Abstract P126: The Single-cell And Spatial Transcriptional Landscape Of Advanced Diabetic And Hypertensive Kidney Disease In Humans

Diabetes and hypertension, the two most common causes of chronic kidney disease (CKD), can both lead to renal inflammation and fibrosis through a complex interplay among multiple cell types. However, the similarities and differences between the two pathogenic mechanisms remain understudied, including the involvement of cell organization and related biological processes. We generated an integrative cell landscape of CKD using single-nucleus gene expression and spatial transcriptome profiling in kidney samples from three patients with advanced diabetic nephropathy (ADN), three patients with advanced hypertensive nephropathy (AHN), and two normal controls. We obtained a total of 56,131 nuclei and 3,992 spatial spots to investigate the cell composition and the context of spatial niches. Significant hallmark changes were observed in both types of CKD, including the presence of an average of 60% (SD 12%) proximal tubule cells showing injured status, fibroblasts activation, mitochondria dysfunction, and a 2.9-fold increased inflammatory immune cell infiltration such as activated T cells and macrophages. Some alterations were more pronounced in AHN, such as a notable podocyte loss, which averaged 89% in AHN versus 66% in ADN, mesangial cell activation by increased collagen production, and a 34% higher proportion of natural killer T cells. Among the predominant cell communication, integrin coding gene ITGB8 was up-regulated in diseased thick ascending limbs (combined p.adj=2.3e-139) and injured proximal tubules (combined p.adj=4.4e-92), which acts as the receptor for collagen and laminin that may play a central role in extracellular matrix remodeling surrounding tubular cells. Additionally, the SPP1-CD44 axis established a broad connection between various tubular cells and pan-immune cells, potentially leading to the wide range of inflammatory responses. The co-localization pattern of this interaction was further supported by contextual evidence derived from spatial niches. Our findings provide a cell landscape of advanced diabetic and hypertensive CKD in humans, shedding light on the cellular and molecular basis of these diseases.