title: Innovative Multispectral Optoacoustic Tomography Strategies for Evaluating Different Aspects of Renal Function
Creators: name: Littlewood, James
Publisher: name: University of Liverpool Repository
Year: 2022

description: Kidney disease carries significant morbidity, mortality, and cost while its prevalence is rising. Preclinical work utilising different kidney injury models to evaluate novel therapies is a valuable step in the transition of treatments from lab to clinic. An accurate measurement of kidney function is important in this setting to make appropriate conclusions about the efficacy of a therapy. Measuring kidney function by dynamic contrast enhanced (DCE) imaging offers the distinct benefit of separately measuring left and right kidney function which can differ even in health. Additionally, measuring both kidneys in a unilateral injury model offers the advantage of an internal control. This thesis aims to assess whether near-infrared (NIR) dyes and their clearance in multispectral optoacoustic tomography (MSOT) can be used to measure the renal excretory functions of glomerular filtration and tubular secretion in health and a surgical model of ischaemia reperfusion injury (IRI). The dyes ABZWCY-HPβCD (glomerular filtration marker) and STAR FLUOR 770 Acid (potential tubular secretion marker) are examined for this purpose. We explore the best metrics of quantifying renal injury in DCE MSOT and whether the application of mathematical models could allow the measurement glomerular filtration rate (GFR) or tubular secretion rate (TSR) in a single kidney. Finally, the MSOT clearance kinetics of these dyes are compared to more standard measures of renal health: sinistrin clearance, histology, and dimercaptosuccinic acid (DMSA) uptake. ABZWCY-HPβCD, STAR FLUOR 770 Acid, and the renal clearance of the two dyes can be detected by MSOT in C57BL/6 albino mice. However, light fluence impairs the accurate absolute quantification of these dyes at the depth of the aorta. ABZWCY-HPβCD shows significantly different MSOT renal kinetics from the current standard MSOT renal contrast agent, IRDye 800CW. In combination with a modified Patlak-Rutland model, ABZWCY-HPβCD can be used to calculate a single kidney GFR. This method showed a greater correlation with GFR measured by sinistrin clearance than MSOT model-free measures. STAR FLUOR 770 Acid has shown significant protein binding and evidence of biliary clearance both in MSOT and fluorescence imaging. However, it is partially cleared by the kidneys and spectrally unchanged following this. DCE MSOT measured STAR FLUOR 770 Acid clearance does not correlate with split renal function measured by the tubular uptake of DMSA. STAR FLUOR 770 Acid clearance shows recovery 3 weeks after IRI, while DMSA uptake and histology show ongoing tubular injury. The results indicate that DCE MSOT is a fast, safe, flexible, and approachable imaging modality for evaluating different renal excretory functions. Further, the NIR dye ABZWCY-HPβCD appears suitable for measuring single kidney GFR in MSOT. STAR FLUOR 770 Acid requires further assessment as a tubular secretion marker. Improvements and validation of fluence correction algorithms will facilitate absolute quantification in MSOT that will further its ability to determine renal clearance rates.