THE PREVENTIVE EFFECT OF SIROLIMUS ON URETERAL STRICTURE FORMATION

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Introduction: Stricture of the transplant kidney ureter occurs in approximately 3% of transplant recipients. Risk factors for ureteral stricture include kidneys coming from marginal donors with advanced age and multiple comorbidities. Additionally, delayed graft function, presence of multiple renal arteries and direct injury during retrieval may increase the risk of this complication. Its clinical presentation is typical with elevated serum creatinine accompanied by hydronephrosis. Although several open and endoscopic techniques have been described to manage this condition, ureteral stricture still increases short and long-term graft loss significantly. An M-TOR inhibitor Sirolimus has been shown to reduce fibrosis. Since the mechanism of stricture formation is also through fibrosis, we analyzed the effect of this immunosuppressive drug on the prevention of ureteral strictures. Methods: 32 New Zealand White rabbits (2500-3000grams) were used in the study. The rabbits were randomly assigned into four groups (n=8). Group 1: A unilateral nephrectomy and subsequent full transection of the contralateral ureter was performed. The transected ureter was reconstructed over a double J ureteral stent by using interrupted 7/0 PDS stitches. Group 2: Same procedure with group 1 with Sirolimus- impregnated (1mg) stent placement Group 3: A unilateral nephrectomy and subsequent full transection of the contralateral ureter was performed. The transected ureter was reconstructed without a stent and 1 ml of saline was instilled over the anastomosis. Group 4: Same with group 3 with 1ml (1mg/ml) of Sirolimus solution instilled over the ureteric anastomosis (Figure 1). On postoperative day 3, serum creatinine levels were measured. On postoperative day 7, an ultrasound of the kidney was performed to evaluate hydronephrosis. On postoperative day 21, all rabbits were explored to evaluate the ureteral anastomosis. Subsequently, all subjects were terminated, and full segment of the ureter was removed for histopathology assessments and tissue hydroxyproline level measurements. Results: Severe hydronephrosis and creatinine elevation were observed in group 3 compared to other groups (Figure 2). Histopathological evaluation of the specimens showed increased fibrosis scores in groups 1 and 3 (Figures 3&4). Tissue hydroxyproline levels in group 4 were found to be lower compared to other groups. Conclusion: Sirolimus-impregnated double J stents may decrease ureteric stricture formation. This effect can be beneficial both in both kidney transplant and endourology practice.Fig. 1.Fig. 2.Fig. 3.