Angiogenesis: A Profibrotic Factor in Kidney Disease Progression?

Background: Peritubular capillary (PTC) rarefaction has long been considered a key factor in the development of tubulo-interstitial fibrosis (TIF) and chronic kidney disease (CKD) progression. Conversely, recent studies have identified various novel biomarkers that indicate activated angiogenesis in patients with CKD. We hypothesize that upregulated angiogenesis contributes to TIF and CKD progression by influencing the immune response. Methods: To test our hypothesis, we conducted morphometric analyses on three-dimensional (3D) images of human kidney biopsies (Figure A) acquired from participants of the Kidney Precision Medicine Project (KPMP). Vessel-Express, a 3D dataset analysis software, was employed to segment vessels and fibrillar collagen within the images (Figure B/C) to quantify PTC metrics and assess their relationships with the degree of TIF. Volumetric Tissue Exploration and Analysis, an Image J plugin for tissue cytometry was used to assess spatial relationships between vascular endothelial cells, immune cells and the extracellular matrix. Results: Comparing KPMP participants with diabetic kidney disease (DKD) to healthy control subjects, we observed that PTC volume density, branch point density and collagen volume density were greater with DKD (Figure E/F/G). PTC and collagen volume densities exhibited a positive linear correlation in DKD (Figure I), indicating more collagen deposition with increased angiogenic activity. In addition, our spatial analysis in healthy subjects revealed that CD31+ endothelial cells, branch points and CD45+ immune cells were distributed evenly throughout the interstitial space. In contrast, vascular endothelial cell, branch point and immune cell densities were significantly higher closer to areas of collagen deposition in DKD (Figure J/K/L). Conclusion: This increase in PTC density in DKD patients with higher degrees of TIF and the greater density of vascular endothelial cells closer to regions of collagen deposition within the interstitial space, challenges current paradigms implicating PTC rarefaction in CKD. Funding: NIDDK Support