BACKGROUND: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. METHODS: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3',5'-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. RESULTS: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. CONCLUSIONS: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.
BACKGROUND:Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCKrats, a validated animal model of PKD. METHODS: Four-week old PCKrats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3',5'-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. RESULTS: Consistent with the development of a polycystic kidney phenotype, control PCKrats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCKrats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. CONCLUSIONS: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.
Authors: Fouad T Chebib; Caroline R Sussman; Xiaofang Wang; Peter C Harris; Vicente E Torres Journal: Nat Rev Nephrol Date: 2015-04-14 Impact factor: 28.314
Authors: William T Abraham; Alireza A Shamshirsaz; Kim McFann; Ron M Oren; Robert W Schrier Journal: J Am Coll Cardiol Date: 2006-03-29 Impact factor: 24.094
Authors: Vicente E Torres; Arlene B Chapman; Olivier Devuyst; Ron T Gansevoort; Ronald D Perrone; Gary Koch; John Ouyang; Robert D McQuade; Jaime D Blais; Frank S Czerwiec; Olga Sergeyeva Journal: N Engl J Med Date: 2017-11-04 Impact factor: 91.245
Authors: Valeriia Y Vasileva; Regina F Sultanova; Anastasia V Sudarikova; Daria V Ilatovskaya Journal: Front Physiol Date: 2021-09-08 Impact factor: 4.566
Authors: Erum A Hartung; Juan S Calle-Toro; Carolina Maya Lopera; Jessica Wen; Robert H Carson; Mohini Dutt; Kathryn Howarth; Susan L Furth; Kassa Darge; Suraj D Serai Journal: Abdom Radiol (NY) Date: 2020-08-05