niendorf, ER,
Grist TM,
Lee FT, Jr,
Brazy PC,
and
Santyr GE.
Rapid in vivo measurement of single-kidney extraction fraction and glomerular filtration rate with MR imaging.
Radiology
206:
791-798,
1998[Abstract].
29.
Rodriguez-Porcel, M,
Lerman LO,
Sheedy PF, II,
and
Romero JC.
Pressure dependency of renal tubular flow.
Am J Physiol Renal Physiol
273:
F667-F673,
1997
30.
Romero, JC,
and
Lerman LO.
Novel noninvasive techniques for studying renal function in man.
Semin Nephrol
20:
456-462,
2000[ISI][Medline].
31.
Rumberger, JA,
and
Bell MR.
Measurement of myocardial perfusion using electron-beam (ultrafast) computed tomography.
In: Marcus Cardiac Imaging: A Companion to Braunwald's Heart Disease (2nd ed.), edited by Skorton DJ,
Schelbert HR,
Wolf GL,
and Brundage BH.. Philadelphia, PA: Saunders, 1996, p. 835-852.
32.
Schmermund, A,
Bell MR,
Lerman LO,
Ritman EL,
and
Rumberger JA.
Quantitative evaluation of regional myocardial perfusion using fast X-ray computed tomography.
Herz
22:
29-39,
1997[ISI][Medline].
33.
Shipley, RE,
and
Study RS.
Changes in renal blood flow, extraction of inulin, glomerular filtration rate, tissue pressure and urine flow with acute alterations of renal artery blood pressure.
Am J Physiol
167:
676-688,
1951[ISI].
34.
Solhaug, MJ,
Wallace MR,
and
Granger JP.
Endothelium-derived nitric oxide modulates renal hemodynamics in the developing piglet.
Pediatr Res
34:
750-754,
1993[Abstract].
35.
Solhaug, MJ,
Wallace MR,
and
Granger JP.
Nitric oxide and angiotensin II regulation of renal hemodynamics in the developing piglet.
Pediatr Res
39:
527-533,
1996[Abstract].
36.
Steinhausen, M,
and
Tanner GA.
Microcirculation and tubular urine flow in mammalian kidney cortex (in vivo microscopy).
In: Sitzungsberichte der Heidelberger Akademie der Wissenschafter, Mathematisch-Naturwissenschaftliche Klasse. New York: Jahrgang, 1976, p. 3.
37.
Thompson, HK,
Starmer F,
Whalen RE,
and
McIntosh HD.
Indicator transit time considered as a gamma variate.
Circ Res
14:
502-515,
1964[ISI].
38.
Tojo, A,
Gross SS,
Zhang L,
Tisher CC,
Schmidt HH,
Wilcox CS,
and
Madsen KM.
Immunocytochemical localization of distinct isoforms of nitric oxide synthase in the juxtaglomerular apparatus of normal rat kidney.
J Am Soc Nephrol
4:
1438-1447,
1994[Abstract].
39.
Weisskoff, RM,
Chesler D,
Boxerman JL,
and
Rosen BR.
Pitfalls in MR measurement of tissue blood flow with intravascular tracers: which mean transit time?
Magn Reson Med
29:
553-538,
1993[ISI][Medline].
40.
Wu, XS,
Ewert DL,
Liu YH,
and
Ritman EL.
In vivo relation of intramyocardial blood volume to myocardial perfusion. Evidence supporting microvascular site for autoregulation.
Circulation
85:
730-737,
1992[Abstract].
41.
Zum Winkel, VK,
Hallwachs O,
and
Steinhausen M.
Kameraszintigraphie und isotopennephrographic an der hundeniere und deren überprüfung durch die intravitalmikroskopie.
Fortschr Geb Rontgenstr Nuklearmed
108:
382-393,
1968[ISI][Medline].