Quantitative magnetization transfer MRI for evaluation of renal fibrosis

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Renal fibrosis is a final pathway and important biomarker of injury common to most forms of kidney disease. For example, in renal vascular disease (RVD) progressive renal fibrosis may induce kidney injury and hypertension. Early identification of fibrosis and adequate intervention may slow down renal disease progression, but adequate noninvasive strategies to detect and quantify renal fibrosis are yet to be identified. Magnetization transfer imaging (MTI) magnetic resonance imaging (MRI) is a novel noninvasive method to evaluate the tissue macromolecular composition. We have demonstrated that MTI can assess stenotic kidney fibrosis in murine and swine models of unilateral RVD. However, the clinical utility of MT-MRI to assess renal fibrosis is currently limited, because it is inherently semi-quantitative. In contrast, quantitative MT (qMT), based on biophysical compartment models, provides more objective measurement of tissue MT properties. A model fitting of MR signal acquired with various MT pulse amplitudes and offset frequencies, combined with scan- specific B0/B1/T1 maps, give rise to a more complete definition of tissue parameters, including a “bound pool fraction”, a direct measure of the macromolecular content in tissue. The hypothesis underlying this proposal is that qMT would reliably detect development of renal fibrosis at both 1.5T and 3.0T in subjects with RVD. To test this hypothesis, which is supported by strong preliminary data, we will initially develop, optimize, and validate qMT for evaluation of fibrosis in the post-stenotic swine kidney. We will correlate qMT-derived renal fibrosis with reference standards, as well as with single-kidney hemodynamics, function, and oxygenation, quantified using cutting-edge multi-detector CT (MDCT) and MRI techniques. We will then determine the ability of qMT to predict renal recovery in pigs with RVD undergoing revascularization. Further, we will perform a pilot study to test the ability of qMT to quantify fibrosis in the post- stenotic human kidney, in comparison to innovative biomarkers of renal dysfunction and tissue damage. Three specific aims will test the hypotheses: Specific Aim 1: qMT in stenotic swine kidneys is feasible, reliable, and reproducible at 1.5 and 3.0 T. Specific Aim 2: qMT predicts renal recovery potential in response to PTRA. Specific Aim 3: qMT in stenotic human kidneys is feasible, reproducible, and predicts recovery. The proposed studies may therefore establish a reliable, noninvasive, and clinically feasible strategy to quantify kidney fibrosis, a key biomarker for renal outcomes and therapeutic success.