#2333 Fetuin-A supplementation as a key treatment strategy to mitigate acute kidney injury and prevent its progression to chronic disease

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Abstract Background and Aims Patients with acute kidney injury (AKI), characterized by a sudden loss of kidney function involving structural damage and functional impairment, are particularly prone to developing chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI), a major cause of AKI, induces oxidative stress, inflammation, and necrosis. The excessive release of calcium phosphate-enriched debris from necrotic cells exacerbates inflammation by triggering cytokine production and promoting further cell death. Fetuin-A (FA), a liver-derived glycoprotein abundant in extracellular fluids, protects tissues by sequestering these cytotoxic minerals. However, severely ill patients often exhibit reduced FA levels, which correlate with increased morbidity and mortality. This study evaluates the therapeutic potential of human plasma-derived FA (hpdFA) to mitigate renal damage, inflammation, and fibrosis during AKI in mice. Additional objectives include investigating sex-specific differences and pharmacokinetics to assess FA as a potential biomarker for AKI. Method Unilateral IRI was induced in young adult wildtype or FA KO mice of both sexes by clamping the renal vessels of the left kidney for 22.5 minutes at 37°C. Two doses of hpdFA or PBS (vehicle control) were administered prophylactically (before surgery) or therapeutically (after surgery). Urine, blood, and kidney tissue samples were collected at 6 or 24 hours post-surgery and analyzed for renal injury, inflammation, and FA levels using immunofluorescence, RT-qPCR, Western blot, and ELISA. Renal fibrosis was assessed histologically three weeks after surgery. Additional in vitro and in vivo characterization of hpdFA included toxicity, calcification propensity, and half-life evaluations. In humans, serum samples from cardiovascular surgery patients were analyzed to assess endogenous FA dynamics during acute inflammation. Results Baseline serum levels of endogenous FA were significantly higher in female mice compared to males, a sex difference not observed in human samples. Acute tissue injury—whether IRI in mice (including sham surgery) or cardiovascular surgery in human patients—caused a rapid decline in circulating FA. In mice, this decline was associated with FA accumulation at injury sites (e.g., renal tissue or muscle). Following IRI, FA depletion correlated with greater renal damage and inflammation in male mice compared to females. In FA KO mice, neutrophil infiltration was significantly increased six hours post-IRI compared to wildtype animals. Prophylactic administration of hpdFA reduced tissue injury markers (e.g., Kim1, Lcn2) and inflammatory mediators (e.g., Ccl2, Ccl5, Tnf) in both sexes 24 hours post-IRI. In contrast, therapeutic hpdFA administration after IRI improved outcomes only in males. Three weeks post-IRI, hpdFA treatment attenuated the expression of fibrotic markers (e.g., Tgfb1, Acta2, Col1a1) and reduced fibrotic remodeling, as assessed by picrosirius red staining. Conclusion Acute inflammation at surgical wounds depletes systemic FA, creating a mismatch between its availability and increased demand in vulnerable tissues like the kidney, exacerbating local damage. FA supplementation addresses this imbalance by disrupting calcium phosphate-driven inflammation, promoting tissue recovery, and preventing progression from AKI to CKD. Higher baseline FA levels, as seen in female mice, partially protect against IRI, while prophylactic FA administration benefits both sexes by increasing systemic and local FA availability before the onset of injury. Post-surgical administration is especially effective in individuals with lower baseline FA levels, such as male mice. Our findings address the critical unmet need for interventions to prevent chronic disease progression and establish FA as both a promising biomarker and therapeutic option for AKI and related conditions.

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