The Role of Platelets and ε-Aminocaproic Acid in Arthrogryposis, Renal Dysfunction, and Cholestasis (ARC) Syndrome Associated Hemorrhage.

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare disorder associated with platelet abnormalities resembling gray platelet syndrome. Affected patients have normal platelet numbers but abnormal morphology and function. Bleeding symptomatology ranges from postprocedural to spontaneous life-threatening hemorrhage. We report a patient with ARC syndrome and compound heterozygous mutations in VPS33B (vacuolar protein sorting 33B) who presented with significant bleeding requiring numerous admissions and transfusions. She was treated with prophylactic platelet transfusions and ε-aminocaproic acid. This was well-tolerated and significantly decreased transfusion requirements and admissions for bleeding. Our experience provides support for consideration of prophylactic measures in these patients as well as the possibility of using prophylaxis in related disorders.

Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO.

Kidney Disease: Improving Global Outcomes (KDIGO) recently published the clinical practice guideline on glomerulonephritis (GN) to assist the practitioner caring for patients with GN. Chapter 4 of the guideline focuses on managing children aged 1-18 years with steroid-resistant nephrotic syndrome (SRNS), defined by an inability to achieve complete remission with corticosteroid therapy. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides both the guideline recommendations and a brief review of relevant treatment trials related to each recommendation. This précis serves as a summary of the complete guidelines recently published.

Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO.

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on glomerulonephritis (GN) is intended to assist the practitioner caring for patients with GN. Two chapters of this guideline focus specifically on nephrotic syndrome in children. Guideline development followed a thorough evidence review, and management recommendations and suggestions were based on the best available evidence. Critical appraisal of the quality of evidence and strength of recommendations followed the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach. Chapters 3 and 4 of the guideline focus on the management of nephrotic syndrome in children aged 1-18 years. Guideline recommendations for children who have steroid-sensitive nephrotic syndrome (SNSS), defined by their response to corticosteroid therapy with complete remission, are addressed here. Recommendations for those with steroid-resistant nephrotic syndrome (SRNS) (i.e., do not achieve complete remission) are discussed in the companion article. Limitations of the evidence, including the paucity of large-scale randomized controlled trials, are discussed. This article provides a short description of the KDIGO process, the guideline recommendations for treatment of SSNS in children and a brief review of relevant treatment trials related to each recommendation.

Ensuring No Death Is Ignored: Development of a Hospital Mortality Review and Notification System.

BACKGROUND AND OBJECTIVES: Standardized review of mortalities may identify potential system improvements. We designed a hospitalwide identification, review, and notification system for inpatient pediatric mortalities. METHODS: Key stakeholders constructed a future state process map for identification and review of deaths. An online mortality review form was modified through a series of Plan-Do-Study-Act cycles and spread to all pediatric services in January 2019. Mortalities occurring within 30 days of discharge were added in December 2019. Our primary outcome was percentage of mortalities reviewed, and the process measure was time to review completion. Additional Plan-Do-Study-Act cycles were used to refine 2 mechanisms for monthly notification of deaths. We surveyed monthly mortality notification e-mail recipients to elicit feedback to further improve notifications. RESULTS: After the pilot, 284 of 328 (86.6%) of mortalities were reviewed. Average time to review completion decreased by 49% compared with baseline after an increase during the first year of the pandemic. Qualitative analysis of a subset of these mortalities showed that 154 of 229 (67.2%) underwent further review. We added a summary of mortalities by unit to a monthly hospitalwide safety report and developed monthly mortality notification e-mails. The survey showed that 89% of respondents (70 of 79) learned about a death they did not know about, 58% (46 of 79) sought additional information through discussion with a colleague, and 76% (65 of 86) agreed that the notifications helped process grief. CONCLUSIONS: We describe an effective and well-received approach to the identification, review, and notification of mortalities at an academic pediatric hospital, which may be useful at other institutions.

Urologic Considerations in Pediatric Chronic Kidney Disease.

Common causes of pediatric ESRD are distinct from those seen in the adult population. In the pediatric population, the most common are congenital anomalies of the kidney and urinary tract (CAKUT), affecting approximately 30% of children with CKD. These structural anomalies often require coordinated care with the pediatric urology team to address voiding issues, bladder involvement, and the potential need for surgical intervention. For pediatric nephrologists and urologists, common CAKUT that are encountered include antenatal hydronephrosis, obstructive uropathies (eg, posterior urethral valves), and vesicoureteral reflux. As more pediatric patients with CAKUT, CKD, and ESRD transition to adult care, it is important for receiving adult nephrologists to understand the clinical presentation, natural history, and prognosis for these diagnoses. This review outlines the diagnosis and potential interventions for these conditions, including strategies to address bladder dysfunction that is often seen in children with CAKUT. A discussion of these management decisions (including surgical intervention) for CAKUT, which are quite common to pediatric nephrology and urology practices, may provide unique learning opportunities for adult nephrologists who lack familiarity with these pediatric conditions.

Specificity of DNA-binding by the FAX-1 and NHR-67 nuclear receptors of Caenorhabditis elegans is partially mediated via a subclass-specific P-box residue.

BACKGROUND: The nuclear receptors of the NR2E class play important roles in pattern formation and nervous system development. Based on a phylogenetic analysis of DNA-binding domains, we define two conserved groups of orthologous NR2E genes: the NR2E1 subclass, which includes C. elegans nhr-67, Drosophila tailless and dissatisfaction, and vertebrate Tlx (NR2E2, NR2E4, NR2E1), and the NR2E3 subclass, which includes C. elegans fax-1 and vertebrate PNR (NR2E5, NR2E3). PNR and Tll nuclear receptors have been shown to bind the hexamer half-site AAGTCA, instead of the hexamer AGGTCA recognized by most other nuclear receptors, suggesting unique DNA-binding properties for NR2E class members. RESULTS: We show that NR2E3 subclass member FAX-1, unlike NHR-67 and other NR2E1 subclass members, binds to hexamer half-sites with relaxed specificity: it will bind hexamers with the sequence ANGTCA, although it prefers a purine to a pyrimidine at the second position. We use site-directed mutagenesis to demonstrate that the difference between FAX-1 and NHR-67 binding preference is partially mediated by a conserved subclass-specific asparagine or aspartate residue at position 19 of the DNA-binding domain. This amino acid position is part of the "P box" that plays a critical role in defining binding site specificity and has been shown to make hydrogen-bond contacts to the second position of the hexamer in co-crystal structures for other nuclear receptors. The relaxed specificity allows FAX-1 to bind a much larger repertoire of half-sites than NHR-67. While NR2E1 class proteins bind both monomeric and dimeric sites, the NR2E3 class proteins bind only dimeric sites. The presence of a single strong site adjacent to a very weak site allows dimeric FAX-1 binding, further increasing the number of dimeric binding sites to which FAX-1 may bind in vivo. CONCLUSION: These findings identify subclass-specific DNA-binding specificities and dimerization properties for the NR2E1 and NR2E3 subclasses. For the NR2E1 protein NHR-67, Asp-19 permits binding to AAGTCA half-sites, while Asn-19 permits binding to AGGTCA half-sites. The apparent conservation of DNA-binding properties between vertebrate and nematode NR2E receptors allows for the possibility of evolutionarily-conserved regulatory patterns.

Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population.

PURPOSE: Acute kidney injury (AKI) occurs commonly in critically ill children and has been associated with increased mortality of up to 50 %. The Kidney Disease: Improving Global Outcomes (KDIGO) AKI working group has proposed a standardized definition of AKI. Utilizing routinely available clinical data, we evaluated the KDIGO AKI criteria and the relationship of AKI with relevant outcomes in a single center tertiary pediatric intensive care (PICU) and cardiac intensive care unit (CICU) population. METHODS: The University of Michigan Pediatric Critical Care Database was probed for all discharges from the pediatric intensive care and cardiac intensive care units between July 2011 and October 2013 (N = 4,645). The KDIGO serum creatinine (SCr)-based criteria staged AKI with the modification that a minimum SCr of greater than 0.5 mg/dL was required to be classified as AKI. Exclusion: end-stage renal disease, new renal transplant, missing PRISM III data, or no measured Cr during intensive care unit (ICU) admission (N = 1,636). RESULTS: AKI occurred in 737 (24.5 %, stage 1 = 193, stage 2 = 189, and stage 3 = 355) of 3,009 discharges (PICU N = 1,870, CICU N = 1,139) that included 2,415 patients. In multivariate analysis AKI was associated with increased ICU length of stay (LOS) in hours (stage I ß = 42.2, p = 0.024, II ß = 74.1, p = 0.003, III ß = 215.8, p < 0.001). Multivariate analysis showed that AKI was associated with increased odds of ICU mortality (OR 3.4, 95 % CI 2.0-6.0) and increased length of mechanical ventilation among those requiring mechanical ventilation (ß = 2.3 days, p < 0.001). CONCLUSIONS: Using the KDIGO criteria to define AKI, we observed a high prevalence of AKI among critically ill children. Worsening stages of AKI were associated with increased ICU LOS, and AKI was independently associated with prolonged mechanical ventilation and increased mortality. The KDIGO criteria describe clinically relevant AKI in a broad pediatric critical care population.

Implications of different fluid overload definitions in pediatric stem cell transplant patients requiring continuous renal replacement therapy.

PURPOSE: In critically ill pediatric patients, fluid overload (FO) >10% has been identified as a threshold for possible interventions, including initiation of continuous renal replacement therapy (CRRT). However, multiple definitions have been reported, and there remains no consensus method for FO calculation. The goal of this study was to compare different methods of FO determination and to assess their relative value in predicting outcomes. METHODS: This is a retrospective single-center review of 21 pediatric stem cell transplant patients (PSCT) that required CRRT from 2004 to 2009. We compared eight definitions (4 weight-based and 4 fluid-balance based) that varied by baseline weights. Outcome measures were pediatric intensive care unit (PICU) mortality and pediatric logistic organ dysfunction (PELOD) scores. RESULTS: The number of patients identified as having >10% FO varied significantly according to the definition used, from 14 to 48% (p = 0.002). Significant intra-subject variability was observed; the median difference between individual minimum and maximum %FO scores was 11.4% (IQR 6.8, 17.1%). %FO was not significantly associated with PICU mortality, but five of eight FO definitions were predictive of higher subsequent PELOD scores. CONCLUSION: Our study is one of the first to compare different FO definitions and the impact on predicting outcomes. Our findings suggest that depending on the FO definition used, there is significant variability in the calculated %FO in PSCT patients, and this has important implications for clinical decision-making. Further studies are necessary to determine an optimal FO definition that is clinically relevant and predictive of important outcomes.

Weight-based determination of fluid overload status and mortality in pediatric intensive care unit patients requiring continuous renal replacement therapy.

PURPOSE: In pediatric intensive care unit (PICU) patients, fluid overload (FO) at initiation of continuous renal replacement therapy (CRRT) has been reported to be an independent risk factor for mortality. Previous studies have calculated FO based on daily fluid balance during ICU admission, which is labor intensive and error prone. We hypothesized that a weight-based definition of FO at CRRT initiation would correlate with the fluid balance method and prove predictive of outcome. METHODS: This is a retrospective single-center review of PICU patients requiring CRRT from July 2006 through February 2010 (n = 113). We compared the degree of FO at CRRT initiation using the standard fluid balance method versus methods based on patient weight changes assessed by both univariate and multivariate analyses. RESULTS: The degree of fluid overload at CRRT initiation was significantly greater in nonsurvivors, irrespective of which method was used. The univariate odds ratio for PICU mortality per 1% increase in FO was 1.056 [95% confidence interval (CI) 1.025, 1.087] by the fluid balance method, 1.044 (95% CI 1.019, 1.069) by the weight-based method using PICU admission weight, and 1.045 (95% CI 1.022, 1.07) by the weight-based method using hospital admission weight. On multivariate analyses, all three methods approached significance in predicting PICU survival. CONCLUSIONS: Our findings suggest that weight-based definitions of FO are useful in defining FO at CRRT initiation and are associated with increased mortality in a broad PICU patient population. This study provides evidence for a more practical weight-based definition of FO that can be used at the bedside.