Low nephron endowment increases susceptibility to renal stress and chronic kidney disease.

Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated potentially novel mouse models with a 30%-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy, followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared with controls with normal nephron number. Mice with low nephron number had reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.

Snapshots of nascent RNA reveal cell- and stimulus-specific responses to acute kidney injury.

The current strategy to detect acute injury of kidney tubular cells relies on changes in serum levels of creatinine. Yet serum creatinine (sCr) is a marker of both functional and pathological processes and does not adequately assay tubular injury. In addition, sCr may require days to reach diagnostic thresholds, yet tubular cells respond with programs of damage and repair within minutes or hours. To detect acute responses to clinically relevant stimuli, we created mice expressing Rosa26-floxed-stop uracil phosphoribosyltransferase (Uprt) and inoculated 4-thiouracil (4-TU) to tag nascent RNA at selected time points. Cre-driven 4-TU-tagged RNA was isolated from intact kidneys and demonstrated that volume depletion and ischemia induced different genetic programs in collecting ducts and intercalated cells. Even lineage-related cell types expressed different genes in response to the 2 stressors. TU tagging also demonstrated the transient nature of the responses. Because we placed Uprt in the ubiquitously active Rosa26 locus, nascent RNAs from many cell types can be tagged in vivo and their roles interrogated under various conditions. In short, 4-TU labeling identifies stimulus-specific, cell-specific, and time-dependent acute responses that are otherwise difficult to detect with other technologies and are entirely obscured when sCr is the sole metric of kidney damage.

Evaluating Newborns at Risk for Early-Onset Sepsis.

Early-onset sepsis (EOS) is an important cause of neonatal morbidity. Despite extensive study, identifying at-risk newborns remains challenging, especially if they are initially well appearing. Existing official EOS recommendations suggest a conservative approach that likely results in overtreatment of a low-risk population. Recent studies indicate that more precise risk assessment and alternative management strategies could decrease the number of infants exposed to blood draws and antibiotics during evaluations for EOS. This article reviews existing guidelines and provides an overview of the Bayesian sepsis calculator and serial observation as an alternative to laboratory studies and empirical antibiotics.

Implementation of a Formal Debriefing Program After Pediatric Rapid Response Team Activations.

BACKGROUND: Debriefing after pediatric rapid response team activations (RRT-As) in a tertiary care children's hospital was identified to occur only sporadically. The lack of routine debriefing after RRT-As was identified as a missed learning opportunity. OBJECTIVE: We implemented a formal debriefing program and assessed staff attitudes toward and experiences with debriefing after pediatric RRT-As. METHODS: Real-time feedback for pediatrics residents captured clinical and debriefing data for each RRT-A from July 2014 to June 2016. The debriefing on physiology, team communication, and anticipation of clinical deterioration was introduced in July 2015. To assess debriefing perceptions, residents, intensive care fellows, nurses, and respiratory therapists participated in anonymous preintervention and postintervention surveys. We also developed a workshop to teach residents how to lead debriefing. RESULTS: Debriefing after RRT-As increased from 26% preintervention to 46% postintervention (P < .0001). A total of 43 of 76 pediatrics residents (57%) attended at least 1 of 4 debriefing workshops. Both preintervention and postintervention, more than 80% (70 of 78 preintervention and 54 of 65 postintervention) of health professionals surveyed strongly agreed or agreed that there was a benefit to debriefing after RRT-As. Postintervention, 65% (26 of 40) of respondents strongly agreed or agreed that debriefing improved their understanding of the RRT-A process. The rate of debriefing was sustained at 46% (6 months after the end of the study period). CONCLUSIONS: Debriefing frequency after pediatric RRT-As significantly increased with the introduction of a formal debriefing program. A majority of health professionals and trainees reported this practice was a valuable experience.

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.

Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1ß phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1ß-IL-6 signaling cascade and Dll1-dependent Notch signaling.

Bri2-23 is a potential cerebrospinal fluid biomarker in multiple sclerosis.

To identify potential multiple sclerosis (MS)-specific biomarkers, we used a proteomic approach to screen cerebrospinal fluid (CSF) from 40 MS patients and 13 controls. We identified seven proteins (Beta-2-microglobulin, Bri2-23, Fetuin-A, Kallikrein-6, Plasminogen, Ribonuclease-1, and Transferrin) that had significantly altered levels in MS compared to controls. Clinical subgroup analysis revealed that decreased CSF levels of Bri2-23, a peptide cleaved from Bri2, were significantly associated with patients having cerebellar dysfunction and cognition impairment. Furthermore, expression levels of Bri2 were specifically decreased in the cerebellum compared to other areas of same brain in MS but not in controls, suggesting that decreased cerebellar Bri2 expression may play a role in cerebellar dysfunction. The association with cognition impairment is also of interest because Bri2 is linked to the amyloid processing pathway in the brain. CSF levels of Bri2-23 may serve as a biomarker of these functions in MS and merits further investigation.