Dissecting Normal and Abnormal Human Kidney Development Using Multi-omics

ABSTRACT Congenital kidney anomalies frequently lead to development of chronic kidney disease (CKD) in children and adults, with limited possibility for accurate prognostication and successful intervention. Causal genetic variants are identified in a minority of individuals, while the biological interpretation of putative genetic variants and their impact on kidney development and CKD remains incompletely understood. Advances in single-cell and spatial multi-omics now enable a deeper biological understanding and interpretation of disease-causing mechanisms of congenital kidney anomalies, holding promise for precise diagnoses, prognostication and treatment for patients. In this review, we provide an overview of multi-omics approaches, including transcriptomics, epigenomics, proteomics and metabolomics, for characterizing and understanding the biology of human kidney development and disease. We will discuss the technical capabilities and challenges in mapping the spatial distribution of normal and abnormal developmental processes in the kidney. Moreover, we present three key multi-omics case studies and discuss their experimental design considerations. Finally, future directions and the potential impact of multi-omics approaches on the biological understanding of kidney disease in development and adulthood are discussed. This review highlights that by integrating molecular insights, multi-omics has the potential to transform our understanding of genetic (or variant-driven) and non-genetic kidney disease mechanisms, and to advance precision diagnostics, prognostics, and therapies for congenital kidney anomalies.