Fig. 1

CKD promotes hypoxic and xenobiotic cell signals and depletes tissue levels of NAD. CKD is caused by primary or systemic diseases and is prevalent among older individuals, women, ethnic minorities and those living in poverty. Independent of the initial cause of injury, CKD progression is irreversible. Injury induces damage, culminating in the production of uremic toxins and the release of enzymes and molecules required for NAD production into the blood. NAD is a substrate for sirtuins (SIRTs) that can inhibit the activity of hypoxia-inducible transcription factor (HIF)-1α, aryl hydrocarbon receptor (AHR), and nuclear factor (NF)-κB but promote HIF-2α stability. AHR exibits crosstalk with NF-κB. HIFs share a dimer partner with AHR to activate genes. In the de novo pathway of NAD biosynthesis, tryptophan metabolites are released into the blood and like uremic toxins, activate AHR. Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD salvage pathway and Preiss-Handler pathway, respectively. Extracellular NAMPT (eNAMPT) and NAPRT (eNAPRT) can be released into the blood and activate toll-like receptor (TLR)-4. In CKD, plasma levels of eNAMPT are elevated. Whether eNAPRT is similarly released to deter NAD production in tissue is not known. NF-κB promotes inflammation and the transcription of HIFs and AHR