Maroun J. Mhanna

Neonatal acute kidney injury

In recent years, there have been significant advancements in our understanding of acute kidney injury (AKI) and its impact on outcomes across medicine. Research based on single-center cohorts suggests that neonatal AKI is very common and associated with poor outcomes. In this state-of-the-art review on neonatal AKI, we highlight the unique aspects of neonatal renal physiology, definition, risk factors, epidemiology, outcomes, evaluation, and management of AKI in neonates. The changes in renal function with gestational and chronologic age are described. We put forth and describe the neonatal modified Kidney Diseases: Improving Global Outcomes AKI criteria and provide the rationale for its use as the standardized definition of neonatal AKI. We discuss risk factors for neonatal AKI and suggest which patient populations may warrant closer surveillance, including neonates <1500 g, infants who experience perinatal asphyxia, near term/ term infants with low Apgar scores, those treated with extracorporeal membrane oxygenation, and those requiring cardiac surgery. We provide recommendations for the evaluation and treatment of these patients, including medications and renal replacement therapies. We discuss the need for long-term follow-up of neonates with AKI to identify those children who will go on to develop chronic kidney disease. This review highlights the deficits in our understanding of neonatal AKI that require further investigation. In an effort to begin to address these needs, the Neonatal Kidney Collaborative was formed in 2014 with the goal of better understanding neonatal AKI, beginning to answer critical questions, and improving outcomes in these vulnerable populations.

Mechanism for substance P-induced relaxation of precontracted airway smooth muscle during development.

Release of substance P (SP) from sensory nerve endings of the tracheobronchial system modulates airway smooth muscle contraction and may cause relaxation of precontracted airways. We sought to elucidate the effect of postnatal maturation on SP-induced relaxation of precontracted airways and determine the roles of endogenously generated nitric oxide (NO) and prostaglandins (PGs). Cylindrical airway segments were isolated from the midtrachea of rats at four different ages, 1, 2, and 4 wk and 3 mo, and contracted to 50-75% of the maximum response induced by bethanechol. SP was then administered in the absence and presence of the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME), the PG inhibitor indomethacin, or both. Relaxation of airways with SP decreased significantly with advancing postnatal age. SP-induced tracheal relaxation was consistently attenuated by pretreatment withl-NAME, indomethacin, or both. In a different group of animals,l-NAME significantly attenuated the relaxant response of airways to PGE2 exposure, but indomethacin had no significant effect on the relaxant response to exogenous NO. We conclude that SP induces a relaxant effect on precontracted airway smooth muscle, which decreases with advancing age and is mediated via SP-induced release of NO and/or PG.

Early and late postnatal identification of isolated lenticulostriate vasculopathy in preterm infants: associated findings.

OBJECTIVES: To determine the incidence, possible etiologies, and neurodevelopmental outcome of premature infants (<35 weeks) with isolated lenticulostriate vasculopathy (LSV).STUDY DESIGN: In a retrospective case-control design, we reviewed the medical records of all premature infants who were admitted to our neonatal intensive care unit between 1996 and 2000.RESULTS: The prevalence of LSV was 4.6% (21 of 453). Patients with late LSV (detected after 10 days of age) had less exposure than controls to prenatal steroids [42.8% (6 of 14) vs. 92.8% (13 of 14), respectively; p<0.01], and prenatal antibiotics [42.8% (6 of 14) vs. 85.7% (12 of 14), respectively; p=0.01]. Fifty-seven percent (8 of 14) of patients with late LSV had a low Apgar score vs. 14.2% (2 of 14) of the control group (p=0.01). Patients with LSV also had more muscle tone abnormalities than controls at 6 months of age [33.3% (5 of 15) vs. 5.2% (1 of 19), respectively; p=0.03].CONCLUSION: Patients with late LSV have less exposure to antenatal steroids and antibiotics, lower Apgar scores, and abnormal muscle tone at 6 months of age.

Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study

Background 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. Funding US National Institutes of Health, University of Alabama at Birmingham, Cincinnati Children’s, University of New Mexico.

Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates: Design of a Retrospective Cohort Study

Introduction Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. Methods and analysis The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly “snapshots”; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. Ethics and dissemination AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. Discussion The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few “lessons learned.” The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.

Efficacy of early immunosuppressive therapy in a child with carbamazepine-associated vanishing bile duct and Stevens-Johnson syndromes.

Acute drug-related vanishing bile duct syndrome (VBDS) is a rare, rapidly progressive destruction of the intrahepatic bile ducts with unknown pathogenesis. Immune-mediated mechanisms have been proposed. Prognosis is variable, and treatment unclear, as biliary cirrhosis has resulted despite aggressive immunosuppression (1, 2). Stevens-Johnson syndrome (SJS) is an acute mucocutaneous disorder secondary to drugor infection-induced immune complex deposition, treated supportively and with steroids (3). We report on a 4-year-old boy who developed carbamazepine-induced SJS concurrent with pancreatitis, hepatitis, and cholestasis. Liver biopsy on day 4 of illness demonstrated early vanishing bile duct syndrome. With aggressive immunosuppression using corticosteroids followed by tacrolimus, the patient’s liver insult did not progress to biliary cirrhosis.

Cardiac phenotype determines survival in Duchenne muscular dystrophy

To identify determinants of survival by comparing cardiopulmonary function in two patient groups: prolonged survivors of Duchenne muscular dystrophy (DMD) versus DMD patients who experienced early death (ED).

Effects of airway pressure release ventilation on blood pressure and urine output in children

Increased intrathoracic pressures during airway pressure release ventilation (APRV) may compromise systemic venous return resulting in decreased cardiac output and renal perfusion. We sought to study the short‐term effect of APRV on blood pressure (BP) and urine output (UO) in children with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).

The value of Ureaplasma urealyticum tracheal culture and treatment in premature infants following an acute respiratory deterioration

OBJECTIVE: To determine if treatment of Ureaplasma urealyticum (Uu), found at the time of an acute respiratory deterioration, decreases the incidence of chronic lung disease (CLD) in very low birth weight infants (VLBW).STUDY DESIGN: Between 1996 and 1999, medical records of all mechanically ventilated VLBW infants, who had an acute respiratory deterioration, were reviewed for gestational age (GA), birth weight (BW), gender, presence of CLD, Uu tracheal cultures, and erythromycin treatment.RESULTS: A total of 100 patients met our inclusion criteria (GA: 26.2±1.7 weeks, BW: 737±167.1 g (mean±SD)). Uu was present in 46.3% (38/82) of patients with CLD versus 50% (9/18) of patients without CLD (odds ratio 0.86 (CI: 0.31 to 2.39); p=0.77). Erythromycin treatment was not found to be protective against the development of CLD (odds ratio: 1.46 (CI: 0.25 to 8.31); p=0.66).CONCLUSION: Following an acute respiratory deterioration, tracheal isolation, and treatment of Uu may not decrease the incidence of CLD in VLBW infants.

Pulmonary hypertension in extremely low birth weight infants: characteristics and outcomes

BackgroundTo determine the characteristics and outcomes of pulmonary arterial hypertension (PAH) in extremely low birth weight (ELBW) infants.MethodsA retrospective case-control study of all ELBW infants admitted to a level III neonatal intensive care unit (NICU) between January 1, 2003 and December 31, 2010.ResultsDuring the study period, 450 ELBW infants were admitted. 6.4% (29/450) were diagnosed with PAH and were matched to 26 controls. The mean gestational age of infants with PAH and their controls were similar [24.5±1.3 vs. 24.9±1.8 weeks (P=0.26)]; however the cases were smaller at birth than were controls [640.7±119.5 vs. 727.0±184.5 g (P=0.04)]. The diagnosis of PAH was made at a mean postnatal age of 131.8±53.7 days. Infants with PAH had a higher rate of intrauterine exposure to illicit maternal drug use [12/29 (41%) vs. 1/25 (4%); P=0.001], a longer duration of initial mechanical ventilation [74.9±28.3 vs. 59.1±27.8 days; P=0.04)], a higher incidence of severe BPD [23/29 (79%) vs. 13/26 (50%); P=0.02], and a greater NICU mortality rate [12/29 (41%) vs. 4/26 (15%); P=0.04].ConclusionPAH in ELBW infants is associated with maternal illicit drug use in pregnancy, longer exposure to mechanical ventilation, severe bronchopulmonary dysplasia and a significant increase in early mortality.