Progressive chronic kidney disease contributes to elevated cell death mechanisms and aggravates post-stroke severity

Chronic kidney disease (CKD) is an independent risk factor that worsens ischemic stroke outcomes. We characterized a gradient-progressive CKD mouse model using adenine injections (i.p.) that showed consistent CKD progression over 4 weeks and evaluated post-stroke outcomes for 2 weeks. Adenine (25-50 mg/Kg; i.p.) injected daily for up to 4 weeks promoted CKD in adult C57BL/6 mice. The progression of CKD in each mouse was tracked weekly using microbubble-assisted ultrasound and comprehensive blood chemistry. To determine if CKD progression has a direct impact on stroke outcomes, transient focal ischemia was induced after 2 and 4 weeks of CKD progression. Brain damage was assessed after 24 h of reperfusion by T2-MRI. To confirm whether the brain damage in CKD cohorts is due to cellular changes rather than flow dynamics, we evaluated cerebral blood flow using laser speckle and microSPECT, cerebral oxygen saturation, cardiac function by ultrasound, and bone density by DEXA scan. To determine the long-term effect of CKD on stroke outcomes, we evaluated motor function and survival up to 14 days of reperfusion. We assessed brain tissue from mice with only stroke and from CKD + stroke mice to identify proteomic changes using an apoptotic protein array. Our results showed that both the early and delayed phases of CKD induced severe brain damage and poor outcomes, and these changes were not due to alterations in flow dynamics but to direct effects on the brain vasculature. In addition, blood levels of kidney dysfunction and coagulant status markers were altered after stroke. We conclude that this is the first study to utilize CKD progression in a mouse model, evaluate synergistic outcomes, and test post-stroke outcomes at different severities of CKD.