Fetal High-Risk APOL1 Genotype Increases Risk for Small for Gestational Age in Term Infants Affected by Preeclampsia.

BACKGROUND: Hypertensive disorders of pregnancy cause fetal growth restriction and increased maternal morbidity and mortality, especially in women of African ancestry. Recently, preeclampsia risk was associated with polymorphisms in the apolipoprotein L1 (APOL1) gene in women of African ancestry. OBJECTIVES: We assessed APOL1 genotype effects on pregnancies with and without preeclampsia. METHOD: We conducted an unmatched case-control study of 1,358 mother-infant pairs from two independent cohorts of black women. RESULTS: Term preeclampsia cases with high-risk APOL1 genotypes were more likely to be small for gestational age compared to APOL1 low-risk term cases (odds ratio [OR] 2.8) and APOL1 high-risk controls (OR 5.5). Among preterm pregnancies, fetal APOL1 genotype was associated with preeclampsia. CONCLUSIONS: Fetal APOL1 genotype was associated with preeclampsia in preterm infants and with altered fetal growth in term infants. This may indicate APOL1 genotype impacts a spectrum of pregnancy complications mediated by a common pathophysiological event of placental insufficiency.

Differences in Serum Alkaline Phosphatase Levels in Infants with Spontaneous Intestinal Perforation versus Necrotizing Enterocolitis with Perforation.

INTRODUCTION: Data on laboratory markers of spontaneous intestinal perforation (SIP) and necrotizing enterocolitis (NEC) remain sparse. OBJECTIVE: To compare serum alkaline phosphatase levels in infants with bowel perforation secondary to SIP versus surgical NEC, and then investigate the possible role of serum alkaline phosphatase in differentiating infants with these conditions. METHODS: A retrospective case-control study of infants admitted with bowel perforation from 2005 to 2015. Demographic and prenatal data, postnatal exposures, and clinical, laboratory, and radiographic findings were extracted from inpatient medical records and analyzed using regression analysis. RESULTS: Of 114 outborn infants included, 48 infants had SIP (cases) and 66 had NEC (controls). Upon admission from the referring hospital, the serum alkaline phosphatase level was significantly higher in infants with SIP, i.e., a median value of 782 versus236 U/L in NEC patients (p < 0.0001), with an adjusted odds ratio (OR) of 4.3 (p < 0.05) when the level was >500 U/L in multivariate regression model. Infants with SIP had significantly younger gestational age, presented earlier in life, primarily with pneumoperitoneum, and had greater exposure to steroids and indomethacin compared to infants with NEC. Alkaline phosphatase levels decreased rapidly in infants with SIP following admission. CONCLUSION: A transient increase in serum alkaline phosphatase level is independently associated with SIP when compared to NEC. Studies to confirm the role of alkaline phosphatase in the diagnosis of SIP are necessary and have potentially significant clinical and prognostic implications.

Association of preeclampsia with infant APOL1 genotype in African Americans.

BACKGROUND: Black women in the United States and Africa are at an increased risk for preeclampsia. Allelic variants in the gene for apolipoprotein LI, APOL1, are found only in populations of African ancestry, and have been shown to contribute significant risk for kidney disease. Recent studies suggest these APOL1 variants also may contribute risk for preeclampsia. METHODS: The association of preeclampsia with carriage of APOL1 risk alleles was evaluated in a case-control study of deliveries from black women at a single center in Cleveland, Ohio that included gross and histopathologic evaluations of placental tissues (395 cases and 282 controls). Using logistic regression models, associations between fetal APOL1 genotype and preeclampsia were evaluated using several case definitions based on prematurity and severity of preeclampsia, with uncomplicated term pregnancies as controls. Associations between APOL1 genotype and pathological features were also examined. RESULTS: The infant APOL1 genotype was significantly associated with preeclampsia in a dominant inheritance pattern with odds ratio of 1.41 (P=0.029, 95% CI 1.037, 1.926). Stratifying preeclampsia cases by preterm birth, significant associations were detected for both recessive (O.R.=1.70, P=0.038) and additive (O.R.=1.33, P=0.028) inheritance patterns. APOL1 genotype, however, was not significantly associated with pathological changes or other perinatal observations. CONCLUSIONS: Preeclampsia appears to be another disease associated with APOL1 variants, however, further studies are needed to increase confidence in the mode of inheritance. By understanding the association of APOL1 variants with preeclampsia, genetic screening tests for APOL1 may be useful to predict at-risk pregnancies and targeted interventions may be developed to improve pregnancy outcomes.

Transitional Hemodynamics in Preterm Neonates: Clinical Relevance.

BACKGROUND: Each newborn enters this world facing tremendous respiratory, hemodynamic and neuroendocrine challenges while going through drastic physiological changes during the process of adaption from fetal to postnatal life. Even though the vast majority of term infants transition smoothly without apparent consequences, this task becomes increasingly arduous for the extremely preterm infant. METHODS & RESULTS: This article reviews the physiology and pathophysiology of cardiovascular adaptation of the very preterm neonate. In particular it describes the physiology of fetal circulation, summarizes the hemodynamic changes occurring during preterm births and discusses the impact of the most frequently seen clinical scenarios that place additional burden on the premature infant during immediate transition. Finally an emphasis is placed on discussing common clinical dilemmas and practical aspects of developmental hemodynamics such as neonatal hypotension and patent ductus arteriosus; clinical presentations the neonatologist encounters on a daily basis. CONCLUSION: The review provides a physiology-based view on the hemodynamics of the immediate postnatal transitional period.

Hemodynamic monitoring of the critically ill neonate: An eye on the future.

By continuous assessment of dynamic changes in systemic and regional perfusion during transition to extrauterine life and beyond, comprehensive neonatal hemodynamic monitoring creates numerous opportunities for both clinical and research applications. In particular, it has the potential of providing additional details about physiologic interactions among the key hemodynamic factors regulating systemic blood flow and blood flow distribution along with the subtle changes that are frequently transient in nature and would not be detected without such systems in place. The data can then be applied for predictive mathematical modeling and validation of physiologically realistic computer models aiming to identify patient subgroups at higher risk for adverse outcomes and/or predicting the response to a particular perturbation or therapeutic intervention. Another emerging application that opens an entirely new era in hemodynamic research is the use of the physiometric data obtained by the monitoring and data acquisition systems in conjunction with genomic information.

Transitional cardiovascular physiology and comprehensive hemodynamic monitoring in the neonate: relevance to research and clinical care.

A thorough understanding of developmental cardiovascular physiology is essential for early recognition of cardiovascular compromise, selective screening of at-risk groups of neonates, and individualized management using pathophysiology-targeted interventions. Although we have gained a better understanding of the physiology and pathophysiology of postnatal cardiovascular transition over the past decade with the use of sophisticated methods to study neonatal hemodynamics, most aspects of neonatal hemodynamics remain incompletely understood. In addition, targeted therapeutic interventions of neonatal hemodynamic compromise have not been shown to improve mortality and clinically relevant outcomes. However, the recent development of comprehensive hemodynamic monitoring systems capable of non-invasive, continuous and simultaneous bedside assessment of cardiac output, organ blood flow, microcirculation, and tissue oxygen delivery has made sophisticated analysis of the obtained physiologic data possible and has created new research opportunities with the potential of direct implications to patient care.

Risk factors associated with acute kidney injury in extremely low birth weight (ELBW) infants.

The aim of this study was to determine the incidence, risk factors, and outcome of acute kidney injury (AKI) in extremely low birth weight (ELBW) infants. In a case-control study, medical records of all ELBW infants who were admitted to our Neonatal Intensive Care Unit (NICU) between 1 January 2000 and 31 January 2008 were reviewed. During the study period, 12.5% (59/472) of all ELBW infants developed AKI. Forty-six infants with available medical records were matched to 46 controls. The mean gestational age and birth weight of infants with AKI and their controls were 24.7 ± 1.8 vs. 24.9 ± 1.9 weeks (p = 0.61) and 614 ± 128 vs. 616 ± 127 g (p = 0.93), respectively. Infants with AKI had a higher mean airway pressure, a lower mean arterial blood pressure, and higher exposure to cefotaxime than their controls. Infants with AKI also had an increased mortality in comparison to their controls [33/46 (70%) vs. 10/46 (22%), respectively; p < 0.0001), and oliguric patients had a higher mortality than nonoliguric patients [31/38 (81%) vs. 2/8 (25%), respectively, p = 0.003]. Based on our results, we conclude that a high mean airway pressure, low blood pressure, and the use of cefotaxime are associated with renal failure in ELBW infants. AKI in ELBW infants is also associated with an increased mortality, especially in the presence of oliguria.

TM4SF10 and ADAP interaction in podocytes: role in Fyn activity and nephrin phosphorylation.

TM4SF10 [transmembrane tetra(4)-span family 10] is a claudin-like cell junction protein that is transiently expressed during podocyte development where its expression is downregulated in differentiating podocytes coincident with the appearance of nephrin at the slit diaphragm. In a yeast two-hybrid screen, we identified adhesion and degranulation-promoting adaptor protein (ADAP), a well-known Fyn substrate and Fyn binding partner, as a TM4SF10 interacting protein in mouse kidney. Using coimmunoprecipitation and immunohistochemistry experiments in cultured human podocytes, we show that TM4SF10 colocalizes with Fyn and ADAP but does not form a stable complex with Fyn. Cytoskeletal changes and phosphorylation events mediated by Fyn activity were reversed by TM4SF10 overexpression, including a decrease in the activating tyrosine phosphorylation of Fyn (Y(421)), suggesting TM4SF10 may have a regulatory role in suppressing Fyn activity. In addition, TM4SF10 was reexpressed following podocyte injury by puromycin aminonucleoside treatment, and its expression enhanced the abundance of high-molecular-weight forms of nephrin indicating it may participate in a mechanism controlling nephrin's appearance at the plasma membrane. Therefore, these studies have identified ADAP as another Fyn adapter protein expressed in podocytes, and that TM4SF10, possibly through ADAP, may regulate Fyn activity. Since TM4SF10 expression is temporally regulated during kidney development, these studies may help define a mechanism by which the slit diaphragm matures as a highly specialized cell junction during podocyte differentiation.