Acute kidney injury (AKI) develops frequently in the course of patients with sepsis and strongly associates with in-hospital mortality. However, diagnosing AKI involves a considerable lag-time because it depends on assessing an increase in serum creatinine, and offers no insight in the underlying pathophysiology. Consequently, identifying a set of proteins reflecting the development of AKI may improve earlier recognition of AKI and the understanding of its pathophysiology. A targeted plasma proteomic approach was performed in early sepsis patients with and without subsequent AKI development in a matched pair design (n = 19 each). Principal component analysis identified 53 proteins associated with development of AKI, which were further analysed using Enrichr gene ontology and pathway analysis. Nine differentially expressed proteins from the targeted proteomics were increased among patients who subsequently developed AKI and correlated with principal components, namely CALCA, CALR, CA12, CLEC1A, PTK7, KIM-1, NPPC, NUCB2 and PGF. We demonstrated the biological insight in the development of AKI in early sepsis compared to non-AKI sepsis.