Inna Linnik1, Parisa Ranjzad2, Adrian S Woolf2, and Steve R Williams1
1University of Manchester, Centre for Imaging Scienses, Manchester, United Kingdom, 2University of Manchester, Institute of Human Development, Manchester, United Kingdom
Synopsis
To assess progressive kidney disease in a folic acid (FA) induced nephropathy model in mice, kidney T1 and volume were quantified using MRI. Mice were imaged at 7 T before and at 1, 4 and 6 weeks after FA or vehicle injection. One week after FA, T1 was significantly higher (P≤0.036) compared to control and correlated with kidney volume (R=0.90). Mice with marked T1 and volume increases 1 week after FA demonstrated severe fibrosis on histology at week 6. In conclusion, T1 mapping may provide a marker of the initiation and severity of later chronic kidney disease.
Introduction and Purpose
Chronic kidney disease is a progressive loss in kidney function over a period of months or years, which eventually requires dialysis or transplantation. It is often triggered by acute kidney injury followed by partial regeneration, but with progressive inflammation and fibrosis; this sequence provides a window of opportunity for novel therapies. Therefore non-invasive monitoring of chronic kidney disease should be critical for diagnosis, treatment planning, and novel therapy development. Here we characterized changes in the longitudinal relaxation time T1 and kidney volume using quantitative MRI and investigated whether these measurements allow an assessment of progressive kidney disease in folic acid (FA) - induced nephropathy in SCID mice.
Methods
Nephropathy was induced in 5 mice aged six weeks by one intraperitoneal dose of folic acid, while 4 control animals were injected with vehicle only. After glomerular filtration, FA crystalizes in kidney tubules, causing acute kidney injury and edema. Over the next weeks, incomplete regeneration is accompanied by progressive fibrosis and tissue atrophy, key features of human chronic kidney disease. Isoflurane-anaesthetised mice were imaged in a7 T magnet before and at 1, 4 and 6 weeks after injection. Kidney volume was calculated from multi-slice Turbo RARE images with the following parameters: TR/TE = 2741.9 ms/33 ms; rare factor 8; 5 axial 1 mm slices, 256x256 matrix, 4 averages; temporal resolution 5 min 51 s. For T1 measurement a fat-saturated IR sequence with multiple inversion times, a non-selective inversion pulse, and an EPI readout were used: TR/TE = 12000/13.5ms, FOV = 30mm x 30mm, 80x64 matrix, 1 average, 1 segment; single 2 mm axial slice; TI 26ms; 17 TI values at increment 400ms; temporal resolution of 3 min 24 s. After the final scan, fibrosis on histology was assessed with periodic acid Schiff staining. Results
Control kidney volumes increased significantly (P≤0.018) in 6 weeks after injection compared with week 0, reflecting normal growth (Fig. a). One week after FA administration, T1 values were significantly higher (P≤0.036) in FA versus the control group (Fig. b). Furthermore, at this time, T1 positively correlated with kidney volume (R=0.90) in the FA group. At 1 week after FA administration, both T1 and volume increased in 2 mice. Notably, at post mortem histology these mice showed fibrosis. Overall, no significant T1 and kidney volume changes were found after 4 or 6 weeks in the FA group. However, in the 2 mice MRI detected marked atrophy of one kidney at 4 & 6 weeks, and this, together with severe fibrosis, were confirmed on histology (Fig. c, d).
Discussion and Conclusion
Alterations of T1 of renal tissue may reflect acute edema due to capillary leakage and cell swelling as well as chronic renal pathology such as fibrosis (1, 2). MRI T1 mapping may provide a marker of the initiation of chronic kidney disease and predict severity of later disease. When chronic disease is established, volume loss detected by MRI corresponds with tissue atrophy and fibrosis.
Acknowledgements
The authors thank Karen Davies, Bettina Wilm and Trish Murray for the help with the study.
References
1. De Miguel MH et al 1994; J Am Soc Nephrol 4:1861–1868
2. Hueper K et al, Eur Radiol. 2014; 24:2252–2260.