A Single Dose of Varenicline Decreases Renal Fibrosis following Murine Pyelonephritis
Albert S T Lee, DO, PharmD, Austin G. Hester, MD, Christina Ho, MD, Daniel Casella, MD.
Children's National Hospital, Washington, DC, USA.
BACKGROUND: The innate inflammatory response is a key mediator of renal scarring and fibrosis following pyelonephritis. We have previously shown that the administration of 4 doses of the alpha-7nAChR agonist, varenicline, limits ischemia-reperfusion injury and long-term renal fibrosis in a murine model of pyelonephritis. Recent evidence suggests that a single activation of alpha-7nAChR can blunt the innate immune response for up to 48 hours. We, therefore, hypothesized that treatment of murine pyelonephritis with antibiotics and a single dose of varenicline would decrease long-term renal fibrosis when compared to treatment with antibiotics alone.
METHODS: The bladders of C3H/HeOuj mice were inoculated with 1 x 108 uropathogenic E-coli via transurethral catheterization. 5 days following inoculation, mice were treated with 5 days of ceftriaxone or 5 days of ceftriaxone and a single dose of varenicline (administered at the time of the first antibiotic dose). Acutely, quantitative PCR was utilized to evaluate the expression of inflammatory markers 14 days following inoculation. 28 days following inoculation, long-term fibrosis was assessed by the expression of pro-fibrotic genes and trichrome staining.
RESULTS: Acutely, there was decreased expression of the inflammatory markers lcn2, c1qb, and ctss in animals treated with ceftriaxone and varenicline. 28 days following bladder inoculation, the kidneys of animals treated with varenicline also demonstrated a decrease in the expression of the pro-fibrotic genes (Col1, Col3, Acta, and vimentin)and histologic evidence of fibrosis. (Figure 1)
CONCLUSIONS: When compared to animals treated with antibiotics alone, treatment of murine pyelonephritis with a single dose of Varenicline and antibiotics decreases long-term renal fibrosis. Varenicline offers a potentially novel, FDA-approved adjunct to the current management of pyelonephritis. 
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