Acute kidney injury (AKI) affects up to 50% of patients undergoing cardiopulmonary bypass, yet early diagnostic biomarkers and targeted therapies remain limited. Although AKI is attributed to bypass-induced renal ischemia, the underlying molecular mechanisms are poorly understood. This study characterizes renal inflammatory dynamics in cardiac surgery patients, beginning intraoperatively. One hundred adults undergoing cardiopulmonary bypass were enrolled at the Quebec Heart and Lung Institute in Canada (July 2021–April 2024). Urine and plasma samples were collected before and up to 5 days post bypass. Proinflammatory P2Y14 receptor ligands (UDP-sugars) were quantified by LC-ESI-MS/MS, and kidney injury marker-1 (KIM-1) and inflammatory mediators were measured by multiplex immunoassays. AKI was defined using modified KDIGO criteria: serum creatinine increase ≥ 0.3 mg/dL or urine output ≤ 0.5 mL/kg/h for 24 h postoperatively. Urinary UDP-sugars increased significantly within 0–4 h post bypass in patients with AKI, whereas plasma levels remained unchanged. Urinary UDP-sugars correlated with KIM-1 at 4 h and preceded proinflammatory cytokines (CXCL1, CCL2, and IL-18), which peaked at 12 h. Immunofluorescence localized P2Y14 to collecting duct apical membranes, and detected CD45⁺/myeloperoxidase (MPO)⁺ neutrophils in ischemic human kidneys. Patients with elevated UDP-sugars showed significantly higher inflammatory markers compared with those with low levels. In conclusion, UDP-sugars released by damaged renal tubules trigger inflammatory cytokine secretion in patients with AKI. The UDP-sugar/P2Y14 axis represents a novel early predictor and therapeutic target for cardiac surgery-associated AKI. The robust expression of P2Y14 and the presence of proinflammatory immune cells in human ischemic kidneys further support the potential of this therapeutic strategy.