While it is known that risk of death from sepsis is higher in patients with pre-existing chronic kidney disease its mechanism is unknown. To study this we established a two-stage mouse model where renal disease was first induced by folic acid injection followed by sub-lethal cecal ligation and puncture to induce sepsis. Septic mice with pre-existing renal disease had significantly higher mortality, serum creatinine, vascular permeability, plasma vascular endothelial growth factor (VEGF) levels, bacteremia, serum IL-10, splenocyte apoptosis and more severe septic shock when compared to septic mice without pre-existing disease. To evaluate the contribution of vascular and immunological dysfunction, we treated the folate-septic mice with soluble Flt-1 to bind VEGF and chloroquine to reduce splenocyte apoptosis. These treatments together resulted in a significant improvement in kidney injury, hemodynamics and survival. Our study shows that the sequential mouse model mimics human sepsis frequently complicated by pre-existing renal disease and might be useful in evaluating preventive and therapeutic strategies.