Longitudinal evaluation of perfusion changes in acute and chronic renal allograft rejection using arterial spin labeling in translational mouse models

Hueper, Katja; Schmidbauer, Martina; Thorenz, Anja; Bräsen, Jan Hinrich; Gutberlet, Marcel; Mengel, Michael; Hartung, Dagmar; Chen, Rongjun; Meier, Martin; Haller, Hermann; Wacker, Frank; Rong, Song; Gueler, Faikah

doi:10.1002/jmri.25713

Cited by 17 publications

(17 citation statements)

References 32 publications

(42 reference statements)

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“…After slice‐selective and global inversion, images were acquired in free breathing in the coronal plane with the following parameters: repetition time (TR)/echo time (TE) = 4.0/2.0 ms, inversion time = 1200 ms, field of view (FOV) = 420 × 420 mm 2 , matrix = 128 × 128, slice thickness = 5 mm, averages = 30 and acquisition time = 4 min. Following motion correction of ASL images with elastic registration, maps of renal perfusion were calculated using MATLAB software (MathWorks, Natick, MA, USA) . Mean cortical perfusion values were determined by two independent readers, both blinded to results of blood values and type of pharmacological intervention, by using regions of interest (ROIs).…”

Section: Methodsmentioning

confidence: 99%

“…Following motion correction of ASL images with elastic registration, maps of renal perfusion were calculated using MATLAB software (MathWorks, Natick, MA, USA). [20] Mean cortical perfusion values were determined by two independent readers, both blinded to results of blood values and type of pharmacological intervention, by using regions of interest (ROIs). ROIs were placed into the upper, middle and lower third of the renal cortex, and mean cortical perfusion of both kidneys was calculated.…”

Section: Mri Protocol and Image Analysismentioning

confidence: 99%

“…[16] Functional magnetic resonance imaging (MRI) with arterial spin labelling (ASL) is a robust method for accurate quantification of renal perfusion [17,18] and is feasible for the longitudinal evaluation of perfusion changes. [19,20] Compared to CEUS, ASL is less investigator-dependent. [21] Compared to PAH clearance, the gold standard renal blood flow measurement, ASL can detect rapid changes of renal perfusion as acquisition time is below 5 min.…”

Section: Introductionmentioning

confidence: 99%

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Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging†

Hellms

Gueler

Gutberlet

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives We investigated changes of renal perfusion after topical and oral diclofenac administration in healthy volunteers using functional magnetic resonance imaging (MRI) with arterial spin labelling (ASL). Methods Twenty‐four healthy human participants (21–51 years) underwent 1.5T MRI before and 1 h after a single oral dose of diclofenac (50 mg). Twelve of 24 participants underwent an additional MRI examination following 3‐day topical diclofenac administration. For renal perfusion imaging, a flow‐sensitive alternating inversion‐recovery TrueFISP ASL sequence was applied. Plasma concentrations of diclofenac and serum concentrations of thromboxane were determined. Key findings After oral diclofenac application, large interindividual differences in plasma concentrations were observed (range <3–4604 nm). Topical diclofenac application did not result in relevant systemic diclofenac levels (range 5–75 nm). MRI showed a significant reduction of renal perfusion in individuals with diclofenac levels ≥225 nm (baseline: 347 ± 7 vs diclofenac: 323 ± 8 ml/min/100 g, P < 0.01); no significant differences were observed in participants with diclofenac levels <225 nm. Diclofenac levels correlated negatively with thromboxane B2 levels pointing towards target engagement. Conclusions Single‐dose diclofenac caused a decrease in renal perfusion in participants with diclofenac levels ≥225 nm. We demonstrated that even a single dose of diclofenac can impair renal perfusion, which could be detrimental in patients with underlying chronic kidney disease or acute kidney injury.

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Section: Methodsmentioning

confidence: 99%

Section: Mri Protocol and Image Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging†

Hellms

Gueler

Gutberlet

et al. 2019

Journal of Pharmacy and Pharmacology

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“…It may well be that the increased expression of C5aR1, C5aR2, and C3aR observed in this study are secondary effects of heme-mediated complement activation. Further studies are required to elucidate the interplay of labile heme and anaphylatoxin receptors by using genetically modified mouse models in renal IRI and kidney transplantation (36,40). Heme has also been proposed to be a danger associated molecular pattern (DAMP) (41) that can amplify TLR4 signaling.…”

Section: Underlying Mechanisms Of Heme-mediated Inflammation After Irimentioning

confidence: 99%

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

et al. 2019

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Background: Ischemia reperfusion injury (IRI) plays a major role in solid organ transplantation. The length of warm ischemia time is critical for the extent of tissue damage in renal IRI. In this experimental study we hypothesized that local release of labile heme in renal tissue is triggered by the duration of warm ischemia (15 vs. 45 min IRI) and mediates complement activation, cytokine release, and inflammation. Methods: To induce IRI, renal pedicle clamping was performed in male C57BL/6 mice for short (15 min) or prolonged (45 min) time periods. Two and 24 h after experimental ischemia tissue injury labile heme levels in the kidney were determined with an apo-horseradish peroxidase assay. Moreover, renal injury, cytokines, and C5a and C3a receptor (C5aR, C3aR) expression were determined by histology, immunohistochemistry and qPCR, respectively. In addition, in vitro studies stimulating bone marrow-derived macrophages with LPS and the combination of LPS and heme were performed and cytokine expression was measured. Results: Inflammation and local tissue injury correlated with the duration of warm ischemia time. Labile heme concentrations in renal tissue were significantly higher after prolonged (45 min) as compared to short (15 min) IRI. Notably, expression of the inducible heme-degrading enzyme heme oxygenase-1 (HO-1) was up-regulated in kidneys after prolonged, but not after short IRI. C5aR, the pro-inflammatory cytokines IL-6 and TNF-α as well as pERK were up-regulated after prolonged, but not after short ischemia times. Consecutively, neutrophil infiltration and up-regulation of pro-fibrotic cytokines such as CTGF and PAI were more pronounced in prolonged IRI in comparison to short IRI. In vitro stimulation of macrophages with LPS revealed that IL-6 expression was enhanced in the presence of heme. Finally, administration of the heme scavenger human serum albumin (HSA) reduced the expression of pro-inflammatory cytokines, C3a receptor and improved tubular function indicated by enhanced alpha 1 microglobulin (A1M) absorption after IRI. Conclusions: Our data show that prolonged duration of warm ischemia time increased labile heme levels in the kidney, which correlates with IRI-dependent inflammation and up-regulation of anaphylatoxin receptor expression.

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“…Development of imaging techniques for graft evaluation and follow-up could contribute to a more reliable graft assessment. Several studies from the research group of Hueper et al, using a kidney transplantation animal model, have shown promising results for the use of MR after transplantation [16][17][18][19]. This same research group and several others have initiated studies to translate these outcomes to the clinical setting, showing significant associations between renal allograft function and several MRI sequences in small and heterogeneous cohorts [20][21][22][23][24].…”

Section: Lessons Learntmentioning

confidence: 99%

Have we forgotten imaging prior to and after kidney transplantation?

et al. 2018

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Longitudinal evaluation of perfusion changes in acute and chronic renal allograft rejection using arterial spin labeling in translational mouse models

Abstract: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1664-1672.

Cited by 17 publications

References 32 publications

Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging†

Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging†

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

Have we forgotten imaging prior to and after kidney transplantation?

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