The goal of this proposal is to develop an effective magnetic resonance (MR) probe for noninvasive, molecular imaging of renal fibrosis. Renal fibrosis is a hallmark of all chronic kidney diseases (CKD). It is estimated that 500 million peopl worldwide are currently suffering from CKD and many of these patients will progress to end- stage renal disease (ESRD), a devastating disorder that requires dialysis or kidney transplantation. The incidence of ESRD has doubled over the last 25 years in the United States, and in fact, treatment of CKD and ESRD accounted for 27% ($60 billion) of Medicare expenses in 2005. Clinical studies have demonstrated a strong correlation between ESRD and the extent of renal fibrosis. Quantification of renal fibrosis should predict long-term outcome of renal function in CKD patients and could also be used to monitor response to new anti- fibrotic therapies. Currently, biopsy is the gold standard for diagnosing renal fibrosis. However, biopsy is not suitable for monitoring disease progression in CKD patients as it is invasive and subject to sampling error. Therefore, there is a major unmet medical need to develop noninvasive strategies to detect and monitor progression of renal fibrosis. This proposal is in response to RFA-DK-13-026, Novel Methods for Detection and Measurement of Organ Fibrosis in Kidney, Bone Marrow, and Urological Diseases. In particular it responds to the specific need for Novel minimally invasive imaging methods for the detection and measurement of organ fibrosis and to detect changes in fibrosis that quantify progression, stabilization, and/or regression over time and to Correlate fibrotic status with organ dysfunction, recovery, and/or regression Renal function progressively declines in response to the excessive accumulation of extracellular matrix proteins. Myofibroblasts secrete collagens, as well as the enzyme lysyl oxidase (LOX) which crosslinks the collagen fibrils. Recently, we have developed a prototype small molecule magnetic resonance (MR) probe, termed Gd-Hyd, with specificity to cross-linked collagen. In preliminary data we have demonstrated that Gd- Hyd can accurately detect renal, liver and pulmonary fibrosis in small animal models. Since LOX-mediated crosslinking of collagen is an aspect of active disease, our hypothesis is that molecular imaging of LOX-mediated collagen crosslinking accurately reflects renal fibrogenesis and thus can be used to detect renal fibrosis and monitor disease progression and response to therapy. The importance of these studies cannot be overstated as CKD is a major worldwide health problem. The accomplishment of our Specific Aims would lead to a new methodology for identifying fibrotic patients at high- risk for disease progression and poor survival and also for monitoring response to anti-fibrotic therapies.

Public Health Relevance

Renal fibrosis is the final common pathway for virtually all chronic kidney diseases and is often a precursor to end-stage renal disease (ESRD), a devastating disorder that requires dialysis or kidney transplantation. The goal of this project is o develop a new magnetic resonance imaging (MRI) probe to noninvasively detect and quantify renal fibrosis, as well as monitor whether new therapies for renal fibrosis are effective.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01DK104302-04S1
Application #
9562731
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Roy, Cindy
Project Start
2017-07-01
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Zhu, Bo; Wei, Lan; Rotile, Nicholas et al. (2017) Combined magnetic resonance elastography and collagen molecular magnetic resonance imaging accurately stage liver fibrosis in a rat model. Hepatology 65:1015-1025
Waghorn, Philip A; Oliveira, Bruno L; Jones, Chloe M et al. (2017) High sensitivity HPLC method for determination of the allysine concentration in tissue by use of a naphthol derivative. J Chromatogr B Analyt Technol Biomed Life Sci 1064:7-13
Waghorn, Philip A; Jones, Chloe M; Rotile, Nicholas J et al. (2017) Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe. Angew Chem Int Ed Engl 56:9825-9828