Here, we performed proteomics of kidneys obtained from patients with obstructive nephropathy and healthy controls (n=11/8), or from unilateral ureteral obstruction (UUO) mice and sham mice (n=6/6). Proteomic measurement of all human kidney samples resulted in a total of 6089 proteins with an average of 5780 proteins per sample. Compared to control kidneys, 614 proteins were up-regulated and 855 proteins were down-regulated (p value < 0.05, q value < 0.05, and fold change > 2 or < 0.5) in human obstructed kidneys. The up-regulated proteins were significantly enriched in collagen formation and immune response. Moreover, the human and mouse kidney proteomics reveled an aberrant NAD+ metabolism and NAD+-related metabolic pathways, including mitochondrial dysfunction, oxidative phosphorylation, and tryptophan metabolism. The expression patterns of several key enzymes catalyzing NAD+ biosynthesis and consumption were dramatically altered in obstructive nephropathy. Moreover, the major NAD+ consumer CD38 was strongly induced in obstructed kidneys which contributed to the decline of renal NAD+ levels. Functional studies demonstrated that CD38 deletion or inhibition significantly recovered renal NAD+ levels and reduced obstruction-induced renal fibrosis.