Adenine-Induced Mouse Model of CKD Shows Rapid Development of Impaired Kidney Function, Anaemia, Muscle Wasting, and Persistent Kidney Fibrosis following Diet Reversal

Background: Translational rodent models are essential to identify more efficacious treatment options for patients with chronic kidney disease (CKD). However, most preclinical CKD models do not demonstrate impaired kidney function as determined by decreased glomerular filtration rate (GFR). Here, we characterized the adenine diet-induced (ADI) mouse model of CKD for functional, biochemical and histological hallmarks of CKD. Methods: Male C57BL/6j mice (11 wks. old) were randomized into study groups (n=8-10/group) based on body weight. ADI mice received a control (ctrl) diet from study day -2 and a CKD-inducing diet 0.2% adenine for up to 5 weeks, while control mice received a ctrl diet served as healthy controls (CTRL mice). All groups received oral vehicle dosing once daily from day 1 until termination. Transdermal GFR (tGFR), urine albumin-to-creatinine ratio (uACR), and plasma cystatin C (pCyC) were evaluated at week 3 and 5. Blood was collected for haemoglobin analysis, and gastrocnemius muscle and kidney tissue were sampled and weighed. Kidneys were processed for histological evaluation of markers of macrophage infiltration (F4/80) and fibrosis (Col1a1). In parallel study, ADI mice (3 weeks on ADI diet) were switched to control diet for 2 weeks (diet reversal) to test for spontaneous regression of kidney biomarker and histological changes (uACR, pCyC, F4/80, Col1a1). Results: Compared to controls, ADI mice showed a significant tGFR decline correlating with increased pCyC levels and marked albuminuria at 3 and 5 weeks after adenine diet-induction. At termination, ADI mice showed significantly decreased haemoglobin and gastrocnemius muscle weight compared to CTRL mice. Furthermore, Quantitative histomorphometric analyses revealed development of renal fibrosis and macrophage infiltration in ADI mice. While diet reversal improved uACR, pCyC, renal fibrosis and macrophage infiltration remained significantly increased in ADI mice. Conclusion: ADI mice rapidly develop functional, biochemical, and histological hallmarks of CKD complicated by anaemia and muscle wasting. Collectively, the ADI mouse model is highly applicable in preclinical target and drug discovery for CKD. Funding: Commercial Support - Gubra