Acute Renal Injury Sequelae in NICU Graduates (ARISING)

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The scientific premise for this proposal is that prenatal factors and neonatal acute kidney injury (nAKI) significantly contribute to chronic kidney disease (CKD) in neonatal intensive care unit (NICU) graduates. Our preliminary data suggests that up to 25% of neonates develop nAKI, which is associated with mortality and CKD. This NIDDK Multi-Center Clinical Study Implementation Planning Grant (U34) will enable us to achieve specific milestones in preparation for a U01-funded, multi-center, prospective cohort study. The Acute Renal Injury Sequela In NICU Graduates (ARISING) study will prospectively capture serum creatinine (SCr) systematically during the first postnatal week and during high-risk clinical scenarios in 1000 (125 across 8 GA strata) neonates admitted to the NICU. The project's central purpose is to bridge fundamental knowledge gaps in the field by providing reliable and precise methods to diagnose nAKI and predict CKD early in the life of NICU graduates. We propose the following 3 inter-related but independent specific aims. Aim 1: Validate a novel 2-stage neonatal AKI definition. The contemporary nAKI definition was not developed with neonatal kidney physiology in mind. Instead, it was adapted from the adult KDIGO AKI definition. Using a retrospective cohort, we developed a novel nAKI definition using the optimal SCr thresholds which predict mortality for different gestational age (GA) groups (≤29 and >29 week GA), and postnatal age (< 7 vs  7 days) Hypothesis 1a: The NKC mild nAKI definition will have greater sensitivity to predict mortality than the stage 1 KDIGO definition Hypothesis 1b: The NKC severe nAKI definition will have better specificity to predict mortality than the stage 2/3 KDIGO definition Aim 2: Determine if AKI is independently associated with CKD at 2 years corrected GA (cGA). Maternal and neonatal risk factors may predispose infants to both nAKI and CKD. We will determine the attributable risk of nAKI on CKD (estimated GFR<90 ml/min/1.73m2, urine protein/creatinine >0.2, blood pressure >95th%tile, and/or total kidney volume (TKV) <95th%tile at 2 years corrected gestational age (cGA). Our hypothesis is that nAKI is associated with a composite CKD after controlling for prenatal factors. Aim 3: Determine which variable(s) available prior to hospital discharge predict CKD at 2 years cGA. We will evaluate metrics of kidney health (TKV, BP, proteinuria, cystatin C, SCr and urine kidney biomarkers) at 38  1 week cGA for preterm and 44  1 weeks cGA for term infants. Our hypothesis is that we can predict with 90% certainty which infants will have composite CKD at 2 years cGA using biological/radiologic markers of kidney disease obtained at term cGA. Answers to these questions are greatly needed to help clinicians provide appropriate and timely care, and help researchers develop interventions designed to improve outcomes in this vulnerable population.