Original contribution
Using functional magnetic resonance imaging to evaluate an acute allograft rejection model in rats

https://doi.org/10.1016/j.mri.2019.01.006Get rights and content

Abstract

Purpose

To assess the longitudinal changes of allograft pathophysiology by intravoxel incoherent motion (IVIM) and blood oxygen level-dependent (BOLD) MRI in a rat model of acute renal allograft rejection.

Materials and methods

Acute rejection (AR) was induced by transplantation of Dark Agouti donor kidneys into Lewis recipients (n = 18). A Lewis-Lewis rat syngeneically transplanted (sTX) model served as the control (n = 6). Acute tubular necrosis (n = 6) and acute calcineurin inhibitor toxicity (n = 6) groups were established using Lewis rats. MRI was performed on postoperative day (POD) 1, 4 and 7 in the allogeneically transplanted (aTX) group and on POD4 in the other groups. Histological evaluation and PCR were performed.

Results

After the allogenic transplantation, all MRI parameters of allograft further decreased until POD7, and the D and ADC values in the cortex were significantly lower than that in the sTX group (1.03 ± 0.09 vs 1.52 ± 0.09 × 10−3 mm2/s, Padj< 0.05; 1.21 ± 0.03 vs 1.78 ± 0.07 × 10−3 mm2/s, Padj< 0.05). The D*, f and R2* values of the aTX group in the cortex and medulla were significantly lower than those in the sTX group on POD7 (cortex, D*: 25.60 ± 4.78 vs 69.32 ± 9.79 × 10−3 mm2/s, Padj< 0.05; f: 7.84 ± 1.83 vs 20.34 ± 3.08%, Padj< 0.05; R2*: 16.61 ± 4.18 vs 31.48 ± 6.43 1/s, Padj< 0.05; medulla, D*: 13.59 ± 6.08 vs 62.75 ± 9.20 × 10−3 mm2/s, Padj< 0.05; f: 7.46 ± 1.62 vs 14.68 ± 2.05%, Padj< 0.05; R2*: 21.59 ± 3.45 vs 39.53 ± 4.34 1/s, Padj< 0.05). AR grafts presented serve interstitial inflammation, tubulitis and infiltration of T-lymphocytes and macrophages. The MRI parameters, including D, ADC, D*, f and R2*, were significantly correlated with the histological changes, cell infiltration and inflammatory cytokine mRNA levels.

Conclusions

IVIM coupled with BOLD MRI allows longitudinal assessment of allograft diffusion, perfusion and oxygen consumption impairment caused by acute renal allograft rejection in rat model.

Introduction

Acute renal allograft rejection is the leading cause of allograft damage and low long-term graft survival [1]. Currently, allograft biopsy is the gold standard for diagnosing acute rejection (AR) and for differentiation from other causes of renal dysfunction. However, as an invasive method, biopsies are not suitable for repeated and dynamic monitoring. Therefore, noninvasive and comprehensive monitoring of allograft pathophysiology would be desirable.

Functional magnetic resonance imaging (fMRI) can show pathophysiological changes in renal allografts without invasiveness in addition to morphological changes [2]. In particular, diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD) MRI have been used to monitor the function of renal allografts in clinical study and experimental study in small animals [[3], [4], [5]]. The apparent diffusion coefficient (ADC), a quantitative parameter derived from DWI, reflects the microscopic motion of water molecules in tissue [6]. BOLD can evaluate renal oxygenation by means of the R2* value (=1/T2) which is inversely correlated with pO2 and positively correlated with deoxyhemoglobin [7]. Le Bihan et al. indicated that microscopic motion in tissue includes microcirculation perfusion and the diffusion of water molecules [8]. Intravoxel incoherent motion (IVIM) can quantitatively assess the renal fluid loading and microvascular dynamics via the parameters, including the pseudo-diffusion coefficient (D*), pure diffusion coefficient (D) and volume fraction (f).

Normal kidneys are characterized by the active diffusion of water molecules and rich blood circulation, whereas AR is characterized by endothelial inflammation, interstitial inflammation, edema and the swelling of small renal arteries. These characteristics can result in changes in the diffusion of water molecules and microcirculation; all of these issues constitute the basis of this study.

The aim of this study was to investigate the value of IVIM and BOLD MRI for evaluating the renal pathophysiology in rat models of AR. Moreover, we intended to compare fMRI parameters with histopathology and real time-polymerase chain reaction (PCR) data. Furthermore, because the cause of delayed graft function during the early stage after renal transplantation needs to be determined, we evaluated whether IVIM can be used to differentiate AR, the acute tubular necrosis (ATN) occurring after ischemia-reperfusion injury (IRI) and the acute calcineurin inhibitor toxicity caused by cyclosporin A (CSA).

Section snippets

Experimental animals and reagents

This study was conducted with the approval of the animal protection committee of the Capital Medical University (approval: AEEI-2017-010). Animals were cared in accordance with the National Institutes of Health guidelines. Eight- to 12-week-old, inbred male Dark Agouti (DA) and Lewis (LEW) rats weighing 200 to 250 g were provided by Vital River (Beijing, China; National Experimental Animal Seed Center). Rats were reared under the conditions as follows: temperature, 22 ± 1 °C; relative humidity,

Renal diffusion changes

The diffusion parameters D and ADC are shown in Fig. 3 and Table 3. The rats with AR had a progressive reduction in D and ADC in the cortex by 3.2% and 7.3%, respectively, compared with that in the sTX group on POD1, and the minimum D (decreased by 32.2%, Padj < 0.01) and ADC (decreased by 32.0%, Padj< 0.01) values occurred on POD7 (Fig. 3a). A similar pattern was observed in the medulla of the aTX group, whereas only the ADC values were significantly lower than that in the sTX group on POD7

Discussion

This experimental study showed that fMRI with IVIM and BOLD could be an effective, noninvasive tool for detection and monitoring the change of pathophysiology of the graft with AR, including diffusion and perfusion impairment, a decrease in oxygen consumption and an increased oxygen concentration. These changes were closely related to evidence of inflammation, the quantity of infiltrating cells and the mRNA levels of CD3 and inflammatory cytokines.

In this study, ADC was significantly lower in

Acknowledgment

We thank Yang Liu and Ying Wang for the assistance in pathological work.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 81670679].

Declarations of interest

None.

References (28)

  • J.L. Zhang et al.

    Functional MRI of the kidneys

    J Magn Reson Imaging

    (2013)
  • K. Hueper et al.

    Diffusion-weighted imaging and diffusion tensor imaging detect delayed graft function and correlate with allograft fibrosis in patients early after kidney transplantation

    J Magn Reson Imaging

    (2016)
  • K. Hueper et al.

    Kidney transplantation: multiparametric functional magnetic resonance imaging for assessment of renal allograft pathophysiology in mice

    Investig Radiol

    (2016)
  • B.C. Kone

    A ‘BOLD’ new approach to renal oxygen economy

    Circulation

    (1996)
  • Cited by (6)

    1

    Song Zeng and Lu Liang contributed equally to this work.

    View full text