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

Fibrosis begins early in autosomal dominant polycystic kidney disease (ADPKD) and drives its progression. Collagen deposition has been observed to increase around cysts in human ADPKD kidneys and livers. Currently, no clinical methods are available to detect early fibrosis before irreversible structural and functional decline. Here, we report fibrosis imaging using Gd-hProCA32.Collagen, a collagen-targeting protein MRI contrast agent for precision molecular MRI (pMRI). Gd-hProCA32.Collagen binds collagen type I with micromolar affinity, exhibiting higher relaxivity than clinical agents at 1.4 T, blood clearance within 72 hours, and no evident acute toxicity. To assess the ability of Gd-hProCA32.Collagen to detect ADPKD-related fibrosis, renal collagen deposition was increased by 11 weeks of age in Pkhd1PCK/PCK (PCK) rats. At 26 weeks, Gd-hProCA32.Collagen, given at a 10-fold lower dose than gadobutrol, produced sustained kidney and liver enhancement through 48 hours, whereas enhancement washed out in wild-type organs and with a non-targeted control protein. Gd-hProCA32.Collagen also increased the number of detected renal cysts per animal by 25% compared with 3% for gadobutrol (P < 0.0001), mainly small and medium cysts outlined by pericystic collagen, and revealed striation-like enhancement at microcyst clusters. Regional enhancement correlated with histological collagen (r = 0.72), whereas gadobutrol enhancement did not (r = 0.21). Kidney and liver enhancement was also observed in a Pkd2 mutant mouse model. These findings reveal a previously inaccessible subclinical fibrotic phase of polycystic kidney and liver disease and support collagen-targeted pMRI for noninvasive detection and mapping of fibrosis when conventional biomarkers remain uninformative.