Effect of Transforming Growth Factor-β Inhibition on Ureteral and Renal Scarring in a Rat Model of Upper Urinary Tract Ablation with Irreversible Electroporation.

Abstract

Objective: To determine whether adjuvant transforming growth factor-β (TGF-β) inhibition with pirfenidone (PFD) can mitigate ureteral wall scarring and related complications in a rat model of upper urinary tract ablation with irreversible electroporation (IRE).

Methods: Transmural ablation of the ureter was performed with IRE in 24 rats. Post-IRE, animals were randomly assigned to receive PFD or no drug, followed by euthanasia at 2-, 5-, or 10-days. The complete urinary tract was extracted, and the dimensions of kidney and ureter were measured. Immunohistochemistry was performed to quantify collagen deposition, α-smooth muscle actin (α-SMA) (myofibroblasts in ureter and kidney) and TGF-β (ureter only).

Results: Enlargement of the kidney and ureteral dilatation were apparent during gross necropsy of rats from both cohorts. The changes in anatomical measurements were significantly reduced in rats receiving PFD at Day 5 and 10 (p = 0.02 and 0.04, respectively). Collagen levels in the ureters gradually increased in rats from both cohorts at Day 2 and 5, but started to reduce by Day 10 in rats receiving PFD when compared with no treatment (p = 0.04). Myofibroblast levels and TGF-β staining in the ureters was lower in rats receiving PFD on Day 5 and 10, respectively (p < 0.01). Collagen levels and myofibroblast staining of the kidneys from rats receiving PFD was significantly lower than control on Days 5 and 10.

Conclusion: Adjuvant PFD can reduce myofibroblast activity and ureteral fibrosis at the site of IRE ablation, enabling safe soft tissue ablation adjacent or involving the upper urinary tract.