A Mouse Model to Evaluate the Long-Term Structural and Functional Outcomes after the Reversal of Prolonged Unilateral...

Clinical management of patients with urinary tract obstruction (UTO) requires early intervention to reverse the cause of the obstruction, but despite this, patients with prolonged UTO are at increased risk of chronic kidney disease (CKD) and recurrent acute kidney injury (AKI). However, other than an early reversal of obstruction and generic therapy to delay CKD progression, no therapies have significantly improved long-term renal outcomes after the reversal of UTO. To address this, a number of laboratories have developed models of reversible UUO (R-UUO), but these are technically challenging and have not been widely adopted. In addition, while mouse models of R-UUO are attractive as they can be used to harness the power of mouse genetics to study disease pathophysiology, these have been particularly challenging as methods used often lead to irreversible UUO if the obstruction lasts >3 days. In addition, because of the nature of these models, few studies have evaluated the long-term functional outcomes of reversing ureteric obstruction. To address this, we recently developed a mouse model of R-UUO with delayed contralateral nephrectomy that allows for the analysis of the long-term effects of reversing prolonged UTO on long-term renal structural and functional outcomes. These studies show that despite near complete histological recovery 3 months after reversal, there was a permanent reduction in renal function and a marked and persistent defect in urinary concentrating capacity, indicative of a defect in renal medullary function. The model requires three major survival surgeries but results in a robust and reproducible long-term reduction in renal function that can be reproduced in different mouse strains by adjusting the period of obstruction. In this article, we provide detailed instructions for performing these surgeries, optimizing conditions for use in different mouse strains, evaluating renal functional outcomes, and harvesting renal tissues.