The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.

A Hospital-Level Intervention to Improve Outcomes of Opioid Exposed Newborns.

PURPOSE: The purpose of this quality improvement project was to determine if non-pharmacologic strategies such as a rooming-in approach to care for newborns at risk of developing neonatal abstinence syndrome (NAS) would reduce total length of stay (LOS) and reduce the need for pharmacologic treatment. DESIGN AND METHODS: This was a quality improvement project utilizing a retrospective chart review. Records of newborns with in-utero methadone or buprenorphine exposure were reviewed who were born between January 2016-July 2017 and July 2017-August 2018 at Wellspan Health York Hospital. Starting in July 2017, newborns exposed to opioids who transitioned normally remained with their mothers for monitoring in the newborn nursery. Monitoring for withdrawal was continued on the pediatric floor after the mother's discharge from the post-partum floor. RESULTS: The primary outcome of total LOS was reduced from 14 days to 10.1 days (p = 0.014). The total length of pharmacologic treatment decreased from 15.68 days to 9.71 days (p = 0.023). CONCLUSIONS: A rooming-in approach to care including management on a pediatric floor can reduce total length of stay and the duration of pharmacologic treatment in newborns with NAS. Newborns with NAS can be safely managed in an inpatient pediatric floor. PRACTICE IMPLICATIONS: Implementing a rooming-in approach to care of newborns at risk of developing NAS can improve outcomes through a decreased length of hospital stay and decreased duration of pharmacologic treatment. This approach improves access to critical care services by safely monitoring newborns with NAS on an inpatient pediatric floor.

An Assessment of Pediatric Primary Care Providers' and Parents' Dental Health Knowledge and Practices.

INTRODUCTION: One in five children aged < 5 years has experienced caries, making it the most prevalent chronic disease in childhood. The failure to address a child's dental health can lead to short-term and long-term complications and problems with permanent dentition. Primary care pediatric providers are in the position to participate in the prevention of caries because of the frequency they see young children before establishing a dental home. METHOD: A retrospective chart review and two surveys were developed to collect data from health care providers and parents of children aged < 6 years about their dental health knowledge and practices. RESULTS: While providers report being comfortable discussing dental health with patients, review of medical records shows inconsistent discussion and documentation of dental health. DISCUSSION: There appears to be a lack of education regarding dental health among parents and health care providers. Primary care providers are not effectively communicating the importance of childhood dental health and are not routinely documenting dental health information.

After the storm: personal experiences following an EF4 tornado.

In April of 2011, an EF4 tornado ripped through the city of Tuscaloosa, AL, leaving in its wake thousands of destroyed homes and businesses. In the hours and days that followed, the health care community of this city, as well as the entire state of Alabama and the southeastern United States, came together to provide care to hundreds of victims, recovery workers, and volunteers.

The receptor for advanced glycation end products is a sensor for cell-free heme.

Heme's interaction with Toll-like receptor 4 (TLR4) does not fully explain the proinflammatory properties of this hemoglobin-derived molecule during intravascular hemolysis. The receptor for advanced glycation end products (RAGE) shares many features with TLR4 such as common ligands and proinflammatory, prothrombotic, and pro-oxidative signaling pathways, prompting us to study its involvement as a heme sensor. Stable RAGE-heme complexes with micromolar affinity were detected as heme-mediated RAGE oligomerization. The heme-binding site was located in the V domain of RAGE. This interaction was Fe3+ -dependent and competitive with carboxymethyllysine, another RAGE ligand. We confirmed a strong basal gene expression of RAGE in mouse lungs. After intraperitoneal heme injection, pulmonary TNF-α, IL1ß, and tissue factor gene expression levels increased in WT mice but were significantly lower in their RAGE-/- littermates. This may be related to the lower activation of ERK1/2 and Akt observed in the lungs of heme-treated, RAGE-/- mice. Overall, heme binds to RAGE with micromolar affinity and could promote proinflammatory and prothrombotic signaling in vivo, suggesting that this interaction could be implicated in heme-overload conditions.

Urine Collection Methods in Children: Which is the Best?

Urinary tract infection is one of the most common bacterial infections in infants and young children. There are 5 collection methods commonly used to obtain a urine sample from an infant or small child: suprapubic aspiration, urethral catheterization, clean catch void, urine collection bag, and urine collection pad. Although invasive, suprapubic aspiration and urethral catheterization are less likely to cause contamination of the specimen. When deciding which method to use, providers must take into consideration the clinical presentation of a child as well as presenting and past medical history, while weighing benefits versus risks.

Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1.

Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in in vitro and in vivo models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, in vitro and in vivo, compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4-known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions.

Characterization of Renal Injury and Inflammation in an Experimental Model of Intravascular Hemolysis.

Intravascular erythrocyte destruction, accompanied by the release of pro-oxidative and pro-inflammatory components hemoglobin and heme, is a common event in the pathogenesis of numerous diseases with heterogeneous etiology and clinical features. A frequent adverse effect related to massive hemolysis is the renal injury and inflammation. Nevertheless, it is still unclear whether heme--a danger-associated molecular pattern--and ligand for TLR4 or upstream hemolysis-derived products are responsible for these effects. Well-characterized animal models of hemolysis with kidney impairment are needed to investigate how hemolysis drives kidney injury and to test novel therapeutic strategies. Here, we characterized the pathological processes leading to acute kidney injury and inflammation during massive intravascular hemolysis, using a mouse model of phenylhydrazine (PHZ)-triggered erythrocyte destruction. We observed profound changes in mRNA levels for markers of tubular damage (Kim-1, NGAL) and regeneration (indirect marker of tubular injury, Ki-67), and tissue and vascular inflammation (IL-6, E-selectin, P-selectin, ICAM-1) in kidneys of PHZ-treated mice, associated with ultrastructural signs of tubular injury. Moreover, mass spectrometry revealed presence of markers of tubular damage in urine, including meprin-α, cytoskeletal keratins, α-1-antitrypsin, and α-1-microglobulin. Signs of renal injury and inflammation rapidly resolved and the renal function was preserved, despite major changes in metabolic parameters of PHZ-injected animals. Mechanistically, renal alterations were largely heme-independent, since injection of free heme could not reproduce them, and scavenging heme with hemopexin in PHZ-administered mice could not prevent them. Reduced overall health status of the mice suggested multiorgan involvement. We detected amylasemia and amylasuria, two markers of acute pancreatitis. We also provide detailed characterization of renal manifestations associated with acute intravascular hemolysis, which may be mediated by hemolysis-derived products upstream of heme release. This analysis provides a platform for further investigations of hemolytic diseases and associated renal injury and the evaluation of novel therapeutic strategies that target intravascular hemolysis.

Ultrastructure of primary afferent terminals and synapses in the rat nucleus of the solitary tract: comparison among the greater superficial petrosal, chorda tympani, and glossopharyngeal nerves.

The greater superficial petrosal (GSP), chorda tympani (CT), and glossopharyngeal (IX) nerves terminate in overlapping patterns in the brainstem in the rat nucleus of the solitary tract (NTS). There is one region, in particular, that receives overlapping inputs from all three nerves and is especially plastic during normal and experimentally altered development. To provide the requisite data necessary ultimately to delineate the circuitry in this region, we characterized the morphology of the synaptic inputs provided by the GSP, CT, and IX nerves through transmission electron microscopy. Although all three nerves had features characteristic of excitatory nerve terminals, ultrastructural analysis revealed dimorphic morphologies differentiating IX terminals from GSP and CT terminals. IX terminals had a larger area than GSP and CT terminals, and more synapses were associated with IX terminals compared with GSP and CT terminals. Additionally, IX terminals formed synapses most often with spines, as opposed to GSP and CT terminals, which formed synapses more often with dendrites. IX terminals also exhibited morphological features often associated with synaptic plasticity more often than was seen for GSP and CT terminals. These normative data form the basis for future studies of developmentally and environmentally induced plasticity in the rodent brainstem.

Gustatory terminal field organization and developmental plasticity in the nucleus of the solitary tract revealed through triple-fluorescence labeling.

Early dietary sodium restriction has profound influences on the organization of the gustatory brainstem. However, the anatomical relationships among multiple gustatory nerve inputs have not been examined. Through the use of triple-fluorescence labeling and confocal laser microscopy, terminal fields of the greater superficial petrosal (GSP), chorda tympani (CT), and glossopharyngeal (IX) nerves were visualized concurrently in the nucleus of the solitary tract (NTS) of developmentally sodium-restricted and control rats. Dietary sodium restriction during pre- and postnatal development resulted in a twofold increase in the volume of both the CT and the IX nerve terminal fields but did not affect the volume of the GSP terminal field. In controls, these nerve terminal fields overlapped considerably. The dietary manipulation significantly increased the overlapping zones among terminal fields, resulting in an extension of CT and IX fields past their normal boundaries. The differences in terminal field volumes were exaggerated when expressed relative to the respective NTS volumes. Furthermore, increased terminal field volumes could not be attributed to an increase in the number of afferents because ganglion cell counts did not differ between groups. Taken together, selective increases in terminal field volume and ensuing overlap among terminal fields suggest an increased convergence of these gustatory nerve terminals onto neurons in the NTS. The genesis of such convergence is likely related to disruption of cellular and molecular mechanisms during the development of individual terminal fields, the consequences of which have implications for corresponding functional and behavioral alterations.

Modifications of gustatory nerve synapses onto nucleus of the solitary tract neurons induced by dietary sodium-restriction during development.

The terminal fields of nerves carrying gustatory information to the rat brainstem show a remarkable amount of expansion in the nucleus of the solitary tract (NTS) as a result of early dietary sodium restriction. However, the extent to which these axonal changes represent corresponding changes in synapses is not known. To identify the synaptic characteristics that accompany the terminal field expansion, the greater superficial petrosal (GSP), chorda tympani (CT), and glossopharyngeal (IX) nerves were labeled in rats fed a sodium-restricted diet during pre- and postnatal development. The morphology of these nerve terminals within the NTS region where the terminal fields of all three nerves overlap was evaluated by transmission electron microscopy. Compared to data from control rats, CT axons were the most profoundly affected. The density of CT arbors and synapses quadrupled as a result of the near life-long dietary manipulation. In contrast, axon and synapse densities of GSP and IX nerves were not modified in sodium-restricted rats. Furthermore, compared to controls, CT terminals displayed more instances of contacts with postsynaptic dendritic protrusions and IX terminals synapsed more frequently with dendritic shafts. Thus, dietary sodium restriction throughout pre- and postnatal development had differential effects on the synaptic organization of the three nerves in the NTS. These anatomical changes may underlie the impact of sensory restriction during development on the functional processing of taste information and taste-related behaviors.