A silent and burgeoning epidemic which has affected over 850 million people worldwide and growing at such an alarming rate to become the fifth leading cause of death in almost a decade- Acute Kidney Injury (AKI), a condition characterized by aberrations in renal tubular metabolism resulting in decreased or even sudden loss of kidney function. Although AKI affects 1 in every 5 individuals worldwide and up to 67% of hospitalized patients, there is no treatment and only very little supportive care. In the epicenter of the metabolic derangements causing cellular disruption and renal insult, lies Nicotinamide Adenine Dinucleotide (NAD+), a co-factor involved in more than 500 enzymatic reactions and evolutionarily conserved signaling pathways such as cellular respiration, DNA repair, lipid and glucose homeostasis and mitochondrial survival. NAD+ also serves as a co-substrate for enzymes such as sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38, which regulate key biological processes making this a mighty and indispensable molecule for maintaining cellular and metabolic homeostasis. Previous studies in both human and animal models have shown that renal NAD+ levels decline in ischemic, septic, and chemo toxic AKI. There is also suppression of all three NAD+ biosynthetic pathways, with de novo synthesis being majorly altered resulting in the accumulation of metabolites causing bottlenecks in the pathway, a fact also supported by preliminary data from our studies. The question that we are attempting to answer here is whether the renal NAD+ decline in AKI is driven by increased consumption of NAD+ by CD38s and PARPs to combat inflammation and DNA repair or decreased biosynthesis due to alterations in the pathways. Based on evidence from published literature put together with our studies, here, we hypothesize that understanding the stress-driven disturbances in the NAD+ metabolism and homeostasis is crucial towards bridging the connection between NAD+ dysregulation and restoring the kidney’s metabolic needs. To achieve this goal, we employ a cisplatin-induced acute kidney injury mouse model to study flux changes of NAD+ and related precursors across the whole body through stable isotope tracing using [2, 4, 5,6- 2H4] nicotinamide (NAM) coupled with liquid chromatography- mass spectrometry (LC-MS). This approach not only provides steady state measurements of metabolites but also measures NAD+ metabolic flux in the whole body. Our data revealed that NAD+ synthesis from NAM is perturbed only in the spleen across the whole body indicating impaired NAD+ turnover. Furthermore, we also found an accumulation of NAM catabolites- methyl nicotinamide (mNAM), N-Me-4PY and N-Me-2PY which are considered potent uremic toxins. These findings will substantially illuminate metabolic shifts and NAD+ perturbation in AKI and guide translational efforts towards identifying the protective role of supplements and nutraceutical therapeutic strategies for AKI. Our future research efforts would be directed towards identifying novel targets and biomarkers for kidney injury and elucidating mechanisms for restoring renal function.