Genetic Analyses in Small for Gestational Age Newborns

Context: Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more CNVs and disturbed methylation and sequence variants may be present in genes known to be associated with fetal growth. Design: A prospective cohort study of subjects with a low birthweight for gestational age. Setting: The study was conducted at an academic pediatric research institute. Patients: A total of 21 SGA newborns with a mean birthweight below the 1st centile and a control cohort of 24 appropriate for gestational age newborns were studied. Intervention: Array comparative genomic hybridization, genome-wide methylation studies and exome sequencing were performed. Main Outcome Measures The numbers of copy number variations, methylation disturbances and sequence variants. Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern and one sequence variant explaining the SGA. Additional methylation disturbances and sequence variants were present 20 patients. In 19 patients, multiple abnormalities were found. Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We conclude that copy number variations, methylation disturbances and sequence variants all contribute to prenatal growth failure. Such genetic workup can be an effective diagnostic approach in SGA newborns

Bench-to-bedside review: Ventilation-induced renal injury through systemic mediator release - just theory or a causal relationship?

We review the current literature on the molecular mechanisms involved in the pathogenesis of acute kidney injury induced by plasma mediators released by mechanical ventilation. A comprehensive literature search in the PubMed database was performed and articles were identified that showed increased plasma levels of mediators where the increase was solely attributable to mechanical ventilation. A subsequent search revealed articles delineating the potential effects of each mediator on the kidney or kidney cells. Limited research has focused specifically on the relationship between mechanical ventilation and acute kidney injury. Only a limited number of plasma mediators has been implicated in mechanical ventilation-associated acute kidney injury. The number of mediators released during mechanical ventilation i

Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria

OBJECTIVE: The present study was undertaken to evaluate the practicability of the proposed pediatric RIFLE (pRIFLE) criteria in a patient population at risk for acute kidney injury (AKI) and to analyze the prevalence and association of AKI as defined by pRIFLE with mortality. DESIGN: Retrospective, descriptive cohort study. SETTING: Single-center, 9-bed PICU facility. PATIENTS: Children with respiratory failure requiring mechanical ventilation for more than 4 days admitted between January 2002 and December 2006. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Data of 103 patients were studied. Median age was 4.5 years (range 1 month-17 years). Six patients received renal replacement therapy. Seventeen patients (17%) died. Sixty patients (58%) developed AKI by pRIFLE. Mean time to attainment of the first RIFLE stratum was 1.9 +/- 1.6 days. By pRIFLE, 34 of the 60 patients fulfilled the maximum AKI criteria on the first day after admission based on the estimated creatinine clearance criterion. Patients with AKI according to the pRIFLE scoring system had five times higher mortality than patients without AKI (25 vs. 5%, P < 0.05). CONCLUSIONS: We observed a high incidence of significant AKI in a PICU population at risk, which was associated with high mortality. Pediatric RIFLE criteria may guide in the early identification of patients at risk for AKI and in the initiation of therapy

Effect of acute renal failure on outcome in children with severe septic shock

Acute renal failure (ARF) requiring renal replacement therapy (RRT) has been associated with an excess risk of mortality in adult patients with septic shock, but it is unknown whether this is also applicable to pediatric patients. We therefore conducted a retrospective pilot study. All children presenting with septic shock between 1st January 1998 and 1st April 2004 were analyzed. Patients with fluid refractory-dopamine resistant shock, necessitating the use of noradrenaline, were included. ARF was defined as the deterioration of renal function to the extent that renal replacement therapy was required (ARF group). This ARF group was compared with patients without ARF (non-ARF group). Out of the 22 children with severe septic shock, seven developed ARF. PIM2 and PRISM scores upon admission were comparable between both groups. Mortality rates were significantly higher in patients with ARF (57.1% vs 6.7%; p=0.02). Pediatric patients with severe septic shock developing ARF have excess mortality compared to pediatric patients who do not develop ARF, although on diagnosis, severity of underlying disease and calculated risk of mortality were comparable. A multicenter trial is necessary to confirm these findings and to determine the contribution of ARF to pediatric sepsis mortality