Molecular pathways of kidney development and their applications to clinical research

Congenital anomalies of the kidney and urinary tract (CAKUT) are the major cause of childhood chronic kidney disease and an antecedent cause of adult-onset cardiovascular and kidney failure. Both genetic and environmental factors have been implicated in human kidney malformations, with pathogenic variants or DNA copy number variations identified in ~16% and 10% of cases, respectively. To date, >60 CAKUT-associated genes have been identified, most of which are established regulators of organogenesis. Although excellent reviews covering the genetic bases of CAKUT exist, new approaches for automated analysis and machine learning require formats that can be easily read and interpreted by computers. Here, we develop and describe fully machine-readable, well-annotated pathways to visualize and analyze key events during kidney development. Pathways include genes controlling nephrogenesis, including glomerulotubular development, the GDNF/RET signaling axis driving ureter branching, the development of the ureteric bud–derived collecting system, and lineage dependencies of all kidney cell types with marker gene expression. These pathways are published on the WikiPathways database. Furthermore, we provide 3 examples of how to apply these molecular pathways to translational clinical research. We demonstrate how they (i) inform the discovery of new CAKUT-associated candidate genes, (ii) illuminate the aberrant transcriptomic panorama in a specific genetic kidney malformation, and (iii) help understand how environmental perturbations may cause kidney malformations. Taken together, this review summarizes and visualizes current knowledge informing kidney maldevelopment and genetic causes of CAKUT and facilitates future advanced data analyses and data integration approaches.