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The Chronic Kidney Disease in Children Study, a prospective cohort study with data collected from 2003 to 2018, provided the first opportunity to characterize the incidence of renal replacement therapy (RRT) initiation over the life course of pediatric kidney diseases. In the current analysis, parametric generalized gamma models were fitted and extrapolated for RRT overall and by specific treatment modality (dialysis or preemptive kidney transplant). Children were stratified by type of diagnosis: nonglomerular (mostly congenital; n = 650), glomerular–hemolytic uremic syndrome (HUS; n = 49), or glomerular–non-HUS (heterogeneous childhood onset; n = 216). Estimated durations of time to RRT after disease onset for 99% of the nonglomerular and glomerular–non-HUS groups were 42.5 years (95% confidence interval (CI): 31.0, 54.1) and 25.4 years (95% CI: 14.9, 36.0), respectively. Since onset for the great majority of children in the nonglomerular group was congenital, disease duration equated with age. A simulation-based estimate of age at RRT for 99% of the glomerular population was 37.9 years (95% CI: 33.6, 63.2). These models performed well in cross-validation. Children with glomerular disease received dialysis earlier and were less likely to have a preemptive kidney transplant, while the timing and proportions of dialysis and transplantation were similar for the nonglomerular group. These diagnosis-specific estimates provide insight into patient-centered prognostic information and can assist in RRT planning efforts for children with moderate-to-severe kidney disease who are receiving regular specialty care.

Background A simple equation for glomerular filtration rate (GFR) measurement based on only plasma samples during the slow compartment after injection of iohexol was previously developed among children with chronic kidney disease and adult men with or at risk of HIV infection [Chronic Kidney Disease in Children (CKiD)-Multicenter AIDS Cohort Study (MACS) equation], but has not been externally validated. We aimed to evaluate the performance of the CKiD-MACS equation among elderly participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who underwent directly measured iohexol GFR. Methods Using data from 287 participants of the MESA-Kidney study who underwent a five-sample measured iohexol GFR (two and three samples in the fast and slow compartments, respectively), we assessed the performance of the CKiD-MACS equation using only plasma samples in the slow compartment by sex, race and age. Agreement was assessed by bias, correlation, proportion within 5 and 10%, and the root mean square error (RMSE). Results The average age and GFR of the participants were 71 years and 70.8 mL/min/1.73 m2, respectively, and 46% were black. The equation yielded excellent agreement within stratified groups with high correlation (>0.96), low bias (≤1.2 mL/min/1.73 m2) and low RMSE ( Conclusions The CKiD-MACS equation demonstrated valid GFR measurement using only samples in the slow compartment in this racially diverse, elderly population. While the equation yielded practically the same results as the original Brochner-Mortensen equation, the CKiD-MACS equation conforms to theoretical principles embedded in the two-compartment model of direct GFR measurement.

Chronic kidney disease (CKD) progression is typically characterized as either time to a clinically meaningful event (such as dialysis or transplant), or longitudinal changes in kidney function. This review describes pediatric kidney disease progression using these two distinct frameworks by reviewing and discussing data from the Chronic Kidney Disease in Children study. We first describe new equations to estimate glomerular filtration rate (GFR) for patients younger than age 25 years, and how the average of serum creatinine-based and cystatin C-based GFR equations yield valid estimates than either alone. Next, we present a life course description of CKD onset to kidney replacement therapy, prediction models based on clinical measurements, and show the importance of diagnosis (broadly classified as nonglomerular and glomerular in origin), GFR level, and proteinuria on progression. Literature on longitudinal GFR in children and young adults are reviewed and new data are presented to characterize nonlinear changes in estimated GFR in patients younger than age 25 years. These models showed accelerated progression associated with glomerular diagnosis, lower GFR level, and higher proteinuria, which was congruent with time-to-event analyses. Descriptions of online tools for GFR estimation and risk stratification for clinical applications are presented and we offer key epidemiologic considerations for the analysis of longitudinal pediatric CKD studies.

BACKGROUND: We investigated the putative associations of alcohol, cigarette, e-cigarette and marijuana use with kidney function and proteinuria among adolescents and young adults (AYA) with pediatric-onset chronic kidney disease (CKD) enrolled in the Chronic Kidney Disease in Children (CKiD) study. METHODS: Participants responded to questions about past year and 30-day substance use. Associations between each substance and kidney function, proteinuria, nephrotic range proteinuria and high blood pressure were separately estimated using repeated measures regression models, adjusting for sociodemographic characteristics. Models controlled for covariates at the present visit (contemporaneous), and additionally controlled for disease severity at the year prior to reporting substance use (lagged). RESULTS: A total of 441 participants ≥16 years contributed 1,245 person-visits with 39% reporting alcohol and 16%, 17% and 15% reporting cigarette, e-cigarette and marijuana use, respectively, over the previous year. In adjusted lagged models, past year and 30-day cigarette use were significantly associated with higher levels of proteinuria (+18.6%, 95%CI: +2.8%, +36.9%; and +20.0%, 95%CI: +0.7%, +43.1%, respectively). Inferences were similar when controlling for secondhand smoke exposure. CONCLUSIONS: In a cohort of AYA with pediatric kidney diseases, substance use was non-trivial, and cigarette use was associated with higher proteinuria, although the prevalence was low. Occasional alcohol, e-cigarette and marijuana use were not associated with proteinuria, disease progression, or elevated blood pressure. Pediatric nephrologists as specialty care providers are well-positioned to discuss substance use and should encourage tobacco prevention/treatment efforts among AYA at high risk for use in order to preserve kidney function and promote well-being.

BACKGROUND: Hypertension is common among children with chronic kidney disease (CKD), and dihydropyridine calcium channel blockers (dhCCBs) are frequently used as treatment. The impact of dhCCBs on proteinuria in children with CKD is unclear. METHODS: Data from 722 participants in the Chronic Kidney Disease in Children (CKiD) longitudinal cohort with a median age of 12 years were used to assess the association between dhCCBs and log transformed urine protein/creatinine levels as well as blood pressure control measured at annual visits. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use was evaluated as an effect measure modifier. RESULTS: Individuals using dhCCBs had 18.8% higher urine protein/creatinine levels compared to those with no history of dhCCB or ACEi and ARB use. Among individuals using ACEi and ARB therapy concomitantly, dhCCB use was not associated with an increase in proteinuria. Those using dhCCBs had higher systolic and diastolic blood pressures. CONCLUSIONS: Use of dhCCBs in children with CKD and hypertension is associated with higher levels of proteinuria and was not found to be associated with improved blood pressure control.

Derek K Ng, Daniel A Antiporta, Matthew B Matheson, Alvaro Muñoz Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USACorrespondence: Alvaro MuñozDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 Wolfe Street Room E7648, Baltimore, MD 21205, USATel +1 410-955-2792Email amunoz@jhu.eduAbstract: Associations between an exposure and multiple competing events are typically described by cause-specific hazard ratios (csHR) or subdistribution hazard ratios (sHR). However, diagnostic tools to assess differences between them have not been described. Under the proportionality assumption for both, it can be shown mathematically that the sHR and csHR must be equal, so reporting different time-constant sHR and csHR implies non-proportionality for at least one. We propose a simple, intuitive approach using the ratio of sHR/csHR to nonparametrically compare these metrics. In general, for the non-null case, there must be at least one event type for which the sHR and csHR differ, and the proposed diagnostic will be useful to identify these cases. Furthermore, once standard methods are used to estimate the csHR, multiplying it with our nonparametric estimate for the sHR/csHR ratio will yield estimates of sHR which fulfill intrinsic linkages of the subhazards that separate analysis may violate. In addition, for non-null cases, at least one must be time dependent (i.e., non-proportional), and thus our tool serves as an indirect test of the proportionality assumption. We applied this proposed diagnostic tool to data from a cohort of children with congenital kidney disease to describe racial differences in the time to first dialysis or first transplant and extend methods to include adjustment for socioeconomic factors.Keywords: survival analysis, nonparametric methods, competing risk analysis, cause-specific hazard ratios, sub-distribution hazard ratios, chronic kidney disease

Contemporary studies of long-term outcomes in children supported on extracorporeal membrane oxygenation (ECMO) in the United States are limited. We enrolled 99 ECMO patients between July 2010 and June 2015 in a two-center prospective observational study that included neurologic and neuropsychologic evaluation at 6 and 12 months, using standardized outcome measures. Pre-ECMO, 20 (20%) had a pre-existing neurologic diagnosis, 40 (40%) had cardiac arrest, and 10 of 47 (21%) children with neuroimaging had acute abnormal findings. Of 50 children eligible for follow-up at 6 or 12 months, 40 (80%) returned for at least one visit. At the follow-up visit of longest interval from ECMO, the median Vineland Adaptive Behavior Scales-II (VABS-II) score was 91 (interquartile range [IQR], 81-98), the median Pediatric Stroke Outcome Measure (PSOM) score was 1 (IQR, 0-2), and the median Mullen Scales of Early Learning composite score was 85 (IQR, 72-96). Presence of new neuroimaging abnormalities during ECMO or within 6 weeks post-ECMO was associated with VABS-II score

Objective To estimate the prevalence of metabolic syndrome (MetS) and examine its association with chronic kidney disease progression in children enrolled in the Chronic Kidney Disease in Children study. Study design MetS was defined as being overweight or obese and having ≥2 cardiometabolic risk factors (CMRFs). Incidence and prevalence of MetS were assessed using pairs of visits approximately 2 years apart. Results A total of 799 pairs of person-visits (contributed by 472 children) were included in the final analysis. Of these, 70% had a normal body mass index (BMI), 14% were overweight, and 16% were obese. At the first visit, the prevalence of MetS in the overweight group was 40% and in the obese group was 60%. In adjusted models, annual percent estimated glomerular filtration rate decline in those who had normal BMI and incident or persistent multiple CMRFs or those with persistent MetS was −6.33%, −6.46%, and −6.08% (respectively) compared with children who never had multiple CMRFs (−3.38%, P = .048, .045, and .036, respectively). Children with normal BMI and incident multiple CMRFs and those with persistent MetS had approximately twice the odds of fast estimated glomerular filtration rate decline (>10% per year) compared with those without multiple CMRFs and normal BMI. Conclusion Children with chronic kidney disease have a high prevalence of MetS. These children as well as those with normal BMI but multiple CMRFs experience a faster decline in kidney function.

Background and objectives African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children. Design, setting, participants, and measurements We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1–16 years with mild to moderate kidney disease. Results A total of 140 AA children in the CKiD study were genotyped. High risk (HR) APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p 3 mg/l (33 vs. 15%, p = 0.12), and obesity (48 vs. 19%, p = 0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium–phosphate product. Conclusion AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of chronic kidney disease and LVH management in this population.

Purpose African American (AA) adults with chronic kidney disease (CKD) have a faster progression to end-stage renal disease and are less likely to receive a kidney transplant. It is unclear whether AA children experience renal replacement therapy (RRT) for end-stage renal disease sooner than non-AA children after accounting for socioeconomic status (SES). Methods Among children with nonglomerular CKD in the Chronic Kidney Disease in Children study, we investigated time to RRT (i.e., first dialysis or transplant) after CKD onset using parametric survival models and accounted for SES differences by inverse probability weights. Results Of 110 AA and 493 non-AA children (median age = 10 years), AA children had shorter time to first RRT: median time was 3.2 years earlier than non-AA children (95% CI: -6.1, -0.3). When accounting for SES, this difference was diminished and nonsignificant (-1.6 years; 95% CI: -4.6, +1.5), and its directionality was consistent with faster glomerular filtration rate decline among AA children (-6.2% vs. -4.4% per year, P = .098). When RRT was deconstructed into dialysis or transplant, the time to dialysis was 37.5% shorter for AA children and 53.7% longer for transplant. These inferences were confirmed by the frequency and timing of transplant after initiating dialysis. Conclusions Racial differences in time to RRT were almost fully accounted for by SES, and the remaining difference was congruent with a faster glomerular filtration rate decline among AA children. Access to transplant occurred later, yet times to dialysis were shorter among AA children even when accounting for SES which may be due to a lack of organ availability.

Background: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 (APOL1) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. Methods: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). Results: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m2; NEPTUNE: 74 versus 94 mL/min/1.73 m2). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: −18 versus −8% per year; NEPTUNE: −13 versus −3% per year). Conclusions: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1-associated glomerular disease. Further study is needed to determine the generalizability of these findings.

Primary liver cancer (PLC) is the third leading cause of cancer mortality globally. In endemic areas of sub-Saharan Africa and Asia, PLC largely arises from chronic infection with hepatitis B virus (HBV) and ingestion of aflatoxins. Although synergistic interactions between these two risk factors have been observed in cohort studies in China, here we determined the impact of agricultural reforms in the 1980s leading to diminished maize consumption and implementation of subsidized universal vaccination against HBV in the 2000s on PLC primary prevention. A population-based cancer registry was used to track PLC mortality in Qidong, China and was compared with the timeline of HBV immunization. Randomly selected serum samples from archived cohort collections from the 1980s to present were analyzed for aflatoxin biomarkers. More than 50% reductions in PLC mortality rates occurred across birth cohorts from the 1960s to the 1980s for Qidongese less than 35 years of age although all were born before universal vaccination of newborns. Median levels of the aflatoxin biomarker decreased from 19.3 pg/mg albumin in 1989 to undetectable (

Study objective We determine the rate at which trauma patients re-present to the emergency department (ED) after discharge from the hospital and determine whether re-presentation is related to race, insurance, and socioeconomic factors such as neighborhood income level. Methods Trauma patients admitted to a Level I trauma center between January 1, 1997, and December 31, 2007, were identified with the hospital's trauma registry. These patients were linked to administrative data to obtain information about re-presentation to the hospital. Neighborhood income was obtained with census block data; multiple imputation was implemented to account for missing income data. Logistic regression analysis was used to determine the predictors of re-presentation. Results There were 6,675 patients who were included in the study. A total of 886 patients (13.3%) returned to the ED within 30 days of discharge from the hospital. Uninsured patients (odds ratio [OR]=1.64; 95% confidence interval [CI] 1.30 to 2.06) and publicly insured patients (OR=1.60; 95% CI 1.20 to 2.14) were more likely to re-present to the ED than those with commercial insurance. Residing in a neighborhood with a median household income less than $20,000 was associated with a higher odds of re-presentation (OR=1.77; 95% CI 1.37 to 2.29). Only 13.2% of patients who came to the ED were readmitted to the hospital. Conclusion A substantial number of trauma patients return to the ED within 30 days of being discharged, but only a small proportion of these patients required readmission. Re-presentation is associated with being uninsured or underinsured and with lower neighborhood income level.