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Assessment of Renal Tissue Oxygenation by BOLD-MRI Imaging:

The kidney medulla, which typically functions in a moderately hypoxic milieu, is highly sensitive to variations in blood flow. Consequently, renal ischemia accounted for almost half of the observed cases of acute renal failure (1). Renal medullary hypoxia may also play a role in the pathophysiology of hypertension and diabetic nephropathy (2). Blood oxygen level-dependent MRI is a noninvasive method capable of providing regional measurements of relative changes in blood oxygen saturation. The BOLD contrast is attributed to the creation of susceptibility-induced magnetic field in homogeneities surrounding blood vessels containing deoxyhemoglobin (dHb) (3). The spin-echo (SE) and gradient-echo (GE) transverse relaxation rates, R2 (=1/T2) and R2* (=1/T2*), of water in blood and in the tissue surrounding the blood vessels are enhanced by the presence of dHb. These relaxation rates vary with the concentration of dHb, [dHb], and as such provide a sensitive measure of changes in blood oxygen saturation. It has been shown that BOLD contrast is able to detect changes in intra-renal oxygenation during an acute reduction of RBF, administration of diuretics, ureteral obstruction and diabetes in human and rodents (4, 5, 6).

(Preliminary BOLD Studies)
In our preliminary kidney imaging studies we utilized a multi-echo GE BOLD method to assess mouse kidney oxygen saturation in three currently utilized VKDC disease models: 1) an ischemia/reperfusion (IR) acute renal failure (IR-ARF) model (PIs, Drs. Takahashi and Hao), 2) an acute tubular necrosis (ATN) disease model (PI, Dr. Srichai) and 3) a renal artery stenosis model (PIs, Drs. Takahashi and Hao). Figure 1 displays example GE images acquired at 6 different echo times of a mouse whose right kidney (displayed on left side) was clamped for 30 minutes, which is a common approach utilized to create the IR-ARF model. These images were collected 1 day following the ischemic injury. The resulting R2* maps of this mouse are illustrated in Figure 2. In our control studies the kidney R2* values ranged from 45-65 sec-1. In the injured kidney cortical R2* values were relatively normal ranging from 50-60 sec-1, where in medulla the R2* values were substantially elevated ranging from 150-250 sec-1 indicating a marked reduction in tissue oxygenation. Interestingly, in the uninjured kidney the R2* values were slightly elevated above normal, ranging from 75-90 sec-1. A compensatory mechanism, such as increased oxygen consumption, is a possible source for the elevated R2* values measured in the uninjured kidney. We found similar, but more substantial changes in the R2* values of kidneys following stenosis of the renal artery. In the injured kidney the mean R2* values were 108 sec-1 which also indicates a drastic reduction in the delivery of oxygen to this tissue.
In the ATN disease model we have also found BOLD imaging to be a useful imaging approach for evaluating the impact of tubular injury. For these studies we also acquired multi-echo GE images following the injection of an intravascular contrast agent in addition to the standard BOLD measurements. This additional scan enabled the computation of relative blood volume maps of the kidneys. Figure 3 presents example pre- and post-contrast GE images (top two images) followed by the computed blood volume map (bottom) for one of the ATN mice. In a small cohort of mice there was a definite trend towards increased R2* values, (mean value ~ 90 sec-1) and an approximately 20-30% reduction in the BV as compared to control mice.

(Developmental BOLD MRI Studies)
To improve upon our capacity to quantify regional oxygenation we are currently investigating the utility of new BOLD MRI methods and models. Specifically, we have developed an approach, called Contrast-Referenced (CR) BOLD MRI, which quantifies changes in the susceptibility of blood following an oxygen or vascular perturbation. These susceptibility variations can be uniquely separated into modulations in blood oxygen saturation and blood volume. In a prior study we applied this approach to study oxygen delivery to a C6 glioma rat tumor model. As shown in Figure 4 the change in the susceptibility of the blood following systematic increases in the inhaled oxygen or the addition of CO2 in a carbogen (CARB) mixture closely matched the changes in Oxylite probe measurements of tissue oxygen partial pressure. CR-BOLD MRI requires four measurements of the transverse relaxation rate (R2*): baseline, with oxygen perturbation, baseline with an intravascular contrast agent, and with oxygen perturbation and contrast agent. To validate this approach we will make CR-BOLD measurements in mice receiving injections of norepinephrin, angiotensin II, L-NAME, prostacyclin and/or bradykinin, which are well-characterized vasoactive agents that alter blood flow and oxygen delivery to renal tissue. Using these measurements and the CR-BOLD model we will calculate maps of relative blood volume, the change in blood volume (delta V/V), and the ratio of the change in blood magnetic susceptibility following oxygen perturbation to the absolute susceptibility of the contrast agent (delta XOXY/ delta XA) for each oxygen perturbation. A negative delta XOXY/ delta X indicates higher blood oxygen saturation whereas a positive delta XOXY/ delta X reflects lower saturation (or increased deoxyhemoglobin concentration). The MRI-derived change in oxygen saturation will be compared to Oxylite measures of tissue oxygen tension before and after the injection of the vasoactive agents.
Local oxygen tension within the kidneys will be measured with a dual channel Oxylite/Oxyflow system (Oxford Optronix, Oxford, England). In this system, each precalibrated fiber optic probe consists of a small optical sensor enclosed in a sleeve with a 280 µm outer diameter. According to manufacturer’s specifications the Oxylite probe samples a volume of tissue equivalent to 4 BOLD MRI voxels (0.25 mm3). The probes will be fixed to micromanipulator electrode holders supplied by Kopf Instruments and advanced into the kidney in incremental steps. Tissue compression is minimized by advancing the probe by a distance slightly greater than the measurement step followed by a short retraction. Measurements (30 to 45 in total) will be made along six to ten tracks through the kidney.

Publications for BOLD-MRI (Tissue oxygenation) (6)

Mason RP. Non-invasive assessment of kidney oxygenation: a role for BOLD MRI. Kidney Int (2006) 70:10-1
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Blood oxygen level-dependent (BOLD) contrast magnetic resonance imaging (MRI) has been applied to investigate kidney oxygenation in human patients. These investigations reflect the progress of radiology from a primarily anatomic discipline to one that provides insight into tissue physiology. In particular, magnetic resonance imaging (MRI) is non-invasive, uses no ionizing radiation, and provides insight into disease development and tissue physiology.

Prasad PV. Evaluation of intra-renal oxygenation by BOLD MRI. Nephron Clin Pract (2006) 103:c58-65
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This is a review of blood oxygenation level-dependent (BOLD) MRI as applied to the kidney. It has been shown that BOLD MRI measurements reflect changes in renal oxygenation, especially in the medulla. Renal medulla functions in a hypoxic milieu and is extremely sensitive to further decrease in blood flow or increase in oxygen consumption. Availability of a non-invasive technique such as BOLD MRI should allow for better understanding of the factors involved in the maintenance of renal oxygenation status, not only in animal models, but also in humans. CI Copyright 2006 S. Karger AG, Basel.

Epstein FH, Veves A, Prasad PV. Effect of diabetes on renal medullary oxygenation during water diuresis. Diabetes Care (2002) 25:575-8
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OBJECTIVES: To study the effect of water diuresis on renal medullary and cortical oxygenation in patients with diabetes using blood oxygenation level--dependent magnetic resonance imaging (BOLD MRI). RESEARCH DESIGN AND METHODS: Nine mild diabetic subjects (48 +/2.7 years of age, six women) and nine nondiabetic subjects of similar age and sex, all without known vascular or renal disease, were studied noninvasively by MRI before and during water diuresis. RESULTS: Water diuresis induced an increase in medullary oxygenation in control subjects, producing a decrease in R2* (apparent spin-spin relaxation time) of 1.89 +/0.27 (P < 0.01), but no significant change in the group of diabetic subjects. CONCLUSIONS: These findings in middle-aged diabetic subjects, which resembled those previously described in elderly subjects >65 years of age, suggest early impairment of adaptive vasodilatation within the renal medulla in diabetes.

Fabry ME, Kennan RP, Paszty C, Costantini F, Rubin EM, Gore JC, Nagel RL. Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease. J Clin Invest (1996) 98:2450-5
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All transgenic mouse models for sickle cell disease express residual levels of mouse globins which complicate the interpretation of experimental results. We now report on a mouse expressing high levels of human betaS and 100% human alpha-globin. These mice were created by breeding the alpha-knockout and the mouse beta(major)-deletion to homozygosity in mice expressing human alphaand betaS-transgenes. These betaS-alpha-knockout mice have accelerated red cell destruction, altered hematological indices, ongoing organ damage, and pathology under ambient conditions which are comparable with those found in alphaH betaS-Ant[betaMDD] mice without introduction of additional mutations which convert betaS into a "super-betaS" such as the doubly mutated betaS-Antilles. This is of particular importance for testing strategies for gene therapy of sickle cell disease. Spin echo magnetic resonance imaging at room air and 100% oxygen demonstrated the presence of blood hypoxia (high levels of deoxygenated hemoglobin) in the liver and kidneys that was absent in control mice. We demonstrate here that transgenic mice can be useful to test new noninvasive diagnostic procedures, since the magnetic resonance imaging technique described here potentially can be applied to patients with sickle cell disease.

Brezis M, Rosen S. Hypoxia of the renal medulla--its implications for disease. N Engl J Med (1995) 332:647-55
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Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med (1990) 14:68-78
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At high magnetic fields (7 and 8.4 T), water proton magnetic resonance images of brains of live mice and rats under pentobarbital anesthetization have been measured by a gradient echo pulse sequence with a spatial resolution of 65 x 65-microns pixel size and 700-microns slice thickness. The contrast in these images depicts anatomical details of the brain by numerous dark lines of various sizes. These lines are absent in the image taken by the usual spin echo sequence. They represent the blood vessels in the image slice and appear when the deoxyhemoglobin content in the red cells increases. This contrast is most pronounced in an anoxy brain but not present in a brain with diamagnetic oxy or carbon monoxide hemoglobin. The local field induced by the magnetic susceptibility change in the blood due to the paramagnetic deoxyhemoglobin causes the intra voxel dephasing of the water signals of the blood and the surrounding tissue. This oxygenation-dependent contrast is appreciable in high field images with high spatial resolution.

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Last updated on 2013-11-06 Moderated by Takamune Takahashi