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(Circulation. 1996;94:3271-3275.)
© 1996 American Heart Association, Inc.

Articles

Noninvasive Evaluation of Intrarenal Oxygenation With BOLD MRI

Pottumarthi V. Prasad, PhD; Robert R. Edelman, MD; Franklin H. Epstein, MD

the Departments of Radiology and Medicine (F.H.E.), Beth Israel Hospital and Harvard Medical School, Boston, Mass.

Correspondence to P.V. Prasad, PhD, Department of Radiology, MRI (Room AN-242), Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215. E-mail pprasad@bidmc.harvard.edu.

	Abstract

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Background The countercurrent arrangement of capillary blood flow in the medulla of mammalian kidneys generates a gradient of oxygen tension between the renal cortex and the papillary tip that results in a state of relative hypoxia within the renal medulla. Exploration of the pathophysiological implications of medullary hypoxia has been hampered by the absence of a noninvasive technique to estimate intrarenal oxygenation in different zones of the kidney. In the present study, we demonstrate the feasibility of such a method on the basis of blood oxygenation level–dependent (BOLD) MRI, which allows sequential measurements in humans in response to a variety of physiological/pharmacological stimuli in health and disease.

Methods and Results BOLD MRI measurements were obtained in healthy young human subjects (n=7), and the effects of three different pharmacological/physiological maneuvers that induce diuresis were studied. Spin-spin relaxation rate, R₂*, was measured, which is directly related to the amount of deoxyhemoglobin in blood and in turn to tissue PO₂. Furosemide but not acetazolamide (n=6 each) increased medullary oxygenation (R₂*=7.62 Hz; P<.01), consistent with the separate sites of action of these diuretics in the nephron and with previous direct measurements of their effects in anesthetized rats with oxygen microelectrodes. A new finding is that water diuresis improves medullary oxygenation (R₂*=6.43 Hz; P<.01) in young human subjects (n=5).

Conclusions BOLD MRI can be used to monitor changes in intrarenal oxygenation in humans in a noninvasive fashion.

Key Words: magnetic resonance imaging • kidney • blood flow • oxygen • hypoxia

	Introduction

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Because of the countercurrent arrangement of vessels and tubules necessary to conserve water and produce concentrated urine, the tubules of the renal medulla of land mammals must actively reabsorb sodium in a milieu poor in oxygen.¹ As a result, there is normally a marked gradient in PO₂ between circulating blood in vessels of the renal cortex and the medulla, so that the medulla has been described as operating habitually on the brink of anoxia.² Medullary hypoxia has important implications for the mechanisms of disease in the kidneys, particularly in acute renal failure resulting from circulatory or toxic insults in which it is hypothesized to be causative.¹

By use of sensitive but fragile and expensive glass microelectrodes, direct measurements of tissue PO₂ in the cortex and medulla of anesthetized rats have shown that loop diuretics (eg, furosemide) increase medullary PO₂ by diminishing the work of transport in medullary thick limbs.³ By contrast, acetazolamide, a proximal tubular diuretic, increases cortical PO₂ slightly but does not raise medullary PO₂.³ These changes in PO₂ are caused largely by changes in oxygen consumption, because little alteration in regional blood flow was noted with laser Doppler probes.³ A major roadblock to extending these observations to human subjects has been the absence of a noninvasive method to assess regional oxygenation within the kidney.

It is known that oxyhemoglobin is diamagnetic and deoxyhemoglobin is paramagnetic.⁴ Microscopic field gradients in the vicinity of red blood cells and vessels are modulated by changes in deoxyhemoglobin concentration. Such magnetic field perturbations within a voxel (volume element) cause a loss of phase coherence and therefore lead to signal attenuation in gradient echo or T₂* (apparent spin-spin relaxation time)–weighted sequences. This phenomenon has been called blood oxygenation level–dependent (BOLD) contrast.⁵

In the present study, we have applied noninvasive BOLD MRI to evaluate the level of oxygenation in the kidney. Specific objectives for the study were (1) to determine whether BOLD MRI in kidneys of humans is feasible; (2) to study the effects of two diuretics previously shown to have different specific effects on the oxygenation of the renal medulla and cortex in rats and the effect of water load on renal oxygenation, which has not been previously investigated; and (3) to distinguish observed changes caused by BOLD effects from possible changes in water content.

	Methods

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Effect of Oxygenation Changes on BOLD MRI Signal Intensity
MRI signal intensity measurements using a gradient-echo sequence were made at several different echo times, and the slope of log_e (intensity) versus echo time was calculated. This slope determines the apparent spin-spin relaxation rate, R₂* (=1/T₂*), which is directly proportional to the tissue content of deoxyhemoglobin (Fig 1). A decrease in the slope (R₂*) implies an increase in the oxygenation of hemoglobin. Because the oxygenation of hemoglobin is proportional to the PO₂ of blood and therefore in equilibrium with tissue PO₂, R₂* is a sensitive indicator of tissue oxygenation. Alternatively, changes in gradient-echo signal intensity made at a single but sufficiently long echo time could be used directly to indicate qualitative changes in tissue oxygenation.

View larger version (19K): [in this window] [in a new window]   Figure 1. Blood oxygenation level–dependent (BOLD) MRI changes with POO2. The deoxygenation of hemoglobin changes its magnetic characteristics, leading to changes in a parameter of magnetic resonance called R2* (apparent spin-spin relaxation rate). R2* can be estimated from signal intensity measurements made at several different echo times (a through e). The slope of loge (intensity) vs echo time determines R2* and is directly related to the amount of deoxygenated blood. A decrease in the slope implies an increase in the POO2 of blood. We can either measure the slope or obtain intensity measurements at a single echo time (eg, d) to detect a difference in POO2. Because blood POO2 is thought to be in rapid equilibrium with tissue POO2, changes in BOLD signal intensity or R2* should reflect changes in the POO2 of the tissue.

Because changes in the water content of tissue in addition to changes in deoxyhemoglobin content might conceivably change R₂*, it is important to control for this variable. Spin-spin relaxation rate (R₂) is known to show significantly less effect from changes in deoxyhemoglobin content⁶ but has been shown to be very sensitive to changes in tissue water content.⁷ To distinguish changes caused by BOLD effect from changes in water content, we obtained additional spin-echo data to estimate R₂.

Human Studies
We studied seven healthy human volunteers (6 men and 1 women; age, 20 to 40 years) who gave informed consent in a protocol approved by the Beth Israel Hospital Committee on Clinical Investigation that conformed to the Declaration of Helsinki. Two or more studies were carried out in each subject. All studies were performed on a 1.5-T whole-body scanner (Vision Magnetom, Siemens Medical Systems) by use of echo planar imaging (EPI) acquisitions. Gradient-echo EPI images were acquired with three or more echo times in the range of 29 to 140 ms. All images were acquired during breathhold in expiration. Conventional MRI techniques, especially those using long echo times, are very sensitive to motion (cardiac, respiratory, peristaltic, etc). EPI is an ultrafast technique, with a typical image acquisition time of <100 ms,⁸ and is therefore ideal for abdominal imaging, especially with long echo times. Other relevant sequence parameters are as follows: field of view=300 mmx300 mm, matrix size=128x128, and slice thickness=4 mm. Each acquisition was repeated three times for averaging purposes.

After scout images were obtained and the optimal positions were chosen, gradient-echo EPI data were acquired at different echo times. All the EPI data were obtained within a 15-minute interval. One of the following three stimuli was then used in each experiment: furosemide, 20-mg IV injection administered over 2 minutes; acetazolamide, 500-mg IV injection administered over 2 minutes; or water diuresis, ingestion of water, 20 mL/kg body weight in about 15 minutes. In these studies, the subject came to the laboratory in the morning after having abstained from food and water overnight. After the baseline BOLD data were obtained, the subject was taken out of the magnet to drink water.

BOLD MRI measurements were then repeated. When furosemide or acetazolamide was administered, MRI data acquisition was started 5 minutes after the injection. With water diuresis, the MRI data acquisition was resumed when urine flow exceeded 5 mL/min as estimated by measurement of the quantity of urine voided at 15-minute intervals after the water load. In four of the volunteers studied with furosemide and three with water load, we also obtained spin-echo EPI images, acquired with three or more echo times (59 to 160 ms), to calculate spin-spin relaxation rate, R₂.

Region of interest (ROI) analysis was used to calculate regional relaxation rates. A T₁-weighted anatomic image was acquired at the same slice position to facilitate placement of the ROIs. R₂* and R₂ were calculated by measuring the slope of straight line fit to the log_e (intensity) versus echo time data. The mean of the three acquisitions was used for each data point in the slope analysis. Fig 2b illustrates an example of propagation of the ROIs. For statistical analysis of change in R₂* and R₂ before versus after stimuli, a two-tailed paired t test was used.

View larger version (186K): [in this window] [in a new window]   Figure 2. A, T2*-weighted echo planar images (echo time [TE]=29, 50, 80, and 100 ms) of the kidney of a human volunteer before (left) and after (right) administration of furosemide (20 mg IV). On the images made before furosemide administration, one can appreciate corticomedullary contrast that increases with echo time. Medulla appears dark (arrows) owing to the presence of more deoxygenated blood. After furosemide administration, the medulla appears lighter, implying improved oxygenation of blood and presumably of extravascular tissue in the medulla as corticomedullary contrast disappears. Note that the collecting system appears dilated after furosemide administration, which is consistent with diuresis. B, Example of a typical data set analyzed with regions of interest. Shown are prefurosemide echo planar images of the same kidney. Also included is the T1-weighted anatomic image. The regions of interest are defined over the anatomic image and then propagated through the echo planar images, and mean signal intensity (SI) within each region of interest is measured and used to generate loge (intensity) vs TE curve, which is then fit to a straight line to determine the slope (R2*). C, R2* calculated in renal medulla (top) and cortex (bottom) before and after administration of furosemide (20 mg IV). R2* decreases with decreased deoxyhemoglobin (or improved blood oxygenation). The difference in R2* seen after furosemide administration implies an increase in the oxygenation of blood in the medulla.

	Results

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BOLD MRI Applied to Intact Human Kidneys: Effects of Diuretics
Furosemide produced a decrease in R₂* in the medulla of all six subjects studied. Typical changes are illustrated in the images of kidneys before and after furosemide administration in a single subject in Fig 2a and the graph of the slopes of log_e (intensity) versus echo time in Fig 2c. In the cortex, R₂* was unchanged by furosemide. Results of all subjects are summarized in the Table and shown in graphical form in Fig 3.

View this table: [in this window] [in a new window]   Table 1. Effects of Furosemide, Acetazolamide, and Water Diuresis on R2* and R2 in Renal Medulla and Cortex of Human Subjects

View larger version (17K): [in this window] [in a new window]   Figure 3. Change (before vs after diuretic) in R2* in medulla and cortex after administration of either furosemide or acetazolamide in human volunteers (n=6 for each). Data are mean±SD. NS=P.05. Also included is R2 data (n=4) with furosemide. Significantly greater change in R2* vs R2 indicates that this MRI technique is primarily responsible for the observed changes after administration of furosemide.

Acetazolamide, on the other hand, produced no significant change in R₂* in medulla or cortex, as summarized for all experiments in Fig 3.

Effects of Water Diuresis
In five subjects (four men and one women; ages, 20 to 40 years), water diuresis caused a consistent and substantial decrease in R₂* in renal medulla, signifying an increase in medullary PO₂. Data from all water diuresis experiments are summarized in the Table and given graphically in Fig 4. Water diuresis did not affect BOLD MRI signals in the renal cortex. As Fig 4 shows, water diuresis did not change R₂ in either medulla or cortex, implying little change in tissue water content.

View larger version (15K): [in this window] [in a new window]   Figure 4. Changes (before vs after diuretic) in R2* (n=5) and R2 (n=3) in medulla and cortex after induction of water diuresis in human volunteers. Columns show mean±SD. NS=P.05. Significantly greater change in R2* vs R2 indicates that BOLD effect is primarily responsible for the observed changes after water load.

	Discussion

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A number of MRI studies have exploited the effect of oxygen on the magnetic state of hemoglobin.^{5 9 10 11 12} Recently, this principle has been used to detect changes in cerebral oxygen tension and/or blood flow. Hoppel et al¹³ detected a decrease in the T₂* of tissue water in rabbit brains during hypoxia. Kwong et al¹⁴ and Bandettini et al¹⁵ demonstrated changes in T₂*-weighted echo planar MRI images of human brain after visual stimulation and breathholding that were attributed to changes in oxygen tension. These and similar studies have stimulated active research in the area of functional MRI of the brain.

Thulborn et al¹⁰ showed that the T₂ relaxation rate of whole blood is a linear function of the square of the fraction of hemoglobin that was deoxygenated. The effect was relatively insensitive to temperature and hematocrit over the physiological range but disappeared when the blood was hemolyzed. Because of the sigmoidal relationship of PO₂ to the oxygenation of hemoglobin,¹⁶ changes in BOLD MR signal produced by changes in blood PO₂ can be expected to be most marked at low levels of PO₂ and relatively less sensitive at a PO₂ >40 mm Hg, at which point most hemoglobin is in the oxygenated form. This makes BOLD MRI ideally suited for oxygenation measurements in the renal medulla, where PO₂ is normally in the range of 15 to 20 mm Hg,^{1 2} rather than in the cortex, where small changes in O₂ tension might go undetected. Because the oxygen tension of blood should mirror that of the tissue being perfused, changes in BOLD signal intensity measured at a sufficiently long echo time, or in R₂*, should reflect changes in the PO₂ of tissue (Fig 1). Calculation of R₂* is more robust and precise, minimizes artifactual errors, and avoids confounding effects such as those caused by changes in the water content of tissues.

The validity of these measurements, at least in a qualitative sense, is strengthened by the correspondence of the changes we observed in humans after furosemide and acetazolamide were administered with those previously measured directly with oxygen microelectrodes in anesthetized rats. Furosemide, which inhibits active transport in the medullary thick ascending limbs, greatly increased medullary PO₂, whereas after administration of acetazolamide, which primarily inhibits proximal tubular reabsorption in the renal cortex, medullary PO₂ did not change. Significant changes in medullary R₂* compared with R₂ validate the presumption that the observed changes are dominated by the BOLD effect rather than changes in regional water content.

New information also is provided by the present study regarding the effects of water diuresis in humans. Water diuresis consistently increased medullary PO₂ in five healthy young subjects to a degree close to that observed after furosemide administration without altering the BOLD MRI signal from the cortex. Although water diuresis does not change total renal blood flow substantially,¹⁷ it is possible that capillary flow to the renal medulla may be selectively increased. It is also likely that water diuresis is associated with a decrease in oxygen consumption in the medulla because of a decrease in active transport by cells lining the medullary thick ascending limbs. At least in young individuals, water diuresis is associated with a marked increase in urinary excretion of prostaglandin E₂ (PGE₂) and dopamine.¹⁸ Both agents have local vasodilating effects and inhibit active reabsorptive transport in medullary tubules, actions that would increase medullary PO₂.^{19 20 21} Vasopressin might also modulate active transport²² and local blood flow to the renal medulla^{23 24} in a way that would increase medullary PO₂ when its influence was removed, as in water diuresis. Because normal aging is associated with a loss of the ability to increase urinary prostaglandin E₂ and dopamine during water diuresis,¹⁸ it will be of interest to see whether aging also diminishes the effect of water diuresis to increase medullary PO₂, as estimated by BOLD MRI.

The precise quantification of tissue PO₂ in absolute terms will require suitable calibration. Furthermore, BOLD MRI cannot, of course, distinguish between changes in oxygenation produced by alterations in the supply of oxygen (blood flow) and in its consumption (active transport). Changes in the hemoglobin-O₂ dissociation curve such as those produced by large changes in pH might also affect BOLD MRI, although the pH of the outer medulla of the kidney (as opposed to the distal portion of the inner medulla) probably does not differ significantly from that of peripheral blood.^{25 26}

The present experiments demonstrate that BOLD MRI can be used to study the effects of physiological and pharmacological perturbations and of disease processes on regional oxygenation within the kidney, sequentially and noninvasively, in human subjects.

	Acknowledgments

 
This work was supported in part by a biomedical engineering research grant from the Whitaker Foundation (Dr Prasad) and NIH (NIDDK) grant RO-18078 (Dr Epstein). We thank Katherine Spokes, John Cannillo, and Dr Wei Li for their technical assistance.

Received May 28, 1996; revision received August 14, 1996; accepted September 1, 1996.

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