Permanent defects in renal medullary structure and function after reversal of urinary obstruction

Urinary obstruction causes injury to the renal medulla, impairing the ability to concentrate urine and increasing the risk of progressive kidney disease. However, the regenerative capacity of the renal medulla after reversal of obstruction is poorly understood. To investigate this, we developed a mouse model of reversible urinary obstruction. Despite robust regeneration and complete histological recovery of the renal medulla, these mice exhibited a permanent defect in urinary concentrating capacity. However, there were lasting changes in the composition, organization, and transcriptional profiles of epithelial, endothelial, and interstitial cells. Persistent inflammatory responses were also seen in patients with renal stone disease, but there were also adaptive responses to the increasingly hypoxic environment of the renal medulla that occurred only after reversal of obstruction. These findings indicate that while partial repair occurs after reversal of urinary obstruction, there are lasting structural and functional changes across all major cellular compartments of the renal medulla. These changes reflect shared and distinct responses to different renal medullary injuries in humans and mice.