Noninvasive quantitative magnetization transfer MRI reveals tubulointerstitial fibrosis in murine kidney

Abstract

Excessive tissue scarring, or fibrosis, is a critical contributor to end stage renal disease, but current clinical tests are not sufficient for assessing renal fibrosis. Quantitative magnetization transfer (qMT) MRI provides indirect information about the macromolecular composition of tissues. We evaluated measurements of the pool size ratio (PSR, the ratio of immobilized macromolecular to free water protons) obtained by qMT as a biomarker of tubulointerstitial fibrosis in a well‐established murine model with progressive renal disease. MR images were acquired from 16‐week‐old fibrotic hHB‐EGFTg/Tg mice and normal wild‐type (WT) mice (N = 12) at 7 T. QMT parameters were derived using a two‐pool five‐parameter fitting model. A normal range of PSR values in the cortex and outer stripe of outer medulla (CR + OSOM) was determined by averaging across voxels within WT kidneys (mean ± 2SD). Regions in diseased mice whose PSR values exceeded the normal range above a threshold value (tPSR) were identified and measured. The spatial distribution of fibrosis was confirmed using picrosirius red stains. Compared with normal WT mice, scattered clusters of high PSR regions were observed in the OSOM of hHB‐EGFTg/Tg mouse kidneys. Moderate increases in mean PSR (mPSR) of CR + OSOM regions were observed across fibrotic kidneys. The abnormally high PSR regions (% area) detected by the tPSR were significantly increased in hHB‐EGFTg/Tg mice, and were highly correlated with regions of fibrosis detected by histological fibrosis indices measured from picrosirius red staining. Renal tubulointerstitial fibrosis in OSOM can thus be assessed by qMT MRI using an appropriate analysis of PSR. This technique may be used as an imaging biomarker for chronic kidney diseases.

Spin‐lock relaxation rate dispersion reveals spatiotemporal changes associated with tubulointerstitial fibrosis in murine kidney

“…Paraffin tissue sections were stained with picrosirius red using standard procedure for histologic confirmation …”

“…The histologic fibrosis index was evaluated using the same procedure as in our previous work …”

“…Recent advances in MRI have raised its role in the diagnostic assessment of renal fibrosis, but novel proposed MRI techniques are still under evaluation . These include BOLD MRI, DWI, magnetic resonance elastography (MRE) and magnetization transfer (MT) imaging . These techniques have limitations even though they have shown potential for detecting renal fibrosis .…”

Quantitative Magnetization Transfer Detects Renal Fibrosis in Murine Kidneys With Renal Artery Stenosis

“…Recently, Wang et al showed the utility of qMT in detecting renal fibrosis in mouse models of diabetic nephropathy 18 and progressive fibrosis 19 using 7.0T MRI. Because only mild or localized fibrosis developed in these models, qMT‐derived pool size ratio (PSR, the ratio between the bound and free pool magnetization) correlated with renal fibrosis by histology only in the renal cortex (CO) 18 or outer strip of outer medulla (OSOM) 19 . The ability of qMT to measure fibrosis in other structurally and functionally distinctive kidney regions, including inner strip of outer medulla, inner medulla (IM), and papilla (P), remains to be tested.…”

Clinical and experimental approaches for imaging of acute kidney injury

“…MT can detect large immobile macromolecules distributed within tissues and evaluate pathophysiological events (e.g., fibrosis, apoptosis) accompanied by changes in macromolecular components. We and others have recently shown that renal fibrosis can be assessed using specific parameter pool-size ratio from the quantitative MT approach based on mathematical modeling or MT ratio from simpler two-point metrics [132,[134][135][136]. Importantly, changes in physiological conditions and hemodynamics can affect measurements on DWI and BOLD imaging, even in the absence of fibrosis.…”