Ureteral Obstruction Promotes Ureteral Inflammation and Fibrosis

Abstract

Background: Hydronephrosis and renal impairment may persist even after relieving an obstruction, particularly in cases of chronic obstruction. Obstruction can cause fibrotic changes of the ureter, potentially contributing to long-term kidney damage.

Objective: To characterise pathophysiological changes of obstructed ureters with focus on inflammatory responses triggering fibrosis and potential impairment of ureteral function.

Design, setting, and participants: Eighty-eight mice were randomly assigned to unilateral ureteral obstruction (UUO) for 2 d, UUO for 7 d, and UUO for 7 d followed by 8 d of recovery, or a control group (no prior surgical intervention).

Outcome measurements and statistical analysis: Peristaltic rate was determined over 2 min by direct visualisation with a microscope, while hydronephrosis was assessed by ultrasound. Obstructed and contralateral ureters were harvested, and underwent histopathological evaluation. We quantified 44 cytokines/chemokines, and five matrix metalloproteases using Luminex technology. Cell composition was characterised via immunofluorescence. Statistical significance was assessed using Welch analysis of variance, Kruskal-Wallis test, and Dunnett's T3 multiple comparison test.

Results and limitations: Obstruction resulted in hydronephrosis and significantly impaired peristalsis. Marked fibrosis was observed in lamina propria, muscle layer, and adventitia. Connective tissue in obstructed ureters showed hyperaemia and leucocyte infiltration. Unsupervised hierarchical clustering demonstrated different cytokine/chemokine patterns between groups. Ureters obstructed for 7 d followed by recovery were notably different from other groups. Inflammatory cytokines, chemoattractants, and matrix metalloproteases increased significantly in obstructed ureters. Contralateral unobstructed ureters showed significantly increased levels of chemokines and matrix metalloproteases. Immunofluorescence confirmed activation of T cells, Th1 and Th2 cells, and M1 macrophages in obstructed and contralateral ureters, and a shift to M2 macrophages following prolonged obstruction.

Conclusions: Ureteral obstruction triggers severe inflammation and fibrosis, which may irreversibly impair ureteral functionality. Function of the unobstructed contralateral ureter may be regulated by a systemic immune response as a result of the obstruction.

Patient summary: Here, we studied in more detail the way the ureter responds to being blocked. We conclude that a strong immune response is activated by the blockage, leading to changes in the structure of the ureter possibly impacting function, which may not be reversible. This immune response also spreads to the opposite ureter, possibly allowing it to change its function to compensate for the reduced functionality of the blocked ureter.

Keywords: Cytokines; Hydronephrosis; Hydroureter; Kidney disease; Matrix metalloproteinase; Peristalsis; Urolithiasis.