BACKGROUND: Proteinuria and hypertension are commonly observed in children with autosomal dominant polycystic kidney disease (ADPKD), but reliable non-invasive biochemical markers for early disease activity or progressio...BACKGROUND: Proteinuria and hypertension are commonly observed in children with autosomal dominant polycystic kidney disease (ADPKD), but reliable non-invasive biochemical markers for early disease activity or progression in pediatric ADPKD are lacking. Allantoin and the allantoin/uric acid ratio are recognized oxidative stress biomarkers in chronic kidney disease and may hold potential for early disease monitoring in ADPKD. METHODS: In this observational study, 34 patients with genotyped PKD1-ADPKD under 18 years with preserved kidney function were compared to 31 healthy controls. Urinary allantoin and adenosine were measured using a validated high-performance liquid chromatography (HPLC)-UV method. Associations with established markers of disease progression, including estimated glomerular filtration rate, total kidney volume (TKV), and the Leuven Imaging Classification (LIC) score, were assessed. RESULTS: Urinary allantoin, adenosine and the urinary allantoin/uric acid ratio did not differ significantly between patients and controls. In the ADPKD cohort, significant negative correlations were found between urinary allantoin and TKV (r = -0.49 P = 0.0043) and between urinary allantoin/uric acid ratio and TKV (r = -0.41 P = 0.0228). No correlations were observed between urinary allantoin and LIC score. Across all participants, urinary allantoin levels negatively correlated with age (r = -0.54 P = 0.0015; r = -0.74 P = 8.75e-007). CONCLUSIONS: Although urinary allantoin, adenosine, and the allantoin/uric acid ratio were comparable between pediatric patients with ADPKD and controls, inverse associations between allantoin and TKV were observed between the groups. However, the lack of correlation with LIC score and the negative correlation with age limit its potential as a marker in pediatric ADPKD.
Pediatric acute kidney injury (AKI) is a complex syndrome that affects a significant proportion of hospitalized children. AKI carries significant short- and long-term sequelae for survivors. As kidney tubular biomarkers...Pediatric acute kidney injury (AKI) is a complex syndrome that affects a significant proportion of hospitalized children. AKI carries significant short- and long-term sequelae for survivors. As kidney tubular biomarkers and risk prediction tools have become more widely available, our ability to identify those at higher risk of AKI has improved. However, AKI prevention in clinical practice relies heavily on traditional kidney protection strategies: fluid management, hemodynamic optimization, and nephrotoxin avoidance. In this review, we explore contemporary risk stratification tools in AKI and briefly review key aspects of AKI pathophysiology relevant to prevention. In addition, this review summarizes established kidney-protective strategies and appraises pharmacological and extracorporeal interventions for preventing AKI in children. Early intervention frameworks, emerging clinical trials, and targeted preventive strategies suggest meaningful progress in the field. Ongoing research continues to refine our approach to pediatric AKI prevention and offers cautious optimism for improved outcomes.
BACKGROUND: APOL1 variants confer increased risk for kidney disease in individuals of African ancestry, particularly in homozygous or compound heterozygous states. A missense variant, p.N264K, has been shown to attenuate...BACKGROUND: APOL1 variants confer increased risk for kidney disease in individuals of African ancestry, particularly in homozygous or compound heterozygous states. A missense variant, p.N264K, has been shown to attenuate this risk when co-inherited with the G2 allele. While these associations are established in adults, data in pediatric populations remain limited. Using the University of Tennessee Health Science Biorepository and Integrative Genomics initiative, we assessed chronic kidney disease (CKD) risk by APOL1 high-risk genotype and the potential protective effect of p.N264K in a diverse pediatric cohort. METHODS: This is a case-control study of African American children enrolled in the BIG initiative at Le Bonheur Children's Hospital (2014-2022). Composite CKD was defined by eGFR < 90 mL/min/1.73 m or albuminuria (UACR > 30 mg/g) on two occasions ≥ 90 days apart. The p.N264K variant status was assessed in patients with APOL1 high-risk (HR). Logistic regression models adjusted for age, sex, and five principal components of ancestry assessed associations with CKD and albuminuria. RESULTS: CKD cases had 8% higher odds of APOL1 HR status (Odds Ratio (OR): 1.08, 95% Confidence Interval (CI): 0.88-1.33). Stronger associations were observed in cases with albuminuria and APOL1 HR status (OR: 1.41, 95% CI: 1.02-1.92, p = 0.03). The p.N264K variant was detected in 4.3% of cases and 4.5% of controls, and appeared to attenuate CKD risk among HR individuals, though sample size limited statistical power. CONCLUSIONS: APOL1 HR genotypes were associated with albuminuria in African American children. The p.N264K variant may modify this risk, warranting further study.
BACKGROUND: Mycophenolate mofetil (MMF) as maintenance therapy after rituximab treatment is effective in preventing relapses in children with complicated frequently relapsing or steroid-dependent nephrotic syndrome. Howe...BACKGROUND: Mycophenolate mofetil (MMF) as maintenance therapy after rituximab treatment is effective in preventing relapses in children with complicated frequently relapsing or steroid-dependent nephrotic syndrome. However, once sustained remission has been achieved by MMF, the outcomes and risk of relapse after discontinuing MMF remain unclear. METHODS: We conducted a two-center, retrospective study of patients with childhood-onset frequently relapsing or steroid-dependent nephrotic syndrome who discontinued MMF because of sustained remission for ≥ 2 years on maintenance MMF after rituximab treatment. Relapse, additional treatment, and risk factors for relapses after MMF discontinuation were analyzed. RESULTS: Sixty patients were enrolled. After tapering or discontinuation of MMF, 35 (58%) patients relapsed, and the median time from tapering to relapse was 276 days. The 50% relapse-free survival was 1.5 years using the Kaplan-Meier method. After relapses, 30 (86%) patients required reinitiation of immunosuppressants or additional rituximab treatment. The history of initial steroid-resistant nephrotic syndrome, relapses < 10 times before the first rituximab treatment with immunosuppressants, and a longer period between the last B-cell recovery and tapering MMF were significantly associated with a lower risk of relapse in a multivariate analysis using the Cox proportional hazards model (all p < 0.05). CONCLUSIONS: Discontinuation of MMF may be considered in selected patients with sustained remission after rituximab treatment, particularly those with identified low-risk factors for relapse. The timing of discontinuation should be individualized according to these factors and patient-specific considerations because resumption of immunosuppressants or additional rituximab treatment is frequently required after relapse following MMF discontinuation.
BACKGROUND: Children with steroid-resistant, frequently relapsing, and steroid-dependent nephrotic syndrome experience high disease and treatment-related morbidity. There are few prediction models for childhood nephrotic...BACKGROUND: Children with steroid-resistant, frequently relapsing, and steroid-dependent nephrotic syndrome experience high disease and treatment-related morbidity. There are few prediction models for childhood nephrotic syndrome outcomes. Our aim was to develop and internally validate outcome prediction models, using machine learning methods. METHODS: We analyzed data from Insight into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics, a prospective observational childhood nephrotic syndrome cohort. We included children (1-18 years) diagnosed from 1996 to 2023 from the Greater Toronto Area, Canada, with baseline data from within 90 days of diagnosis. Outcomes were frequent relapses or steroid dependence by 1 year, relapse occurrence by 1 year, steroid-sparing medication initiation by 2 years, and initial steroid resistance. We developed and compared the performance of nine different machine learning algorithms for each outcome. Predictors included sociodemographic, clinical, and laboratory features. RESULTS: We included 515 children diagnosed with nephrotic syndrome. Of these, 484 (94%) were steroid-sensitive and 31 (6%) were steroid-resistant. Nine machine learning models were developed and optimized by hyperparameter tuning for each outcome. The random forest model had the best performance for predicting frequent relapses or steroid dependence, although its predictive ability was low (AUC 0.60). Machine learning models also had weak predictive ability for relapse occurrence (AUC 0.62; logistic regression with recursive feature elimination), steroid-sparing medication initiation (AUC 0.61; XGBoost), and steroid resistance (AUC 0.64; XGBoost). CONCLUSIONS: Routinely collected sociodemographic, clinical, and laboratory features at nephrotic syndrome diagnosis are weakly predictive of subsequent relapses and treatment response, using machine learning methods. Discovery of novel biomarkers may improve future prediction and proactive treatment.
BACKGROUND: Pre-emptive kidney transplantation (PKT) improves both lifespan and quality of life for children with stage 5 chronic kidney disease (CKD 5) and is the preferred modality of kidney replacement therapy. The po...BACKGROUND: Pre-emptive kidney transplantation (PKT) improves both lifespan and quality of life for children with stage 5 chronic kidney disease (CKD 5) and is the preferred modality of kidney replacement therapy. The potential crucial role of family and social support (FSS) in PKT is often overlooked. The objective of this study was to determine whether a supportive FSS is associated with improved access to PKT. METHODS: Retrospective single-center study examining associations among demographic, clinical, socioeconomic factors, and psychosocial and family assessments in children with CKD 5 from 2010 to 2020. Children who received a PKT were compared with dialysis-only and dialysis followed by KT recipients using Fisher's exact test, chi-square test, t-test, or Wilcoxon test, as appropriate. Multivariable logistic regression identified key predictors of PKT. RESULTS: PKT was observed in 19.2% of the 177 patients who received a KT and was more prevalent among White males with underlying non-glomerular etiology, with private insurance, and with two caregivers. Living donors (LDs) were more common among recipients of a PKT. PKT recipients were more likely to report an adequate FSS network (97.1% vs. 71.2%, p = 0.001), greater parental supervision (94.1% vs. 75.5%, p = 0.017), and fewer comorbid psychiatric conditions (5.9% vs. 30.4%, p = 0.002). FSS was more strongly associated with the recipients of LDs than deceased donors' kidneys (98.5% vs. 68.4%, p < 0.001). Candidates with adequate FSS had an 8.86-fold higher odds of PKT (p = 0.038). CONCLUSIONS: Adequate family social support was significantly associated with access to PKT. Emphasis should be placed on strengthening family support networks and bolstering caregivers' resilience to increase the likelihood of PKT among pediatric candidates.
BACKGROUND: Ceftriaxone-associated biliary pseudolithiasis is well reported, but the true risk of urolithiasis remains less clearly defined. Prior reviews frequently combine biliary and urinary tract calcifications or re...BACKGROUND: Ceftriaxone-associated biliary pseudolithiasis is well reported, but the true risk of urolithiasis remains less clearly defined. Prior reviews frequently combine biliary and urinary tract calcifications or rely mainly on descriptive findings, limiting accurate incidence estimates. OBJECTIVE: This systematic review and meta-analysis aimed to provide the first pooled frequency estimate specifically for ceftriaxone-induced urolithiasis in children. DATA SOURCES: A systematic search of PubMed, Google Scholar, Web of Science, and Scopus was conducted up to November 2025. STUDY ELIGIBILITY CRITERIA: Studies reporting the cases of urolithiasis in pediatric patients receiving ceftriaxone were included. STUDY APPRAISAL AND DATA SYNTHESIS: Data extraction and synthesis were performed by two independent reviewers and analyzed by Stata 19.5. Pooled proportions were calculated using a random-effects model with REML estimation to determine overall frequency, between-study variance (τ), and 95% prediction intervals (PI). RESULTS: Eight studies met the inclusion criteria. The pooled frequency of ceftriaxone-induced urolithiasis was 7% (95% CI: 2-12%). Heterogeneity was substantial (I = 89.8%; τ = 0.0034), and the 95% PI ranged from 2.7 to 15.8%. Subgroup analyses showed that retrospective studies from Asian regions reported markedly higher rates (up to 34%), whereas prospective Western studies consistently demonstrated lower frequencies. Sensitivity analysis excluding the main outlier reduced the pooled estimate to 4% (p = 0.004). Publication bias was detected (Egger's test, p = 0.006), indicating underreporting of studies with low event rates. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This meta-analysis suggests that ceftriaxone-associated urinary tract lithiasis occurs in approximately 7% of pediatric patients, with substantial variability driven by study design and diagnostic approach. Well-powered, prospective studies with standardized imaging protocols are required to define the true incidence and modifiable risk factors. SYSTEMATIC REVIEW REGISTRATION NUMBER: (CRD42024598001).
Infections after kidney transplantation are a principal cause of morbidity, allograft failure and mortality. Paediatric recipients are less likely to have immunity through prior exposure to pathogens linked to graft fail...Infections after kidney transplantation are a principal cause of morbidity, allograft failure and mortality. Paediatric recipients are less likely to have immunity through prior exposure to pathogens linked to graft failure such as CMV and EBV. This immunological naivety results in a need for meticulous donor screening, the deployment of strategies to minimise the risk of severe disease, and prompt treatment once infection is diagnosed. This review provides an up-to-date overview of major pathogens contributing to infection in paediatric kidney transplant recipients and we discuss prophylaxis, treatment and lifestyle modifications that can be employed to mitigate infection risk.
BACKGROUND: COVID-19 infection has been associated with significant morbidity and mortality across all age groups, yet data on pediatric kidney transplant outcomes associated with COVID-19 positive (COVID +) donors remai...BACKGROUND: COVID-19 infection has been associated with significant morbidity and mortality across all age groups, yet data on pediatric kidney transplant outcomes associated with COVID-19 positive (COVID +) donors remain limited. METHODS: Using the Scientific Registry of Transplant Recipients, we identified 143 pediatric kidney recipients (< 18 years) of COVID + donors transplanted between September 2020 and February 2025 and compared them with 1808 recipients of COVID-19 negative (COVID -) donors using propensity score weighting to account for transplant year, age at transplant, sex, race, human leukocyte antigen mismatch, prior transplant, and immunosuppression. RESULTS: Among 1940 pediatric recipients, 7.3% received kidneys from COVID + donors, with utilization increasing from 2.5% in 2020 to 10.5% in 2025. No statistically significant differences were observed in patient survival (HR 0.83, 95% CI 0.10-6.73, p = 0.86) and overall graft failure (HR 1.35, 95% CI 0.67-2.73, p = 0.41) between COVID + and COVID - groups over a median follow-up of 1.2 years. Delayed graft function (7.7% vs. 7.2%) and median initial hospital stay (8.0 vs. 8.0 days) were also comparable. CONCLUSIONS: The use of COVID + donors for pediatric kidney transplantation has increased over time. The posttransplant outcomes are similar between COVID + and COVID - pediatric recipients, supporting the use of COVID + donors in this population.
BACKGROUND: To characterize severe hemorrhage and determine its frequency, risk factors, and consequences in the perioperative period of pediatric kidney transplantation. METHODS: Single-center retrospective study of chi...BACKGROUND: To characterize severe hemorrhage and determine its frequency, risk factors, and consequences in the perioperative period of pediatric kidney transplantation. METHODS: Single-center retrospective study of children undergoing their first kidney transplant between 2008 and 2015. Severe hemorrhage was defined using a data-driven cluster analysis to identify patients with high perioperative bleeding volume and blood component requirements. Additionally, severe hemorrhage was defined by the need for reoperation or administration of activated factor VII or fibrinogen for bleeding related to transplant. Thirty-eight exposure variables were examined, including clinical and laboratory data, donor and recipient characteristics, surgical technical variables, and medications. Analysis of hemorrhage consequences considered the occurrence of delayed renal function, hospitalization length during transplantation, estimated glomerular filtration rate post-transplantation, and five-year graft and patient survival. RESULTS: Severe hemorrhage occurred in 16/218 cases (7.3%). In unadjusted logistic analyses, higher risk was observed among younger and smaller recipients, those receiving kidneys from older and living donors, and those exposed to a higher graft dose. Among laboratory markers, postoperative platelet count was associated with hemorrhage. Five-year graft survival was lower in children with severe hemorrhage compared with those without (62.5% vs. 91.5%, p < 0.001). CONCLUSION: The frequency of severe hemorrhage in children treated with kidney transplantation in our center was higher than reported in the literature. The type of donor and the combination of small recipients and large donors were the main risk factors. The need for a larger abdominal dissection area in small children receiving large grafts, contributing to the risk of bleeding, is a possible explanation for this finding.
Chronic kidney disease (CKD) is a major global health burden that disproportionately impacts people of recent African ancestry. The discovery of risk variants in the apolipoprotein L1 (APOL1) gene has transformed the und...Chronic kidney disease (CKD) is a major global health burden that disproportionately impacts people of recent African ancestry. The discovery of risk variants in the apolipoprotein L1 (APOL1) gene has transformed the understanding of racial disparities in CKD. In particular, APOL1 variants have been associated with increased risk of focal segmental glomerulosclerosis, virus-associated nephropathy, and other glomerular diseases in Black adults. While approximately 10-15% of Black Americans have a high-risk APOL1 genotype, disease penetrance is variable and is likely mediated by additional genetic and environmental "second hits." Variants in APOL1 have also been implicated in kidney transplant outcomes and pregnancy complications, underscoring its broad clinical relevance. Advances in therapeutic strategies, including small molecule inhibitors of APOL1 pore function, APOL1 antisense oligonucleotides, and JAK-STAT pathway modulation, offer promise for targeted interventions in adult populations. Emerging data in children highlight similar genotype-phenotype associations, with evidence of high-risk APOL1 genotype impacting steroid-resistant nephrotic syndrome and CKD progression. However, pediatric studies remain limited and underpowered, leaving critical gaps in the understanding of disease epidemiology, mechanisms, and long-term outcomes. This review will explore current knowledge of APOL1 kidney disease (AMKD) with a particular focus on pediatric populations and highlight the need for inclusion of children in future studies.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease in children. Although prenatal ultrasound enables early detection, its ability to predict postnatal renal outco...Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease in children. Although prenatal ultrasound enables early detection, its ability to predict postnatal renal outcome, particularly in bilateral cases, remains limited due to substantial phenotypic variability and the inability of imaging to capture ongoing disease processes. Genetic testing improves etiological classification but shows weak genotype-phenotype correlations and limited prognostic value, reflecting the multifactorial nature of CAKUT and prompting investigation of molecular biomarkers in prenatal body fluids. This review summarizes current prenatal prognostic strategies in CAKUT, including imaging, genetics, and downstream molecular approaches such as transcriptomics, metabolomics, and proteomics, with particular emphasis on peptide-based profiling. Among these, prenatal peptide signatures derived from fetal urine or amniotic fluid have demonstrated strong prognostic performance for predicting postnatal renal outcome and may capture early molecular processes related to tissue remodeling and inflammation. However, translation into clinical practice remains challenging. Validation requires large prospective multicenter studies that are difficult to conduct in rare diseases and often lack sustained funding. In addition, implementation will likely rely on mass spectrometry-based assays in clinical laboratories. Despite these hurdles, integrating molecular peptide profiling with improved and standardized imaging approaches may enhance prenatal counselling and clinical decision-making in CAKUT.
BACKGROUND: IgA vasculitis nephritis (IgAVN) develops in 20-80% of patients with IgA vasculitis (IgAV), yet diagnosis is often delayed. Readily available biomarkers can help identify patients at risk earlier. OBJECTIVE:...BACKGROUND: IgA vasculitis nephritis (IgAVN) develops in 20-80% of patients with IgA vasculitis (IgAV), yet diagnosis is often delayed. Readily available biomarkers can help identify patients at risk earlier. OBJECTIVE: To conduct a systematic review and meta-analysis of all available serum and urinary biomarkers to evaluate their prognostic potential in predicting IgAVN in paediatric patients. DATA SOURCES: A comprehensive search was performed in PubMed, EMBASE and Cochrane Library on November 9, 2024, covering publications from inception. The search strategy included three domains: paediatric population, IgAV diagnosis and studied biomarkers. No language or additional restrictions were applied. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: We included original retrospective, prospective and cross-sectional studies that involved paediatric IgAV patients and reported biomarker levels in patients with and without nephritis. Two reviewers independently screened studies, and a third reviewer resolved conflicts. STUDY APPRAISAL AND SYNTHESIS METHODS: Data extraction was performed by two independent reviewers. A random-effects model was used for analysis. The review followed PRISMA guidelines, and study quality was assessed using the QUIPS tool. Outcomes were reported as mean or standardised mean differences with 95% confidence intervals (CI). Where possible, odds ratios (OR) and diagnostic performance measures were also evaluated. RESULTS: Of 10,611 records screened, 129 studies including 23,726 patients were included. The neutrophil-to-lymphocyte ratio (NLR) was significantly higher in patients with nephritis (0.48; 95% CI 0.04-0.93), with notable effects in the Turkish population (0.86; 95% CI 0.19-1.52) but not in the Chinese population (- 0.02; 95% CI - 0.75-0.72). The platelet-to-lymphocyte ratio (PLR) showed a similar pattern, being higher in the Turkish subgroup (21.9; 95% CI 9.64-34.16) and lower in the Chinese subgroup (- 6.75; 95% CI - 11.27-2.22). A positive faecal occult blood test (FOBT) was associated with increased odds of kidney involvement (OR 2.04; 95% CI 1.05-3.96). LIMITATIONS: This study has limitations, including the predominance of retrospective data, limited reporting of diagnostic accuracy metrics (e.g. sensitivity, specificity), and substantial inter-study heterogeneity in nephritis definitions, measurement methods and study populations, which restrict firm conclusions about biomarker performance. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: While statistically significant biomarker associations exist, clinically actionable predictors of IgAVN remain lacking. NLR, PLR and FOBT warrant prospective validation in multicentre cohorts with standardised protocols. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42024593928.
Muniz VM, de Paiva Souza Klippel L, Freitas KLF
… +8 more, Dos Santos Barbosa K, Libardi MC, de Paula Alves Bezerra OM, da Cunha AC, Naseri AP, Netto AL, Mendonça HXM, Salaroli LB
BACKGROUND: Pediatric chronic kidney disease (CKD) is a serious public health problem and represents a considerable burden on health systems, particularly in low- and middle-income countries (LMICs). Despite well-documen...BACKGROUND: Pediatric chronic kidney disease (CKD) is a serious public health problem and represents a considerable burden on health systems, particularly in low- and middle-income countries (LMICs). Despite well-documented global disparities in CKD management, the extent of these differences across continents remains insufficiently explored, particularly in pediatric populations. OBJECTIVE: To explore the body of recent evidence on clinical complications and anthropometric indicators of CKD in childhood and to identify gaps in knowledge that can guide the development of future studies of CKD in childhood, in the global context. DATA SOURCES: Studies were searched in following electronic databases: PubMed/Medline, Embase, Web of Science, and Google Scholar. STUDY ELIGIBILITY CRITERIA: Inclusion criteria consisted of observational quantitative articles (cohort, cross-sectional, case-control studies) in English that evaluated CKD in children. We excluded studies without reported data findings, case studies with fewer than 50 individuals and conducted with the same cohort. PARTICIPANTS AND INTERVENTIONS: Children and adolescents aged 0 to 18 years old with CKD. STUDY APPRAISAL AND SYNTHESIS METHODS: This research did not aim to evaluate the quality of individual studies, since the main objective of a scoping review is to map the evidence and identify strengths and weaknesses. We conducted a scoping review structured using the methodology developed by Arksey and O'Malley expanded by Levac et al. to map the existing literature. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) extension were adopted to increase methodological rigor. Two coders reviewed articles for descriptive information to create summary tables comparing variables of interest. RESULTS: Fifteen studies met inclusion criteria for this scoping review. Baseline clinical characteristics of individuals were analysed, with 889 from LMICs and 2564 from high-income countries (HICs). Inequality in access to treatment for pediatric patients with CKD between HICs and LMICs was evident. LIMITATIONS: Scoping reviews typically have limitations due to their broad research focus and lack of in-depth analysis of a specific problem; therefore, a meta-analysis is not possible. We limited the included studies to those published in English to avoid translation/interpretation errors. Finally, information biases may be present since the data were mostly extracted from observational studies based on secondary information sources. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Future studies should:1) Focus on standardizing variable definitions and measurement to reduce heterogeneity in the presentation of results; 2) Explore barriers and facilitators to access to treatment among of children with CKD from LMICs; 3) Promote the development of large multicenter collaborative cohorts of pediatric CKD in LMICs, enabling more representative data, longitudinal follow-up, and evidence-based strategies to improve outcomes. REGISTRATION NUMBER: Open Science Framework protocol https://doi.org/10.17605/OSF.IO/Q4HN8.