KEY POINTS:C3 glomerulopathy and immune complex-associated membranoproliferative glomerulonephritis in children have similar degrees of proteinuria, hypoalbuminemia, hypertension, and hypocomplementemia at diagnosis. C3 glomerulopathy and immune complex-associated membranoproliferative glomerulonephritis in children progress similarly to a composite outcome of CKD, dialysis, or kidney transplantation. A low level of C3 at baseline is associated with achieving the composite outcome. BACKGROUND:C3 glomerulopathy (C3G) and immune complex-associated membranoproliferative glomerulonephritis (IC-MPGN) are rare complement-mediated kidney diseases with a high risk of progression to kidney failure. Little is known about the natural history of these diseases in children, limiting our understanding of risk factors for progressive kidney disease. METHODS:Using a computable phenotype algorithm, a pediatric cohort with C3G or IC-MPGN was identified at seven institutions in PEDSnet, a national network of pediatric health systems which aggregate electronic health record data and collaborate on pragmatic research studies. Discrete data elements were captured from electronic health records, and additional clinical and histopathologic data were extracted by standardized chart review by pediatric nephrologists. Biopsy diagnosis was classified as C3G or IC-MPGN by applying an algorithm on the basis of immunofluorescence and electron microscopy and supplemented with manual chart review. Kaplan-Meier survival curves were used to compare the risk of reaching a composite kidney outcome of 50% reduction in eGFR, initiation of maintenance dialysis, or kidney transplantation. RESULTS:Of 204 patients with membranoproliferative glomerulonephritis identified by the computable phenotype algorithm and chart review, 159 could be further classified as C3G or IC-MPGN on the basis of available biopsy data. There were no significant differences in baseline serum albumin, C3 level, urine protein/creatinine ratio, or eGFR between C3G and IC-MPGN. Patients with C3G and IC-MPGN had similar rates of progression to the composite kidney outcome, and a low serum C3 level at baseline was associated with this composite outcome. CONCLUSION:Using large-scale, real-world multi-institutional data, we investigated the natural history of a large contemporary cohort of children with membranoproliferative glomerulonephritis. Because patients classified as having C3G compared with IC-MPGN had similar baseline clinical characteristics and rates of progressive disease despite untargeted treatment approaches, the availability of newer complement-targeted agents hold the promise of benefit to this population.

BACKGROUND:Whether treatment with balanced crystalloid fluid leads to better outcomes than 0.9% saline in children treated for septic shock is debated. METHODS: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. RESULTS: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. CONCLUSIONS: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.).

BK polyomavirus (BKPyV) can cause disease in transplant recipients. Virus-specific T-cell (VST) therapy is effective in decreasing virus levels in many individuals. BKPyV genetic variation can impact replication kinetics and immune responses. Here, we present the near full-length BKPyV genome sequences from two VST recipients in which genotype IV was isolated.

OBJECTIVES:Long-term kidney outcomes after extracorporeal membrane oxygenation (ECMO) are little quantified and understood. We aimed to describe the frequency of kidney dysfunction screening during follow-up and the prevalence of long-term kidney disease.DESIGN:Retrospective cohort of pediatric ECMO patients with estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) using all post-discharge serum creatinine values to define three kidney outcomes: 1) acute kidney injury (AKI), with eGFR of less than 60 mL/min/1.73 m2, which subsequently improved to normal (>= 90 mL/min/1.73 m2); 2) abnormal eGFR of less than 90 mL/min/1.73 m2 at last follow-up; and 3) chronic kidney disease (CKD) with eGFR of less than 90 mL/min/1.73 m2 on at least two occasions separated by greater than or equal to 90 days, without an intervening or subsequently normal eGFR.SETTING:Single-center tertiary care children's hospital system.PATIENTS:All pediatric patients surviving ECMO from 2009 to 2019.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:In the 10-year cohort of 666 patients, 399 (60%) survived at least 3 months post-discharge. Of these, 382 of 399 (96%) were followed at our institution for a median of 5 years (interquartile range, 3-8 yr). Two hundred sixty-four of 382 (69%) had at least one creatinine value post-discharge, and 209 of 382 (55%) had at least two values three months apart. Of the 264 with at least one creatinine value, 61 (23%) had an abnormal eGFR; of the 209 with at least two values greater than or equal to 90 days apart, 18 (9%) met criteria for CKD. Of those with CKD, 12 of 18 had AKI during ECMO, and seven of 18 had AKI events post-discharge (range, 1-6 episodes).CONCLUSIONS:This 2009-2019 pediatric ECMO cohort of survivors, followed for a median of 5 years, shows the subsequent high burden of kidney disease. We found that monitoring and following kidney function was not complete in this population, which is a concern since the rate of later AKI events and CKD is significant. Further study is needed to mitigate this post-ECMO vulnerability.

Background: Differentiating acute kidney injury (AKI) from chronic kidney disease (CKD) in children remains a critical unmet need due to the limitations of current clinical and biochemical markers. Conventional ultrasound lacks the sensitivity to discern subtle parenchymal alterations. This study explores the application of ultrasound radiomics—a novel, non-invasive, and quantitative image analysis method—for distinguishing AKI from CKD in pediatric patients. Methods: In this retrospective cross-sectional pilot study, kidney ultrasound images were obtained from 31 pediatric subjects: 8 with oliguric AKI, 14 with CKD, and 9 healthy controls. Renal parenchyma was manually segmented, and 124 advanced texture features were extracted using the open-source ©PyFeats. Features encompassed multiple categories (e.g., GLCM, GLSZM, WP). Statistical comparisons evaluated intergroup differences. Principal Component Analysis identified the top 10 most informative features, which were used to train supervised machine learning models. Model performance used five-fold cross-validation. Results: Radiomic analysis revealed significant intergroup differences (p < 0.05). CKD cases exhibited increased echogenicity and heterogeneity, particularly in GLCM and GLSZM features, consistent with chronic fibrosis. AKI cases displayed more homogeneous texture, likely reflecting edema or acute inflammation. While echogenicity separated diseased from healthy kidneys, it lacked specificity between AKI and CKD. Among ML models, XGBoost achieved the highest macro-averaged F1 score (0.90), followed closely by SVM and Random Forest, demonstrating strong classification performance. Conclusions: Radiomics-based texture analysis of grayscale ultrasound images effectively differentiated AKI from CKD in this pilot study, offering a promising, non-invasive imaging biomarker for pediatric kidney disease. These preliminary findings justify prospective validation in larger, multicenter cohorts.

OBJECTIVE:Severe acute kidney injury (AKI) portends poor outcomes in pediatric sepsis. We evaluated the trajectory and prognostic utility of AKI biomarkers in pediatric septic shock using a subset of participants in the ongoing Pragmatic Pediatric Trial of Balanced vs. Normal Saline Fluid in Sepsis (PRoMPT BOLUS) trial, NCT04102371. We tested whether fluid volume is associated with persistent elevation of urine neutrophil gelatinase-associated lipocalin (Ur-NGAL). DESIGN:Prospective, non-prespecified cohort study within the PRoMPT BOLUS trial. SETTING:Three children's hospitals in the United States. PATIENTS:Four hundred seventy-eight patients aged 2 months to younger than 18 years old with septic shock. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Ur-NGAL, kidney injury molecule-1, liver fatty acid binding protein, and interleukin-18 and plasma cystatin C were collected at presentation (T1), days 2-3 (T2), and before discharge/death (T3). At presentation, 418 (88%) had no or only stage 1 AKI and 60 (12%) had stage 2/3 AKI defined using Kidney Disease Improving Global Outcomes creatinine thresholds. All biomarkers were higher with stage 2/3 compared with no/stage 1 AKI at T1 and T2, but only cystatin C remained higher at T3. Among patients with no/stage 1 AKI at presentation, those with Ur-NGAL greater than or equal to 150 vs. less than 150 ng/mL had fewer hospital-free days (21 [interquartile range (IQR) 15-24] vs. 23 d [IQR 19-25], p = 0.05). After applying inverse probability treatment weighting to balance covariates, 14% of patients who received greater than 100 mL/kg within 48 hours had persistently elevated Ur-NGAL over time compared with 6% who received 40-100 mL/kg (odds ratio 2.7 [95% CI, 1.1-6.2]). Hospital-free days were no different across fluid volume groups. CONCLUSIONS:Although kidney injury biomarkers mirrored serum creatinine in children with septic shock, elevated Ur-NGAL identified a subset with subclinical AKI with fewer hospital-free days despite no/stage 1 AKI by creatinine. Children receiving greater than 100 mL/kg fluid had greater odds of early and persistently elevated Ur-NGAL, suggesting high fluid volumes may perpetuate initial kidney damage.

BK polyomavirus (BKPyV) is a non-enveloped, double-stranded, circular DNA virus that is a member of the Polyomaviridae family. The BKPyV genome is divided into three regions, including the non-coding control region (NCCR), the early region, and the late region. BKPyV has one of the highest mutation rates among DNA viruses, and four genotypes have been identified based on amino acid variation within the VP1 region. Mutations within the NCCR have been noted, and this region exhibits hypervariability. Here, we show that many of the point mutations observed within the NCCR are genotype-associated, termed genotype-associated polymorphisms (GAPs). These GAPs correlate with regions of hypervariability, are inherent to their genotype, and can be used to genotype clinical strains, separate from other genomic regions. We also show that these GAPs fall within predicted transcription factor binding sites and therefore provide targets for further functional studies.IMPORTANCEBK Polyomavirus (BKPyV) is the cause of hemorrhagic cystitis in hematopoietic cell transplant recipients and BKPyV-associated nephropathy in renal transplant recipients and thus is an important determinant of transplant outcome. The viral mechanisms leading to disease manifestation remain to be thoroughly explored, but viral genetic variation has emerged as an area of interest. Understanding genomic diversity between and within BKPyV genotypes can provide sites of interest that may ultimately improve screening strategies and provide insights into the viral factors that contribute to disease.

Cardiopulmonary bypass (CPB) is associated with hemolysis and acute kidney injury (AKI). The study aim was to determine if urine dipstick blood in infants after CPB was associated with AKI and urine neutrophil gelatinase-associated lipocalin (NGAL). Infants who underwent CPB at a single center were enrolled prospectively between October 2017 and June 2019. Urine samples prior to CPB and 6 h after CPB cessation were analyzed in batch for NGAL and dipstick blood. AKI was defined using creatinine-based KDIGO criteria within 72 h of CPB. Spearman correlation examined associations between urine dipstick blood and NGAL at each time point. Linear regression estimated the associations between urine dipstick blood and log-transformed NGAL 6 h after CPB. Logistic regression estimated associations and compared discrimination between urine dipstick blood and NGAL for predicting AKI. At baseline, 7/63 samples (11

BK polyomavirus (BKPyV) is associated with disease in transplant patients. BKPyV genomic diversity is thought to contribute to functional differences in virulence factors. Here, we present the near full-length BKPyV genome sequence from a patient who underwent hematopoietic cell transplant and was infected with subtype III, a rare subtype.

The role of viral diversity in the pathogenesis of BK polyomavirus (BKPyV)-associated disease is poorly understood. Here, we report near full-length BKPyV genome sequences from two allogeneic hematopoietic cell transplant recipients infected with BKPyV genotype II, which is uncommon in the USA.

IntroductionBK polyomavirus (BKPyV) is associated with cystitis, nephropathy and transplant-associated thrombotic microangiopathy (TA-TMA) in hematopoietic stem cell transplant (HSCT) recipients. Massive BKPyV propagation alone is insufficient for disease and many patients are asymptomatic despite high viral loads. We previously identified intracellular BKPyV in circulating endothelial cells from HSCT recipients with BKPyV viremia, confirming BKPyV infects the endothelium. In this study, we hypothesized that differences in endothelial cell and host immune responses to BKPyV viremia influence BKPyV disease.ObjectivesWe sought to identify biological pathways that influence BKPyV disease in HSCT recipients.MethodsWe performed single cell RNA-seq (scRNAseq) in two settings. First, we used an in vitro model to study BKPyV infection in primary kidney endothelial cells. Cells were cultured with BKPyV and harvested at 1 and 5 days post-infection (DPI). We then studied the transcriptomes of peripheral blood mononuclear cells (PBMCs) from HSCT recipients with high BKPyV viremia (>10,000 copies/mL, n=3) and without BKPyV viremia or viruria (n=3) at day 60 after HSCT.ResultsCellular BKPyV infection was measured with microscopy (Fig. 1A) and scRNAseq. At 1 DPI endothelial cells were 37% infected and 99% at 5 DPI. We compared the transcriptomes from the top quartile of infected endothelial cells to the bottom quartile of infected cells (including uninfected cells, Fig. 1B) at 5 DPI. Pathway analysis of differentially expressed genes (DEGs) found hypoxia, TNFα signaling, PI3 kinase signaling and complement pathways were significantly different (Fig. 1C). Two cell clusters were identified (Fig. 1B) and we compared “high” infected cells in cluster 1 to “high” infected cells in cluster 2 (Fig. 1D). Pathway analysis showed PI3K signaling was significantly different. Both cell clusters in this comparison had high levels of BKPyV transcript which means PI3K signaling was not related to BKPyV infection alone.Single cell RNAseq of PBMCs from patients with and without BKPyV viremia identified DEGs across all cell types (Fig.2A). NK cells and mucosal-associated invariant T-cells (MAIT cells) had notable differences on UMAP (Fig. 2B) and cell composition analysis (Fig. 2C/E). Pathway analysis of NK and MAIT cells showed similar pathway changes observed in our model, including TNFα signaling, hypoxia, complement and PI3K signaling (Fig. 2D/F). These pathways and cell types are likely involved in the in vivo response to BKPyV viremia and may contribute to symptomatic disease.ConclusionThis study identified novel yet plausible innate and cellular immunity pathways that are likely involved in the host response to BKPyV. Furthermore, the role of MAIT cells in BKPyV has not been described. Complement and PI3K activation may be integral to BKPyV-related diseases such as cystitis and TA-TMA.