A risk-stratified assessment of biomarker-based acute kidney injury phenotypes in children.

BACKGROUND: The functional acute kidney injury (AKI) diagnostic tests serum creatinine (SCr) and urine output are imprecise and make management challenging. Combining tubular injury biomarkers with functional markers reveal AKI phenotypes that may facilitate personalized care. However, when and in whom to obtain injury biomarkers remains unclear. METHODS: This was a prospective, observational study of patients admitted to a pediatric intensive care unit (PICU). Using the Renal Angina Index (RAI), subjects were screened for the presence (RAI+) or absence (RAI-) of renal angina 12 h post-admission and assigned an AKI phenotype using urinary NGAL (NGAL+: ≥150 ng/ml) and SCr (SCr+: ≥KDIGO Stage 1). Outcomes for each AKI phenotype were assessed and compared by RAI status. RESULTS: In all, 200/247 (81%) subjects were RAI+. RAI+ subjects who were NGAL+ had higher risk of Day 3 AKI, renal replacement therapy use, and mortality and fewer ventilator- and PICU-free days, compared to NGAL-, irrespective of Day 0 SCr. Similar findings were not demonstrated in RAI- subjects, though NGAL+/SCr+ was associated with fewer ventilator- and PICU-free days compared to NGAL-/SCr+. CONCLUSIONS: NGAL- and SCr-based AKI phenotypes provide improved prognostic information in children with renal angina (RAI+) and/or with SCr elevation. These populations may be appropriate for targeted biomarker testing. IMPACT: New consensus recommendations encourage the integration of kidney tubular injury biomarkers such as urinary NGAL with serum creatinine for diagnosis and staging of acute kidney injury; however, no structured testing framework exists guiding when to test and in whom. Urinary NGAL- and serum creatinine-based acute kidney injury phenotypes increase diagnostic precision in critically ill children experiencing renal angina (RAI+) or serum creatinine-defined acute kidney injury. These data provide preliminary evidence for a proposed framework for directed urinary NGAL assessment in the pediatric intensive care unit.

Use of extracorporeal immunomodulation in a toddler with hemophagocytic lymphohistiocytosis and multisystem organ failure.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a dysregulated immune disorder in children, associated with Epstein-Barr virus (EBV) infection or malignancies. In severe forms, HLH presents with signs and symptoms of hyperinflammation that progress to life-threatening multiorgan failure. Intervention with an extracorporeal immunomodulatory treatment utilizing a selective cytopheretic device (SCD) could be beneficial. The SCD with regional citrate anticoagulation selectively binds the most highly activated circulating neutrophils and monocytes and deactivates them before release to the systemic circulation. Multiple clinical studies, including a multicenter study in children, demonstrate SCD therapy attenuates hyperinflammation, resolves ongoing tissue injury and allows progression to functional organ recovery. We report the first case of SCD therapy in a patient with HLH and multi-organ failure. CASE DIAGNOSIS/TREATMENT: A previously healthy 22-month-old toddler presented with fever, abdominal distension, organomegaly, pancytopenia, and signs of hyperinflammation. EBV PCR returned at > 25 million copies. The clinical and laboratory pictures were consistent with systemic EBV-positive T-cell lymphoma with symptoms secondary to HLH. The patient met inclusion criteria for an ongoing study of integration of the SCD with a continuous kidney replacement therapy (CKRT) as part of standard of care. The patient received CKRT-SCD for 4 days with normalization of serum markers of sepsis and inflammation. The patient underwent hematopoietic stem cell transplantation 52 days after presentation and has engrafted with normal kidney function 8 months later. CONCLUSIONS: SCD treatment resulted in improvement of poor tissue perfusion reflected by rapid decline in serum lactate levels, lessened systemic capillary leak with discontinuation of vasoactive agents, and repair and recovery of lung and kidney function with extubation and removal of hemodialysis support.

Association between Elevated Urine Neutrophil Gelatinase-Associated Lipocalin and Postoperative Acute Kidney Injury in Neonates.

OBJECTIVE: To examine the incidence of postoperative neonatal acute kidney injury (AKI) following general surgical procedures and to test the hypothesis that postoperative urine neutrophil gelatinase-associated lipocalin (uNGAL) concentrations predict AKI. The secondary objective was to evaluate for an association between AKI and hospital mortality. STUDY DESIGN: Prospective observational study of infants undergoing abdominal and thoracic surgical procedures in the neonatal intensive care unit from October 2018 to March 2020. The primary outcome was incidence of neonatal AKI (defined by the neonatal modified Kidney Diseases Improving Global Outcomes criteria) following each procedure to postoperative day 5. Severe AKI was defined as stage 2 or 3 AKI. Urine samples were obtained pre- and postoperatively at 6 time points to evaluate for levels of uNGAL. Secondary outcomes were in-hospital mortality and length of stay. RESULTS: Subjects (n = 141) underwent a total of 192 general surgical procedures during the study period. Neonatal AKI and severe AKI occurred following 36 (18%) and 15 (8%) procedures (n = 33 subjects). Percent change of uNGAL from 24 hours preoperatively to 24 hours postoperatively was greater in subjects with neonatal AKI (190.2% [IQR 0.0, 1666.7%] vs 0.7% [IQR -31.2%,140.2%], P = .0374). The strongest association of uNGAL and AKI occurred at 24 hours postoperatively (area under the receiver operator curves of 0.81, 95% CI 0.72, 0.89). Increased mortality risk was observed in subjects with any postoperative AKI (aOR 11.1 95% CI 2.0, 62.8, P = .0063) and severe AKI (aOR 13.8; 95% CI 3.0, 63.1, P = .0007). CONCLUSION: Elevation in uNGAL 24 hours postoperative was associated with AKI. Neonates with postoperative AKI had increased mortality.

Urinary neutrophil gelatinase-associated lipocalin rules out nephrotoxic acute kidney injury in children.

BACKGROUND: Nephrotoxic medication exposure is a common cause of acute kidney injury (AKI) in hospitalized children. A key component of the NINJA quality improvement initiative is systematic daily serum creatinine assessment in non-critically ill children exposed to ≥ 3 nephrotoxic medications on 1 day, or intravenous aminoglycoside or vancomycin for ≥ 3 days. Daily venipuncture is invasive and associated with disposable and personnel healthcare costs. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a marker of renal tubular injury associated with certain nephrotoxic medications. We investigated whether uNGAL is a reliable screening tool for AKI in NINJA and could decrease the need for daily venipuncture. METHODS: This two-center prospective study enrolled 113 children who met NINJA criteria from May 2018 through March 2019. Daily urine samples were obtained for up to the first 7 days of qualifying exposure and 2 days after exposure ended. Our primary outcome was severe AKI (KDIGO stage 2 or 3 AKI). Maximum uNGAL was highest concentration on the day of, or 3 days prior to, severe AKI. The highest uNGAL level from all assessment days was used for patients who did not develop AKI or severe AKI. RESULTS: Urine NGAL thresholds of 150 and 300 ng/ml demonstrated excellent specificity (92.4 and 97.1% respectively) and negative predictive values (93.3 and 92.8% respectively) for ruling out severe AKI. CONCLUSIONS: We suggest that uNGAL could be used to supplant some of the daily serum creatinine venipunctures in NINJA. The most optimal combination of serum creatinine and uNGAL assessment requires further study.

Characterization of the Glucocorticoid Receptor in Children Undergoing Cardiac Surgery.

OBJECTIVES: Postoperative administration of corticosteroids is common practice for managing catecholamine refractory low cardiac output syndrome. Since corticosteroid activity is dependent on the glucocorticoid receptor, we sought to characterize glucocorticoid receptor levels in children undergoing cardiac surgery and examined the association between glucocorticoid receptor levels and cardiovascular dysfunction. DESIGN: Prospective observational cohort study. SETTING: Large, tertiary pediatric cardiac center. SUBJECTS: Children undergoing corrective or palliative cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A prospective observational cohort study was conducted in 83 children with congenital heart disease. Total glucocorticoid receptor levels were measured in the peripheral WBCs using flow cytometry. In addition, blood samples were collected for total cortisol levels. The primary outcome studied was the time to being inotrope free. An increase in glucocorticoid receptor level from postoperative day 1 to postoperative day 3 was associated with a longer time to being inotrope free (hazard ratio, 0.49 [0.29-0.81]; p = 0.01) in the univariate analysis. This association remained significant after adjusting for age, weight, cardiopulmonary bypass time, cross clamp time, Risk Adjustment for Congenital Heart Surgery-1 score, and postoperative steroid use (hazard ratio, 0.53 [0.29-0.99]; p = 0.05). Postoperative day 3 glucocorticoid receptor level showed a trend to have longer time to being inotrope free (hazard ratio, 0.66 [0.42-1.02]; p = 0.0.06). The cortisol levels minimally increased during the study duration and did not correlate with glucocorticoid receptor levels. CONCLUSIONS: Increasing glucocorticoid receptor levels in peripheral WBCs of children undergoing cardiac surgery are associated with a longer time to being inotrope free. Cortisol levels minimally increased during the study duration. These results suggest that exposure to high-dose perioperative corticosteroids may suppress the hypothalamic-pituitary-adrenal axis leading to increase in glucocorticoid receptor levels in response to a low cortisol environment. Further studies are required to better delineate the interplay between glucocorticoid receptor levels, cortisol levels, corticosteroid exposure, and postoperative inotropic requirements.