Purpose <p>Acute kidney injury (AKI) is a common complication after major surgery and is associated with increased morbidity and mortality. Kidney protection strategies may help prevent moderate or severe AKI in high-risk patients. This study aims to assess the effect of the Kidney Disease: Improving Global Outcomes (KDIGO) kidney protection strategy for the&#xa0;prevention of AKI in patients after major surgery.</p> Methods <p>We conducted a systematic review and individual participant data&#xa0;(IPD) meta-analysis of randomized controlled trials (RCTs) comparing the kidney protection strategy recommended by international guidelines consisting of hemodynamic and fluid status optimization, avoidance of nephrotoxins or radiocontrast agents, regular monitoring of kidney function, and glycemic control to standard care in high-risk patients after major surgery with an enrichment strategy based on renal biomarkers. The primary outcome was moderate or severe AKI (KDIGO stage ≥ 2) within 72&#xa0;h after surgery. MEDLINE via PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2000, to September 1, 2025. References of eligible trials and related reviews were hand-searched. Two reviewers independently assessed trial quality using the Cochrane Risk of Bias tool&#xa0;version 2.0. Certainty of the evidence was assessed using GRADE. IPD were pooled. Odds ratios (ORs) and mean difference with 95% confidence intervals (CIs) were computed with one-stage IPD meta-analysis. Heterogeneity was assessed by <i>I</i>² and Cochran’s <i>Q</i>.</p> Results <p>We identified four RCTs, two single-center trials and two multinational-multicenter trials. We pooled IPD from all four trials. The final cohort included 1,851 participants with 921 participants in the intervention group and 930 participants in the control group. Moderate or severe AKI occurred significantly less frequently in the intervention group (162/918 participants (17.7%)) compared to the control group (252/929 participants (27.1%)) (OR 0.55, 95% CI 0.44–0.70; <i>p</i> &lt; 0.0001). There was no evidence of heterogeneity across studies (<i>p</i> = 0.7309, <i>I</i>² = 0.0%, <i>τ</i>² = 0). Secondary endpoints varied across trials and did not demonstrate major differences between groups. When measured, the intervention tended to result in fewer persistent AKI events and larger decreases in renal tubular stress biomarkers.</p> Conclusion <p>The implementation of a kidney protection strategy reduces the rates of moderate or severe AKI in biomarker-enriched high-risk patients after major surgery compared to standard of care, while the incremental clinical value of biomarker-guided selection itself remains uncertain.</p> Registration <p>The study was registered at the international, prospective register of systematic reviews PROSPERO. Identifier: PROSPERO 2025 CRD420251138328.</p> Visual abstract <p></p>