ABSTRACT Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally, healthy individuals efficiently control C. albicans infection. However, in certain pre-disposing conditions such as immunosuppression, antibiotic therapy, abdominal surgery, use of invasive medical interventions or kidney diseases, C. albicans can cause life-threatening disseminated candidiasis (DC). Although hemodialysis is a major cause of bloodstream infection in patients with kidney disease, mortality due to DC is 2 times higher in patients with kidney impairment than individuals without renal dysfunction. Thus, kidney disease is a separate and major risk factor for death from DC in these patients, which has largely been overlooked. It is unknown why patients with renal ailment are inept to fight DC compared to individuals with normal kidney function. Using a clinically relevant mouse model of renal disease, we show that mice with kidney dysfunction are far more susceptible to DC than control animals. Nevertheless, the underlying mechanisms of defect in antifungal immunity in kidney disease are poorly defined. Interestingly, we have discovered an unanticipated role for uremia, characterized by the accumulation of uremic toxin(s) in the blood in the absence of kidney function, in causing neutrophil dysfunction in DC. Our data imply that uremia induces a defect in reactive oxygen species (ROS) generation by neutrophils, which is essential for the elimination of fungi. In part, we show that this is due to a defect in glucose transporter1-mediated uptake of glucose by neutrophils, required for glycolytic pathways upstream of ROS generation. Our hypothesis is that neutrophil-intrinsic impairment in candidacidal function of neutrophils makes uremic patients more susceptible to death from DC. In Aim 1, we will employ series of in vitro and in vivo approaches to define the underlying cellular and molecular mechanisms of defect in glucose uptake and subsequent impairment in ROS production and antifungal activity of neutrophils during uremia. Knowledge gained from these studies will be utilized to identify potential uremic toxin(s) with neutrophil inhibitory activity. We will also device novel therapeutic approaches to correct the abnormalities in cell metabolic pathways and neutrophil dysfunction in kidney diseases. In Aim 2, we will translate and validate our mouse model findings in patients with kidney disease by collecting biospecimens from pre- and post-hemodialysis patients and compare antifungal activity of neutrophils to healthy subjects. The goal of this proposal is to define the mechanisms of defect in antifungal activity of neutrophils in kidney disease and eventually to exploit this information for therapeutic benefit. Our long-term objective is to reduce the mortality associated with this devastating nosocomial infection in patients with kidney disease.