Near Patient Acute Kidney Injury Biomarker Analysis in Critically Ill Neonates

Acute kidney injury (AKI) contributes to mortality and morbidity in critically ill neonates. The identification and treatment of AKI are currently based on serum creatinine (sCr) levels; however, mounting evidence suggests that sCr alone is insufficient to predict or prevent renal injury. sCr is in fact a measure of renal function, not injury; sCr levels usually rise many hours after a renal injury, require a substantial magnitude of renal dysfunction for detection and are diminished by fluid overload. Earlier detection of acute kidney injury, coupled with improved characterization of the underlying etiology, may halt the progression to severe kidney injury and improve long term damage. Measurement of sCr levels alone is insufficient to achieve this goal. In response to RFA-18-028, this Fast-Track SBIR project aims to develop a novel microfluidic platform (FINDER) for near patient, minimally invasive analyses of multiple AKI biomarkers in critically ill neonates. The system will rapidly and simultaneously measure creatinine (Cr) plus four highly specific AKI biomarkers (Neutrophil Gelatinase-Associated Lipocalin, NGAL; Cystatin C, CysC; Interleukin-18, IL-18; and Kidney Injury Molecule-1, KIM-1) from a single (50 μl) drop of whole blood or urine. NGAL, CysC, IL-18 and KIM-1 each have different temporal profiles in relation to the duration of renal injury, and different magnitudes of increase depending upon the precipitating insult (e.g. ischemic vs. toxic). The combined analysis of Cr with these 4 biomarkers will provide critical information on the probable cause and temporal course of AKI and may help delineate ongoing injury vs. previous damage. The automated FINDER AKI system can be used in various distributed settings and will perform all assays in approximately 45 minutes. Results of the AKI system will allow clinicians to: (a) diagnose AKI; (b) differentiate the etiology of AKI; and (c) predict clinical outcomes of critically ill infants. The Specific Aims for Phase I of this project include: 1) develop an automated panel of assays for five critical AKI biomarkers (Cr, NGAL, CysC, IL-18 and KIM-1) on the single-use digital microfluidic cartridge; 2) perform preliminary analytical validations of each individual assay; and 3) demonstrate preliminary feasibility of the individual assays on discarded serum and urine samples. Upon successful completion of all assays on- cartridge with high reliability and precision, the focus of Phase II will be to: 1) optimize reagent formulations for on-cartridge drying and storage; 2) multiplex all assays to perform simultaneously on the same cartridge; and 3) preliminary clinical validation of the complete AKI testing panel by method comparison to standard reference tests. The final product will be commercializable for the rapid, efficient and accurate measurement of AKI biomarkers in both urine and blood from critically ill newborns. We will seek FDA approval of the final product, which will initially be marketed for use in pediatric patients in U.S. hospitals, with a potential future market towards other patients who may benefit from the innovative features of the platform.