Developing imaging nanoprobes to advance prognosis of kidney fibrosis

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Project Summary Chronic kidney disease (CKD) has a high global prevalence, estimated at 11-13%, and it is ranked third highest for years of life lost due to premature mortality. Interstitial fibrosis is a chronic and progressive process affecting kidneys during CKD progression, regardless of cause. It can disrupt kidney architecture, reduce blood supply, disturb renal function, and ultimately cause kidney failure. Histologically, the degree of kidney interstitial fibrosis correlates with the severity of CKD. Hence, assessment of kidney fibrosis can facilitate prognosis and guide therapy in CKD progression. Currently, biopsy remains the gold standard for assessing kidney fibrosis, but complications and limitations exist. Hence, novel noninvasive imaging probes or methods are in high demand for the evaluation and follow-up of patients with CKD. Recently, we and others have shown that macrophages play a key role in the progression of kidney fibrosis. Macrophage accumulation significantly correlates with the degree of the extent of interstitial fibrosis and tubular atrophy in the mouse models of CKD and in human kidney diseases and chronic allograft injury. Therefore, developing novel imaging probes to noninvasively assess kidney interstitial profibrotic macrophages will help diagnose and quantify kidney fibrosis, and thus be useful to prognosticate CKD progression. This proposal presents a potential shift in current approaches to develop a novel molecular imaging probe that specifically target profibrotic macrophages in the kidneys to sensitively and specifically report renal fibrosis in the course of CKD progression. Nanoparticles have become increasingly attractive as a candidate tool to serve as effective diagnostic agents to reduce undesirable systemic side effects and overcome several physical and physiological barriers following systemic administration. Among these, dendrimers have become one of the most versatile compositionally and structurally controlled nanoscale building blocks for use as contrast agents in the field of biomedical imaging. To test this hypothesis, we propose to first engineer dendrimer nanoprobes that specifically target profibrotic macrophages (Aim 1) and then to assess dendrimer nanoprobe efficacy for diagnosis and quantification of kidney fibrosis in the mouse models of CKD (Aim 2). This application will provide us the opportunity to develop innovative nanoprobes that can be tested preclinically to non-invasively report kidney fibrosis.