Complement Activation in Sepsis

Every year, more than 75,000 children and 750,000 adults in the United States are admitted to an Intensive Care unit with a diagnosis of sepsis. Sepsis-associated acute kidney injury (SA-AKI) has a high morbidity and mortality rate and unfortunately there are no methods to predict, prevent, or treat SA-AKI.

Emerging evidence implicate the role of complement activation as a key driver of SA-AKI development. We have shown that urine complement factor Ba is associated with incident AKI in both critically ill children and adults with sepsis. However, whether complement activation is involved in SA-AKI pathogenesis in critically ill

children and adults is unknown. We hypothesize that urine Ba elevation temporally precedes development of SA-AKI and associates with urine cellular changes. This proposal will examine the association between urine

Ba and AKI in critically ill patients with sepsis. First, we will prospectively enroll critically ill children with sepsis and longitudinally obtain urine Ba levels to determine the association between urine Ba levels and severe AKI outcomes, and then validate these findings in a large multicenter trial of pediatric sepsis (Aim 1). We will

validate this association through two biorepositories from clinical trials in critically ill septic adults (Aim 2). This will determine when urine Ba peaks and identify cutoff values and identification of an ideal window to study use of therapeutic trials of factor B inhibition in the future. Finally, we will measure complement deposition on shed

tubular epithelial cells in the urine to determine if complement activation is occurring in the kidney (Aim 3). As an Assistant Professor in Pediatric Critical Care with a strong publication record, I am establishing myself in the field of critical care nephrology. A K23 Career development award would support the following

research goals: 1) strengthen the evidence implicating the complement cascade’s role in SA-AKI development; 2) identify a potential therapeutic window to stratify patients for treatment with a complement therapeutic in future R01 proposals; 3) obtain mechanistic insight discriminating systemic versus localized kidney

complement activation. My career development plan includes dedicated time to 1) train and gain experience in conducting patient-oriented research and clinical trials; 2) work with a multidisciplinary team of experts in Adult and Pediatric Nephrology, Emergency/Critical Care, and Biostatistics; 3) pursue training in biostatistics and

biomarker analytics; 4) gain skills in interpretation of complement quantification methods; 5) develop professional skills including manuscript preparation, grant writing, presentation skills, etc.; and 6) establish the foundation for an independent research career aimed at improving outcomes for critically ill patients with SA-

AKI. My training environment is outstanding with mentorship from Dr. Kendrick, an adult nephrologist with clinical research expertise and a strong record of successful mentoring, and co-mentors Drs. Thurman and You, as well as a robust team of methods advisors. At the completion of this project, I will be well-equipped to

develop an independent research program focused on intervenable mechanisms that relate sepsis with AKI.