Kevin M. Bennett, Ph.D. - US grants

DESCRIPTION (provided by applicant): The broad, long-term goal of this work is to measure kidney nephron and glomerular volume endowment in humans, in vivo. Each nephron contains a glomerulus, which functions as a high-pressure filter of blood macromolecules. Deficits in nephrons and glomeruli have been correlated with renal diseases such as diabetes, obesity, and hypertension. There is currently no noninvasive technique to count the total number of functioning renal glomeruli and nephrons in vivo. Such a technique would enable studies of kidney and systemic disease in humans, and would open a new area of animal studies of the susceptibility to renal disease. We propose that contrast-enhanced MRI, using MRI-detectable nanoparticles targeted to the glomerular basement membrane, can be used to accurately count the total number of glomeruli and measure glomerular volume in the whole, intact kidney. This proposal is focused on establishing this technique in mice. We further propose to assess the accuracy of the technique in the presence of systemic deficits in nephron endowment in mice. Once completed, the proposed work will open the possibility of real-time, in vivo glomerular counts and volume in studies of renal and systemic diseases in animals and humans.

PROJECT SUMMARY/ABSTRACT The broad, long-term goal of this multi-disciplinary collaborative of biomedical engineers and physician- scientists is to develop a framework to rapidly and accurately assess the quality of kidneys donated for transplant. Current methods to assess the quality of a donated kidney are derived from population-based surrogates and the limited functional measurements of the individual kidney are only moderately predictive of long-term survival. Additionally, there are no direct, noninvasive clinical measurements of the vasculature or tubulointerstitial compartments. This proposal focuses on the use of novel, noninvasive, MRI-based biomarkers to evaluate human kidneys to individualize and improve the assessment of allograft quality while remaining within the current standards of clinical practice. This work has three Specific Aims: 1) Noninvasively compare MRI-based biomarkers of the glomeruli in human kidneys to metrics currently used in clinical practice (KDPI score and renal resistance by machine perfusion), 2) Noninvasively compare MRI-based biomarkers of microvascular structure in human kidneys to metrics currently used in clinical practice and 3) Develop noninvasive MRI biomarkers of microstructural tubulointerstitial damage that can discriminate reversible from irreversible damage. We will synthesize these aims into a comprehensive view of the renal allograft. The long term goal of this work will be a software platform that integrates all available data (both MRI-based and clinical parameters) from glomerular, vascular, and tubulointerstitial compartments to provide a superior metric of allograft quality. At the conclusion of this project, we will have the first comprehensive, integrated evaluation of the microstructure of the human kidney, powerful data to inform the translation of these MRI-based biomarkers for future studies to improve longevity matching and long-term allograft survival.

Project Summary/Abstract The broad, long-term goal of this multi-disciplinary collaborative of biomedical engineers and physician- scientists is to develop early, non-invasive methods to identify individuals at risk of developing chronic kidney disease (CKD). Current methods to detect kidney disease are only useful when more than half of the filtering units of the kidney, nephrons, are nonfunctional. Nephron number is determined at birth, declines over the lifespan of a human and is directly related to the development of chronic kidney and cardiovascular disease. Unfortunately, there are no techniques to count the total number of functioning nephrons in living individuals. Additionally, there is no way to integrate the major compartments of the kidney, such as glomerular changes to those in the vasculature or tubulointerstitial space. A diagnostic biomarker to assess renal microstructure, such as number and volume of glomeruli, could significantly benefit patients: earlier therapeutic intervention, novel endpoints for assessing renal safety in clinical trials for drug development, and for renal allografts allocation. This work has three Specific Aims: 1) We will assess the changes in the glomeruli by MRI during the development of CKD using two mouse models: a congenital reduction in nephron number and a glomerulosclerosis model of CKD. We will compare the changes in glomerular microstructure to the vascular and tubular compartments and to traditional biomarkers of renal disease. 2) We will determine the time course of tubulointerstitial pathology using MRI in mouse model representing the transition from acute kidney injury to chronic kidney disease. 3) We will determine the effect of ACE inhibition of the microstructure of the kidney in a mouse model of essential hypertension. At the conclusion of this project, we will have the first comprehensive, integrated MRI-based evaluation of the kidney, powerful data to inform the translation of these MRI-based biomarkers for future studies to predict kidney disease progression.

PROJECT SUMMARY This work is aimed to improve outcomes in patients with kidney disease through improved diagnostics. Nephron mass is a measure of the functional capacity of the kidney. Its measurement could be transformative in detecting susceptibility to and progression of kidney diseases. However, no clinical tools or assays currently exist to directly measure nephron mass. We have developed tools using a novel targeted contrast agent (RadioCF) to directly measure nephron mass using positron emission tomography (PET). This technology, RadioCF-PET, has the potential to provide a more accurate assessment of kidney health and aid clinical decisions for patient treatment. RadioCF-PET also has the potential to be used in the assessment and allocation of renal transplants. This proposal will establish the feasibility of RadioCF-PET to measure nephron mass using a human recombinant form of RadioCF (HrRadioCF) to minimize toxicity, control synthesis and demonstrate the potential of this technology for clinical use. We will measure nephron mass in mice in vivo using RadioCF-PET with human recombinant RadioCF. We will perform initial toxicity studies with HrRadioCF to establish the safety of this radiotracer in mice that will inform the safety and efficacy testing in a Phase II proposal. In Phase II, we will perform extensive toxicity studies and characterization of the agent to support an exploratory investigational new drug application. Future application of RadioCF-PET will first focus on the evaluation of donor kidneys before transplant in both live and deceased donors to monitor allograft health during transit, and then will be adapted to monitor graft function after transplantation. Transplant evaluation provides a pathway to in-patient use of this technology as a new screening tool to monitor kidney health. This technology also has the potential to monitor patients at risk for kidney disease, such as patients with diabetes, indicating a large potential market for impact.