Unmasking Early Renal Fibrosis in Polycystic Kidney Disease Using Noninvasive Precision Molecular MRI of Collagen

<jats:p> Fibrotic remodeling of extracellular matrix is a central driver of autosomal dominant polycystic kidney disease (ADPKD) progression since early stages of the disease. Unfortunately, it cannot be assessed with currently available methodologies before irreversible structural and functional decline, creating a diagnostic blind spot that hinders accurate early risk stratification and management. Here, we report the development of Gd-hProCA32. Collagen, a collagen-targeted protein MRI contrast agent that enables precision molecular MRI (pMRI) of early fibrosis by directly imaging collagen type I deposition <jats:italic>in vivo</jats:italic> before conventional laboratory and imaging methods detect changes in kidneys and liver of <jats:italic>Pkhd1</jats:italic> <jats:sup>PCK/PCK</jats:sup> (PCK) rats and <jats:italic>Pkd2</jats:italic> mutant mice. Gd-hProCA32. Collagen, used at 10-fold lower dose, outperformed the widely clinically used agent gadobutrol (Gadovist), detecting approximately 2.8-fold greater total renal cyst volume (~8,500 vs ~3,000 mm <jats:sup>3</jats:sup> , p&lt;0.0001) and 1.5-fold higher total cyst count (~245 vs ~160, p&lt;0.0001), with superior T1W and T2W kidney AUC (p&lt;0.01 and p&lt;0.001) and preferential sensitivity to small and medium cysts. Signal enhancement in kidneys and liver correlated strongly with histological collagen burden quantified by Sirius red staining, whereas Gadovist showed no meaningful correlation. Gd-hProCA32. Collagen also enabled <jats:italic>in vivo</jats:italic> visualization of previously undetectable changes resembling radial striations at sites of microcyst cluster-adjacent microfibrosis and sustained delayed MRI enhancement due to specific collagen binding. These results reveal a previously inaccessible subclinical fibrotic phase of cystic kidney and liver disease and establish collagen-targeted pMRI as a strategy for early noninvasive detection and spatial mapping of multi-organ extracellular matrix remodeling when conventional biomarkers remain non-discriminating. </jats:p>