Quantitative Blood Oxygenation Level Dependent Magnetic Resonance Imaging for Estimating Intra-renal Oxygen Availability Demonstrates Kidneys Are Hypoxemic in Human CKD

Abstract

Introduction: Kidney blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) has shown great promise in evaluating relative oxygen availability. This method is quite efficacious in evaluating acute responses to physiological and pharmacologic maneuvers. Its outcome parameter, R2∗ is defined as the apparent spin-spin relaxation rate measured in the presence of magnetic susceptibility differences and it is measured using gradient echo MRI. Although associations between R2∗ and renal function decline have been described, it remains uncertain to what extent R2∗ is a true reflection of tissue oxygenation. This is primarily because of not taking into account the confounding factors, especially fractional blood volume (fBV) in tissue.

Methods: This case-control study included 7 healthy controls and 6 patients with diabetes and chronic kidney disease (CKD). Using data before and after administration of ferumoxytol, a blood pool MRI contrast media, the fBVs in kidney cortex and medulla were measured.

Results: This pilot study independently measured fBV in kidney cortex (0.23 ± 0.03 vs. 0.17 ± 0.03) and medulla (0.36 ± 0.08 vs. 0.25 ± 0.03) in a small number of healthy controls (n = 7) versus CKD (n = 6). These were then combined with BOLD MRI measurements to estimate oxygen saturation of hemoglobin (StO₂) (0.87 ± 0.03 vs. 0.72 ± 0.10 in cortex; 0.82 ± 0.05 vs. 0.72 ± 0.06 in medulla) and partial pressure of oxygen in blood (bloodPO₂) (55.4 ± 6.5 vs. 38.4 ± 7.6 mm Hg in cortex; 48.4 ± 6.2 vs. 38.1 ± 4.5 mm Hg in medulla) in control versus CKD. The results for the first time demonstrate that cortex is normoxemic in controls and moderately hypoxemic in CKD. In the medulla, it is mildly hypoxemic in controls and moderately hypoxemic in CKD. Whereas fBV, StO₂, and bloodPO₂ were strongly associated with estimated glomerular filtration rate (eGFR), R2∗ was not.

Conclusion: Our results support the feasibility of quantitatively assessing oxygen availability using noninvasive quantitative BOLD MRI that could be translated to the clinic.

Keywords: BOLD; CKD; MRI oxygenation; kidney.

Graphical abstract

Figure 1

R2∗ and R2 maps acquired at baseline and post-ferumoxytol (5 mg/kg) in a representative control (eGFR 77) (Left) and individual with CKD (eGFR 23) (Top Right). The R2∗ maps for control and CKD used the same color bar. Note the substantial increase in R2∗ following ferumoxytol both in the cortex and medulla, but much smaller increase in the individual with CKD, suggesting reduced fBV. Though R2 also shows a similar trend of increase (Bottom), the magnitude of change is much smaller. Both R2∗ and R2 show a higher degree of enhancement in the medulla compared to the cortex, suggesting higher fBV in the medulla. CKD, chronic kidney disease.

Figure 2

Illustration of manually defined regions of interest (ROI) in the cortex and medulla (Left). (Right) shows same image without overlaid ROIs. FireVoxel considers all the ROIs of same color to be a single ROI whether or not the pixels are all connected. For the defined ROIs, we get an output of 4 measures: Left_cortex, Left_medulla, Right_cortex, and Right_medulla. We combine Left and Right values for each region per participant.

Figure 3

Individual scatter plots summarizing R2∗, fBV, StO₂, and blood pO₂ in both the cortex and medulla obtained in the 2 groups of individuals participated in the study (CKD vs. Control). Note the significantly lower values in CKD for fBV, StO₂, and blood pO₂ whereas R2∗ shows only minimal differences. Further, R2∗ in the medulla is lower in CKD, which may be wrongly interpreted as the oxygenation to be improved in CKD. ∗P < 0.05 and ∗∗P < 0.01 by nonparametric Mann-Whitney test. CKD, chronic kidney disease; fBV, fractional blood volume.

Figure 4

Post-ferumoxytol R2∗ maps acquired pre-furosemide and post-furosemide (0.5 mg/kg) with maximum dose of 40 mg (Top). Plots showing individual responses to furosemide in both the cortex and medulla in each of the 2 groups of participants (Bottom). Note the minimal change in median R2∗ post-furosemide in either group of participants. CKD, chronic kidney disease.