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IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA - DRB1 (OR=1.55, P=1.1×10 -25 ) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10 -20 ) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10 -9 ) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR . Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR , INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS , and ANKRD55 .

Background: Continuous kidney replacement therapy (CKRT) is often used for acute kidney injury (AKI) or fluid overload (FO) in children ≤ 10 kg. Intensive care unit (ICU) mortality in children ≤ 10 kg reported by the prospective pediatric CRRT (ppCRRT, 2001-2003) registry was 57%. We aimed to evaluate characteristics associated with ICU mortality using a contemporary registry., Methods: The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry is a retrospective, multinational, observational study of children and young adults aged 0-25 years receiving CKRT (2015-2021) for AKI or FO. This analysis included patients ≤ 10 kg at hospital admission., Primary and Secondary Outcomes: ICU mortality and major adverse kidney events at 90 days (MAKE-90) defined as death, persistent kidney dysfunction, or dialysis within 90 days, respectively., Results: A total of 210 patients were included (median age 0.53 years (IQR, 0.1, 0.9)). ICU mortality was 46.5%. MAKE-90 occurred in 150/207 (72%). CKRT was initiated at a median 3 days (IQR 1, 9) after ICU admission and lasted a median 6 days (IQR 3, 16). On multivariable analysis, pediatric logistic organ dysfunction score (PELOD-2) at CKRT initiation was associated with increased odds of ICU mortality (aOR 2.64, 95% CI 1.68-4.16), and increased odds of MAKE-90 (aOR 2.2, 95% CI 1.31-3.69). Absence of comorbidity was associated with lower MAKE-90 (aOR 0.29, 95%CI 0.13-0.65)., Conclusions: We report on a contemporary cohort of children ≤ 10 kg treated with CKRT for acute kidney injury and/or fluid overload. ICU mortality is decreased compared to ppCRRT. The extended risk of death and morbidity at 90 days highlights the importance of close follow-up., Competing Interests: Declarations. Conflict of interest: All authors declare no real or perceived conflicts of interest that could affect the study design, collection, analysis and interpretation of data, writing of the report, or the decision to submit for publication. For full disclosure, we provide here an additional list of other authors’ commitments and funding sources that are not directly related to this study: Katja Gist is a consultant for Bioporto Diagnostics and Potrero Medical. Shina Menon is a consultant for Medtronic, Inc. and Nuwellis, Inc. Theresa A. Mottes is a consultant for Medtronic Inc. Melissa Muff-Luett is a consultant for Medtronic Inc. Michael Zappitelli has completed consultant work for Bioporto Diagnostics Inc. No other competing interests were reported., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objectives: Continuous renal replacement therapy (CRRT) and shock are both associated with high morbidity and mortality in the ICU. Adult data suggest renoprotective effects of vasopressin vs. catecholamines (norepinephrine and epinephrine). We aimed to determine whether vasopressin use during CRRT was associated with improved kidney outcomes in children and young adults., Design: Secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), a multicenter, retrospective cohort study., Setting: Neonatal, cardiac, PICUs at 34 centers internationally from January 1, 2015, to December 31, 2021., Patients/subjects: Patients younger than 25 years receiving CRRT for acute kidney injury and/or fluid overload and requiring vasopressors. Patients receiving vasopressin were compared with patients receiving only norepinephrine/epinephrine. The impact of timing of vasopressin relative to CRRT start was assessed by categorizing patients as: early (on or before day 0), intermediate (days 1-2), and late (days 3-7)., Interventions: None., Measurements and Main Results: Of 1016 patients, 665 (65%) required vasopressors in the first week of CRRT. Of 665, 248 (37%) received vasopressin, 473 (71%) experienced Major Adverse Kidney Events at 90 days (MAKE-90) (death, renal replacement therapy dependence, and/or > 125% increase in serum creatinine from baseline 90 days from CRRT initiation), and 195 (29%) liberated from CRRT on the first attempt within 28 days. Receipt of vasopressin was associated with higher odds of MAKE-90 (adjusted odds ratio [aOR], 1.80; 95% CI, 1.20-2.71; p = 0.005) but not liberation success. In the vasopressin group, intermediate/late initiation was associated with higher odds of MAKE-90 (aOR, 2.67; 95% CI, 1.17-6.11; p = 0.02) compared with early initiation., Conclusions: Nearly two-thirds of children and young adults receiving CRRT required vasopressors, including over one-third who received vasopressin. Receipt of vasopressin was associated with more MAKE-90, although earlier initiation in those who received it appears beneficial. Prospective studies are needed to understand the appropriate timing, dose, and subpopulation for use of vasopressin., Competing Interests: Dr. Stanski received funding from the National Institute of General Medical Sciences (K23GM151444-01). Dr. Gist is a consultant for BioPorto Diagnostics and Potrero Medical; she received funding from the Gerber Foundation. Dr. Stenson received funding from the National Institute of Child Health and Development (K12HD047349). Dr. Ollberding serves as a consultant for SeaStar Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: Cardiac surgery-associated acute kidney injury (CS-AKI) is associated with adverse outcomes. Single-center studies suggest that the prevalence of CS-AKI is high after the Norwood procedure, or stage 1 palliation (S1P), but multicenter data are lacking., Design: A secondary analysis of the Neonatal and Pediatric Heart and Renal Outcomes Network (NEPHRON) multicenter cohort who underwent S1P. Using neonatal modification of Kidney Disease Improving Global Outcomes (KDIGO) criteria, perioperative associations between CS-AKI with morbidity and mortality were examined. Sensitivity analysis, with the exclusion of prophylactic peritoneal dialysis (PD) patients, was performed., Setting: Twenty-two hospitals participating in the Pediatric Cardiac Critical Care Consortium (PC 4 ) and contributing to NEPHRON., Patients: Three hundred forty-seven neonates (< 30 d old) with S1P managed between September 2015 and January 2018., Interventions: None., Measurements and Main Results: Of 347 patients, CS-AKI occurred in 231 (67%). The maximum stages were as follows: stage 1, in 141 of 347 (41%); stage 2, in 51 of 347 (15%); and stage 3, in 39 of 347 (11%). Severe CS-AKI (stages 2 and 3) peaked on the first postoperative day. In multivariable analysis, preoperative feeding was associated with lower odds of CS-AKI (odds ratio [OR] 0.48; 95% CI, 0.27-0.86), whereas prophylactic PD was associated with greater odds of severe CS-AKI (OR 3.67 [95% CI, 1.88-7.19]). We failed to identify an association between prophylactic PD and increased creatinine (OR 1.85 [95% CI, 0.82-4.14]) but cannot exclude the possibility of a four-fold increase in odds. Hospital mortality was 5.5% ( n = 19). After adjusting for risk covariates and center effect, severe CS-AKI was associated with greater odds of hospital mortality (OR 3.67 [95% CI, 1.11-12.16]). We failed to find associations between severe CS-AKI and respiratory support or length of stay. The sensitivity analysis using PD failed to show associations between severe CS-AKI and outcome., Conclusions: KDIGO-defined CS-AKI occurred frequently and early postoperatively in this 2015-2018 multicenter PC 4 /NEPHRON cohort of neonates after S1P. We failed to identify associations between resource utilization and CS-AKI, but there was an association between severe CS-AKI and greater odds of mortality in this high-risk cohort. Improving the precision for defining clinically relevant neonatal CS-AKI remains a priority., Competing Interests: Dr. Gist’s institution received funding from Bioporto Diagnostics; she received funding from the Gerber Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Fontan physiology leads to chronic changes in other organ systems that may affect long-term survival and the success of heart transplantation. Inadequate assessment and treatment of the extra-cardiac effects of Fontan may contribute to poor outcomes. Severity-graded/ordinal consensus definitions of Fontan complications are lacking, which limits understanding of how Fontan-specific morbidity affects patients' outcomes., Methods and Results: A panel of Fontan patient and physiology experts, including pediatric, adult congenital, heart failure, and critical-care cardiology as well as pediatric nephrology, hepatology and psychology, convened to develop definitions of Fontan complications. Definitions were created by using a severity-graded ordinal scale: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, disabling or life threatening. Following definition creation, a second panel of 21 experts in Fontan circulatory failure used a modified Delphi methodology to modify and vote on definitions until consensus (> 90% agreement without recommended further modification) was reached on final definitions. After 3 rounds of modifications and voting, consensus agreement was achieved on all Fontan-specific definitions. The defined complications and morbidities of Fontan include: anatomic Fontan pathway obstruction, cyanosis, systemic venous abnormalities resulting from venous insufficiency, atrial arrhythmia, ventricular arrhythmia, bradycardia, chronic pleural effusions, chronic ascites, protein-losing enteropathy, plastic bronchitis, hemoptysis and pulmonary hemorrhage, sleep apnea, Fontan-associated liver disease, portal and hepatic variceal disease, acute kidney injury affecting clinical treatment, polycythemia, thrombotic disease, recurrent or severe bacterial infection, skin atrophy, adrenal insufficiency, physical impact of previous stroke, mood/behavior disorder, and neurodevelopmental disorder., Conclusion: Consensus and severity-graded definitions of Fontan-specific cardiac and extra-cardiac complications were achieved and are available for use in research. They will allow future robust analyses of Fontan patient outcomes., Competing Interests: Disclosures The authors report no conflicts of interest or competing interests with the content of the current study., (Copyright © 2024. Published by Elsevier Inc.)

The nutritional management of neonates with kidney disease is complex. There may be significant differences in nutritional needs based on the duration and cause of kidney dysfunction, including acute kidney injury (AKI) and chronic kidney disease (CKD). Furthermore, the treatment modality, including acute (continuous renal replacement therapy and peritoneal dialysis [PD]) and chronic (intermittent hemodialysis and PD) approaches may differentially affect nutritional losses and dietary needs. In this review, we discuss the pathophysiology of compromised nutrition in neonates with AKI and CKD. We also summarize the existing data and consensus recommendations on the provision of nutrition to neonates with AKI and CKD. We highlight the paucity of data on micronutrient losses and the need for future prospective studies to enhance nutritional supplementation to hopefully improve outcomes in these patients., (Copyright © 2024 by the American Academy of Pediatrics.)

Introduction: Drug-induced acute kidney injury (DI-AKI) is a frequent adverse event. The identification of DI-AKI is challenged by competing etiologies, clinical heterogeneity among patients, and a lack of accurate diagnostic tools. Our research aims to describe the clinical characteristics and predictive variables of DI-AKI., Methods: We analyzed data from the Drug-Induced Renal Injury Consortium (DIRECT) study (NCT02159209), an international, multicenter, observational cohort study of enriched clinically adjudicated DI-AKI cases. Cases met the primary inclusion criteria if the patient was exposed to at least 1 nephrotoxic drug for a minimum of 24 hours prior to AKI onset. Cases were clinically adjudicated, and inter-rater reliability (IRR) was measured using Krippendorff's alpha. Variables associated with DI-AKI were identified using L1 regularized multivariable logistic regression. Model performance was assessed using the area under the receiver operating characteristic curve (ROC AUC)., Results: A total of 314 AKI cases met the eligibility criteria for this analysis, and 271 (86%) cases were adjudicated as DI-AKI. The majority of the AKI cases were recruited from the United States (68%). The most frequent causal nephrotoxic drugs were vancomycin (48.7%), nonsteroidal antiinflammatory drugs (18.2%), and piperacillin/tazobactam (17.8%). The IRR for DI-AKI adjudication was 0.309. The multivariable model identified age, vascular capacity, hyperglycemia, infections, pyuria, serum creatinine (SCr) trends, and contrast media as significant predictors of DI-AKI with good performance (ROC AUC 0.86)., Conclusion: The identification of DI-AKI is challenging even with comprehensive adjudication by experienced nephrologists. Our analysis identified key clinical characteristics and outcomes of DI-AKI compared to other AKI etiologies., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors., Methods: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation., Results: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups., Conclusions: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function., (Copyright © 2023 by the American Society of Nephrology.)

Background: The purpose of this Neonatal and Pediatric Heart and Renal Outcomes Network study was to describe the epidemiology and outcomes of cardiac surgery-associated acute kidney injury (CS-AKI) after cardiac surgery without cardiopulmonary bypass (non-CPB)., Methods: We performed a retrospective study of neonates (≤30 days) who underwent non-CPB cardiac surgery at 22 centers affiliated with the Pediatric Cardiac Critical Care Consortium. CS-AKI was defined using the modified Kidney Disease: Improving Global Outcomes serum creatinine and urine output criteria from postoperative days 0 to 6. CS-AKI defined by serum creatinine was further subclassified into transient (resolved by postoperative day 3) and persistent/late (≥3 days). Multivariable regression analyses were used to determine risk factors for CS-AKI and associations with outcomes of ventilation hours and cardiac intensive care unit length of stay., Results: Five hundred eighty-two neonates (median age at surgery, 9 days [interquartile range, 5-15], 25% functional single ventricle] were included. CS-AKI occurred in 38.3%: Rate and severity varied across centers. Aggregate daily CS-AKI prevalence peaked on postoperative day 1 (17.1%). No stage of CS-AKI was associated with ventilation hours or length of stay. Persistent/late CS-AKI occurred in 48 patients (8%). Prostaglandin use and single-ventricle surgery were associated with persistent/late CS-AKI. Higher baseline serum creatinine but not persistent/late CS-AKI was associated with longer ventilation duration and intensive care unit length of stay after adjusting for confounders., Conclusions: Kidney Disease: Improving Global Outcomes-defined CS-AKI occurred commonly in neonates undergoing non-CPB cardiac surgery. However most CS-AKI was transient, and no CS-AKI classification was associated with worse outcomes. Further work is needed to determine the CS-AKI definition that best associates with outcomes in this cohort., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Importance: Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge., Objective: To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy., Evidence Review: At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations., Findings: The meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy., Conclusions and Relevance: Existing evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.

Furosemide is a potent loop diuretic commonly and variably used by neonatologists to improve oxygenation and lung compliance in premature infants. There are several safety concerns with use of furosemide in premature infants, specifically the risk of sensorineural hearing loss (SNHL), and nephrocalcinosis/nephrolithiasis (NC/NL). We conducted a systematic review of all trials and observational studies examining the association between these outcomes with exposure to furosemide in premature infants. We searched MEDLINE, EMBASE, CINAHL, and clinicaltrials.gov. We included studies reporting either SNHL or NC/NL in premature infants (< 37 weeks completed gestational age) who received at least one dose of enteral or intravenous furosemide. Thirty-two studies met full inclusion criteria for the review, including 12 studies examining SNHL and 20 studies examining NC/NL. Only one randomized controlled trial was identified in this review. We found no evidence that furosemide exposure increases the risk of SNHL or NC/NL in premature infants, with varying quality of studies and found the strength of evidence for both outcomes to be low. The most common limitation in these studies was the lack of control for confounding factors. The evidence for the risk of SNHL and NC/NL in premature infants exposed to furosemide is low. Further randomized controlled trials of furosemide in premature infants are urgently needed to adequately assess the risk of SNHL and NC/NL, provide evidence for improved FDA labeling, and promote safer prescribing practices., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background and Objectives: Steroid-resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end-stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation and factors that predict response to immunosuppression following recurrence., Methods: Multicenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006 and 12/2015. Demographics, clinical course, and biopsy data were collected. Patients with primary-SRNS (PSRNS) were defined as those initially resistant to corticosteroid therapy at diagnosis, and patients with late-SRNS (LSRNS) as those initially responsive to steroids who subsequently developed steroid resistance. We performed logistic regression to determine risk factors associated with nephrotic syndrome (NS) recurrence., Results: We analyzed 158 patients; 64 (41%) had recurrence of NS in their renal allograft. Disease recurrence occurred in 78% of patients with LSRNS compared to 39% of those with PSRNS. Patients with MCD on initial native kidney biopsy had a 76% recurrence rate compared with a 40% recurrence rate in those with FSGS. Multivariable analysis showed that MCD histology (OR; 95% CI 5.6; 1.3-23.7) compared to FSGS predicted disease recurrence., Conclusions: Pediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence.

Several centers have examined the implementation of immunosuppression protocols that minimize steroid exposure. This study retrospectively examined cardiovascular risk factors in 70 pediatric renal transplant recipients on steroid avoidance-based immunosuppression over three yr compared to matched pediatric patients maintained on chronic corticosteroids. Although higher rates of acute rejection were noted in the steroid-avoidant group (22% vs. 16%, p = 0.034), graft function was similar (67 + 10 mL/min/1.73 m(2) vs. 72 + 12 mL/min/1.73 m(2)) (p = 0.053). The steroid-avoidant group demonstrated improved growth (height z-score -0.41 + 5.9 vs. -1.1 + 0.041) with a decrease in the prevalence of obesity (24% vs. 34%, p = 0.021). Indexed systolic blood pressures were lower beginning at six months post-transplant in the steroid-avoidant group (1.21 + 0.15 vs. 1.51 + 0.22, p = 0.020). Indexed diastolic blood pressures were lower beginning at 12 months post-transplant (0.91 + 0.11 vs. 1.12 + 0.18, p = 0.037). Differences in total serum cholesterol values and serum glucose values were not statistically significant. Beginning at 12 months, a statistically significant decrease in left ventricular mass index (39.2 + 11.3 vs. 49.4 + 14.5, p = 0.014) was noted in patients on steroid-avoidant immunosuppression, which corresponded to a significant decrease in the prevalence of left ventricular hypertrophy in these patients by two yr post-transplant (35% vs. 48%, p = 0.012). Systolic blood pressure and BMI were independent predictors of left ventricular hypertrophy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Natalizumab is a humanized IgG4κ monoclonal antibody that is a selective adhesion molecule inhibitor, which prevents adhesion of leukocytes to endothelial cells. It is the first monoclonal antibody approved by the FDA for the treatment of relapsing-remitting MS. This article will review the mechanism of action and clinical role of this agent.