Scott L. Weiss

Background The pathobiology of acute kidney injury during diabetic ketoacidosis (DKA) is not completely understood. We hypothesized that mitochondrial function is impaired during DKA as a mechanism of acute kidney injury. Methods We isolated kidney samples from 4 to 5 week-old rats with normoglycemia (NG, controls; n = 7), hyperglycemia (HG; n = 5), acute DKA (DKA; n = 5), and after 24 h of DKA treatment (DKA-24; n = 5). Kidney tissue homogenates were prepared from frozen tissue for measurement of mitochondrial electron transport system (ETS) complex I + III, II + III, and IV activity and citrate synthase activity using spectrophotometry and ETS complex protein expression using Western blots. Results Mitochondrial ETS complex I + III activity (mean ± SD) exhibited a stepwise decrease from HG (113 ± 54 nmol/min/mg tissue protein) to DKA (64 ± 32; p < 0.05 compared to NG) and trended toward NG control levels (143 ± 37) in DKA-24 (135 ± 39). Mitochondrial content, including citrate synthase activity and ETS complex proteins I, II, IV, and V, did not differ between groups, except that ETS complex III increased in HG and DKA and subsequently decreased in DKA-24. Conclusions In a juvenile rat model of DKA, increasing glycemic stress caused a reversible change in kidney mitochondrial complex I function and complex III expression. Impact Acute kidney injury during diabetic ketoacidosis (DKA) increases risk of future diabetic kidney disease, but the underlying pathobiology is not understood. In a juvenile rat model of DKA, we found that increasing glycemic stress caused a reversible change in kidney mitochondrial complex I function and complex III expression. These data support further investigation to determine if mitochondrial dysfunction may contribute to DKA-related acute kidney injury.

BACKGROUND. Sepsis is a leading cause of morbidity and mortality in critically ill children, yet heterogeneous immune responses complicate the development of targeted therapies and the host immune factors driving sepsis pathobiology remain unclear. METHODS. We integrated deep immune phenotyping, plasma proteomics, single-cell transcriptomics, and phosphoflow cytometry in a prospective cohort of 88 critically ill children to elucidate the mechanisms underlying immune heterogeneity. RESULTS. Unsupervised clustering of plasma cytokines identified three immunologic subgroups, including a high-severity group (“Group C”) characterized by hypercytokinemia driven by IL-6 and IFN-γ. Group C exhibited distinct alterations in immune cell frequency and activation, with a strong association between hyperinflammatory cytokine signaling and lymphocyte dysfunction. Single-cell RNA sequencing revealed transcriptional signatures of T cell activation and metabolic stress, with suppression of a lymphoid protective gene program across CD8⁺ T cell subsets. Despite increased expression of activation markers, T cell receptor repertoire analysis revealed no dominant clonotypes, consistent with bystander activation. Phosphoflow cytometry demonstrated baseline STAT1/STAT3 hyperactivation in Group C CD8⁺ T cells, which failed to respond to αCD3/αCD28/αCD49d stimulation. CONCLUSIONS. These findings define an IL‑6/IFN‑γ–driven endotype of T cell dysfunction in pediatric sepsis and highlight the JAK/STAT axis as a rational target for immunomodulatory therapy. FUNDING. K12HD047349, K23GM159013, K08AI135091, R01HD095976, Thrasher Research Foundation, Burroughs Wellcome Fund CAMS, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute

BACKGROUND: Acute kidney injury (AKI) is common in critically ill children and is associated with high morbidity and mortality. Risk prediction models designed for clinical decision support implementation can facilitate early identification and proactive mitigation of AKI risk. Existing models have primarily been validated using single-center data, partly because of the lack of appropriately detailed multicenter datasets. OBJECTIVE: To determine the performance of a single-center model to predict new AKI at 72 hours of ICU admission in children across two multicenter datasets and refine this model to improve prediction performance while maintaining acceptable alert burden. DERIVATION AND VALIDATION COHORTS: We analyzed two datasets: the Pediatric Learning Health System Network–Virtual Pediatric Systems (PEDSNET-VPS) dataset, created through the linkage of PEDSnet electronic health record (EHR) extraction with VPS (LLC, http://www.myvps.org), and the PICU Data Collaborative dataset, created through EHR extraction and harmonization from eight participating institutions. We divided each dataset into a derivation and test split. PREDICTION MODEL: We first recalibrated an existing single-center model and measured discrimination (area under the receiver operating characteristic curve [AUROC] and area under the precision-recall curve [AUPRC]) and performance at multiple cutpoints. We next added features available at 12 hours of ICU admission, optimizing by precision and recall. We measured discrimination and performance at multiple cutpoints and identified the features contributing most to the risk score. RESULTS: In total we analyzed 186,540 ICU admissions. We found early AKI by serum creatinine criteria within 72 hours of admission in 2.2–2.7%. Initial recalibration of an existing single-center model demonstrated poor discrimination (AUROC 0.65–0.78; AUPRC 0.10–0.12). Following the addition of new features, the model had higher AUROC (0.80–0.88) and AUPRC (0.13–0.22). CONCLUSIONS: In this first use of two new multicenter datasets, we found improved performance in a model designed using features available at 12 hours of ICU admission, balancing sensitivity and precision to predict patients at risk for AKI development.

Whether treatment with balanced crystalloid fluid leads to better outcomes than 0.9% saline in children treated for septic shock is debated. In this pragmatic clinical trial conducted at 47 emergency departments in five countries, patients (2 months to <18 years of age) with suspected septic shock and abnormal perfusion were randomly assigned to receive fluid resuscitation with either balanced fluid or 0.9% saline for up to 48 hours. The primary outcome was a major adverse kidney event (a composite of death, new renal-replacement therapy, or persistent kidney dysfunction) at 30 days after enrollment or hospital discharge, whichever occurred first. Of 9041 enrolled patients, 277 (6.1%) in the balanced-fluid group and 282 (6.2%) in the 0.9%-saline group withdrew from the trial, leaving 4235 and 4247 patients, respectively, for analysis. A primary-outcome event occurred in 137 patients (3.4%) in the balanced-fluid group and in 124 (3.0%) in the 0.9%-saline group (difference, 0.4 percentage points; 95% confidence interval [CI], -0.5 to 1.3; risk ratio, 1.10; 95% CI, 0.88 to 1.40; P = 0.85). The median number of hospital-free days during 28 days after enrollment was 23 (interquartile range, 19 to 25) in both groups. Hyperchloremia occurred in 868 patients (31.4%) in the balanced-fluid group and in 1383 (49.0%) in the 0.9%-saline group; hypernatremia in 52 (1.8%) and 89 (3.1%), respectively; and hyperlactatemia in 260 (19.8%) and 228 (16.7%). No differences in other safety outcomes or adverse events were seen. Among children treated for septic shock, no significant difference was seen in the incidence of death, new renal-replacement therapy, or persistent kidney dysfunction when fluid resuscitation was administered with balanced fluid as compared with 0.9% saline. (Funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; PRoMPT BOLUS ClinicalTrials.gov number, NCT04102371.).

Objective: Sepsis-associated acute kidney injury (SAKI) is a heterogeneous condition that lacks disease-modifying treatments, and precision medicine approaches are needed. We previously derived two reproducible pediatric SAKI subphenotypes (pSAKI-1 and pSAKI-2) from readily available clinical data. We aimed to externally validate the prognostic relevance of these subphenotypes, evaluate their molecular signatures, and assess for heterogeneity of treatment effect (HTE) across subphenotypes with sepsis therapies. Design: Secondary analysis of an ongoing multicenter, prospective, observational study of children. Setting: Ten PICUs in the United States from January 2002 to February 2025. Patients: Patients 1 week to 18 years old with early (day 1–2) SAKI. Interventions: None. Measurements and Main Results: Among 871 patients, 665 (76%) were assigned pSAKI-1 and 206 (24%) to pSAKI-2. On day 1–2, the pSAKI-2 cohort had greater severity of illness, including higher acute kidney injury stage and vasoactive burden, lower platelet counts, and higher lactate values and International Normalized Ratios. These pSAKI-2 patients also had uniformly worse outcomes, including independently higher odds of day 7 severe acute kidney injury (adjusted odds ratio [aOR] 3.2; 95% CI, 2.1–4.7; p < 0.001), death (aOR 2.7; 95% CI, 1.6–4.4; p < 0.001), and fewer PICU-free and vasoactive-free days ( p < 0.001). The biomarker signature of pSAKI-2 was characterized by greater inflammation, endothelial dysfunction, and hyperreninemia. On propensity score matched (PSM) analysis, pSAKI-1 patients who received corticosteroids had more day 7 severe acute kidney injury (28% vs. 19%, p = 0.023), 2 fewer PICU-free days ( p = 0.04) and greater mortality (10% vs. 3.7%, p = 0.008); no differences were seen in pSAKI-2 patients. Although no HTE was identified on PSM analysis for vasopressin, inverse probability treatment weighting analysis demonstrated a significant interaction between subphenotype-, vasopressin- and vasoactive-free days ( p = 0.003). Conclusions: We externally validated the prognostic relevance of two pSAKI subphenotypes derived from readily available data. These subphenotypes have unique biomarker signatures and differential responses to treatment, representing a potential mechanism for bedside enrichment.

Objectives: To update evidence-based management recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with sepsis or septic shock. Design: A panel of 68 international experts, representing 13 international organizations, as well as six methodologists, was convened. A formal conflict-of-interest policy was developed at the onset of the process and applied throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and subgroup leads as well as within subgroups, served as an integral part of the guideline development process. Methods: New priority topics and recommendations from the prior guideline iteration were used to identify Population, Intervention, Control, and Outcomes (PICO) questions likely to have new or updated evidence. We conducted a systematic review to identify the best available evidence, summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or conditional, or as a good practice statement. “In our practice,” statements were included when evidence was inconclusive to issue a recommendation but the panel felt that some guidance based on practice patterns may be appropriate. Results: The panel provided 61 statements on the management of children with sepsis or septic shock. Overall, five were strong recommendations, 24 were conditional recommendations, and ten were good practice statements. For 22 PICO questions, no recommendations could be made, but, for seven of these, “in our practice” statements were provided. Compared with the 2020 guidelines, 20 recommendations were new, 13 were updated for clarity and/or new evidence, six were reviewed but not changed, and 22 were carried forward based on consensus of the panel that new evidence was not available. Only three recommendations were based on high or moderate certainty of evidence. Conclusions: Updated management guidelines were issued by a panel of international experts for the best care of children with sepsis or septic shock, acknowledging that most aspects of care continue to have relatively low quality of evidence.

Objective To update evidence-based management recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with sepsis or septic shock. Design A panel of 68 international experts, representing 13 international organizations, as well as six methodologists, was convened. A formal conflict-of-interest policy was developed at the onset of the process and applied throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and subgroup leads, as well as within subgroups, served as an integral part of the guideline development process. Methods New priority topics and recommendations from the prior guideline iteration were used to identify Population, Intervention, Control, and Outcomes (PICO) questions likely to have new or updated evidence. We conducted a systematic review to identify the best available evidence, summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or conditional, or as a good practice statement. “In our practice,” statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. Results The panel provided 61 statements on the management of children with sepsis or septic shock. Overall, five were strong recommendations, 24 were conditional recommendations, and ten were good practice statements. For 22 PICO questions, no recommendations could be made, but for seven of these, “in our practice” statements were provided. Compared with the 2020 guidelines, 20 recommendations were new, 13 were updated for clarity and/or new evidence, six were reviewed but not changed, and 22 were carried forward based on consensus of the panel that new evidence was not available. Only three recommendations were based on high or moderate certainty of evidence. Conclusions Updated management guidelines were issued by a panel of international experts for the best care of children with sepsis or septic shock, acknowledging that most aspects of care continue to have relatively low quality of evidence.

Rationale: In patients with severe lung injury, extracorporeal life support can enable lung rest, but the optimal strategy is unknown. Objective: To compare liquid lung rest versus standard gas rest ventilation in a porcine model of acute lung injury and extracorporeal life support. Methods: Twenty neonatal pigs with lung injury after systemic injection of oleic acid were placed on extracorporeal life support. Pigs were ventilated with standard rest settings (peak inspiratory pressure: 20 cmH ₂ O; end expiratory pressure: 10 cmH ₂ O; rate: 10 breaths/minute) and randomized to receive no additional therapy (gas ventilation) or 5 mL/kg perfluorooctylbromide instilled endotracheally (liquid lung rest). The study continued for 4 hours with hourly pulmonary compliance measurements. After euthanasia, lung samples were taken for histologic analysis. Inflammation was quantified via blood and lung tissue cytokines. Measurements and Main Results: All pigs achieved significant lung injury; static compliance decreased by a mean of 54%. After 4 hours of lung rest, static compliance was higher with liquid lung rest compared to gas ventilation (0.88±0.05 mL/kg/cmH ₂ O versus 0.57±0.05, p<0.001). Histology revealed 2.1-fold greater airspace in dependent lung regions with liquid lung rest (p<0.001) and a reduced airspace heterogeneity index (LLR: 0.071±0.004, gas: 0.095±0.010, p=0.04), suggesting more uniform alveolar recruitment. Cytokine analysis demonstrated a 3.7-fold decrease in tissue interleukin-10 levels with liquid lung rest (p=0.02). Conclusions: Liquid lung rest improved pulmonary compliance, achieved better alveolar recruitment, and decreased tissue interleukin-10 levels compared to standard gas ventilation. This strategy may enhance lung recovery in acute lung injury requiring extracorporeal life support.