Fibrosis is a common denominator and an important determinant of outcomes in chronic kidney disease (CKD). Extracellular matrix deposition is a specific and potentially useful biomarker to identify scarred kidneys. Magnetization transfer imaging (MTI) is a powerful noninvasive technique based on molecular magnetic resonance imaging (MRI), which is capable of detecting excessive collagen deposition. Therefore, MTI could be invaluable to assess individual kidneys, yet its potential to detect renal fibrosis has no been fully explored. Renal vascular disease (RVD), which is becoming increasingly common in the aging population of the Western world, may induce kidney ischemia and fibrosis. As a result of permanent injury, revascularization of the stenotic renal artery by percutaneous transluminal renal angioplasty (PTRA) often fails to restore kidney function and arrest progression of CKD. We have shown that failure to restore renal function after PTRA in RVD is directly linked with the extent of intra-renal injury. Alas, specific tools to detect renal fibrosis and adequately predct renal outcomes in RVD are yet to be identified and remain in dire need. We have characterized novel experimental models of RVD that closely mimic human pathophysiology and allow translational studies relevant to clinical medicine. We have also developed and refined unique imaging techniques ideally suited for probing renal adaptive processes. These tools now provide an opportunity to assess renal function and structure associated with development of fibrosis and outcomes in RVD. The working hypothesis underlying this proposal is that MTI can detect in the post-stenotic murine and swine kidneys development of fibrosis, which correlates with subsequent kidney recovery capacity. To test this hypothesis, we will study development and progression of stenotic kidney fibrosis, dysfunction, and hypoxia using cutting-edge noninvasive imaging. Furthermore, the ability of MTI-derived indices of collagen deposition to predict renal recovery will be tested in RVD pigs undergoing PTRA and stenting.
Three specific aims will be pursued:
Specific Aim 1 will test the hypothesis that MTI can detect development of kidney fibrosis in RAS mice using high-field MRI.
Specific Aim 2 will test the hypothesis that MTI can detect development of renal fibrosis using a clinical MRI in RVD pigs.
Specific Aim 3 will test the hypothesis that MTI would predict renal recovery potential in response to PTRA. Noninvasive assessment of extracellular matrix deposition using MTI is a promising, cutting edge technique, which will likely contribute significantly towards management of kidney disease. The proposed studies may have broad ramifications and establish this novel, clinically feasible diagnostic strategy for RVD and CKD.

Public Health Relevance

Adequate strategies to detect fibrosis and remodeling within the kidney in chronic kidney disease are yet to be identified and remain in dire need. Magnetization transfer imaging (MTI) is a novel non-invasive experimental strategy that can detect scar tissue, but is yet to be tested in the kidney. The proposed studies may establish this clinically feasible diagnostic strategy and will likely contribute significantly towards management of patients with chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DK104273-01
Application #
8822483
Study Section
Special Emphasis Panel (ZDK1-GRB-S (O5))
Program Officer
Flessner, Michael Francis
Project Start
2014-09-24
Project End
2019-06-30
Budget Start
2014-09-24
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$347,893
Indirect Cost
$129,092
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Eirin, Alfonso; Lerman, Amir; Lerman, Lilach O (2015) Mitochondria: a pathogenic paradigm in hypertensive renal disease. Hypertension 65:264-70