Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut ^−/− mice as a stable transgene under the control of an albumin (INS-Alb- Mut ) promoter. Mut ^−/− ;Tg ^{INS-Alb- Mut} mice, although completely rescued from neonatal lethality that was displayed by Mut ^−/− mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut ^−/− ;Tg ^{INS-Alb- Mut} kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort ( ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut ^−/− ;Tg ^{INS-Alb- Mut} mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.