Ureteral obstruction can cause persistent hydronephrosis and lasting kidney damage.^1,2 The most common cause for ureteral obstruction are calculi; urolithiasis affects 7%–13% of North Americans.³

We hypothesized that ureteral dysfunction due to obstruction might contribute to long-term adverse effects. We sought to better understand pathophysiological changes in the ureter following ureteral obstruction.

We employed a mouse model to study histomorphological changes after a 2-day or 7-day ureteral obstruction and 8 days after relieving a 7-day ureteral obstruction in ipsilateral and contralateral ureters. Obstruction was induced by placing an atraumatic vascular clip on the distal ureter. Mice without prior surgery served as controls. A grading system was developed to compare the degree of inflammation and fibrosis. Furthermore, we determined concentrations of 44 chemokines and cytokines, and 5 matrix-metalloproteases using an immunoassay and studied the composition of cells involved in the inflammatory response by immunofluorescence.

Mice developed severe hydronephrosis after 2 days of obstruction, and peristaltic frequency was significantly reduced. Peristalsis partially recovered after the relief of obstruction; hydronephrosis, however, increased in our model.

Following obstruction, the ureters significantly dilated and the ureteral wall thickened. We observed inflammation of ureteral tissue, demarked as hyperemia and diffuse infiltration of mononuclear cells in the lamina propria as well as clusters of mononuclear cells in the adventitia. Moreover, obstruction resulted in fibrosis of the lamina propria, muscle layer, and adventitia (see Figure).

Unsupervised hierarchical clustering of chemokine/cytokine concentrations showed clustering based on the condition (control ureters, 2-day- and 7-day-obstructed and contralateral ureters, and 7 days obstructed followed by 8 days recovery). Interestingly, proinflammatory cytokines were also increased in contralateral ureters; however, the increase was less pronounced. These results indicate that specific cytokine patterns drive the acute and chronic inflammatory response and suggest systemic inflammation. Immunohistochemistry showed that the primary immune response is driven by T cells, Th-1 cells, and M1 macrophages. We observed a shift to M2 macrophages with prolonged obstruction, indicating resolution of inflammation and a pro-fibrotic environment.^4,5

Correspondingly, levels of matrix-metalloproteases and their inhibitor, TIMP-1, a group of enzymes associated with tissue remodeling, were increased in obstructed and their contralateral ureters.

While the main focus of the literature has been put on the impact of ureteral obstruction on the kidney in the past, we studied how obstruction affects the ureter. We demonstrated that obstruction caused an acute inflammatory response, triggering tissue remodeling. Obstruction resulted in fibrosis of obstructed ureters. While an increase of inflammatory cytokines/chemokines, matrix-metalloproteases, and TIMP-1 suggest that obstruction affects both obstructed and contralateral ureters, ­histomorphological changes were limited to the obstructed ureter.

Fibrosis of smooth muscle is known to impair intestinal peristalsis and airway function due to decreased contractility.^6,7 In the context of ureteral obstruction, fibrosis likely impairs ureteral functionality and causes stiffness of the ureteral tissue. Therefore, we hypothesize that the observed changes might contribute to chronic kidney disease.

Figure. A–D, representative histology of murine obstructed and unobstructed ureters. A, low magnification image of a nonobstructed ureter, transverse. B and D, unilateral ureteral obstruction for 7 days showing urothelial changes (arrow, B) and thickened muscular layer (double-headed arrow, B and D) and collagen fibers in smooth muscle layer (star) and adventitia (arrowhead, D). C, high-magnification images of collagen fiber distribution in lamina propria and adventitia of unobstructed ureter. Staining: A and B, hematoxylin-eosin; C and D, sirius red in polarized light.

To date, not much is known about the impact of obstruction on the contralateral ureter. Previous studies have shown that obstruction alters the peristaltic frequency of obstructed and contralateral ureters.^8,9 We presumed that this “cross-talk” between ureters might be based on cytokines. Our results support the hypothesis and suggest a systemic inflammatory response.

We conclude that ureteral obstruction triggers an inflammatory response and fibrosis that contributes to functional changes. The findings warrant future investigation, as targeting obstruction-induced inflammation might prevent ureteral remodeling and positively affect ureteral and subsequent kidney function.