Beyond Kidney Volume: 3D Mapping of Parenchymal, Cortical and Medullary Thickness with Disease, Anthropometry and Kidney Adiposity

Introduction Kidney volume is associated with renal function, but conventional whole-organ measurements may miss regional changes in kidney substructures. We used magnetic resonance imaging (MRI) to test whether kidney substructure volumes and three-dimensional (3D) thickness phenotypes are associated with disease, adiposity, and incident outcomes. Methods Automated abdominal MRI segmentations from 70,270 UK Biobank participants were used to quantify left and right kidney cortex, medulla, and parenchyma volumes and mesh-based thickness maps. Mass univariate regression generated statistical parametric maps linking regional thickness to anthropometric traits and disease (CKD, type-2 diabetes [T2D], hypertension). Bidirectional causal mediation analyses were performed using kidney substructure volumetric, thickness PCs and kidney adiposity. Longitudinal changes were assessed in 2,610 participants with repeat imaging. Cox proportional hazards models tested the associations between kidney volumes and principal component (PC) scores of thickness and incident CKD, T2D, hypertension, cardiovascular disease (CVD), and mortality. Results CKD was associated with thinning of the parenchyma and most pronounced in the medulla (87.7% left, 72.8% right), whereas associations in the cortex were mixed. In contrast, T2D and hypertension were predominantly associated with increased thickness, most extensively in the cortex (T2D: 84.39% left, 96.35% right; hypertension: 94.8% left, 99.9% right). Age-disease interactions were associated with reduced thickness across all conditions. Smaller medulla volume and lower cortical thickness mediated the association between CKD and renal sinus fat. Kidney substructure volume was inversely associated with incident CKD across all substructures and both kidney sides (p<0.05), but positively associated with incident hypertension and mortality (p<0.05). Thickness PC scores also predicted outcomes independently of volume, with PC3 in the left cortex (HR 0.91 [0.84– 0.98]), reflecting inferior pole/hilar thickness, associated with incident CKD. Conclusions MRI-derived kidney substructure volumes and 3D thickness maps provide complementary, spatially-resolved markers of kidney morphology, that are mechanistically linked to renal adiposity and future disease risk. Translational Statement / Lay Summary This study used MRI scans from the UK Biobank to examine kidney structure in much greater detail than is possible with standard measurements of kidney size or volume. Instead of treating the kidney as a single organ, we measured tissue thickness at thousands of locations across its three main layers: the cortex (outer layer), medulla (inner layer), and parenchyma (the main functional tissue). Thinning of these regions can indicate tissue loss, while thickening may reflect swelling or other structural changes. We found that ageing, body composition, fat around and within the kidney, and conditions such as chronic kidney disease, type 2 diabetes, and hypertension were each associated with distinct patterns of structural change thickening across different parts of the kidney. These detailed 3D thickness maps reveal changes that are not captured by simple measurements of kidney size and could help identify early signs of kidney disease before more obvious damage occurs