Background <p>The neonatal-modified Kidney Disease: Improving Global Outcomes acute kidney injury (KDIGO-AKI) serum creatinine (SCr) definition is widely used to characterize neonatal AKI. In extremely preterm neonates born &lt; 28 weeks’ gestational age (GA), this definition has limitations. We evaluated whether GA- and postnatal age-specific SCr thresholds during the first postnatal week could identify additional neonates at risk for mortality.</p> Methods <p>In a secondary analysis of prospectively collected data from the Preterm Erythropoietin Neuroprotection Trial, daily 95th percentile SCr thresholds were derived over the first week of life for two GA groups (24–25 and 26–27 weeks) using neonates without KDIGO-AKI. Neonates were classified sequentially into three cohorts: KDIGO-AKI; 95th-AKI, defined by at least one SCr exceeding the daily 95th percentile thresholds in the absence of KDIGO-AKI; and controls with no AKI. Time-varying Cox proportional hazards models assessed associations with in-hospital mortality.</p> Results <p>Among 918 extremely preterm neonates, 106 (12%) had KDIGO-AKI, 72 (8%) had 95th-AKI, and 740 (81%) had no AKI in the first postnatal week. In-hospital mortality was higher with 95th-AKI (18%) or KDIGO-AKI (18%) than with no AKI (9%) (<i>p</i> = 0.003). After adjusting for confounding factors, 95th-AKI was associated with an increased in-hospital mortality (adjusted HR 2.16, 95% CI 1.12–4.18), but KDIGO-AKI was not (adjusted HR 0.99, 95% CI 0.49–2.02).</p> Conclusions <p>Extremely preterm neonates without KDIGO-AKI but with elevated SCr in the first postnatal week had an increased risk of in-hospital mortality. GA- and postnatal age-specific SCr thresholds may improve early detection of at-risk neonates.</p> Trial registration <p>ClinicalTrials.gov Identifier: NCT01378273.</p> Graphical abstract <p>A higher resolution version of the Graphical abstract is available as <InternalRef RefID="MOESM1">Supplementary information</InternalRef>.</p> <p></p>