Renal Molecular Imaging of Mesangial Cell Function with Tc-99m-Tilmanocept

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In 2017 the International Diabetes Federation estimated that the worldwide prevalence of diabetes would increase from 415 million in 2015 to 642 million in 2040. Approximately 40% of individuals with diabetes develop diabetic nephropathy (DN). Twenty percent of these individuals do not follow the typical path toward chronic kidney disease, which is a slow multi-decade increase in albuminuria and serum creatinine, the current standard-of-care for surveillance of chronic kidney disease (KD). Consequently, there is an unmet clinical need for routine surveillance during the first decade of chronic KD. We propose external imaging of mesangial cell function as a biomarker for diabetic nephropathy. Our reasoning is based on the following. Mesangial cell matrix (MCM) expansion is a histologic hallmark of diabetic nephropathy, which precedes the reduction of a patient’s glomerular filtration rate or increase in albuminuria. Additionally, all the clinical manifestations of diabetic nephropathy are highly correlated with MCM expansion. There currently does not exist an imaging, serum, or urine biomarker that is sensitive to mesangial cell function. Current imaging agents and biomarkers are only sensitive to glomerular filtration, effective renal plasma flow, or albuminuria, which are altered late in the disease when therapeutic intervention is not effective. We propose a Phase 1 clinical trial of Tc-99m-tilmanocept, which accumulates in the liver and kidneys. The molecular mechanism is binding to CD206, which resides on the cell surface of fixed macrophages within the liver and mesangial cells within the kidney. We present preliminary data consisting of human SPECT/CT and rat microPET images of renal cortex. Additionally, we present evidence of sensitivity to MCM expansion via Tc- 99m-tilmanocept dynamic imaging of db/db mice, an accepted disease model of diabetic nephropathy. We propose an open-label study to investigate the biodistribution at two dose levels (2.0 & 20 nmol) of Tc- 99m-tilmanocept. We will study 5 groups at each dose (10 subjects each): 1) Advance DN, 2) early DN, 3) diabetes with no kidney disease, 4) advanced hypertension (HTN) with KD, and 5) HTN without KD. The study will include a 30-min dynamic followed be a 30-min kidney SPECT/CT, and periodic blood and urine sampling. Dynamic imaging will yield plasma clearance half-lifes, and liver and kidney accumulation rates; SPECT/CT will yield SUVs for the heart, liver, renal cortex, renal medulla. We will also calculate urinary bladder accumulation. We expect the renograms and biodistribution data to reflect the following pathology: Group 1, severe MCM expansion; G2, mild MCM expansion; G3 & G5, no MCM expansion; and G4, low MCM expansion. This study is the necessary first step toward FDA-approval of Tc-99m-tilmancoept as a kidney imaging agent. The study will also provide evidence of imaging sensitivity to MCM expansion in DN patients, and insensitivity to patients with HTN. This senerio will be required if Tc-99m-tilmanocept renograms as “first-line” diagnostic test for diabetic patients.