Emmeli F. R. Mikkelsen1, Thomas S. Nørlinger1, Haiyun Qi1, Ulrich Koellisch2, Rolf F. Schulte3, Michael Pedersen1, Hans Stødkilde-Jørgensen1, and Christoffer Laustsen1
1MRI Research Centre, Aarhus University Hospital, Aarhus N, Denmark, 2Institute of Medical Engineering, Technische Universität München, Munich, Germany, 3GE Global Research, Munich, Germany
Synopsis
Positron Emission Tomography (PET) using carbon-11
acetate has previously been used to reveal the oxidative metabolism in the
kidneys. It has been found that renal carbon-11 acetate turnover measured by
PET was significantly correlated with renal oxygen consumption and tubular
sodium reabsorption measured by an invasive approach. Hyperpolarized MRI is an
alternative method to obtain similar intracellular measures of acetate, and the
aim of this study was therefore to evaluate the rate constants of
hyperpolarized [1-13C]-acetate in rat kidneys. The intrarenal oxygen
level was altered by diuretics, and measures of acetate rate constants were
calculated before and after injection of furosemide.Purpose
To measure the intrarenal acetate turnover in response
to furosemide using hyperpolarized [1-
13C]-acetate.
Methods
Ten female adult Wistar
rats (256.0±7.0 g) were included. Blood glucose levels were measured as 7.1±0.7
mmol/L from the tail capillary blood with a Contour blood glucose meter. Tail
vein catheterization was performed for administration of hyperpolarized [1-
13C]-acetate
and furosemide. The animal was anaesthetized with 3% sevoflurane in oxygen as
breathing gas. [1-
13C]-acetate was polarized in a SpinLab (GE
Healthcare). MRI measurements were performed on a 3 T GE HDx scanner (GE
Healthcare) equipped with a hydrogen/carbon-RF quadrature transmit/receive-coil
(GE Healthcare). A dynamic (120 sec, 1 image/sec) sequence was initiated at
start of [1-
13C]-acetate injection. A second dynamic scan was
performed 20 min after an iv bolus of furosemide (10 mg/ml).
Regions-of-interests of left and right kidney parenchyma were manually
segmented in order to measure the mean renal activity-curve, and a region
inside the abdominal aorta was used to obtain the arterial input curve (AIF).
The AIF was then fitted by a gamma variate function (using the nonlinear
Levenberg-Marquardt method) for the initial 30 sec after [1-
13C]-acetate
injection to account for recirculation. Next, graphical analysis, by means of
the Patlak plot, was used to estimate the intracellular [1-
13C]-acetate
conversion rate (k) in units of min
-1, using the approximation that
the intracellular pharmacokinetics of acetate is considered being
monocompartmental and irreversible
1.
Results
Hyperpolarized [1-
13C]-acetate
(fig. 1) accumulated in both
kidneys following arterial filling. The acetate turnover or rate constants
increased from 2.64 ± 0.78 min
-1 to 4.19 ± 1.50 min
-1 (paired
t-test: p = 0.0021) after
administration of furosemide (fig. 2).
Discussion
The rate constants
in rat kidneys found in this study was two orders of magnitude larger than
those reported with radioactive carbon-11 acetate measured by PET by Juillard et al
1.
This discrepancy may be explained by the general allometric (log-scale)
differences in size and metabolism between pigs and rats. This explanation is
supported by the rate constants found in rat myocardium, demonstrating
carbon-11 acetate rate constants around 1.5 min
-1 2. The increased
conversion rate of [1-
13C]-acetate following furosemide supports the
view that this diuretic drug decreases the intrarenal oxygen consumption
(reduction in the sodium reabsorption), thus increasing the cortical blood
perfusion.
Conclusion
This study demonstrated
the potential of hyperpolarized [1-
13C]-acetate MRI as a novel
method of assessing renal oxidative metabolism via acetate turnover mapping.
Acknowledgements
Henrik Vestergaard is acknowledged for his laboratory
assistance.References
1. Juillard, L., et al., Validation of Renal Oxidative Metabolism Measurement by
Positron-Emission Tomography. Hypertension, 2007. 50(1): p. 242-247.
2. Bentourkia, M., et al., Cardiac studies in rats with <sup>11</sup>C-acetate and
PET: a comparison with <sup>13</sup>N-ammonia. Nuclear Science,
IEEE Transactions on, 2002. 49(5):
p. 2322-2327.