UNLABELLED: Observational studies have linked uric acid (UA) levels and kidney disease to amino acid homeostasis, but the causal relationship is unclear. This study aims to determine if elevated UA affects amino acid levels and whether amino acids mediate this relationship, focusing on the causal links between UA, circulating amino acids, and kidney disease. METHODS: This study utilized Uox-KO mice as a hyperuricemia model, assessed renal injury through blood biochemistry and pathology, analyzed serum amino acid changes via targeted amino acidomics, and employed Mendelian randomization to investigate the causal links between uric acid, amino acids, and renal disease. RESULTS: Hyperuricemia Uox-KO mice have significantly higher serum UA and renal impairment markers, with histopathological analysis showing extensive renal tissue damage. Changes in amino acid balance were found in the mice's serum, with key metabolites like alanine, isoleucine, leucine, aspartic acid, cysteine, glutamate, and glycine potentially influencing UA pathophysiology. Genetically predicted UA was positively correlated with chronic renal failure (CRF) and blood urea nitrogen(BUN) levels and negatively with serum cystatin C (eGFRcys) and serum creatinine (eGFRcrea). Alanine (Ala) mediated the effect of UA on elevated CRF and BUN risk, accounting for 4.5% of the UA-CRF relationship and 14.4% of the UA-BUN association. CONCLUSION: In hyperuricemia mice, serum amino acids undergo metabolic changes. Genetically predicted UA levels are positively linked to CRF and BUN, but negatively linked to eGFRcys and eGFRcrea. Ala mediates UA's effect on CRF and BUN risk, indicating Ala could be a target for preventing renal diseases caused by hyperuricemia.