AKI and AKD Predispose to a Dysregulated Immune Response to Infection

About This Grant

Background and Innovation: Infection is a leading cause of death after acute kidney injury (AK). Poor innate immune function, dysregulated cytokine production and clearance, and other comorbid conditions are often implicated as reasons for the high rates of infections in individuals with AKI. However, there is little consensus or progress in understanding the unique immunodeficiency AKI creates in a host, and if acute kidney disease (AKD), defined as a more subacute decline in kidney function that encompasses many individuals with and without AKI predisposes to similar risk. We propose a series of highly innovative studies to study and intervene on this apparent immunodeficiency: 1) we have developed novel animal models of AKI and AKD, which are sequentially paired with peritoneal infection to recreate a complex but common human disease with high fidelity, 2) we test both immune blocking, and immune stimulating therapies in our model, establishing a translational rationale for treating individuals with AKI and AKD, 3) we propose using state of the art approaches: non-invasive kidney function monitoring, spectral flow cytometry, and transfer of donor inflammatory cells into our AKI and AKD rodents with immunodeficiency to test our hypotheses. Significance and Impact to Veterans Healthcare: AKI and AKD are extraordinarily common in the Veteran population, both in and out of the intensive care unit (ICU). Very few therapeutic approaches have demonstrated benefit to improve the outcomes of veterans with AKI or AKD. As mentioned, infection is a leading cause of death after AKI, and even without AKI, infection rates are higher in veterans than the general population. Our studies will effectively “reverse model” a common clinical scenario appreciated all to common in veterans, then screen therapeutics which can be rapidly translated to clinical trials. Path to translation/implementation: Data from our studies will inform the approach to treat patients with AKI and AKD with subsequent infection. Given that trials of these therapies in individuals with sepsis are already ongoing, our approaches may rapidly expand the indications for this therapy, but in a different population who has a unique predisposition to sepsis. Notably, we are designing our animal studies to mirror many of the approaches used in these ongoing human clinical trials. This will add heightened translational impact to our results. Outside the immediate clinical translational potential, the novel animal model system we have built can effectively screen many other therapeutics and provide a more rapid bench to bedside pipeline.