Kidney time-activity curves of 99mTc-tilmanocept are altered in diabetic mice

414 Objectives: An unmet need is a predictive measurement of diabetic nephropathy during the first decade of the disease, when there is silent loss of kidney function and glomerular filtration rate (GFR) measurements are insensitive. Tc-99m-tilmanocept binds to CD206 within lymph node macrophages and intra-glomerular mesangial cells within the kidney, and is currently FDA and EMA approved for sentinel lymph node mapping. Earlier studies of Ga-68-fluorescent-tilmanocept in rats demonstrated receptor-mediated binding in the renal cortex and co-localization with glomerular CD206. Prior to optimizing tilmanocept for molecular imaging of the renal cortex, we designed this study to test the sensitivity of Tc-99m-tilmanocept renal time-activity curves to chronic kidney disease. The db/db mouse is a widely accepted model of diabetic nephropathy, where the histologic hallmark is expansion of the mesangial cell matrix, a process that precedes GFR-reduction. Methods: Molecular imaging (ventral view) of diabetic db/db mice (age: 4.9 wk, n=6; 7.3 wk, n=4; 13.3 wk, n=6) and non-diabetic db/m mice (4.1 wk, n=6) was performed with Tc-99m-tilmanocept (18.5 MBq, 2.6 nmol). Thirty minutes after injection, blood, liver, kidneys, and urine were assayed for radioactivity and weight. Left kidney time-activity curves were generated. Results: The db/db mice displayed multi-phasic (1 uptake mode and 1 clearance mode) renal time-activity curves with high urinary bladder accumulation; the non-diabetic mice exhibited a renal curve dominated by a single uptake mode with low bladder accumulation. The renal %ID/g (both kidneys 80.4 ± 8.3 %/g) of by non-diabetic db/m mice far exceeded the renal accumulation (both kidneys) of the diabetic db/db mice at all three ages (4.9 wk =31.5± 5.8 %/g, 7.3 wk=34.3 ± 5.7 %/g, 13.3 wk=23.0 ± 4.3 %/g). The average time at which the non-diabetic db/m renal curves peaked (22.4 ± 3.7 min) was significantly (P < 0.005) longer than the average time-to-peak value of the curves from the 4.9 week-old db/db diabetic mice (2.64 ± 1.58 min), the 7.3 wk db/db mice (1.67 ± 0.24 min), and the curves from the 13.3 wk db/db mice (2.02 ± 0.65 min). Conclusions: This study demonstrated kinetic sensitivity of tilmanocept time-activity curves to chronic kidney disease. Given the early role of mesangial cells during the progression of diabetic nephropathy, SPECT renal imaging of Tc-99m-tilmanocept may provide a non-invasive quantitative assessment of renal function and an early predictive tool to manage patients with diabetes.