Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Courtney Fletcher, PharmD

Second Advisor

Lani Zimmerman, PhD

Third Advisor

Kimberly Scarsi, PharmD, MS

Fourth Advisor

DJ Murry, PharmD

MeSH Headings

pediatrics, acute kidney injury, renal biomarkers, therapeutic drug monitoring, pharmacokinetics

Abstract

Acute kidney injury (AKI) is a serious and common complication in critically ill pediatric patients. The incidence of pediatric AKI continues to increase, especially in patients who undergo surgical correction of congenital heart defects. Serum creatinine and urine output are the most commonly used tools to assess renal function, with international guidelines standardizing AKI-definitions based upon these parameters. However, changes in serum creatinine can occur 24 hours or later after a renal insult event, delaying the diagnosis and potential interventions to reverse injury. It is critical to identify endogenous renal biomarkers within the pediatric population that are both timely and accurate in the early stages of AKI. Further, it is important to begin to examine the relationship of AKI biomarkers and glomerular filtration rate (GFR), independent of creatinine. The potential use of renal biomarkers to estimate GFR can further direct clinicians to adjust medications that are renally eliminated, especially medications that require therapeutic drug monitoring. There are a growing number of pediatric medications that warrant therapeutic drug monitoring to optimize clinical outcomes. Milrinone, a phosphodiesterase inhibitor which increases cardiac output following cardiac surgery, is such an agent. Emerging evidence suggests that milrinone has a targeted therapeutic range, yet therapeutic drug monitoring is rarely performed despite the inter-subject variability between dose and concentration. Early identification of patients developing AKI through the use of renal biomarkers can assist clinicians in initiating therapeutic drug monitoring, especially for those medications with a narrow therapeutic index or in those agents where a therapeutic range has not been formally established. In addition, the adoption of AKI biomarkers into pharmacokinetic modeling programs has the potential to optimize milrinone therapeutic drug monitoring. This proof-of-concept dissertation begins to explore the potential use of renal biomarkers in pediatric AKI to guide therapeutic drug monitoring of milrinone, the challenges of conducting pediatric clinical research, and the need for future clinical studies to assess GFR in the pediatric patient population.

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