BackgroundSingle-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.MethodsAll 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.FindingsIncidence 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].InterpretationNeonatal 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.FundingUS National Institutes of Health, University of Alabama at Birmingham, Cincinnati Children’s, University of New Mexico.
SUMMARY Acute kidney injury (AKI) is an under-recognized morbidity of neonates; the incidence remains unclear due to the absence of a unified definition of AKI in this population and because previous studies have varied greatly in screening for AKI with serum creatinine and urine output assessments. Premature infants may be born with less than half of the nephrons compared with term neonates, predisposing them to chronic kidney disease (CKD) early on in life and as they age. AKI can also lead to CKD, and premature infants with AKI may be at very high risk for long-term kidney problems. AKI in neonates is often multifactorial and may result from prenatal, perinatal, or postnatal insults as well as any combination thereof. This review focuses on the causes of AKI, the importance of early detection, the management of AKI in neonates, and long-term sequela of AKI in neonates.
Background Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD) and has a proposed genetic etiology. BAV is categorized by cusp fusion with Right-Left (R-L) cusp fusion being associated with additional CHD and Right-Noncoronary cusp (R-NC) fusion being associated with aortic valve dysfunction. Loss of murine Gata5, which encodes a cardiac transcription factor, results in a partially penetrant R-NC BAV, and we hypothesize that mutations in GATA5 are associated with R-NC BAV in humans. Methods A cohort of 78 BAV patients (50 with isolated BAV and 28 with associated aortic coarctation) was analyzed using Sanger sequencing to identify GATA5 sequence variants. Biochemical assays were performed to identify functional deficits of identified sequence variants. Results We identified two rare heterozygous non-synonymous variants, p.Gln3Arg and p.Leu233Pro, for a frequency of 2.6% (2/78). Both individuals with non-synonymous variants had BAV and aortic coarctation, one R-L and one R-NC subtype. Of the non-synonymous variants, only p.Gln3Arg demonstrated decreased transcriptional activity in vitro. Conclusions Rare sequence variants in GATA5 are associated with human BAV. Our findings suggest a genotype-phenotype correlation in regards to associated CHD but not cusp fusion.
BackgroundBicuspid aortic valve (BAV) is the most common type of congenital heart disease with a population prevalence of 1-2%. While BAV is known to be highly heritable, mutations in single genes (such as GATA5 and NOTCH1) have been reported in few human BAV cases. Traditional gene sequencing methods are time and labor intensive, while next-generation high throughput sequencing remains costly for large patient cohorts and requires extensive bioinformatics processing. Here we describe an approach to targeted multi-gene sequencing with combinatorial pooling of samples from BAV patients.MethodsWe studied a previously described cohort of 78 unrelated subjects with echocardiogram-identified BAV. Subjects were identified as having isolated BAV or BAV associated with coarctation of aorta (BAV-CoA). BAV cusp fusion morphology was defined as right-left cusp fusion, right non-coronary cusp fusion, or left non-coronary cusp fusion. Samples were combined into 19 pools using a uniquely overlapping combinatorial design; a given mutation could be attributed to a single individual on the basis of which pools contained the mutation. A custom gene capture of 97 candidate genes was sequenced on the Illumina HiSeq 2000. Multistep bioinformatics processing was performed for base calling, variant identification, and in-silico analysis of putative disease-causing variants.ResultsTargeted capture identified 42 rare, non-synonymous, exonic variants involving 35 of the 97 candidate genes. Among these variants, in-silico analysis classified 33 of these variants as putative disease-causing changes. Sanger sequencing confirmed thirty-one of these variants, found among 16 individuals. There were no significant differences in variant burden among BAV fusion phenotypes or isolated BAV versus BAV-CoA. Pathway analysis suggests a role for the WNT signaling pathway in human BAV.ConclusionWe successfully developed a pooling and targeted capture strategy that enabled rapid and cost effective next generation sequencing of target genes in a large patient cohort. This approach identified a large number of putative disease-causing variants in a cohort of patients with BAV, including variants in 26 genes not previously associated with human BAV. The data suggest that BAV heritability is complex and polygenic. Our pooling approach saved over $39,350 compared to an unpooled, targeted capture sequencing strategy.
BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.
16 on behalf of the Neonatal Kidney Collaborative BACKGROUND: We evaluated the epidemiology of fluid balance (FB) over the first postnatal week and its impact on outcomes in a multi-center cohort of premature neonates from the AWAKEN study. METHODS: Retrospective analysis of infants <36 weeks' gestational age from the AWAKEN study (N = 1007). FB was defined by percentage of change from birth weight. Outcome: Mechanical ventilation (MV) at postnatal day 7. RESULTS: One hundred and forty-nine (14.8%) were on MV at postnatal day 7. The median peak FB was 0% (IQR: −2.9, 2) and occurred on postnatal day 2 (IQR: 1,5). Multivariable models showed that the peak FB (aOR 1.14, 95% CI 1.10-1.19), lowest FB in first postnatal week (aOR 1.12, 95% CI 1.07-1.16), and FB on postnatal day 7 (aOR 1.10, 95% CI 1.06-1.13) were independently associated with MV on postnatal day 7. In a similar analysis, a negative FB at postnatal day 7 protected against the need for MV at postnatal day 7 (aOR 0.21, 95% CI 0.12-0.35). CONCLUSIONS: Positive peak FB during the first postnatal week and more positive FB on postnatal day 7 were independently associated with MV at postnatal day 7. Those with a negative FB at postnatal day 7 were less likely to require MV.
15 on behalf of the Neonatal Kidney Collaborative BACKGROUND: In sick neonates admitted to the NICU, improper fluid balance can lead to fluid overload. We report the impact of fluid balance in the first postnatal week on outcomes in critically ill near-term/term neonates. METHODS: This analysis includes infants ≥36 weeks gestational age from the Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN) study (N = 645). Fluid balance: percent weight change from birthweight. Primary outcome: mechanical ventilation (MV) on postnatal day 7. RESULTS: The median peak fluid balance was 1.0% (IQR: −0.5, 4.6) and occurred on postnatal day 3 (IQR: 1, 5). Nine percent required MV at postnatal day 7. Multivariable models showed the peak fluid balance (aOR 1.12, 95%CI 1.08-1.17), lowest fluid balance in 1st postnatal week (aOR 1.14, 95%CI 1.07-1.22), fluid balance on postnatal day 7 (aOR 1.12, 95%CI 1.07-1.17), and negative fluid balance at postnatal day 7 (aOR 0.3, 95%CI 0.16-0.67) were independently associated with MV on postnatal day 7. CONCLUSIONS: We describe the impact of fluid balance in critically ill near-term/term neonates over the first postnatal week. Higher peak fluid balance during the first postnatal week and higher fluid balance on postnatal day 7 were independently associated with MV at postnatal day 7.
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