Browsing by Author "Askenazi, David J."
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Item Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates(American Medical Association, 2023-08-01) Starr, Michelle C.; Griffin, Russell L.; Harer, Matthew W.; Soranno, Danielle E.; Gist, Katja M.; Segar, Jeffrey L.; Menon, Shina; Gordon, Lindsey; Askenazi, David J.; Selewski, David T.; Pediatrics, School of MedicineImportance: Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI. Objective: To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes. Design, setting, and participants: This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022. Exposure: Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]). Main outcomes and measures: The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ2 test or Fisher exact test. The t test and Wilcoxon rank sums test were used to compare continuous and ordinal variables, respectively. Odds ratios (ORs) and 95% CIs for the association of exposure with outcomes of interest were estimated using unconditional logistic regression models. Results: A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64). Conclusions and relevance: In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance.Item Advances in Neonatal Acute Kidney Injury(AAP, 2021-11) Starr, Michelle C.; Charlton, Jennifer R.; Guillet, Ronnie; Reidy, Kimberly; Tipple, Trent E.; Jetton, Jennifer G.; Kent, Alison L.; Abitbol, Carolyn L.; Ambalavanan, Namasivayam; Mhanna, Maroun J.; Askenazi, David J.; Selewski, David T.; Harer, Matthew W.; Pediatrics, School of MedicineIn this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in “crosstalk” between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase–associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.Item Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates: A Secondary Analysis of a Randomized Clinical Trial(American Medical Association, 2022-12-01) Starr, Michelle C.; Griffin, Russell; Gist, Katja M.; Segar, Jeffrey L.; Raina, Rupesh; Guillet, Ronnie; Nesargi, Saudamini; Menon, Shina; Anderson, Nekayla; Askenazi, David J.; Selewski, David T.; Pediatrics, School of MedicineImportance: Extremely low gestational age neonates are at risk of disorders of fluid balance (FB), defined as change in fluid weight over a specific period. Few data exist on the association between FB and respiratory outcomes in this population. Objective: To describe FB patterns and evaluate the association of FB with respiratory outcomes in a cohort of extremely low gestational age neonates. Design, setting, and participants: This study is a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3 placebo-controlled randomized clinical trial of erythropoietin in extremely premature neonates conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 874 extremely premature neonates born at 24 to 27 weeks' gestation who were enrolled in the PENUT study. Secondary analysis was performed in November 2021. Exposures: Primary exposure was peak FB during the first 14 postnatal days. The FB was calculated as percent change in weight from birth weight (BW) as a surrogate for FB. Main outcomes and measures: The primary outcome was mechanical ventilation on postnatal day 14. The secondary outcome was a composite of severe bronchopulmonary dysplasia (BPD) or death. Results: A total of 874 neonates (449 [51.4%] male; mean [SD] BW, 801 [188] g; 187 [21.4%] Hispanic, 676 [77.3%] non-Hispanic, and 11 [1.3%] of unknown ethnicity; 226 [25.9%] Black, 569 [65.1%] White, 51 [5.8%] of other race, and 28 [3.2%] of unknown race) were included in this analysis. Of these 874 neonates, 458 (52.4%) received mechanical ventilation on postnatal day 14, and 291 (33.3%) had severe BPD or had died. Median peak positive FB was 11% (IQR, 4%-20%), occurring on postnatal day 13 (IQR, 9-14). A total of 93 (10.6%) never decreased below their BW. Neonates requiring mechanical ventilation at postnatal day 14 had a higher peak FB compared with those who did not require mechanical ventilation (15% above BW vs 8% above BW, P < .001). On postnatal day 3, neonates requiring mechanical ventilation were more likely to have a higher FB (5% below BW vs 8% below BW, P < .001). The median time to return to BW was shorter in neonates who received mechanical ventilation (7 vs 8 days, P < .001) and those with severe BPD (7 vs 8 days, P < .001). After adjusting for confounding variables, for every 10% increase in peak FB during the first 14 postnatal days, there was 103% increased odds of receiving mechanical ventilation at postnatal day 14 (adjusted odds ratio, 2.03; 95% CI, 1.64-2.51). Conclusions and relevance: In this secondary analysis of a randomized clinical trial, peak FB was associated with mechanical ventilation on postnatal day 14 and severe BPD or death. Fluid balance in the first 3 postnatal days and time to return to BW may be potential targets to help guide management and improve respiratory outcomes.Item Consensus-Based Recommendations on Priority Activities to Address Acute Kidney Injury in Children: A Modified Delphi Consensus Statement(American Medical Association, 2022-09-01) Goldstein, Stuart L.; Akcan-Arikan, Ayse; Alobaidi, Rashid; Askenazi, David J.; Bagshaw, Sean M.; Barhight, Matthew; Barreto, Erin; Bayrakci, Benan; Bignall, Orville N. R.; Bjornstad, Erica; Brophy, Patrick D.; Chanchlani, Rahul; Charlton, Jennifer R.; Conroy, Andrea L.; Deep, Akash; Devarajan, Prasad; Dolan, Kristin; Fuhrman, Dana Y.; Gist, Katja M.; Gorga, Stephen M.; Greenberg, Jason H.; Hasson, Denise; Heydari Ulrich, Emma; Iyengar, Arpana; Jetton, Jennifer G.; Krawczeski, Catherine; Meigs, Leslie; Menon, Shina; Morgan, Jolyn; Morgan, Catherine J.; Mottes, Theresa; Neumayr, Tara M.; Ricci, Zaccaria; Selewski, David; Soranno, Danielle E.; Starr, Michelle; Stanski, Natalja L.; Sutherland, Scott M.; Symons, Jordan; Tavares, Marcelo S.; Wong Vega, Molly; Zappitelli, Michael; Ronco, Claudio; Mehta, Ravindra L.; Kellum, John; Ostermann, Marlies; Basu, Rajit K.; Pediatric ADQI Collaborative; Pediatrics, School of MedicineImportance: Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge. Objective: To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy. Evidence review: At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations. Findings: The meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy. Conclusions and relevance: Existing evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.Item Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study(Elsevier, 2017-11) Jetton, Jennifer G.; Boohaker, Louis J.; Sethi, Sidharth K.; Wazir, Sanjay; Rohatgi, Smriti; Soranno, Danielle E.; Chishti, Aftab S.; Woroniecki, Robert; Mammen, Cherry; Swanson, Jonathan R.; Sridhar, Shanty; Wong, Craig S.; Kupferman, Juan C.; Griffin, Russell L.; Askenazi, David J.; Pediatrics, School of MedicineBackground: Single-center studies suggest that neonatal acute kidney injury (AKI) is associated with poor outcomes. However, inferences regarding the association between AKI, mortality, and hospital length of stay are limited due to the small sample size of those studies. In order to determine whether neonatal AKI is independently associated with increased mortality and longer hospital stay, we analyzed the Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) database. Methods: All neonates admitted to 24 participating neonatal intensive care units from four countries (Australia, Canada, India, United States) between January 1 and March 31, 2014, were screened. Of 4273 neonates screened, 2022 (47·3%) met study criteria. Exclusion criteria included: no intravenous fluids ≥48 hours, admission ≥14 days of life, congenital heart disease requiring surgical repair at <7 days of life, lethal chromosomal anomaly, death within 48 hours, inability to determine AKI status or severe congenital kidney abnormalities. AKI was defined using a standardized definition -i.e., serum creatinine rise of ≥0.3 mg/dL (26.5 mcmol/L) or ≥50% from previous lowest value, and/or if urine output was <1 mL/kg/h on postnatal days 2 to 7. Findings: Incidence of AKI was 605/2022 (29·9%). Rates varied by gestational age groups (i.e., ≥22 to <29 weeks =47·9%; ≥29 to <36 weeks =18·3%; and ≥36 weeks =36·7%). Even after adjusting for multiple potential confounding factors, infants with AKI had higher mortality compared to those without AKI [(59/605 (9·7%) vs. 20/1417 (1·4%); p< 0.001; adjusted OR=4·6 (95% CI=2·5-8·3); p=<0·0001], and longer hospital stay [adjusted parameter estimate 8·8 days (95% CI=6·1-11·5); p<0·0001]. Interpretation: Neonatal AKI is a common and independent risk factor for mortality and longer hospital stay. These data suggest that neonates may be impacted by AKI in a manner similar to pediatric and adult patients.Item Pediatric AKI in the real world: changing outcomes through education and advocacy-a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference(Springer, 2024) Mottes, Theresa; Menon, Shina; Conroy, Andrea; Jetton, Jennifer; Dolan, Kristin; Arikan, Ayse Akcan; Basu, Rajit K.; Goldstein, Stuart L.; Symons, Jordan M.; Alobaid, Rashid; Askenazi, David J.; Bagshaw, Sean M.; Barhight, Matthew; Barreto, Erin; Bayrakci, Benan; Bignall, O. N., II; Bjornstad, Erica; Brophy, Patrick; Charlton, Jennifer; Chanchlani, Rahul; Conroy, Andrea L.; Deep, Akash; Devarajan, Prasad; Fuhrman, Dana; Gist, Katja M.; Gorga, Stephen M.; Greenberg, Jason H.; Hasson, Denise; Heydari, Emma; Iyengar, Arpana; Krawczeski, Catherine; Meigs, Leslie; Morgan, Catherine; Morgan, Jolyn; Neumayr, Tara; Ricci, Zaccaria; Selewski, David T.; Soranno, Danielle; Stanski, Natalja; Starr, Michelle; Sutherland, Scott M.; Symons, Jordan; Tavares, Marcelo; Vega, Molly; Zappitelli, Michael; Ronco, Claudio; Mehta, Ravindra L.; Kellum, John; Ostermann, Marlies; ADQI 26 workgroup; Pediatrics, School of MedicineBackground: Acute kidney injury (AKI) is independently associated with increased morbidity and mortality across the life course, yet care for AKI remains mostly supportive. Raising awareness of this life-threatening clinical syndrome through education and advocacy efforts is the key to improving patient outcomes. Here, we describe the unique roles education and advocacy play in the care of children with AKI, discuss the importance of customizing educational outreach efforts to individual groups and contexts, and highlight the opportunities created through innovations and partnerships to optimize lifelong health outcomes. Methods: During the 26th Acute Disease Quality Initiative (ADQI) consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations on AKI research, education, practice, and advocacy in children. Results: The consensus statements developed in response to three critical questions about the role of education and advocacy in pediatric AKI care are presented here along with a summary of available evidence and recommendations for both clinical care and research. Conclusions: These consensus statements emphasize that high-quality care for patients with AKI begins in the community with education and awareness campaigns to identify those at risk for AKI. Education is the key across all healthcare and non-healthcare settings to enhance early diagnosis and develop mitigation strategies, thereby improving outcomes for children with AKI. Strong advocacy efforts are essential for implementing these programs and building critical collaborations across all stakeholders and settings.Item Premature infants born <28 weeks with acute kidney injury have increased bronchopulmonary dysplasia rates(Springer Nature, 2023) Starr, Michelle C.; Schmicker, Robert H.; Halloran, Brian A.; Heagerty, Patrick; Brophy, Patrick; Goldstein, Stuart L.; Juul, Sandra E.; Hingorani, Sangeeta; Askenazi, David J.; PENUT Trial Consortium; Pediatrics, School of MedicineBackground: Despite a growing understanding of bronchopulmonary dysplasia (BPD) and advances in management, BPD rates remain stable. There is mounting evidence that BPD may be due to a systemic insult, such as acute kidney injury (AKI). Our hypothesis was that severe AKI would be associated with BPD. Methods: We conducted a secondary analysis of premature infants [24-27 weeks gestation] in the Recombinant Erythropoietin for Protection of Infant Renal Disease cohort (N = 885). We evaluated the composite outcome of Grade 2/3 BPD or death using generalized estimating equations. In an exploratory analysis, urinary biomarkers of angiogenesis (ANG1, ANG2, EPO, PIGF, TIE2, FGF, and VEGFA/D) were analyzed. Results: 594 (67.1%) of infants had the primary composite outcome of Grade 2/3 BPD or death. Infants with AKI (aOR: 1.69, 95% CI: 1.16-2.46) and severe AKI (aOR: 2.05, 95% CI: 1.19-3.54). had increased risk of the composite outcome after multivariable adjustment Among 106 infants with urinary biomarkers assessed, three biomarkers (VEGFA, VEGFD, and TIE2) had AUC > 0.60 to predict BPD. Conclusions: Infants with AKI had a higher likelihood of developing BPD/death, with the strongest relationship seen in those with more severe AKI. Three urinary biomarkers of angiogenesis may have potential to predict BPD development. Impact: AKI is associated with lung disease in extremely premature infants, and urinary biomarkers may predict this relationship. Infants with AKI and severe AKI have higher odds of BPD or death. Three urinary angiogenesis biomarkers are altered in infants that develop BPD. These findings have the potential to drive future work to better understand the mechanistic pathways of BPD, setting the framework for future interventions to decrease BPD rates. A better understanding of the mechanisms of BPD development and the role of AKI would have clinical care, cost, and quality of life implications given the long-term effects of BPD.