Identification and Validation of Biological Sub-phenotypes of Sepsis-induced Acute Kidney Injury: A Precision Medicine Approach to Improve Clinical Outcomes

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PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is the most common form of organ failure in sepsis and sepsis-induced AKI is associated with prolonged hospitalization, need for acute dialysis, persistent AKI, and death. Despite this public health impact, no effective pharmacotherapy exists for the treatment of sepsis -induced AKI. One reason may be that heterogeneity is present within AKI, thereby concealing unique pathophysiologic processes specific to certain AKI populations. The applicant is an early career investigator who has generated preliminary data demonstrating that two novel AKI sub-phenotypes are present within the larger heterogeneous AKI clinical population. Our group demonstrated that these AKI sub-phenotypes have differing risk for clinical outcomes and response to vasopressin therapy, independent of traditional criteria to risk stratify AKI. We also identified a 3-variable model that included plasma markers of endothelial dysfunction and inflammation to identify the two AKI sub-phenotypes. These findings were subsequently replicated by an independent research group. Through this body of work, we have consistently shown in sepsis-induced AKI that these two AKI sub-phenotypes are reproducible, prognostic and predictive. Important next steps for translating these findings to the bedside include: 1) expanding the pool of candidate biomarkers to identify these or alternative AKI sub-phenotypes in the emergency room (ER), an earlier and critical time to implement strategies to prevent or treat AKI; 2) evaluating response of AKI sub-phenotypes to volume of intravenous fluids, a therapy given to almost all patients with sepsis-induced AKI; and 3) probing whether the AKI sub-phenotypes different in terms of pathophysiologic mechanisms. We will complete the proposed Aims in two ongoing NIH-funded studies, 1) Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis (CLOVERS) and 2) Kidney Precision Medicine Project (KPMP). In Aim 1, we will identify sepsis-induced AKI sub-phenotypes using biospecimens collected in the ER and determine associations with clinical outcomes in CLOVERS. We will apply two innovative approaches to identify AKI sub-phenotypes (an unsupervised clustering and a previously developed 3-variable model). In Aim 2, we will determine whether sepsis-induced AKI sub-phenotypes respond differently to a restrictive fluid/early vasopressor versus a liberal fluid/late vasopressor resuscitation strategy. In Aim 3, we will identify histological lesions from kidney biopsy tissue and urinary proteins associated with sepsis-induced AKI sub-phenotypes in biospecimens collected during AKI in KPMP. The outstanding qualifications of our team in the field of AKI, sepsis, molecular epidemiology, and interventional clinical trials uniquely position us to align clinical care with underlying molecular mechanisms to inform a ‘precision’ approach to the study and care of patients with sepsis-induced AKI.