Background <p>Preclinical studies have suggested that Ras-related C3 botulinum toxin substrate 1 (RAC1) accelerates diabetic kidney disease (DKD) progression by triggering renal inflammation/fibrosis. Nevertheless, the clinical relevance of RAC1 with DKD is undefined. In this study, we aimed to investigate the association between circulating RAC1 levels and early DKD to evaluate its potential as a novel biomarker for early disease detection.</p> Methods <p>A total of 150 participants were recruited. They were divided into three groups: the type-2 diabetes mellitus (T2DM) group, the early DKD group, and the healthy volunteers (HVs). We measured the circulating level of RAC1 with ELISAs. In addition, we measured levels of two indicators of inflammation (NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, and interleukin (IL)-1β) and two serological indicators reflecting renal fibrosis (fibrillin 1 (FBN1) and matrix metalloproteinase-10 (MMP-10)).</p> Results <p>The serum level of RAC1 was increased in individuals with early DKD. The serum level of RAC1 was positively correlated with urinary clinical biomarkers, including the urine albumin-to-creatinine ratio (UACR), urine microalbumin (UMA), and α1-microglobulin (α1-MG), but inversely associated with the estimated glomerular filtration rate (eGFR). Serum levels of RAC1, NLRP3, IL-1β, and MMP-10 were strongly inter-correlated in DKD patients. In addition, after correction for pertinent clinical features and the other four biomarkers, an increased risk of early DKD was linked to a higher serum RAC1 level. Analyses of receiver operating characteristic (ROC) curves revealed the area under the ROC curve of serum levels of RAC1, NLRP3, IL-1β, and MMP-10 for identifying early DKD to be 0.785, 0.728, 0.697, and 0.714, respectively.</p> Conclusions <p>The circulating RAC1 level was associated with early DKD and might be a biomarker for the early stages of DKD.</p>