PET Imaging of Renal Fibrosis

Project Summary Chronic kidney disease (CKD) is the most under-recognized public health issue in the US affecting more than 35 million adults and it is projected that 47% of 30-year-olds will develop CKD in their lifetime. CKD is also one of the strongest risk factors for cardiovascular disease. Treatments to slow progression are limited and clinical trials to develop new therapies lag many other fields, partly due to limitations of existing clinical endpoints. Progression to end-stage kidney disease (ESKD) may take decades making trials expensive and slow, while biomarkers like serum creatinine lack sensitivity and predictive value. ESKD requires kidney replacement therapy either by transplantation or dialysis. Kidney biopsy is the only diagnostic tool to differentiate active and potentially reversible tissue pathology from chronic irreversible one, and is also used for surveillance in transplant patients to rule out allograft dysfunction. Renal fibrosis is the final common pathway in nearly all CKD cases, and presence of fibrosis predicts progression to kidney replacement therapy. The presence of interstitial fibrosis in transplant predicts chronic allograft nephropathy and can be prevented if detected early. However kidney biopsy is invasive, carries risk, and is prone to sampling error because only a small fraction of the kidney is sampled. There is an urgent unmet need to non-invasively quantify renal fibrosis throughout the entire kidney tool to evaluate donor tissue, to predict clinical outcomes in transplantation and high-risk CKD patients, and to monitor response to novel therapeutics. Allysine is post translational amino acid formed on collagens by the action of lysyl oxidase enzymes that are upregulated during fibrogenesis to crosslink newly formed collagen matrix. Recently, we reported allysine- targeted magnetic resonance probes that could noninvasively detect and stage renal fibrogenesis in mouse models of nephrotoxic nephritis, Alport syndrome, and renal ischemia-reperfusion injury. To accelerate clinical translation of this technology, we adapted the probes for positron emission tomography (PET) imaging since PET probes require only small amounts of material and an abbreviated safety/toxicology program compared to MR probes. Also, unlike MRI which requires a scan before injecting the probe and another scan afterwards, PET only requires a single scan. The overall goal of this project is to develop an optimized allysine-targeted PET probe and validate it in animal models and with human renal biopsy samples. We will perform additional IND- enabling studies such as radiation dosimetry estimation in nonhuman primates, GLP toxicology, and develop a GMP manufacturing process. Success in this project will have us poised for subsequent human clinical trials.