The Study of the Epidemiology of Pediatric Hypertension Registry (SUPERHERO): Rationale and Methods.

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.

Is mild dehydration a risk for progression of childhood chronic kidney disease?

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.

A proposed framework for advancing acute kidney injury risk stratification and diagnosis in children: a report from the 26th Acute Disease Quality Initiative (ADQI) conference.

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.

Pediatric AKI in the real world: changing outcomes through education and advocacy-a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

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.

Long-term Health Care Utilization and Associated Costs After Dialysis-Treated Acute Kidney Injury in Children.

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.

Biomarkers for acute kidney injury in children - where are we now?

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.

Elevated tacrolimus levels after treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19 infection in a child with a kidney transplant.

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.

Association of clinical characteristics with urine uromodulin in children with chronic kidney disease.

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 log2-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 m2 (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 log2(Umod/Cr) and 0.20 (13%) lower log2(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.

Biomarkers of eGFR decline after cardiac surgery in children: findings from the ASSESS-AKI study.

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 ß = 0.04 (95% CI: 0.00-0.09; p = 0.07) IL-18 ß = 0.07 (95% CI: 0.01-0.13; p = 0.04), ml/min/1.73 m2 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.

Does This Child With High Blood Pressure Have Secondary Hypertension?: The Rational Clinical Examination Systematic Review.

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.

Prevalence of Secondary Hypertension in Otherwise Healthy Youths with a New Diagnosis of Hypertension: A Meta-Analysis.

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.

Associations of Plasma Biomarkers of Inflammation, Fibrosis, and Kidney Tubular Injury With Progression of Diabetic Kidney Disease: A Cohort Study.

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/1.73m2 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/1.73m2 after adjustment for established risk factors.

An initiative to improve pneumococcal immunization counseling in children with nephrotic syndrome.

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.

Long-Term Kidney Outcomes Following Dialysis-Treated Childhood Acute Kidney Injury: A Population-Based Cohort Study.

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.

Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

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 1.73m2. 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.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

Kidney Outcomes and Hypertension in Survivors of Wilms Tumor: A Prospective Cohort Study.

OBJECTIVE: To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT). STUDY DESIGN: This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with preexisting hypertension, prior dialysis, or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90th percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for kidney injury molecule-1, interleukin-18, epidermal growth factor, albumin, and creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the bedside chronic kidney disease in children equation. Recent kidney ultrasound examinations and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy, respectively. Clinical follow-up data were collected for approximately 2 years after study enrollment. RESULTS: Thirty-two participants (median age, 13.6 years [IQR, 10.5-16.3 years]; 75% stage 3 or higher WT) were evaluated at a median of 8.7 years (IQR, 6.5-10.8 years) after therapy; 29 participants underwent unilateral radical nephrectomy, 2 bilateral partial nephrectomy, and 1 radical and contralateral partial nephrectomy. In this cohort, 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 mL/min/1.73 m2 (IQR, 84.6-114.0; 11 [34%] had an eGFR of <90 mL/min/1.73 m2). Abnormal ABPM results were found in 22 of 29 participants (76%), masked hypertension in 10 of 29 (34%), and microalbuminuria in 2 of 32 (6%). Of the 32 participants, 22 (69%) had abnormal epidermal growth factor; few had abnormal kidney injury molecule-1 or interleukin-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had left ventricular hypertrophy. CONCLUSIONS: In survivors of WT, adverse kidney outcomes were common and should be closely monitored.

The Association of COVID-19 With Acute Kidney Injury Independent of Severity of Illness: A Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Although coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury (AKI), it is unclear whether this association is independent of traditional risk factors such as hypotension, nephrotoxin exposure, and inflammation. We tested the independent association of COVID-19 with AKI. STUDY DESIGN: Multicenter, observational, cohort study. SETTING & PARTICIPANTS: Patients admitted to 1 of 6 hospitals within the Yale New Haven Health System between March 10, 2020, and August 31, 2020, with results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing via polymerase chain reaction of a nasopharyngeal sample. EXPOSURE: Positive test for SARS-CoV-2. OUTCOME: AKI by KDIGO (Kidney Disease: Improving Global Outcomes) criteria. ANALYTICAL APPROACH: Evaluated the association of COVID-19 with AKI after controlling for time-invariant factors at admission (eg, demographic characteristics, comorbidities) and time-varying factors updated continuously during hospitalization (eg, vital signs, medications, laboratory results, respiratory failure) using time-updated Cox proportional hazard models. RESULTS: Of the 22,122 patients hospitalized, 2,600 tested positive and 19,522 tested negative for SARS-CoV-2. Compared with patients who tested negative, patients with COVID-19 had more AKI (30.6% vs 18.2%; absolute risk difference, 12.5% [95% CI, 10.6%-14.3%]) and dialysis-requiring AKI (8.5% vs 3.6%) and lower rates of recovery from AKI (58% vs 69.8%). Compared with patients without COVID-19, patients with COVID-19 had higher inflammatory marker levels (C-reactive protein, ferritin) and greater use of vasopressors and diuretic agents. Compared with patients without COVID-19, patients with COVID-19 had a higher rate of AKI in univariable analysis (hazard ratio, 1.84 [95% CI, 1.73-1.95]). In a fully adjusted model controlling for demographic variables, comorbidities, vital signs, medications, and laboratory results, COVID-19 remained associated with a high rate of AKI (adjusted hazard ratio, 1.40 [95% CI, 1.29-1.53]). LIMITATIONS: Possibility of residual confounding. CONCLUSIONS: COVID-19 is associated with high rates of AKI not fully explained by adjustment for known risk factors. This suggests the presence of mechanisms of AKI not accounted for in this analysis, which may include a direct effect of COVID-19 on the kidney or other unmeasured mediators. Future studies should evaluate the possible unique pathways by which COVID-19 may cause AKI.

24-hour ambulatory blood pressure monitoring 9 years after pediatric cardiac surgery: a pilot and feasibility study.

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 [eBPSingleVisit]; HTNSingleVisit); 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 eBPSingleVisit 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.

A Time-Updated, Parsimonious Model to Predict AKI in Hospitalized Children.

BACKGROUND: Timely prediction of AKI in children can allow for targeted interventions, but the wealth of data in the electronic health record poses unique modeling challenges. METHODS: We retrospectively reviewed the electronic medical records of all children younger than 18 years old who had at least two creatinine values measured during a hospital admission from January 2014 through January 2018. We divided the study population into derivation, and internal and external validation cohorts, and used five feature selection techniques to select 10 of 720 potentially predictive variables from the electronic health records. Model performance was assessed by the area under the receiver operating characteristic curve in the validation cohorts. The primary outcome was development of AKI (per the Kidney Disease Improving Global Outcomes creatinine definition) within a moving 48-hour window. Secondary outcomes included severe AKI (stage 2 or 3), inpatient mortality, and length of stay. RESULTS: Among 8473 encounters studied, AKI occurred in 516 (10.2%), 207 (9%), and 27 (2.5%) encounters in the derivation, and internal and external validation cohorts, respectively. The highest-performing model used a machine learning-based genetic algorithm, with an overall receiver operating characteristic curve in the internal validation cohort of 0.76 [95% confidence interval (CI), 0.72 to 0.79] for AKI, 0.79 (95% CI, 0.74 to 0.83) for severe AKI, and 0.81 (95% CI, 0.77 to 0.86) for neonatal AKI. To translate this prediction model into a clinical risk-stratification tool, we identified high- and low-risk threshold points. CONCLUSIONS: Using various machine learning algorithms, we identified and validated a time-updated prediction model of ten readily available electronic health record variables to accurately predict imminent AKI in hospitalized children.