Efficacy of preventive interventions for iodinated contrast-induced acute kidney injury evaluated by intrarenal oxygenation as an early marker

Abstract

Objective: The objective of this study was to evaluate the effects of potential renoprotective interventions such as the administration of N-acetylcysteine (NAC; antioxidant) and furosemide (diuretic) on intrarenal oxygenation as evaluated by blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in combination with urinary neutrophil gelatinase-associated lipocalin (NGAL) measurements.

Materials and methods: Rats received nitric oxide synthase inhibitor L-NAME (10 mg/kg) and cyclooxygenase inhibitor indomethacin (10 mg/kg) to induce the risk for developing iodinated contrast-induced acute kidney injury before receiving one of the interventions: NAC, furosemide, or placebo. One of the 3 iodinated contrast agents (iohexol, ioxaglate, or iodixanol) was then administered (1600-mg organic iodine per kilogram body weight). Fifty-four Sprague-Dawley rats were allocated in a random order into 9 groups on the basis of the intervention and the contrast agent received.Blood-oxygen-level-dependent MRI-weighted images were acquired on a Siemens 3.0-T scanner using a multiple gradient recalled echo sequence at baseline, after L-NAME, indomethacin, interventions or placebo, and iodinated contrast agents. Data acquisition and analysis were performed in a blind fashion. R2* (=1/T2*) maps were generated inline on the scanner. A mixed-effects growth curve model with first-order autoregressive variance-covariance was used to analyze the temporal data. Urinary NGAL, a marker of acute kidney injury, was measured at baseline, 2 and 4 hours after the contrast injection.

Results: Compared with the placebo-treated rats, those treated with furosemide showed a significantly lower rate of increase in R2* (P < 0.05) in the renal inner stripe of the outer medulla. The rats treated with NAC showed a lower rate of increase in R2* compared with the controls, but the difference did not reach statistical significance. Urinary NGAL showed little to no increase in R2* after administration of iodixanol in the rats pretreated with furosemide but demonstrated significant increase in the rats pretreated with NAC or placebo (P < 0.05).

Conclusions: This is the first study to evaluate the effects of interventions to mitigate the deleterious effects of contrast media using BOLD MRI. The rate of increase in R2* after administration of iodinated contrast is associated with acute renal injury as evaluated by NGAL. Further studies are warranted to determine the optimum dose of furosemide and NAC for mitigating the ill effects of contrast media. Because NGAL has been shown to be useful in humans to document iodinated contrast-induced acute kidney injury, the method presented in this study using BOLD MRI and NGAL measurements can be translated to humans.

FIGURE 1

A representative anatomical image of a kidney in a control rat that received placebo in the intervention phase and iodixanol. The typical ROI positions are indicated as the inner medulla (IM), the inner and outer stripe of outer medulla (IOSM and OSOM), as well as the cortex (CO). The R2* maps are displayed with the same window settings. Note the brightness increases after each chemical (progressively increasing R2* values) suggesting increasing levels of hypoxia, especially in the ISOM.

FIGURE 2

A, The summary of the temporal changes in R2* (R2*/baseline) measurements in the 4 renal regions in all animal groups based on 3 CM and 4 renal regions. R2* values were normalized to baseline values to allow combining data from the different groups. Each data point is the average of R2* measurements in 6 rats in the experimental time. Each time course consisted of 40 time points. The vertical lines show the time of administration of pretreatments, intervention (or placebo), and CM agents. B, The ISOM data in the rats that received iodixanol are highlighted. C, The temporal R2* changes in renal ISOM from the control rats that received different contrasts.

FIGURE 3

The normalized NGAL (NGAL/urine creatinine, mean ± SE) from all groups.