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Background: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. Methods: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. Results: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. Conclusions: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is common in hospitalized children and increases the risk of chronic kidney disease (CKD) and hypertension, but little is known about the patient level risk factors for pediatric hypertension after AKI. The aims of this study are to evaluate the prevalence and risk factors for new onset hypertension in hospitalized children with AKI and to better understand the role of acute kidney disease (AKD) in the development of hypertension. Methods: This study was an observational cohort of all children ≤ 18 years old admitted to a single tertiary care children's hospital from 2015 to 2019 with a diagnosis of AKI. Hypertension was defined as blood pressure > 95th percentile for sex, age, height, diagnosis of hypertension on the problem list, or prescription of antihypertensive medication for > 90 days after AKI. Results: A total of 410 children were included in the cohort. Of these, 78 (19%) developed hypertension > 90 days after AKI. A multivariable logistic regression model identified AKD, need for kidney replacement therapy, congenital heart disease, and non-kidney solid organ transplantation as risk factors for hypertension after AKI. Conclusions: Incident hypertension after 3 months is common among hospitalized children with AKI, and AKD, need for dialysis, congenital heart disease, and non-kidney solid organ transplant are significant risk factors for hypertension after AKI. Monitoring for hypertension development in these high-risk children is critical to mitigate long-term adverse kidney and cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Cardiac surgery‐associated acute kidney injury (CS‐AKI) occurs in approximately 65% of neonates undergoing cardiac surgery on cardiopulmonary bypass and contributes to morbidity and mortality. Caffeine may reduce CS‐AKI by counteracting adenosine receptor upregulation after bypass, but pharmacokinetics (PK) in this population are unknown. The goal of our analysis is to address knowledge gaps in age‐, disease‐, and bypass‐related effects on caffeine disposition and explore preliminary associations between caffeine exposure and CS‐AKI using population PK modeling techniques and an opportunistic, electronic health record‐integrated trial design. We prospectively enrolled neonates receiving preoperative caffeine per standard of care and collected PK samples. We retrospectively identified neonates without caffeine exposure undergoing surgery on bypass as a control cohort. We followed US Food and Drug Administration guidance for population PK model development using NONMEM. Effects of clinical covariates on PK parameters were evaluated. We simulated perioperative exposures and used multivariable logistic regression to evaluate the association between caffeine exposure and CS‐AKI. Twenty‐seven neonates were included in model development. A 1‐compartment model with bypass time as a covariate on clearance and volume of distribution best fit the data. Twenty‐three neonates with caffeine exposure and 109 controls were included in the exposure‐response analysis. Over half of neonates developed CS‐AKI. On multivariable analysis, there were no significant differences between CS‐AKI with and without caffeine exposure. Neonates with single‐ventricle heart disease without CS‐AKI had consistently higher simulated caffeine exposures. Our results highlight areas for further study to better understand disease‐ and bypass‐specific effects on drug disposition and identify populations where caffeine may be beneficial. [ABSTRACT FROM AUTHOR]

Background: Studies in adults have shown that persistent kidney dysfunction ≥7–90 days following acute kidney injury (AKI), termed acute kidney disease (AKD), increases chronic kidney disease (CKD) and mortality risk. Little is known about the factors associated with the transition of AKI to AKD and the impact of AKD on outcomes in children. The aim of this study is to evaluate risk factors for progression of AKI to AKD in hospitalized children and to determine if AKD is a risk factor for CKD. Methods: Retrospective cohort study of children age ≤18 years admitted with AKI to all pediatric units at a single tertiary-care children's hospital between 2015 and 2019. Exclusion criteria included insufficient serum creatinine values to evaluate for AKD, chronic dialysis, or previous kidney transplant. Results: A total of 528 children with AKI were included in the study. There were 297 (56.3%) hospitalized AKI survivors who developed AKD. Among children with AKD, 45.5% developed CKD compared to 18.7% in the group without AKD (OR 4.0, 95% CI 2.1–7.4, p-value <0.001 using multivariable logistic regression analysis including other covariates). Multivariable logistic regression model identified age at AKI diagnosis, PCICU and NICU admission, prematurity, malignancy, bone marrow transplant, previous AKI, mechanical ventilation, AKI stage, duration of kidney injury, and need for kidney replacement therapy during day 1–7 as risk factors for AKD after AKI. Conclusions: AKD is common among hospitalized children with AKI and multiple risk factors are associated with AKD. Children that progress from AKI to AKD are at higher risk of developing CKD. [ABSTRACT FROM AUTHOR]

Background: Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene ( TNXB) as a cause of PVUR with joint hypermobility. Methods: To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants in TNXB and the tenascin C gene ( TNC) after excluding mutations in ROBO2 and SOX17. Results: The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9 %) families had FPVUR and 2/55 (4 %) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12 %) families (9 % in TNXB and 3 % in ROBO2). Conclusions: In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts. [ABSTRACT FROM AUTHOR]

Background: The Patient Reported Outcomes Measurement Information System (PROMIS) II is a prospective study that evaluates patient reported outcomes in pediatric chronic diseases as a measure of health-related quality of life (HRQOL). We have evaluated the influence of disease duration on HRQOL and, for the first time, compared the findings of the PROMIS measures to those of the PedsQL™ 4.0 Generic Scales (PedsQL) from the PROMIS II nephrotic syndrome (NS) longitudinal cohort. Methods: This was a prospective study in which 127 children (age range 8-17 years) with active NS from 14 centers were enrolled. Children with active NS defined as the presence of nephrotic range proteinuria (>2+ urinalysis and edema or urine protein/creatinine ratio >2 g/g) were eligible. Comparisons were made between children with prevalent ( N = 67) and incident ( N = 60) disease at the study enrollment visit. Results: The PROMIS scores were worse in prevalent patients in the domains of peer relationship ( p = 0.01) and pain interference ( p < 0.01). The PedsQL showed worse scores in prevalent patients for social functioning ( p < 0.01) and school functioning ( p = 0.03). Multivariable analyses showed that prevalent patients had worse scores in PROMIS pain interference ( p = 0.02) and PedsQL social functioning ( p < 0.01). Conclusion: The PROMIS measures detected a significant impact of disease duration on HRQOL in children, such that peer relationships were worse and pain interfered with daily life to a greater degree among those with longer disease duration. These findings were in agreement with those for similar domains in the PedsQL legacy instrument. [ABSTRACT FROM AUTHOR]

Background and objectives: Chronic kidney disease is a persistent chronic health condition commonly seen in pediatric nephrology programs. Our study aims to evaluate the sensitivity of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric instrument to indicators of disease severity and activity in pediatric chronic kidney disease. Methods: This cross sectional study included 233 children 8-17 years old, with chronic kidney disease from 16 participating institutions in North America. Disease activity indicators, including hospitalization in the previous 6 months, edema, and number of medications consumed daily, as well as disease severity indicators of kidney function and coexisting medical conditions were captured. PROMIS domains, including depression, anxiety, social-peer relationships, pain interference, fatigue, mobility, and upper extremity function, were administered via web-based questionnaires. Absolute effect sizes (AES) were generated to demonstrate the impact of disease on domain scores. Four children were excluded because of missing glomerular filtration rate (GFR) estimations. Results: Of the 229 children included in the final analysis, 221 completed the entire PROMIS questionnaire. Unadjusted PROMIS domains were responsive to chronic kidney disease activity indicators and number of coexisting conditions. PROMIS domain scores were worse in the presence of recent hospitalizations (depression AES 0.33, anxiety AES 0.42, pain interference AES 0.46, fatigue AES 0.50, mobility AES 0.49), edema (depression AES 0.50, anxiety AES 0.60, pain interference AES 0.77, mobility AES 0.54) and coexisting medical conditions (social peer-relationships AES 0.66, fatigue AES 0.83, mobility AES 0.60, upper extremity function AES 0.48). Conclusions: The PROMIS pediatric domains of depression, anxiety, social-peer relationships, pain interference, and mobility were sensitive to the clinical status of children with chronic kidney disease in this multi-center cross sectional study. We demonstrated that a number of important clinical characteristics including recent history of hospitalization and edema, affected patient perceptions of depression, anxiety, pain interference, fatigue and mobility. The PROMIS instruments provide a potentially valuable tool to study the impact of chronic kidney disease. Additional studies will be required to assess responsiveness in PROMIS score with changes in disease status over time. [ABSTRACT FROM AUTHOR]

The article discusses strategies for integrating physician-scientist research and development into clinical training programs which were implemented in three academic medical centers in the U.S. Topics discussed include physician-scientist training programs (PSTPs) for trainees, funding opportunities for sustaining successful physician-scientist pipelines, and metrics of success of physician-scientist development programs.