Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

Hyperphosphatemia in chronic kidney disease (CKD) patients is a risk factor for cardiovascular events, progressive kidney failure, and mortality. Improved therapeutic interventions to control hyperphosphatemia depend greatly on robust animal models that recapitulate the CKD disease process. Murine-based models of CKD as compared to rat models present significant advantages due to available genetic knockout lines that permit mechanistic dissection of CKD etiologies. The rat adenine model of renal failure has been extensively studied, and studies are now emerging describing adenine-induced renal failure in murine models. However, these newly developed murine models have not fully described the responses to calcitriol and phosphate binders, and the reported effects of adenine on serum phosphate is often lacking in murine models. Therefore, the objectives of this study were: 1) To induce hyperphosphatemia in mice using adenine with minimal mortality, and 2) Report the influence of calcitriol and phosphate binders on the disease process through measurement of serum phosphate and histology. In one approach, C57BL/6 male mice gavaged with 4 or 6 mg adenine/day, as compared to 0 mg adenine/day developed hyperphosphatemia, with low mortality. In a second approach, calcitriol exacerbated adenine-induced increases in serum phosphate at day 7 of adenine administration (p<0.05). Notably, adenine treated mice had 4-fold increased stomach weights vs. non-adenine treated mice (p<0.0001). The addition of a phosphate binder (experiment 3, sevelamer hydrochloride) was ineffective at preventing an adenine-induced increase in blood phosphate, a finding that likely resulted from adenine’s inhibition of gastric emptying. We report the successful use of adenine to induce hyperphosphatemia, that the hyperphosphatemic status is exacerbated by calcitriol, and a limitation of the model for studying oral therapies for hyperphosphatemia. Correspondence to: Mark E Cook, Animal Science Department, 1675 Observatory Drive, University of Wisconsin, Madison, WI, 53706, USA, Fax: 6082625157; Tel: 6082627747; E-mail: [email protected]