The low\phenylalanine (Phe) diet with amino acid (AA) medical foods is associated with low bone mineral density (BMD) and renal dysfunction in human phenylketonuria (PKU). in hematoxylin and eosin (H&E) stained renal sections, femoral biomechanical parameters, or femoral bone mineral content (BMC). Significantly lower femoral BMC and Anle138b strength occurred in versus WT mice, with greater decline in female mice. Polyuria and mild vacuolation in the proximal convoluted tubules were observed in male and WT mice fed the high\acid AA diet versus absent/minimal cortical vacuolation in males fed the GMP, BAA, or casein diets. Vacuole contents in male mice were proteinaceous. Cortical vacuolation was absent in female mice. Dilated medullary tubules were observed in all mice, except for male mice fed the GMP diet. In summary, the PKU genotype and diet showed differential effects on renal and bone status in male and female mice. Renal status improved in male mice fed the GMP diet. murine model of deficiency shows an association between long\term adherence to a low\Phe diet supplemented with AAs and the presence of chronic kidney disease (Hennermann et al. 2013; Stroup et al. 2017; Burton et al. 2018), as Anle138b well as skeletal fragility characterized by low bone mineral density (BMD) and increased risk of fractures (Modan\Moses et al. 2007; Groot et al. 2012; Hansen and Ney, 2014; Coakley et al. 2016; Choukair et al. 2017). Our research indicates that the standard low\Phe, high\acid AA diet used in studies with the murine model of deficiency induces metabolic stress and increases renal workload based on greater renal mass, fluid intake, and polyuria Anle138b in both and wild\type (WT) mice (Solverson et al. 2012). In addition, femurs from mice are weaker and show lower bone mineral content (BMC) than femurs from WT mice, and this bone phenotype is exacerbated by the low\Phe, high\acid AA diet (Solverson et al. 2012). In eight human subjects with PKU, we demonstrated threefold greater renal net acid excretion with ingestion of high\acid AA Wisp1 medical foods, that could become ameliorated by ingestion from the low\acidity GMP medical foods (Stroup et al. 2017). In this same study, proteinuria and hyperexcretion of urinary creatinine were observed in 38C63% of subjects with PKU with self\reported lifelong compliance with high\acid AA medical foods (Stroup et al. 2017). Consistent with this evidence of renal dysfunction in humans with PKU, reduced glomerular filtration rate (GFR) and increased urinary calcium excretion were correlated with graduated increases in ingestion of elemental AAs from medical foods in 67 adolescents and adults with PKU (Hennermann et al. 2013). A retrospective case\controlled study in the United States found significantly greater prevalence ratios of renal insufficiency (with and without hypertension) and osteoporosis in 3691 subjects with PKU compared to 18,455 controls (Burton et al. 2018). Together, these studies suggest that renal dysfunction is a significant complication for individuals with PKU compliant with AA medical foods, but the relative contributions of the PKU genotype, hyperphenylalaninemia, dietary protein source (intact protein vs. AAs), and dietary acid load remain unclear. Long\term ingestion of a high dietary acid load, especially with a concomitant decline in renal function as observed in the elderly population, contributes to osteopenia and osteoporosis (Jehle et al. 2006; Moseley et al. 2012; Jehle et al. 2013). One underlying mechanism for this response is skeletal buffering of an acid load to maintain systemic pH homeostasis (Remer and Manz, 1995; Lemann et al. 2003; Remer et al. 2011). Our objective was to investigate the impact of diets differing in dietary protein source, Phe content, and acid load on bone and renal outcomes in male and female and WT mice. By reducing the dietary acid load with the buffered AA (BAA) diet, we successfully reduced renal net acid excretion, but did not observe significant improvements in overall bone and renal status. Methods Animals and experimental design The University of Wisconsin\Madison Institutional Animal Care and Use Committee approved the facilities and protocols used in this study. Experimental animals were produced from a breeding colony (Strain: B6.BTBR\by intercrossing mice (mutation. The test used a 2??2??4 factorial style to regulate for sex (female or male), genotype (PKU, mice given the AA, BAA, GMP, or casein diet programs (or WT), and diet plan (AA, BAA, casein, GMP), and genotype by diet plan discussion. Anle138b Fisher’s least factor test was utilized to identify differences among organizations. If statistical assumptions weren’t met following the log change was performed, rank variables from reliant variables had been Anle138b calculated using PROC RANK after that. After that, using PROC GLM, ANOVA was performed using the rank ideals. Changes in bodyweight were analyzed utilizing a repeated actions model.