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Children with chronic kidney disease (CKD) can have an inherent vulnerability to dehydration. Younger children are unable to freely access water, and CKD aetiology and stage can associate with reduced kidney concentrating capacity, which can also impact risk. This article aims to review the risk factors and consequences of mild dehydration and underhydration in CKD, with a particular focus on evidence for risk of CKD progression. We discuss that assessment of dehydration in the CKD population is more challenging than in the healthy population, thus complicating the definition of adequate hydration and clinical research in this field. We review pathophysiologic studies that suggest mild dehydration and underhydration may cause hyperfiltration injury and impact renal function, with arginine vasopressin as a key mediator. Randomised controlled trials in adults have not shown an impact of improved hydration in CKD outcomes, but more vulnerable populations with baseline low fluid intake or poor kidney concentrating capacity need to be studied. There is little published data on the frequency of dehydration, and risk of complications, acute or chronic, in children with CKD. Despite conflicting evidence and the need for more research, we propose that paediatric CKD management should routinely include an assessment of individual dehydration risk along with a treatment plan, and we provide a framework that could be used in outpatient settings., (© 2024. Crown.)

Despite increasing prevalence of hypertension in youth and high adult cardiovascular mortality rates, the long-term consequences of youth-onset hypertension remain unknown. This is due to limitations of prior research such as small sample sizes, reliance on manual record review, and limited analytic methods that did not address major biases. The Study of the Epidemiology of Pediatric Hypertension (SUPERHERO) is a multisite retrospective Registry of youth evaluated by subspecialists for hypertension disorders. Sites obtain harmonized electronic health record data using standardized biomedical informatics scripts validated with randomized manual record review. Inclusion criteria are index visit for International Classification of Diseases Diagnostic Codes, 10th Revision (ICD-10 code)-defined hypertension disorder ≥January 1, 2015 and age <19 years. We exclude patients with ICD-10 code-defined pregnancy, kidney failure on dialysis, or kidney transplantation. Data include demographics, anthropomorphics, U.S. Census Bureau tract, histories, blood pressure, ICD-10 codes, medications, laboratory and imaging results, and ambulatory blood pressure. SUPERHERO leverages expertise in epidemiology, statistics, clinical care, and biomedical informatics to create the largest and most diverse registry of youth with newly diagnosed hypertension disorders. SUPERHERO's goals are to (i) reduce CVD burden across the life course and (ii) establish gold-standard biomedical informatics methods for youth with hypertension disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD., Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS])., Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 and without diabetes in the ARIC, REGARDS, and MESA studies., Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1., Outcome: Incident CKD or end-stage kidney disease., Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts., Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m 2 . In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31)., Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts., Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria., (© 2024 The Authors.)

Importance: COVID-19 infection is associated with a high incidence of acute kidney injury (AKI). Although rapid kidney function decline has been reported in the first few months after COVID-19-associated AKI (COVID-AKI), the longer-term association of COVID-AKI with kidney function remains unknown., Objective: To assess long-term kidney outcomes of patients who had COVID-19-associated AKI., Design, Setting, and Participants: This was a retrospective longitudinal multicenter cohort study conducted in a large hospital system using electronic health records data on adult hospitalized patients with AKI and COVID-19 or other illnesses. Included patients were hospitalized during the COVID-19 pandemic (March 2020-June 2022), were screened for SARS-CoV-2, had AKI, and survived to discharge, or had been hospitalized during the 5 years before the pandemic (October 2016-January 2020), had a positive influenza A or B test result, had AKI, and survived to discharge. Patients were followed up for a maximum of 2 years after hospital discharge. Data analyses were performed from December 2022 to November 2023., Exposure: COVID-19 and influenza., Main Outcomes and Measures: The primary outcome was major adverse kidney events (MAKE), defined as a composite of mortality and worsened kidney function (estimated glomerular filtration rate [eGFR] decline by ≥25% from discharge eGFR or kidney failure requiring dialysis). Multivariable time-to-event analyses were performed to compare MAKE between individuals with COVID-AKI and those who had AKI associated with other illnesses hospitalized during the same period. For further comparison, this outcome was assessed for a historic cohort of patients with influenza-associated AKI., Results: The study cohort included 9624 hospitalized patients (mean [SD] age, 69.0 [15.7] years; 4955 [51.5%] females) with AKI, including 987 patients with COVID-AKI, 276 with influenza-associated AKI, and 8361 with AKI associated with other illnesses (other-AKI). Compared with the other 2 groups, patients with COVID-19-associated AKI were slightly younger in age, had a higher baseline eGFR, worse baseline comorbidity scores, higher markers of illness severity, and longer hospital stay. Compared with the other-AKI group, the COVID-AKI group had lower MAKE (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.59-0.75) due to lower all-cause mortality (aHR, 0.31; 95% CI, 0.24-0.39) and lower rates of worsened kidney function (aHR, 0.78; 95% CI, 0.69-0.88)., Conclusions and Relevance: The findings of this multicenter cohort study indicate that survivors of hospitalization with COVID-AKI experience lower rates of MAKE, long-term kidney function decline, and mortality compared with patients with AKI associated with other illnesses.

Acute kidney injury (AKI) in children is associated with increased morbidity, reduced health-related quality of life, greater resource utilization, and higher mortality. Improvements in the timeliness and precision of AKI diagnosis in children are needed. In this report, we highlight existing, novel, and on-the-horizon diagnostic and risk-stratification tools for pediatric AKI, and outline opportunities for integration into clinical practice. We also summarize pediatric-specific high-risk diagnoses and exposures for AKI, as well as the potential role of real-time risk stratification and clinical decision support to improve outcomes. Lastly, the key characteristics of important pediatric AKI phenotypes will be outlined. Throughout, we identify key knowledge gaps, which represent prioritized areas of focus for future research that will facilitate a comprehensive, timely and personalized approach to pediatric AKI diagnosis and management., (© 2023. The Author(s).)

Background: Acute kidney injury (AKI) is independently associated with increased morbidity and mortality across the life course, yet care for AKI remains mostly supportive. Raising awareness of this life-threatening clinical syndrome through education and advocacy efforts is the key to improving patient outcomes. Here, we describe the unique roles education and advocacy play in the care of children with AKI, discuss the importance of customizing educational outreach efforts to individual groups and contexts, and highlight the opportunities created through innovations and partnerships to optimize lifelong health outcomes., Methods: During the 26th Acute Disease Quality Initiative (ADQI) consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations on AKI research, education, practice, and advocacy in children., Results: The consensus statements developed in response to three critical questions about the role of education and advocacy in pediatric AKI care are presented here along with a summary of available evidence and recommendations for both clinical care and research., Conclusions: These consensus statements emphasize that high-quality care for patients with AKI begins in the community with education and awareness campaigns to identify those at risk for AKI. Education is the key across all healthcare and non-healthcare settings to enhance early diagnosis and develop mitigation strategies, thereby improving outcomes for children with AKI. Strong advocacy efforts are essential for implementing these programs and building critical collaborations across all stakeholders and settings., (© 2023. The Author(s).)

Background: Limited research has examined associations between exposure to ambient temperature, air pollution, and kidney function or injury during the preadolescent period. We examined associations between exposure to ambient temperature and particulate matter with aerodynamic diameter ≤ 2.5 μm (PM 2.5 ) with preadolescent estimated glomerular filtration rate (eGFR) and urinary kidney injury biomarkers., Methods: Participants included 437 children without cardiovascular or kidney disease enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors birth cohort study in Mexico City. eGFR and urinary kidney injury biomarkers were assessed at 8-12 years. Validated satellite-based spatio-temporal models were used to estimate mean daily temperature and PM 2.5 levels at each participant's residence 7- and 30-days prior to the date of visit. Linear regression and distributed lag nonlinear models (DLNM) were used to examine associations between daily mean temperature and PM 2.5 exposure and kidney outcomes, adjusted for covariates., Results: In single linear regressions, higher seven-day average PM 2.5 was associated with higher urinary alpha-1-microglobulin and eGFR. In DLNM analyses, higher temperature exposure in the seven days prior to date of visit was associated with a decrease in urinary cystatin C of -0.56 ng/mL (95 % confidence interval (CI): -1.08, -0.04) and in osteopontin of -0.08 ng/mL (95 % CI: -0.15, -0.001). PM 2.5 exposure over the seven days prior to date of visit was associated with an increase in eGFR of 1.77 mL/min/1.73m 2 (95 % CI: 0.55, 2.99) and urinary cystatin C of 0.19 ng/mL (95 % CI: 0.03, 0.35)., Conclusions: Recent exposure to ambient temperature and PM 2.5 were associated with increased and decreased urinary kidney injury biomarkers that may reflect subclinical glomerular or tubular injury in children. Further research is required to assess environmental exposures and worsening subclinical kidney injury across development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maria Jose Rosa reports financial support was provided by National Institute of Environmental Health Sciences. Alison P. Sanders reports financial support was provided by National Institute of Environmental Health Sciences. Allan Just reports financial support was provided by National Institute of Environmental Health Sciences. Martha M. Tellez-Rojo reports financial support was provided by National Institute of Environmental Health Sciences. Maria D. Politis reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Due to the complexity of chronic kidney disease (CKD) pathophysiology, biomarkers representing different mechanistic pathways have been targeted for the study and development of novel biomarkers. The discovery of clinically useful CKD biomarkers would allow for the identification of those children at the highest risk of kidney function decline for timely interventions and enrollment in clinical trials., Summary: Glomerular filtration rate and proteinuria are traditional biomarkers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and an improved knowledge of CKD pathophysiology. This review highlights promising biomarkers associated with the progression of CKD that could potentially serve as future prognostic markers in children with CKD., Key Messages: Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management., (© 2023 S. Karger AG, Basel.)

Competing Interests: The authors report no conflicts of interest.

Background: Uromodulin is the most abundant protein in the urine of healthy adults, and higher urine concentrations mark better tubular health. Greater kidney size and function are predictors of higher uromodulin levels in adults. Urine uromodulin has not yet been studied in children with chronic kidney disease (CKD). Thus, we sought to determine the relationship between age and kidney function with urine uromodulin levels in children with CKD., Methods: In the CKD in Children (CKiD) cohort, we utilized multivariable linear regression to evaluate the relationship of age and eGFR with urine uromodulin levels. The primary outcome was uromodulin indexed to urine creatinine (Umod/Cr, mg/g), which was log 2 -transformed given its skewed distribution., Results: Among 677 CKiD participants, the median age was 11.8 years (8.2-15.3), the median eGFR was 49 ml/min/1.73 m 2 (37-63), the etiology of CKD was glomerular disease in 31%, and the median Umod/Cr level was 0.114 mg/g (0.045-0.226). In the multivariable models, each one-year older age was associated with 0.18 (12%) lower log 2 (Umod/Cr) and 0.20 (13%) lower log 2 (Umod/Cr) among those with non-glomerular and glomerular disease, respectively (p < 0.001). However, we did not find a statistically significant association between eGFR and Umod/Cr in either participants with non-glomerular or glomerular disease (p = 0.13 and p = 0.58, respectively)., Conclusions: Among children with CKD, older age is significantly associated with lower Umod/Cr, independent of eGFR. Further studies are needed to comprehensively evaluate age-specific reference ranges for urine uromodulin and to evaluate the longitudinal relationship of uromodulin with both age and eGFR in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Children who require surgery for congenital heart disease have increased risk for long-term chronic kidney disease (CKD). Clinical factors as well as urine biomarkers of tubular health and injury may help improve the prognostication of estimated glomerular filtration rate (eGFR) decline., Methods: We enrolled children from 1 month to 18 years old undergoing cardiac surgery in the ASSESS-AKI cohort. We used mixed-effect models to assess the association between urinary biomarkers (log2-transformed uromodulin, NGAL, KIM-1, IL-18, L-FABP) measured 3 months after cardiac surgery and cyanotic heart disease with the rate of eGFR decline at annual in-person visits over 4 years., Results: Of the 117 children enrolled, 30 (24%) had cyanotic heart disease. During 48 months of follow-up, the median eGFR in the subgroup of children with cyanotic heart disease was lower at all study visits as compared with children with acyanotic heart disease (p = 0.01). In the overall cohort, lower levels of both urine uromodulin and IL-18 after discharge were associated with eGFR decline. After adjustment for age, RACHS-1 surgical complexity score, proteinuria, and eGFR at the 3-month study visit, lower concentrations of urine uromodulin and IL-18 were associated with a monthly decline in eGFR (uromodulin β = 0.04 (95% CI: 0.00-0.09; p = 0.07) IL-18 β = 0.07 (95% CI: 0.01-0.13; p = 0.04), ml/min/1.73 m 2 per month)., Conclusions: At 3 months after cardiac surgery, children with lower urine uromodulin and IL-18 concentrations experienced a significantly faster decline in eGFR. Children with cyanotic heart disease had a lower median eGFR at all time points but did not experience faster eGFR decline. A higher-resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Markers of glomerular disease, estimated glomerular filtration rate (eGFR) and albuminuria, are associated with cardiac structural abnormalities and incident cardiovascular disease (CVD). We aimed to determine whether biomarkers of kidney tubule injury, function, and systemic inflammation are associated with cardiac structural abnormalities. Among 393 Multi-Ethnic Study of Atherosclerosis participants without diabetes, CVD, or chronic kidney disease, we assessed the association of 12 biomarkers of kidney tubule injury, function, and systemic inflammation with the left ventricular mass/volume ratio (LVmvr) and left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging using linear regression. The average age was 60 ± 10 years; 48% were men; mean eGFR was 96±16 ml/min/1.73 m 2 ; mean LVmvr was 0.93±0.18 g/ml, and mean LVEF was 62±6%. Each twofold greater concentration of plasma soluble urokinase plasminogen activator receptor was associated with a 0.04 g/ml (95% confidence interval [CI] 0.01 to 0.08 g/ml) higher LVmvr and 2.1% (95% CI 0.6 to 3.5%) lower LVEF, independent of risk factors for CVD, eGFR, and albuminuria. Each twofold greater plasma monocyte chemoattractant protein 1 was associated with higher LVmvr with a similar coefficient to that of plasma soluble urokinase plasminogen activator receptor. Each twofold greater concentration of plasma chitinase-3-like protein 1 and urine alpha-1-microglobulin was associated with a 1.1% (95% CI 0.4 to 1.7%) and 1.2% (95% CI 0.2 to 2.2%) lower LVEF, respectively. In conclusion, abnormal kidney tubule health may lead to cardiac dysfunction above and beyond eGFR and albuminuria., Competing Interests: Disclosures Dr. Gutierrez receives grant funding and honoraria from Amgen and Akebia. He receives honoraria from AstraZeneca, Reata, and Ardelyx and serves on a Data Monitoring Committee for QED Therapeutics. Dr. Bonventre is cofounder and holds equity in Goldfinch Bio and Autonomous Medical Devices, is coinventor on KIM-1 patents assigned to Mass General Brigham, and has received consulting income and/or equity from Cadent, Renalytix, Sarepta, and Seagen and laboratory support from Kantum Pharma. He has equity in Pacific Biosciences, DxNow, and MediBeacon. Dr. Bonventre's interests were reviewed and are managed by BWH and MGB in accordance with their conflict-of-interest policies. Dr. Kimmel is a coeditor with Mark Rosenberg of Chronic Renal Disease Academic Press and a coeditor with Daniel Cukor and Scott D. Cohen of Psychosocial Aspects of Chronic Kidney Disease Academic Press. Dr. Shlipak is on advisory boards and receives honoraria from Bayer, Boehringer-Ingelheim, Astra-Zeneca. He receives grant support from Bayer. Dr. Ix has grant support from Baxter International. He is on advisory boards for Akebia, AstraZeneka, Ardelyx, Alpha Young, and Bayer. He serves on a Data and Safety Monitoring Board from Sanifit International. The remaining authors have no conflicts of interest to declare., (Published by Elsevier Inc.)

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 - 1.14, p = 0.0003). The primary outcome - a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 - 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977., (© 2023. The Author(s).)

Background Although hypertensive blood pressure measurements are common in hospitalized children, the degree of inpatient hypertension and blood pressure variability (BPV) associated with end organ complications like acute kidney injury (AKI) is unknown. Methods and Results All analyses are based on a retrospective cohort of children aged 1 to 17 years with ≥2 creatinine measurements during admission from 2014 to 2018. We used time-updated Cox models to evaluate the association between BPV and hypertension with AKI. Time-varying BPV and hypertension were based on blood pressure in the preceding 72 hours. For the analysis of hypertension and AKI, we excluded patients on vasopressors to ensure comparison between hypertensive and normotensive patients. During 5425 pediatric encounters, 258 430 blood pressure measurements were recorded (median [interquartile range] 22 [11-47] readings per encounter). Among all measurements, 32.7% were ≥95th percentile and 18.9% were ≥99th percentile for age, sex, and height. AKI occurred in 389 (7.2%) encounters. We observed a U-shaped relationship between mean blood pressure and incident AKI. BPV was associated with AKI, with the largest effect sizes in the systolic and mean arterial pressure variability measures. Multiple hypertension thresholds were associated with AKI after controlling for confounders. In an additional multivariable model adjusted for BPV, the association between hypertension and AKI was attenuated but remained significant for hypertension defined as three stage 2 measurements in 1 day (hazard ratio, 1.43 [95% CI, 1.01-2.01]). Conclusions Hypertension and BPV are associated with AKI in hospitalized children. Future studies are needed to determine how pharmacologic and nonpharmacologic interventions modify AKI risk in pediatric inpatients with hypertension.

Purpose of Review: Review the literature over the last 2 years on commonly evaluated biomarkers of acute kidney injury (AKI) and highlight the findings of these biomarkers., Recent Findings: Among several studied AKI biomarkers, urine neutrophil gelatinase-associated lipocalin (NGAL) and the combination of urine tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) have been recently studied most frequently as diagnostic biomarkers of AKI and for AKI risk stratification. Urine NGAL has continued to show good discriminative value to predict and diagnose AKI in childhood. Urine TIMP-2∗IGFBP7 can provide modest improvement to clinical models of AKI., Summary: Prior research supports that AKI biomarkers may identify AKI at an earlier time point and indicate clinically meaningful tubular injury. More effort should be made to understand if AKI biomarkers can guide treatments and improve outcomes., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Paxlovid (nirmatrelvir/ritonavir) is a novel drug available under emergency use authorization by the Food and Drug Administration for the treatment of COVID-19 infection. Tacrolimus, a calcineurin inhibitor, is commonly used as an immunosuppressant medication in children with kidney transplants. While tacrolimus is metabolized by the cytochrome P450 system (CYP3A4), ritonavir is a potent CYP3A4 inhibitor. There is a paucity of data regarding the drug-drug interaction between nirmatrelvir/ritonavir and tacrolimus in children with kidney transplants., Case-Diagnosis/treatment: This is a case report of a 14-year-old female with a history of a kidney transplant, maintained on tacrolimus and prednisone, who starts nirmatrelvir/ritonavir for a COVID-19 infection. She subsequently develops supratherapeutic tacrolimus levels and an increase in serum creatinine. Her tacrolimus was held, and the nirmatrelvir/ritonavir was stopped. Over time, her kidney function returned to baseline, her tacrolimus levels returned to the therapeutic goal, and her tacrolimus was resumed., Conclusions: Our case report highlights the strong interaction with concomitant use of tacrolimus and nirmatrelvir/ritonavir in a pediatric kidney transplant recipient and the development of supratherapeutic tacrolimus levels. Providers should therefore be cautious when prescribing nirmatrelvir/ritonavir to a pediatric patient currently on tacrolimus., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Importance: Guidelines recommend that all children and adolescents with hypertension undergo evaluation for secondary causes. Identifying clinical factors associated with secondary hypertension may decrease unnecessary testing for those with primary hypertension., Objective: To determine the utility of the clinical history, physical examination, and 24-hour ambulatory blood pressure monitoring for differentiating primary hypertension from secondary hypertension in children and adolescents (aged ≤21 years)., Data Sources and Study Selection: The databases of MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library were searched from inception to January 2022 without language limits. Two authors identified studies describing clinical characteristics in children and adolescents with primary and secondary hypertension., Data Extraction and Synthesis: For each clinical finding in each study, a 2 × 2 table was created that included the number of patients with and without the finding who had primary vs secondary hypertension. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool., Main Outcomes and Measures: Random-effects modeling was used to calculate sensitivity, specificity, and likelihood ratios (LRs)., Results: Of 3254 unique titles and abstracts screened, 30 studies met inclusion criteria for the meta-analysis and 23 (N = 4210 children and adolescents) were used for pooling in the meta-analysis. In the 3 studies conducted at primary care clinics or school-based screening clinics, the prevalence of secondary hypertension was 9.0% (95% CI, 4.5%-15.0%). In the 20 studies conducted at subspecialty clinics, the prevalence of secondary hypertension was 44% (95% CI, 36%-53%). The demographic findings most strongly associated with secondary hypertension were family history of secondary hypertension (sensitivity, 0.46; specificity, 0.90; LR, 4.7 [95% CI, 2.9-7.6]), weight in the 10th percentile or lower for age and sex (sensitivity, 0.27; specificity, 0.94; LR, 4.5 [95% CI, 1.2-18]), history of prematurity (sensitivity range, 0.17-0.33; specificity range, 0.86-0.94; LR range, 2.3-2.8), and age of 6 years or younger (sensitivity range, 0.25-0.36; specificity range, 0.86-0.88; LR range, 2.2-2.6). Laboratory studies most associated with secondary hypertension were microalbuminuria (sensitivity, 0.13; specificity, 0.99; LR, 13 [95% CI, 3.1-53]) and serum uric acid concentration of 5.5 mg/dL or lower (sensitivity range, 0.70-0.73; specificity range, 0.65-0.89; LR range, 2.1-6.3). Increased daytime diastolic blood pressure load combined with increased nocturnal systolic blood pressure load on 24-hour ambulatory blood pressure monitoring was associated with secondary hypertension (sensitivity, 0.40; specificity, 0.82; LR, 4.8 [95% CI, 1.2-20]). Findings associated with a decreased likelihood of secondary hypertension were asymptomatic presentation (LR range, 0.19-0.36), obesity (LR, 0.34 [95% CI, 0.13-0.90]), and family history of any hypertension (LR, 0.42 [95% CI, 0.30-0.57]). Hypertension stage, headache, and left ventricular hypertrophy did not distinguish secondary from primary hypertension., Conclusions and Relevance: Family history of secondary hypertension, younger age, lower body weight, and increased blood pressure load using 24-hour ambulatory blood pressure monitoring were associated with a higher likelihood of secondary hypertension. No individual sign or symptom definitively differentiates secondary hypertension from primary hypertension.

Background: Treatment of severe inpatient hypertension (HTN) that develops during hospitalization is not informed by guidelines. Intravenous (i.v.) antihypertensives are used to manage severe HTN even in the absence of acute target organ damage; however they may result in unpredictable blood pressure (BP) reduction and cardiovascular events. Our goal was to assess the association between i.v. antihypertensives and clinical outcomes in this population., Methods: This is a multihospital retrospective study of adults admitted for reasons other than HTN who develop severe HTN during hospitalization without acute target end organ damage. We defined severe HTN as BP elevation of systolic >180 or diastolic >110 mmHg. Treatment was defined as receiving i.v. antihypertensives within 3 h of BP elevation. We used overlap propensity score weighted Cox models to study the association between treatment and clinical outcomes during index hospitalization., Results: Of 224 265 unique, nonintensive care unit hospitalizations, 20 383 (9%) developed severe HTN, of which 5% received i.v. antihypertensives and 79% were untreated within 3 h of severe BP elevation. In the overlap propensity weighted population, patients who received i.v. antihypertensives were more likely to develop myocardial injury (5.9% in treated versus 3.6% in untreated; hazard ratio [HR]: 1.6 [1.13, 2.24]). Treatment was not associated with increased risk of stroke (HR: 0.7 [0.3, 1.62]), acute kidney injury (HR: 0.97 [0.81, 1.17]), or death (HR: 0.86 [0.49, 1.51])., Conclusions: Intravenous antihypertensives were associated with increased risk of myocardial injury in patients who develop severe HTN during hospitalization. These results suggest that i.v. antihypertensives should be used with caution in patients without acute target organ damage., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Spreading depolarizations (SD) refer to the near-complete depolarization of neurons that is associated with brain injuries such as ischemic stroke. The present gold standard for SD monitoring in humans is invasive electrocorticography (ECoG). A promising non-invasive alternative to ECoG is diffuse optical monitoring of SD-related flow and hemoglobin transients. To investigate the clinical utility of flow and hemoglobin transients, we analyzed their association with infarction in rat focal brain ischemia. Optical images of flow, oxy-hemoglobin, and deoxy-hemoglobin were continuously acquired with Laser Speckle and Optical Intrinsic Signal imaging for 2 h after photochemically induced distal middle cerebral artery occlusion in Sprague-Dawley rats (n = 10). Imaging was performed through a 6 × 6 mm window centered 3 mm posterior and 4 mm lateral to Bregma. Rats were sacrificed after 24 h, and the brain slices were stained for assessment of infarction. We mapped the infarcted area onto the imaging data and used nine circular regions of interest (ROI) to distinguish infarcted from non-infarcted tissue. Transients propagating through each ROI were characterized with six parameters (negative, positive, and total amplitude; negative and positive slope; duration). Transients were also classified into three morphology types (positive monophasic, biphasic, negative monophasic). Flow transient morphology, positive amplitude, positive slope, and total amplitude were all strongly associated with infarction (p < 0.001). Associations with infarction were also observed for oxy-hemoglobin morphology, oxy-hemoglobin positive amplitude and slope, and deoxy-hemoglobin positive slope and duration (all p < 0.01). These results suggest that flow and hemoglobin transients accompanying SD have value for detecting infarction., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Rationale & Objective: Acute kidney injury (AKI) is common among hospitalized children and is associated with increased hospital length of stay and costs. However, there are limited data on postdischarge health care utilization after AKI hospitalization. Our objectives were to evaluate health care utilization and physician follow-up patterns after dialysis-treated AKI in a pediatric population., Study Design: Retrospective cohort study, using provincial health administrative databases., Setting & Participants: All children (0-18 years) hospitalized between 1996 and 2017 in Ontario, Canada. Excluded individuals comprised non-Ontario residents; those with metabolic disorders or poisoning; and those who received dialysis or kidney transplant before admission, a kidney transplant by 104 days after discharge, or were receiving dialysis 76-104 days from dialysis start date., Exposure: Episodes of dialysis-treated AKI, identified using validated health administrative codes. AKI survivors were matched to 4 hospitalized controls without dialysis-treated AKI by age, sex, and admission year., Outcome: Our primary outcome was postdischarge hospitalizations, emergency department visits, and outpatient physician visits. Secondary outcomes included outpatient visits by physician type and composite health care costs., Analytical Approach: Proportions with≥1 event and rates (per 1,000 person-years). Total and median composite health care costs. Adjusted rate ratios using negative binomial regression models., Results: We included 1,688 pediatric dialysis-treated AKI survivors and 6,752 matched controls. Dialysis-treated AKI survivors had higher rehospitalization and emergency department visit rates during the analyzed follow-up periods (0-1, 0-5, and 0-10 years postdischarge, and throughout follow-up), and higher outpatient visit rates in the 0-1-year follow-up period. The overall adjusted rate ratio for rehospitalization was 1.46 (95% CI, 1.25-1.69; P<0.0001) and for outpatient visits was 1.16 (95% CI, 1.09-1.23; P=0.01). Dialysis-treated AKI survivors also had higher health care costs. Nephrologist follow-up was infrequent among dialysis-treated AKI survivors (18.6% by 1 year postdischarge)., Limitations: Potential miscoding of study exposures or outcomes. Residual uncontrolled confounding. Data for health care costs and emergency department visits was unavailable before 2006 and 2001, respectively., Conclusions: Dialysis-treated AKI survivors had greater postdischarge health care utilization and costs versus hospitalized controls. Strategies are needed to improve follow-up care for children after dialysis-treated AKI to prevent long-term complications., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Prenatal exposure to arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) may be nephrotoxic, yet limited studies have examined subclinical kidney injury biomarkers in children. We assessed whether metal exposure in the second trimester (2T), a crucial time of kidney development, is associated with altered urine kidney injury and function biomarkers in preadolescent children. Analyses included 494 children participating in a birth cohort study in Mexico City. Concentrations of As, Cd, and Pb were measured from pregnant women in 2T blood and urine, and Hg in urine only. Kidney biomarkers were measured from children in urine at age 8-12 years. We assessed the associations between individual metals and (1) kidney biomarkers using linear regression and (2) a multi-protein kidney mixture using weighted quantile sum (WQS) regression. Associations of separate urine and blood metal mixtures with individual kidney biomarkers were assessed via WQS. Within the multi-protein mixture, the association with increased urinary As was predominated by urine alpha-1-microglobulin (A1M), interferon gamma-induced protein 10 (IP10), and fatty acid binding protein 1; the association with increased urinary Cd was predominated by A1M, clusterin, and albumin. The urine metal mixture was associated with increased albumin (0.23 ng/mL; 95% confidence interval (CI): 0.10, 0.37), IP10 (0.15 ng/mL; 95% CI: 0.02, 0.28), and cystatin C (0.17 ng/mL; 95% CI: 0.04, 0.31); these associations were mainly driven by urinary As and Cd. We observed null associations between prenatal blood or urine metal mixtures and estimated glomerular filtration rate. Higher prenatal urinary metals, individually and as a mixture were associated with altered kidney injury biomarkers in children. Further research and longer participant follow-up are required to ascertain the risk of kidney disease later in life.

Background: Uromodulin regulates activity of the sodium-potassium-two-chloride transporter in the loop of Henle. In adults, higher urine uromodulin levels are associated with greater rise in blood pressure (BP) in response to salt intake. We hypothesized that higher urine uromodulin levels would be associated with higher BP in children with chronic kidney disease, and that there would be an interaction of dietary sodium on this association., Methods: In the chronic kidney disease in children Cohort, we utilized univariable and multivariable linear regression models to evaluate the relationship between baseline spot urine uromodulin levels indexed to urine creatinine (Umod/Cr mg/g) and 24-hour mean systolic and diastolic BP, as well as baseline clinic BP. We also tested whether sodium intake (g/day) modified these relationships., Results: Among 436 participants, the median age was 12.4 years (8.9-15.2), median estimated glomerular filtration rate was 50 mL/min per 1.73 m 2 (36-62), and median 24-hour mean systolic BP was 112 mm Hg (104-119). The etiology of chronic kidney disease was glomerular disease in 27%. In univariable models, each 2-fold higher Umod/Cr ratio was associated with a 1.66 mm Hg (95% CI, -2.31 to -1.00) lower 24-hour mean systolic and a 1.71 mm Hg (-2.45 to -0.97) lower clinic systolic BP. However, there was no statistically significant association between Umod/Cr and either 24-hour or clinic BP in multivariable models. We did not find a significant interaction between uromodulin and sodium intake in their effect on BP ( P >0.05 in all models)., Conclusions: Urine uromodulin levels are not associated with BP in the chronic kidney disease in children cohort. Further studies are needed to confirm this finding in healthy pediatric cohorts.

Significance: Cerebral metabolic rate of oxygen ( CMRO 2 ) consumption is a key physiological variable that characterizes brain metabolism in a steady state and during functional activation., Aim: We aim to develop a minimally invasive optical technique for real-time measurement of CMRO 2 concurrently with cerebral blood flow (CBF)., Approach: We used a pair of macromolecular phosphorescent probes with nonoverlapping optical spectra, which were localized in the intra- and extravascular compartments of the brain tissue, thus providing a readout of oxygen gradients between these two compartments. In parallel, we measured CBF using laser speckle contrast imaging., Results: The method enables computation and tracking of CMRO 2 during functional activation with high temporal resolution ( ∼ 7    Hz ). In contrast to other approaches, our assessment of CMRO 2 does not require measurements of CBF or hemoglobin oxygen saturation., Conclusions: The independent records of intravascular and extravascular partial pressures of oxygen, CBF, and CMRO 2 provide information about the physiological events that accompany neuronal activation, creating opportunities for dynamic quantification of brain metabolism., (© 2022 The Authors.)

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.

Background: Immunization is essential in preventing life-threatening pneumococcal infections in children with nephrotic syndrome. An additional 23-valent pneumococcal polysaccharide vaccine (PPSV23) series is required for children with nephrotic syndrome. Despite current practice guidelines, many children with nephrotic syndrome do not receive PPSV23., Methods: Our nephrology clinic conducted a quality improvement project to improve the overall rate of PPSV23 counseling to more than 70% within a 12-month period by applying several targeted interventions to raise providers' awareness, improve communication with primary care providers, and increase provider adherence. Data was collected from the electronic health record (EHR), and monthly performance was tracked via monthly control charts and overall immunization counseling rate charts., Results: We increased adherence to PPSV23 vaccination counseling from a baseline of 12 to 86%. The first intervention that effectively increased the vaccine counseling rate from 12 to 30% was improving a provider's awareness of the PPSV23 literature and vaccine guidelines. Other interventions included regular performance reviews at division meetings, creating an immunization protocol, posting performance charts on the office bulletin board, and unifying vaccine recommendation templates. Lastly, specific and timely EHR reminders improved the total counseling rate from 52 to 86% and maintained adherence until the completion of the project., Conclusion: Bridging the knowledge gap in provider awareness and using specific EHR reminders can improve adherence to PPSV23 counseling in children with nephrotic syndrome. Such interventions could be applied to similar groups of immunocompromised patients in whom additional vaccines are indicated. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Rationale & Objective: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes., Study Design: Cohort study., Setting & Participants: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR)<60mL/min/1.73m 2 at baseline., Exposures: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit., Outcomes: Incident kidney failure with replacement therapy (KFRT)., Analytical Approach: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR)., Results: A total of 98 KFRT events were observed over a mean of 6.2±3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from-0.08 to-0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT., Limitations: Single biomarker measurement, lack of follow-up eGFR assessments., Conclusions: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR<60mL/min/1.73m 2 after adjustment for established risk factors., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence of secondary hypertension among otherwise healthy children with hypertension diagnosed in the outpatient setting., Study Design: The MEDLINE, PubMed Central, Embase, Web of Science, and Cochrane Library databases were systematically searched for observational studies reporting the prevalence of secondary hypertension in children who underwent evaluation for hypertension and had no known comorbidities associated with hypertension at the time of diagnosis. Two authors independently extracted the study-specific prevalence of secondary hypertension in children evaluated for hypertension. Prevalence estimates for secondary hypertension were pooled in a random-effects meta-analysis., Results: Nineteen prospective studies and 7 retrospective studies including 2575 children with hypertension were analyzed, with a median of 65 participants (range, 9-486) in each study. Studies conducted in primary care or school settings reported a lower prevalence of secondary hypertension (3.7%; 95% CI, 1.2%-7.2%) compared with studies conducted in referral clinics (20.1%; 95% CI, 11.5%-30.3%). When stratified by study setting, there were no significant subgroup differences according to study design, country, participant age range, hypertension definition, blood pressure device, or study quality. Although the studies applied different approaches to diagnosing secondary hypertension, diagnostic evaluations were at least as involved as the limited testing recommended by current guidelines., Conclusions: The low prevalence of secondary hypertension among children with a new diagnosis of hypertension identified on screening reinforces clinical practice guidelines to avoid extensive testing in the primary care setting for secondary causes in most children with hypertension., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Tubulointerstitial damage in diabetes and chronic kidney disease (CKD) is poorly captured by estimated glomerular filtration rate (eGFR) and albuminuria. Urine biomarkers of kidney health may better elucidate disease progression in persons with diabetes and CKD., Methods: Per case-cohort design, we randomly selected a subcohort of 560 study participants of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study from 1092 adults with diabetes and baseline eGFR <60 ml/min per 1.73 m 2 and registered a total of 161 end-stage kidney disease (ESKD) cases ( n  = 93 from the subcohort; n  = 68 from outside the subcohort) during 4.3 ± 2.7 years mean follow-up. We measured urine biomarkers of kidney tubule injury (kidney injury molecule-1 [KIM-1]), inflammation and fibrosis (monocyte chemoattractant protein-1 [MCP-1]), repair (chitinase-3-like protein 1 [YKL-40]), and tubule function, including reabsorption (alpha-1-microglobulin [α1m]) and synthetic capacity (epidermal growth factor [EGF] and uromodulin [UMOD]). Weighted Cox regression models estimated ESKD risk adjusting for demographics, ESKD risk factors, and baseline eGFR and urine albumin. Least absolute shrinkage and selection operator (LASSO) regression identified a subset of biomarkers most strongly associated with ESKD., Results: At baseline, subcohort participants had mean age of 70 ± 9 years, mean eGFR of 40 ±13 ml/min per 1.73 m 2 , and median urine albumin-to-creatinine ratio of 33 (interquartile range 10-213) mg/g. Adjusting for baseline eGFR and albuminuria, each 2-fold higher urine KIM-1 (hazard ratio = 1.43 [95% CI: 1.17-1.75]), α1m (hazard ratio = 1.47 [1.19-1.82]), and MCP-1 (hazard ratio = 1.27 [1.06-1.53]) were independently associated with ESKD. LASSO retained KIM-1 and α1m for associations with ESKD., Conclusion: Among adults with diabetes and eGFR <60 ml/min per 1.73 m 2 , higher urine KIM-1, α1m, and MCP-1 are independently associated with incident ESKD, providing insight into kidney disease progression in persons with diabetes and CKD., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Earlier identification of individuals at high risk of chronic kidney disease (CKD) may facilitate improved risk factor mitigation., Methods: We evaluated the association of novel plasma biomarkers with incident CKD using a case-cohort design in participants without diabetes and with baseline estimated glomerular filtration rate (eGFR) ≥ 60 ml/min per 1.73 m 2 in the Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohorts. Incident CKD was defined as development of eGFR < 60 ml/min per 1.73 m 2 and ≥40% decline in eGFR from baseline. We measured plasma markers of inflammation/fibrosis-soluble tumor necrosis factor receptors (TNFRs) 1 and 2 (TNFR-1 and TNFR-2), monocyte chemotactic protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble urokinase-type plasminogen activator receptor (suPAR)-and tubular injury (kidney injury molecule 1 [KIM-1]). Cox regression models weighted for the case-cohort design were used to estimate hazard ratios (HRs) of incident CKD after adjustment for CKD risk factors, eGFR, and albuminuria., Results: In MESA (median follow-up of 9.2 years), there were 497 individuals in the random subcohort and 163 incident CKD cases. In REGARDS (median follow-up of 9.4 years), there were 497 individuals in the random subcohort and 497 incident CKD cases. Each 2-fold higher plasma KIM-1 (adjusted HR 1.38 [95% CI 1.05-1.81]), suPAR (1.96 [1.10-3.49]), TNFR-1 (1.65 [1.04-2.62]), TNFR-2 (2.02 [1.21-3.38]), and YKL-40 (1.38 [1.09-1.75]) concentrations were associated with incident CKD in MESA. In REGARDS, TNFR-1 (1.99 [1.43-2.76]) and TNFR-2 (1.76 [1.22-2.54]) were associated with incident CKD., Conclusion: Plasma concentrations of soluble TNFR-1 and TNFR-2 are consistently associated with incident CKD in nondiabetic community-living individuals in MESA and REGARDS., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Acute kidney injury (AKI) in deceased donors is not associated with graft failure (GF). We hypothesize that hemodynamic AKI (hAKI) comprises the majority of donor AKI and may explain this lack of association., Methods: In this ancillary analysis of the Deceased Donor Study, 428 donors with available charts were selected to identify those with and without AKI. AKI cases were classified as hAKI, intrinsic (iAKI), or mixed (mAKI) based on majority adjudication by three nephrologists. We evaluated the associations between AKI phenotypes and delayed graft function (DGF), 1-year eGFR and GF. We also evaluated differences in urine biomarkers among AKI phenotypes., Results: Of the 291 (68%) donors with AKI, 106 (36%) were adjudicated as hAKI, 84 (29%) as iAKI and 101 (35%) as mAKI. Of the 856 potential kidneys, 669 were transplanted with 32% developing DGF and 5% experiencing GF. Median 1-year eGFR was 53 (IQR: 41-70) ml/min/1.73m2. Compared to non-AKI, donors with iAKI had higher odds DGF [aOR (95%CI); 4.83 (2.29, 10.22)] and had lower 1-year eGFR [adjusted B coefficient (95% CI): -11 (-19, -3) mL/min/1.73 m2]. hAKI and mAKI were not associated with DGF or 1-year eGFR. Rates of GF were not different among AKI phenotypes and non-AKI. Urine biomarkers such as NGAL, LFABP, MCP-1, YKL-40, cystatin-C and albumin were higher in iAKI., Conclusion: iAKI was associated with higher DGF and lower 1-year eGFR but not with GF. Clinically phenotyped donor AKI is biologically different based on biomarkers and may help inform decisions regarding organ utilization., Competing Interests: The authors have declared that no competing interests exist.

Background: Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression., Methods: We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α -1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m 2 . Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period., Results: Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α -1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression., Conclusions: After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α -1 microglobulin concentrations were each associated with CKD progression in children., (Copyright © 2021 by the American Society of Nephrology.)

Serum creatinine and level of proteinuria, as biomarkers of chronic kidney disease (CKD) progression, inadequately explain the variability of glomerular filtration rate decline, and are late markers of glomerular filtration rate decline. Recent studies have identified plasma and urine biomarkers at higher levels in children with CKD and also associate independently with CKD progression, even after adjustment for serum creatinine and proteinuria. These novel biomarkers represent diverse biologic pathways of tubular injury, tubular dysfunction, inflammation, and tubular health, and can be used as a liquid biopsy to better characterize CKD in children. In this review, we highlight the biomarker findings from the Chronic Kidney Disease in Children cohort, a large longitudinal study of children with CKD, and compare results with those from other pediatric CKD cohorts. The biomarkers in focus in this review include plasma kidney injury molecule-1, monocyte chemoattractant protein-1, fibroblast growth factor-23, tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, soluble urokinase plasminogen activator receptor, and chitinase-3-like protein 1, as well as urine epidermal growth factor, α-1 microglobulin, kidney injury molecule-1, monocyte chemoattractant protein-1, and chitinase-3-like protein 1. Blood and urine biomarkers improve our ability to prognosticate CKD progression and may improve our understanding of CKD pathophysiology. Further research is required to establish how these biomarkers can be used in the clinical setting to improve the clinical management of CKD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: AKI is common during pediatric hospitalizations and associated with adverse short-term outcomes. However, long-term outcomes among survivors of pediatric AKI who received dialysis remain uncertain., Methods: To determine the long-term risk of kidney failure (defined as receipt of chronic dialysis or kidney transplant) or death over a 22-year period for pediatric survivors of dialysis-treated AKI, we used province-wide health administrative databases to perform a retrospective cohort study of all neonates and children (aged 0-18 years) hospitalized in Ontario, Canada, from April 1, 1996, to March 31, 2017, who survived a dialysis-treated AKI episode. Each AKI survivor was matched to four hospitalized pediatric comparators without dialysis-treated AKI, on the basis of age, sex, and admission year. We reported the incidence of each outcome and performed Cox proportional hazards regression analyses, adjusting for relevant covariates., Results: We identified 1688 pediatric dialysis-treated AKI survivors (median age 5 years) and 6752 matched comparators. Among AKI survivors, 53.7% underwent mechanical ventilation and 33.6% had cardiac surgery. During a median 9.6-year follow-up, AKI survivors were at significantly increased risk of a composite outcome of kidney failure or death versus comparators. Death occurred in 113 (6.7%) AKI survivors, 44 (2.6%) developed kidney failure, 174 (12.1%) developed hypertension, 213 (13.1%) developed CKD, and 237 (14.0%) had subsequent AKI. AKI survivors had significantly higher risks of developing CKD and hypertension versus comparators. Risks were greatest in the first year after discharge and gradually decreased over time., Conclusions: Survivors of pediatric dialysis-treated AKI are at higher long-term risks of kidney failure, death, CKD, and hypertension, compared with a matched hospitalized cohort., (Copyright © 2021 by the American Society of Nephrology.)

Rationale & Objective: Biomarker studies are important for generating mechanistic insight and providing clinically useful predictors of chronic kidney disease (CKD) progression. However, variability across studies can often muddy the evidence waters. Here we evaluated real-world variability in biomarker studies using two published studies, independently conducted, of the novel plasma marker soluble urokinase-type plasminogen activator receptor (suPAR) for predicting CKD progression in children with CKD., Study Design: A comparison of 2 prospective cohort studies., Setting & Participants: 541 children from the Chronic Kidney Disease in Children (CKiD) study, median age 12 years, median glomerular filtration rate (GFR) of 54 mL/min/1.73m 2 ., Outcome: The first occurrence of either a 50% decline in GFR from baseline or incident end-stage kidney disease., Analytical Approach: The suPAR plasma marker was measured using the Quantikine ELISA immunoassay in the first study and Meso Scale Discovery (MSD) platform in the second. The analytical approaches varied. We used suPAR data from the 2 assays and mimicked each analytical approach in an overlapping subset., Results: We found that switching assays had the greatest impact on inferences, resulting in a 38% to 66% change in the magnitude of the effect estimates. Covariate and modeling choices resulted in an additional 8% to 40% variability in the effect estimate. The cumulative variability led to different inferences despite using a similar sample of CKiD participants and addressing the same question., Limitations: The estimated variability does not represent optimal repeatability but instead illustrates real-world variability that may be present in the CKD biomarker literature., Conclusions: Our results highlight the importance of validation, avoiding conclusions based on P value thresholds, and providing comparable metrics. Further transparency of data and equal weighting of negative and positive findings in explorations of novel biomarkers will allow investigators to more quickly weed out less promising biomarkers., (© 2021 The Authors.)

Background: Children undergoing cardiac surgery are at risk of high blood pressure (BP), a risk factor for cardiovascular and kidney disease. Twenty-four-hour ambulatory BP monitoring (ABPM) is a reference standard hypertension (HTN) test. Little data exist on ABPM abnormalities in children several years post cardiac surgery. This study aimed to (a) determine ABPM feasibility; (b) describe and compare ABPM measures and abnormalities (percent load, masked HTN [MH]; non-dipping, mean systolic/diastolic BP > 95th percentile; pre-HTN (ABPM); white-coat HTN [WCH]) to casual BP; and (c) compare BP in patients with and without acute kidney injury (AKI)., Methods: Prospective, follow-up pilot study of children (0-18 years) who underwent cardiac surgery from 2007 to 2009 at Montreal Children's Hospital. We recorded if participants had post-operative AKI and assessed the following outcomes at 9-year follow-up: casual BP classified by three single-visit measures (normal; elevated BP [eBP SingleVisit ]; HTN SingleVisit ); ABPM. Bivariable analyses were used to compare characteristics between groups., Results: Twenty-three patients (median [interquartile range], 8.6 [8.0, 9.0] years post cardiac surgery) were included; 16 (70%) male. Six participants (26%) had eBP SingleVisit or higher. On ABPM, 11 (48%) had ≥ 1 abnormality: 9 (39%) had non-dipping; 3 (13%) had pre-HTN; 3 (13%) had WCH; none had HTN or MH. There were no differences in ABPM according to AKI status., Conclusion: Our pilot study determined that ABPM was feasible in children years after cardiac surgery and frequently identified ABPM abnormalities. Future research in larger populations is needed to define specific risk factors for HTN in children after cardiac surgery.