Noninvasive assessment of renal fibrosis in kidney transplant recipients bymulti-contrast magnetic resonance imaging

Project Summary Kidney transplantation is considered the treatment of choice for patients with end-stage renal disease. While short-term kidney transplant outcomes are excellent, late renal allograft loss remains an important clinical problem. The most common cause of kidney graft failure after the first year is chronic allograft dysfunction, which is characterized by a progressive loss of graft function with development of interstitial fibrosis and tubular atrophy. Moderate to severe forms of interstitial fibrosis are found in 66% of patients at 5 years after transplantation, increasing to 90% at 10 years. Although kidney biopsy remains the gold standard to detect and quantify renal fibrosis, it is an invasive procedure, and thus not suitable for routine monitoring of kidney graft health. This research proposal aims to address the clinical need for noninvasive biomarkers of renal allograft fibrosis by (i) providing a new magnetic resonance imaging sequence (MT-DWI) that combines diffusion measurements (DWI) with magnetization transfer (MT) contrast to sensitize the DWI signal to the elevated macromolecular content in fibrotic kidney transplant, and (ii) applying intravoxel incoherent motion (IVIM) analysis to concurrently assess the vascular/tubular flow and microstructural integrity. The overarching goal of this proposal is to improve the sensitivity and specificity of MRI to interstitial fibrosis. Implementing this novel MRI method for applications in kidney transplant recipients will require expertise in DWI and MTI methodology, MR pulse sequence programming, renal physiology, and clinical research design and conduct. Following a comprehensive training in these areas, three specific aims will be pursued: Under Aim 1, I will develop an MT-DWI pulse sequence for 3-Tesla MRI scanners and establish a clinically feasible acquisition protocol. Under Aim 2, I will assess repeatability and robustness of the proposed method in 10 renal allograft recipients. Under Aim 3, I will evaluate the potential clinical value of MT-DWI for detecting renal fibrosis in 72 kidney transplant patients referred for renal allograft biopsy. I hypothesize that the proposed technique will correlate better with the severity of interstitial fibrosis and will have higher sensitivity and specificity to renal fibrosis than eGFR and conventional DWI. The Pathway to Independence Award will be supported by excellent resources at Kennedy Krieger Institute and Johns Hopkins University, and training from a mentoring team of globally recognized leaders in the fields of MRI, renal physiology, and clinical and translational kidney research. The immediate impact of my research proposal will be a new way to non-invasively detect and assess the severity of fibrosis in renal transplant patients, potentially allowing for longitudinal monitoring and treatment evaluation.