Investigating Metabolic Reprogramming in Polycystic Kidney Disease Using Hyperpolarized 13C Metabolic Imaging
Abstract
This proposal addresses the FY21 PRMRP Topic Area of polycystic kidney disease (PKD). The overall goal of this project is to develop a novel imaging method for detecting and classifying inherited polycystic kidney disease (ADPKD). This form of kidney disease affects approximately 1 in 2500 to 1 in 1000 men and women of all races and ethnicities worldwide. In ADPKD, cysts, i.e., sacs filled with fluid, growing on the kidneys cause pain, reduced kidney function, and high blood pressure among other complications. There is no cure for ADPKD, and the so far only approved drug only slows down the cyst growth. In many patients, the disease will progress to end-stage kidney disease, when kidney function becomes so low that patients will have to go on dialysis or receive a kidney transplant to survive. Therefore, therapies that will completely stop or prevent renal cyst formation are still an unmet clinical need. It is increasingly recognized that metabolic disturbances underlie the pathogenesis of ADPKD. Specifically, polycystic kidneys might rely on carbohydrates as energy source more than on oxygen. Therapies that are known to affect carbohydrate metabolism, in particular energy metabolism of kidney cells, have shown some early promising results. However, a current limitation of the methods investigating metabolic processes in ADPKD is that they do not measure metabolism in the normal microenvironment of the cells as they rely on in vitro assays, i.e., measurements of isolated cells. Therefore, we propose to develop a novel, noninvasive method to investigate kidney metabolism to specifically address the abnormalities present in ADPKD. This method uses a form of magnetic resonance imaging (MRI). Regular MRI scans show the anatomy inside the body; it has long been used to image tumors but cannot classify their biochemical type. We want to use a new type of MRI imaging in which we use so-called hyperpolarized chemical compounds to detect and precisely quantify active biochemical processes in the body. Hyperpolarization transiently boosts the MRI signal of the hyperpolarized compound by factors of tens to hundreds of thousands, but does not use or produce ionizing radiation and is non-toxic. These hyperpolarized substances are biological molecules that occur in the body naturally. We will use pyruvate as the hyperpolarized compound as it plays an important role in cellular energy metabolism and is already used in clinical research, e.g., cancer, heart disease, and traumatic brain injury. Hyperpolarization lasts only a few minutes, after which the substance returns to its normal (non-hyperpolarized) state. We will apply this method in a mouse model of ADPKD that closely resembles the human disease. Specifically, we will first develop an optimized acquisition method that allows robust assessment of pyruvate metabolism of the kidney during the short time the hyperpolarization lasts. Then we will perform a longitudinal study to investigate whether the metabolic defects are a primary cause of the cysts rather than the non-specific consequence of end-stage kidney disease. While the specific application is focused on pyruvate metabolism, other metabolic changes can be investigated using a different hyperpolarized compound that is involved in the respective metabolic pathway. For example, vitamin C, glutamine, or arginine are all compounds that are implicated in metabolic processes altered in PKD, and all have already been hyperpolarized. Therefore, hyperpolarized metabolic imaging, as both a preclinical and clinical tool, could augment the understanding of the metabolic basis of ADPKD, aid in identifying therapeutic targets and drugs, and assist in identifying and monitoring patients at higher risk for progressing to end-stage renal disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210014
Entities
People
- Dirk Mayer
Organizations
- United States Army
- University of Maryland, Baltimore