Monitoring urea transport in rat kidney in vivo using hyperpolarized¹³C magnetic resonance imaging

Abstract

DB. Monitoring urea transport in rat kidney in vivo using hyperpolarized 13 C magnetic resonance imaging. Am J Physiol Renal Physiol 302: F1658 -F1662, 2012. First published April 4, 2012 doi:10.1152/ajprenal.00640.2011.-Urea functions as a key osmolyte in the urinary concentrating mechanism of the inner medulla. The urea transporter UT-A1 is upregulated by antidiuretic hormone, facilitating faster equilibration of urea between the lumen and interstitium of the inner medullary collecting duct, resulting in the formation of more highly concentrated urine. New methods in dynamic nuclear polarization, providing ϳ50,000-fold enhancement of nuclear magnetic resonance signals in the liquid state, offer a novel means to monitor this process in vivo using magnetic resonance imaging. In this study, we detected significant signal differences in the rat kidney between acute diuretic and antidiuretic states, using dynamic 13 C magnetic resonance imaging following a bolus infusion of hyperpolarized [13 C]urea. More rapid medullary enhancement was observed under antidiuresis, consistent with known upregulation of UT-A1. dynamic nuclear polarization; diuresis; urinary concentrating mechanism; UT-A1 UREA PLAYS A VITAL ROLE in the urinary concentrating mechanism by functioning as a key osmolyte (19). While sodium chloride is the dominant solute in the outer medullary interstitium, urea is important in the inner medulla. In the inner medullary collecting duct (IMCD), facilitated transporters UT-A1 and UT-A3 allow specific reabsorption of urea from the luminal fluid, followed by reabsorption of water down the resulting osmotic gradient via aquaporins. A knockout mouse lacking UT-A1 and UT-A3 has been shown to have a urinary concentrating defect (4). Transport is required since urea is a highly polar molecule with subsequently low diffusivity across lipid bilayers. Activity of UT-A1 is acutely sensitive to antidiuretic hormone (or vasopressin) (11,22), facilitating faster equilibration in the concentration of urea between luminal and interstitial spaces of the inner medulla, resulting in the formation of more highly concentrated urine.Dynamic nuclear polarization (DNP) with recently developed rapid dissolution technology has enabled ϳ50,000-fold enhancement of nuclear magnetic resonance (NMR) signals in the liquid state (1). Hyperpolarization persists for a limited time according to the longitudinal T 1 relaxation time of the nucleus (on the order of 1 min for 13 C nuclei of interest). By overcoming the limitation of poor sensitivity that hampered previous studies with 13 C-labeled compounds, this development has introduced a new set of 13 C-labeled contrast agents for magnetic resonance imaging (MRI), such as [1-13 C]pyruvate, whose distribution and enzymatic conversion to lactate may be monitored in vivo (8). A current clinical trial using hyperpolarized [1-13 C]pyruvate as a MRI contrast agent in prostate cancer patients demonstrates the feasibility of this approach to investigate human disease (14). Urea, which as an end produ...

Diabetes induced renal urea transport alterations assessed with 3D hyperpolarized13C,15N-Urea

“…This is supported by our recent study showing maintained sodium and urea gradients in the early diabetic kidney (two weeks after induction of diabetes) (18), while the intrarenal urea T2 relaxation time was reduced significantly already at 2 weeks due to increased oxygen consumption (23). The oxygen sensitivity of hyperpolarized urea has been shown to be a particular sensitive surrogate marker of metabolic status showing the altered demand during antidiuresis and diuresis in addition to the altered distribution (8,18,24). Albeit a similar intrarenal relaxation gradient is seen in both healthy and diabetic kidneys (23,24), it is unlikely that these relaxation effects dominates the distribution pattern seen here, but they are believed to contribute to the apparent intrarenal signal gradient as the balanced steady state sequence is sensitive to both T1 and T2 relaxation.…”

Chemistry and biochemistry of13C hyperpolarized magnetic resonance using dynamic nuclear polarization

“…64 Recent work has shown that it can also be used to measure absorption in diuresis and assess kidney function. 65 While many clinical studies employ CT and MR contrast agents, these tend to use high concentrations of iodinated contrast or Gd-chelates, which are not safe for patients with renal disease. 66,67 Thus perfusion imaging using HP 13 C urea has high potential for clinical translation.…”

The use of hyperpolarized carbon-13 magnetic resonance for molecular imaging

“…Another in vivo rat study demonstrated that the T 2 of [ 13 C, 15 N]urea in kidneys was greater than ten seconds, as opposed to 1.3 seconds in blood, likely due to deoxyhemoglobin-induced paramagnetic relaxation in blood [119]. Finally, an in vivo rat study demonstrated more rapid medullary [ 13 C]urea enhancement in the antidiuretic state, suggesting that [ 13 C]urea could be used as a marker for urea transporter UT-A1 activity [261]. …”