Publications by authors named "Joseph T Flynn"

160 Publications

L-type calcium channel blocker use and proteinuria among children with chronic kidney diseases.

Pediatr Nephrol 2021 Feb 15. Epub 2021 Feb 15.

Department of Pediatrics, University of Washington; Division of Nephrology, Seattle Children's Hospital, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1007/s00467-021-04967-3DOI Listing
February 2021

Social Determinants of Cardiovascular Health in African American Children With CKD: An Analysis of the Chronic Kidney Disease in Children (CKiD) Study.

Am J Kidney Dis 2021 Jan 5. Epub 2021 Jan 5.

Children's National Hospital, Washington DC, Division of Nephrology.

Rationale & Objective: To identify differences in socioeconomic factors (SES) and subclinical CVD markers by race among CKiD participants and determine whether differences in CVD markers persist after adjusting for SES.

Study Design: Analysis of 3103 visits with repeated measures from 628 children (497 Caucasian; 131 African American) enrolled in the CKiD study.

Setting & Participants: Children with mild-moderate CKD with at least 1 CV parameter (ambulatory blood pressure, left ventricular mass index [LVMI], or lipid profile) measured.

Exposures: African American race OUTCOMES: Ambulatory hypertension, LVMI, triglycerides, high-density lipoprotein-cholesterol.

Analytical Approach: Due to increased CV risks of glomerular disease, the analysis was stratified by CKD etiology. Inverse probability weighting was used to adjust for SES (health insurance, household income, maternal education, food insecurity, abnormal birth history). Linear and logistic regression were used to evaluate association of race with CV markers.

Results: African American children were disproportionately affected by adverse SES. African Americans with non-glomerular CKD had more ambulatory hypertension and higher LVMI, but more favorable lipid profile; after adjustment for SES, age, and sex, the magnitude of differences in these CV markers attenuated but remained statistically significant. Only LVMI differed by race in the glomerular CKD group, despite adjustment for SES.

Limitations: Study design limits causal inference.

Conclusion: African American children with CKD are disproportionately affected by socioeconomic disadvantages compared with Caucasians. The degree to which CV markers differ by race is influenced by disease etiology. African Americans with non-glomerular CKD have increased LVMI, more ambulatory hypertension and favorable lipid profile, but a trend towards attenuation in magnitude after adjustment for SES was observed. African Americans with glomerular CKD have increased LVMI, which persisted after SES adjustment. As many social determinants of health were not captured, future research should examine effects of systemic racism on CV health in this population.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.013DOI Listing
January 2021

The hypertensive neonate.

Authors:
Joseph T Flynn

Semin Fetal Neonatal Med 2020 Oct 12;25(5):101138. Epub 2020 Jul 12.

Department of Pediatrics, University of Washington School of Medicine, And Division of Nephrology, Seattle Children's Hospital, Seattle, WA, USA. Electronic address:

Hypertension in neonates is increasingly recognized because of improvements in neonatal intensive care that have led to improved survival of premature infants. Although normative data on neonatal blood pressure remain limited, several factors appear to be important in determining blood pressure levels in neonates, especially gestational age, birth weight and maternal factors. Incidence is around 1% in most studies and identification depends on careful blood pressure measurement. Common causes of neonatal hypertension include umbilical catheter associated thrombosis, renal parenchymal disease, and chronic lung disease, and can usually be identified with careful diagnostic evaluation. Given limited data on long-term outcomes and use of antihypertensive medications in these infants, clinical expertise may need to be relied upon to decide the best approach to treatment. This review will discuss these concepts and identify evidence gaps that should be addressed.
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http://dx.doi.org/10.1016/j.siny.2020.101138DOI Listing
October 2020

Achieved clinic blood pressure level and chronic kidney disease progression in children: a report from the Chronic Kidney Disease in Children cohort.

Pediatr Nephrol 2020 Nov 16. Epub 2020 Nov 16.

Division of Nephrology, Children's Mercy Kansas City, Kansas City, MO, USA.

Background: Control of hypertension delays progression of pediatric chronic kidney disease (CKD), yet few data are available regarding what clinic blood pressure (BP) levels may slow progression.

Methods: Longitudinal BP data from children in the Chronic Kidney Disease in Children cohort study who had hypertension or an auscultatory BP ≥ 90th percentile were studied. BP categories were defined as the maximum systolic or diastolic BP percentile (< 50th, 50th to 75th, 75th to 90th, and ≥ 90th percentile) with time-updated classifications corresponding to annual study visits. The primary outcome was time to kidney replacement therapy or a 30% decline in estimated glomerular filtration rate. Cox proportional hazard models described the effect of each BP category compared to BP ≥ 90th percentile.

Results: Seven hundred fifty-four participants (median age 9.9 years at study entry) met inclusion criteria; 65% were male and 26% had glomerular CKD. Any BP < 90th percentile was associated with a decreased risk of progression for those with glomerular CKD (hazard ratio (HR), 0.63; 95% CI, 0.28-1.39 (< 50th); HR, 0.59; 95% CI, 0.28-1.26 (50th-75th); HR, 0.40; 95% CI, 0.18-0.93 (75th-90th)). Similar results were found for those with non-glomerular CKD: any BP < 90th percentile was associated with decreased risk of progression (HR, 0.78; 90% CI, 0.49-1.25 (< 50th); HR, 0.53; 95% CI, 0.33-0.84 (50th-75th); HR, 0.71; 95% CI, 0.46-1.08 (75th-90th)).

Conclusions: Achieved clinic BP < 90th percentile was associated with slower CKD progression in children with glomerular or non-glomerular CKD. These data provide guidance for management of children with CKD in the office setting. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04833-8DOI Listing
November 2020

An Alternative View of Childhood Blood Pressure Screening: Reframing the Question.

Authors:
Joseph T Flynn

JAMA Netw Open 2020 11 2;3(11):e2027964. Epub 2020 Nov 2.

Department of Pediatrics, University of Washington School of Medicine, Seattle.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.27964DOI Listing
November 2020

Kidney transplant patients don't dip on ambulatory blood pressure monitoring: What should be done about it?

Authors:
Joseph T Flynn

Pediatr Transplant 2020 12 26;24(8):e13878. Epub 2020 Oct 26.

Division of Nephrology, Seattle Children's Hospital, Seattle, WA, USA.

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http://dx.doi.org/10.1111/petr.13878DOI Listing
December 2020

2020 update on the renin-angiotensin-aldosterone system in pediatric kidney disease and its interactions with coronavirus.

Pediatr Nephrol 2020 Sep 29. Epub 2020 Sep 29.

Pediatric Nephrology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, 98105, USA.

The last decade was crucial for our understanding of the renin-angiotensin-aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.
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http://dx.doi.org/10.1007/s00467-020-04759-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524035PMC
September 2020

Stability of Blood Pressure and Diagnosis of Hypertension in Childhood.

Authors:
Joseph T Flynn

Pediatrics 2020 10 18;146(4). Epub 2020 Sep 18.

Department of Pediatrics, School of Medicine, University of Washington; and Division of Nephrology, Seattle Children's Hospital, Seattle, Washington

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http://dx.doi.org/10.1542/peds.2020-018481DOI Listing
October 2020

Renal Survival in Children with Glomerulonephritis with Crescents: A Pediatric Nephrology Research Consortium Cohort Study.

J Clin Med 2020 Jul 26;9(8). Epub 2020 Jul 26.

Pediatric Nephrology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium's Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1-21). The percentage of crescents was 3-100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1-11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival ( = 0.003) and a 2% decrease in log odds of renal survival at last follow-up ( < 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials.
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http://dx.doi.org/10.3390/jcm9082385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464981PMC
July 2020

Use of Automated Office Blood Pressure Measurement in the Evaluation of Elevated Blood Pressures in Children and Adolescents.

J Pediatr 2020 12 4;227:204-211.e6. Epub 2020 Jul 4.

Division of Nephrology, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA.

Objectives: To determine the level of agreement between automated office blood pressures (AOBP), auscultated or manual office BP (manual office blood pressure), and 24-hour ABPM, and to explore the ability of AOBP and manual office blood pressure to correctly identify daytime ambulatory hypertension in children.

Study Design: We retrospectively compared BPs obtained by AOBP and manual office blood pressure to predict daytime hypertension on ABPM. Six BPs were taken by AOBP followed by manual office blood pressure. Office hypertension was defined by BPs ≥95th percentile for sex and height percentiles for those <13 years of age and a BP of ≥130/80 mm Hg for ages ≥13 years. Daytime ambulatory hypertension was diagnosed if mean wake BPs were ≥95th percentile and BP loads were ≥25%. Application of adult ABPM thresholds for daytime hypertension (130/80 mm Hg) was assessed in ages ≥13 years. Sensitivity and specificity were calculated considering ABPM as the reference.

Results: Complete data were available for 187 patient encounters. Overall, the best agreement was found if both AOBP and manual office blood pressure showed hypertension, but owing to low sensitivity up to 49% of children with hypertension would be misclassified. The use of adult thresholds for ABPM did not improve agreement.

Conclusions: Neither AOBP nor manual office blood pressure confirm or exclude daytime ambulatory hypertension with confidence. These results suggest an ongoing role for ABPM in evaluation of hypertension in children.
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http://dx.doi.org/10.1016/j.jpeds.2020.06.059DOI Listing
December 2020

The Improving Renal Outcomes Collaborative: Blood Pressure Measurement in Transplant Recipients.

Pediatrics 2020 07 9;146(1). Epub 2020 Jun 9.

Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio;

Background And Objectives: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients.

Methods: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions.

Results: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits.

Conclusions: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.
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http://dx.doi.org/10.1542/peds.2019-2833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329257PMC
July 2020

ACE2 (Angiotensin-Converting Enzyme 2), COVID-19, and ACE Inhibitor and Ang II (Angiotensin II) Receptor Blocker Use During the Pandemic: The Pediatric Perspective.

Hypertension 2020 07 5;76(1):16-22. Epub 2020 May 5.

Department of Pediatrics, University of Washington School of Medicine and Division of Nephrology, Seattle Children's Hospital (J.T.F.).

Potential but unconfirmed risk factors for coronavirus disease 2019 (COVID-19) in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, ACE (angiotensin-converting enzyme) inhibitors, and Ang II (angiotensin II) receptor blockers. Coronavirus binding to ACE2 (angiotensin-converting enzyme 2), a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus, but the reasons are unclear. This review will highlight the relationship of COVID-19 with hypertension, use of ACE inhibitors and Ang II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the ACE 2/Ang-(1-7) pathway in children and the clinical evidence for how ACE inhibitors and Ang II receptor blockers affect this important pathway. Given the importance of the ACE 2/Ang-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe COVID-19.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289676PMC
July 2020

Subclinical Systolic and Diastolic Dysfunction Is Evident in Youth With Elevated Blood Pressure.

Hypertension 2020 Jun 4;75(6):1551-1556. Epub 2020 May 4.

From the Cincinnati Children's Hospital Medical Center, OH (A.H.T., L.J.M., M.M., E.M.U.).

Hypertension is associated with cardiovascular events in adults. Subclinical changes to left ventricular strain and diastolic function have been found before development of decreased left ventricular ejection fraction and cardiovascular events. Our objective was to study effects of blood pressure (BP) on ventricular function in youth across the BP spectrum. Vital signs and labs were obtained in 346 participants aged 11 to 19 years who had BP categorized as low-risk (N=144; systolic BP <75th percentile), mid-risk (N=83; systolic BP ≥80th and <90th percentile), and high-risk (N=119; systolic BP ≥90th percentile). Echocardiography was performed to assess left ventricular strain and diastolic function. Differences between groups were analyzed by ANOVA. General linear models were constructed to determine independent predictors of systolic and diastolic function. Mid-risk and high-risk participants had greater adiposity and more adverse metabolic labs (lower HDL [high-density lipoprotein], higher glucose, and higher insulin) than the low-risk group. Mid-risk and high-risk participants had significantly lower left ventricular ejection fraction and peak global longitudinal strain than the low-risk group (both ≤0.05). The E/e' ratio was higher in the high-risk group versus the low-risk and mid-risk groups, and the e'/a' ratio was lower in the high-risk versus the low-risk group (both ≤0.05). BP and adiposity were statistically significant determinants of left ventricular systolic and diastolic function. Subclinical changes in left ventricular systolic and diastolic function can be detected even at BP levels below the hypertensive range as currently defined.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266265PMC
June 2020

Prognostic Value of Ambulatory Blood Pressure Load in Pediatric CKD.

Clin J Am Soc Nephrol 2020 04 11;15(4):493-500. Epub 2020 Mar 11.

Division of Pediatric Nephrology, University of California San Francisco, San Francisco, California.

Background And Objectives: Elevated BP load is part of the criteria for ambulatory hypertension in pediatric but not adult guidelines. Our objectives were to determine the prevalence of isolated BP load elevation and associated risk with adverse outcomes in children with CKD, and to ascertain whether BP load offers risk discrimination independently or in conjunction with mean ambulatory BPs.

Design, Setting, Participants, & Measurements: We studied 533 children in the CKD in Children (CKiD) Study to determine the prevalence of normotension, isolated BP load elevation (≥25% of all readings elevated but mean BP normal), and ambulatory hypertension. We examined the association between these categories of BP control and adverse outcomes (left ventricular hypertrophy [LVH] or ESKD). We used c-statistics to determine risk discrimination for outcomes by BP load used either independently or in conjunction with other BP parameters.

Results: Overall, 23% of the cohort had isolated BP load elevation, but isolated BP load elevation was not statistically significantly associated with LVH in cross-section (odds ratio, 1.8; 95% CI, 0.8 to 4.2) or time to ESKD (hazard ratio, 1.2; 95% CI, 0.7 to 2.0). In unadjusted cross-sectional analysis, every 10% higher systolic BP load was associated with 1.1-times higher odds of LVH (95% CI, 1.0 to 1.3), but discrimination for LVH was poor (c=0.61). In unadjusted longitudinal analysis, every 10% higher systolic BP load was associated with a 1.2-times higher risk of ESKD (95% CI, 1.1 to 1.2), but discrimination for ESKD was also poor (c=0.60). After accounting for mean systolic BP, systolic BP load was not statistically significantly associated with either LVH or ESKD. Findings were similar with diastolic BP load.

Conclusions: BP load does not provide additive value in discriminating outcomes when used independently or in conjunction with mean systolic BP in children with CKD.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_03_11_CPOD10130819.mp3.
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http://dx.doi.org/10.2215/CJN.10130819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133128PMC
April 2020

Increased history of ischemic stroke and decreased neurocognitive performance in children with chronic kidney disease.

Pediatr Nephrol 2020 07 24;35(7):1315-1321. Epub 2020 Feb 24.

Departments of Allied Health Sciences and Psychiatry, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.

Background: This study aimed to determine stroke incidence and assess the association between stroke and neurocognitive functioning in children with chronic kidney disease (CKD).

Methods: Data was derived from the Chronic Kidney Disease in Children (CKiD) cohort study. Stroke incidence was calculated after confirming self-reports of stroke occurrence by chart review. Each participant with stroke was matched with three stroke-free participants and performance on selected neurocognitive measures was compared. Wilcoxon rank-sum tests were used to compare neurocognitive test scores. Effect size (ES) was estimated using a modified version of Cohen's U metric that measures the excess percentage of the stroke group worse than the median of the control group.

Results: Of 891 subjects, five (0.56%) had a confirmed stroke prior to study entry. Median time at risk was 15.7 years [interquartile range, 12.5-18.4]. Estimated incidence rate of history of stroke was 36.8 per 100,000 children per year (95% confidence interval 15.3, 88.5). Controls and subjects with stroke were similar in age, CKD duration, race, and maternal education. ES for many of the neurocognitive comparisons was moderate to large. Subjects in the CKID cohort with a history of stroke had lower scores on spatial span reverse, spatial span forward, and design fluency, and worse parent ratings on BRIEF Metacognition Index compared to a matched sample of children with CKD without stroke.

Conclusions: Children with CKD have an increased incidence of prior ischemic stroke compared to the general pediatric population. A stroke history was associated with poorer performance on neurocognitive measures. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04503-9DOI Listing
July 2020

The CKiD study: overview and summary of findings related to kidney disease progression.

Pediatr Nephrol 2021 Mar 3;36(3):527-538. Epub 2020 Feb 3.

Seattle Children's Hospital, Seattle, WA, 98105, USA.

The Chronic Kidney Disease in Children (CKiD) cohort study is a North American (USA and Canada) multicenter, prospective study of children with chronic kidney disease (CKD). The original aims of the study were (1) to identify novel risk factors for CKD progression; (2) to measure the impact of kidney function decline on growth, cognition, and behavior; and (3) to characterize the evolution of cardiovascular disease risk factors. CKiD has developed into a national and international resource for the investigation of a variety of factors related to CKD in children. This review highlights notable findings in the area of CKD progression and outlines ongoing opportunities to enhance understanding of CKD progression in children. CKiD's contributions to the clinical care of children with CKD include updated and more accurate glomerular filtration rate estimating equations for children and young adults, and resources designed to help estimate the CKD progression timeline. In addition, results from CKiD have strengthened the evidence that treatment of hypertension and proteinuria should continue as a primary strategy for slowing the rate of disease progression in children.
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http://dx.doi.org/10.1007/s00467-019-04458-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396280PMC
March 2021

Using Electronic Health Record Data to Rapidly Identify Children with Glomerular Disease for Clinical Research.

J Am Soc Nephrol 2019 12 15;30(12):2427-2435. Epub 2019 Nov 15.

Division of Nephrology.

Background: The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients.

Methods: The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (=800) and nonglomerular cases (=798).

Results: The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months.

Conclusions: The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.
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http://dx.doi.org/10.1681/ASN.2019040365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900784PMC
December 2019

Change in Dyslipidemia with Declining Glomerular Filtration Rate and Increasing Proteinuria in Children with CKD.

Clin J Am Soc Nephrol 2019 12 11;14(12):1711-1718. Epub 2019 Nov 11.

Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and.

Background And Objectives: Dyslipidemia, a risk factor for cardiovascular disease, is common in CKD but its change over time and how that change is influenced by concurrent progression of CKD have not been previously described.

Design, Setting, Participants, & Measurements: In the CKD in Children study we prospectively followed children with progressive CKD and utilized multivariable, linear mixed-effects models to quantify the longitudinal relationship between within-subject changes in lipid measures (HDL cholesterol, non-HDL cholesterol, triglycerides) and within-subject changes in GFR, proteinuria, and body mass index (BMI).

Results: A total of 508 children (76% nonglomerular CKD, 24% glomerular CKD) had 2-6 lipid measurements each, with a median follow-up time of 4 (interquartile range [IQR], 2.1-6.0) years. Among children with nonglomerular CKD, dyslipidemia was common at baseline (35%) and increased significantly as children aged; 43% of children with glomerular CKD had dyslipidemia at baseline and demonstrated persistent levels as they aged. Longitudinal increases in proteinuria were independently associated with significant concomitant increases in non-HDL cholesterol (nonglomerular: 4.9 [IQR, 3.4-6.4] mg/dl; glomerular: 8.5 [IQR, 6.0-11.1] mg/dl) and triglycerides (nonglomerular: 3% [IQR, 0.8%-6%]; glomerular: 5% [IQR, 0.6%-9%]). Decreases in GFR over follow-up were significantly associated with concomitant decreases of HDL cholesterol in children with nonglomerular CKD (-1.2 mg/dl; IQR, -2.1 to -0.4 mg/dl) and increases of non-HDL cholesterol in children with glomerular CKD (3.9 mg/dl; IQR, 1.4-6.5 mg/dl). The effects of increased BMI also affected multiple lipid changes over time. Collectively, glomerular CKD displayed stronger, deleterious associations between within-subject change in non-HDL cholesterol (9 mg/dl versus 1.2 mg/dl; <0.001) and triglycerides (14% versus 3%; =0.004), and within-subject change in BMI; similar but quantitatively smaller differences between the two types of CKD were noted for associations of within-subject change in lipids to within-subject change in GFR and proteinuria.

Conclusions: Dyslipidemia is a common and persistent complication in children with CKD and it worsens in proportion to declining GFR, worsening proteinuria, and increasing BMI.
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http://dx.doi.org/10.2215/CJN.03110319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895497PMC
December 2019

Predictors of time to first cannulation for arteriovenous fistula in pediatric hemodialysis patients: Midwest Pediatric Nephrology Consortium study.

Pediatr Nephrol 2020 02 6;35(2):287-295. Epub 2019 Nov 6.

Department of Pediatrics, Division of Pediatric Nephrology, SSM Cardinal Glennon Children's Hospital, Saint Louis University, St. Louis, MO, USA.

Background: Permanent vascular access (PVA) is preferred for long-term hemodialysis. Arteriovenous fistulae (AVF) have the best patency and the lowest complication rates compared to arteriovenous grafts (AVG) and tunneled cuffed catheters (TCC). However, AVF need time to mature. This study aimed to investigate predictors of time to first cannulation for AVF in pediatric hemodialysis patients.

Methods: Data on first AVF and AVG of patients at 20 pediatric dialysis centers were collected retrospectively, including demographics, clinical information, dialysis markers, and surgical data. Statistical modeling was used to investigate predictors of outcome.

Results: First PVA was created in 117 children: 103 (88%) AVF and 14 (12%) AVG. Mean age at AVF creation was 15.0 ± 3.3 years. AVF successfully matured in 89 children (86.4%), and mean time to first cannulation was 3.6 ± 2.5 months. In a multivariable regression model, study center, age, duration of non-permanent vascular access (NPVA), and Kt/V at AVF creation predicted time to first cannulation, with study center as the strongest predictor (p < 0.01). Time to first cannulation decreased with increasing age (p = 0.03) and with increasing Kt/V (p = 0.01), and increased with duration of NPVA (p = 0.03). Secondary failure occurred in 10 AVF (11.8%). Time to first cannulation did not predict secondary failure (p = 0.29), but longer time to first cannulation tended towards longer secondary patency (p = 0.06).

Conclusions: Study center is the strongest predictor of time to first cannulation for AVF and deserves further investigation. Time to first cannulation is significantly shorter in older children, with more efficient dialysis treatments, and increases with longer NPVA duration.
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http://dx.doi.org/10.1007/s00467-019-04396-3DOI Listing
February 2020

Changes in Ambulatory Blood Pressure Phenotype over Time in Children and Adolescents with Elevated Blood Pressures.

J Pediatr 2020 01 1;216:37-43.e2. Epub 2019 Nov 1.

Division of Nephrology, Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA.

Objective: To determine the stability of ambulatory blood pressure monitoring (ABPM) over time in children referred for evaluation of elevated BPs and assess for factors predicting change.

Study Design: This retrospective chart review conducted at Seattle Children's Hospital and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh identified 124 children referred for elevated BPs with 2 ABPM studies at least 6 months apart. All subjects received lifestyle counseling. Subjects with secondary hypertension (HTN) or on antihypertensive medication were excluded. ABPM phenotype was classified using American Heart Association guidelines as showing normal BP, prehypertension, and HTN. Generalized linear mixed effect regression models were used to regress stable, improving, or worsening HTN outcomes at study follow-up on baseline BP index and load variables.

Results: The median age of patients was 14.1 years (73% males) and the median interval between studies was 18 months. ABPM phenotype changed in 58 of 124 children, with 16% worsening and 31% improving. Older age was associated with persistence of HTN. Although not significant, decrease in body mass index z-score tracked with sustained normal ambulatory BPs.

Conclusions: Although the sample size is small, our study suggests ABPM phenotype shows variability over time. Further study is required to identify factors supporting risk for progression of ABPM phenotype over time.
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http://dx.doi.org/10.1016/j.jpeds.2019.09.070DOI Listing
January 2020

Blood pressure in children with chronic kidney disease: lessons learned from the Chronic Kidney Disease in Children Cohort Study.

Pediatr Nephrol 2020 07 8;35(7):1203-1209. Epub 2019 Aug 8.

Division of Nephrology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA.

Cardiovascular disease (CVD) is common among children and adolescents with chronic kidney disease (CKD) and end-stage kidney disease (ESRD). However, the early accrual of CVD risk factors in children with CKD has not been well studied. The Chronic Kidney Disease in Children (CKiD) Study, a multicenter, prospective cohort study of children with mild-to-moderate CKD at study entry counts among its primary aims investigation of the drivers of CVD risk in this population. As the most prevalent CVD risk factor in children with CKD, blood pressure (BP) has been a major focus of investigation for the CKiD Study Group. Over the first 15 years of the study, landmark publications have better defined the prevalence of hypertension, the frequency with which it is under-recognized and thus undertreated, and the consequences of elevated BP in this cohort. The purpose of this review is to summarize the contributions made by the CKiD Study in advancing knowledge of BP in this high-risk population, and to highlight areas in need of further study.
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http://dx.doi.org/10.1007/s00467-019-04288-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007321PMC
July 2020

Association of Blood Pressure Level With Left Ventricular Mass in Adolescents.

Hypertension 2019 09 22;74(3):590-596. Epub 2019 Jul 22.

Division of Nephrology; Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine (C.H., J.T.F.).

Hypertension is associated with left ventricular hypertrophy (LVH), a risk factor for cardiovascular events. Since cardiovascular events in youth are rare, hypertension has historically been defined by the 95th percentile of the normal blood pressure (BP) distribution in healthy children. The optimal BP percentile associated with LVH in youth is unknown. We aimed to determine the association of systolic BP (SBP) percentile, independent of obesity, on left ventricular mass index (LVMI), and to estimate which SBP percentile best predicts LVH in youth. We evaluated SBP, anthropometrics, and echocardiogram in 303 adolescents (mean age 15.6 years, 63% white, 55% male) classified by SBP as low-risk (L=141, <80th percentile), mid-risk (M=71, 80-<90th percentile), or high-risk (H=91, ≥90th percentile) using the mean of 6 measurements at 2 visits according to the 2017 guidelines. Logistic regression was used to determine the sensitivity and specificity of various SBP percentiles associated with LVH. Results: BP groups did not differ by age or demographics but differed slightly by body mass index. Mean BP, LVMI, and prevalence of LVH increased across groups (BP: L=111/75, M=125/82, and H=133/92 mm Hg; LVMI: L=31.2, M=34.2, and H=34.9 g/m; LVH: L=13%, M=21%, H=27%, all P<0.03). SBP percentile remained a significant determinant of LVMI after adjusting for covariates. The 90th percentile for SBP resulted in the best balance between sensitivity and specificity for predicting LVH (LVMI≥38.6 g/m). Abnormalities in cardiac structure in youth can be found at BP levels below those used to define hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13027DOI Listing
September 2019

Are There Consequences of Adolescent Blood Pressure on Kidney Function in Adulthood?

Am J Kidney Dis 2019 10 27;74(4):567-569. Epub 2019 Jun 27.

Division of Nephrology, Children's Mercy Hospital, Kansas City, MO. Electronic address:

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http://dx.doi.org/10.1053/j.ajkd.2019.05.006DOI Listing
October 2019

Correction to: Neonatal hypertension: cases, causes, and clinical approach.

Pediatr Nephrol 2019 Sep;34(9):1637

Division of Nephrology, Department of Pediatrics, Seattle Children's Hospital and University of Washington School of Medicine, 4800 Sand Point Way NE, M/S OC.9.820, Seattle, WA, 98105, USA.

The original version of this article unfortunately contained a mistake. Due to a production error, the wrong "Key summary points" were included. The correct key summary points are listed below.
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http://dx.doi.org/10.1007/s00467-019-04273-zDOI Listing
September 2019

Does treatment-resistant hypertension exist in children? A review of the evidence.

Pediatr Nephrol 2020 06 30;35(6):969-976. Epub 2019 May 30.

Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA, 98105, USA.

Treatment-resistant hypertension (TRH) is a well-described condition in adult patients that is associated with poor clinical outcomes. While case reports of hypertension resistant to therapy in children have been published, it is unclear if TRH truly exists in childhood. This educational review will briefly summarize recent evidence and recommendations for TRH in adults, as well as will review the literature regarding medically resistant hypertension in children and adolescents. Finally, we propose a clinical approach for evaluation hypertensive children and adolescents with apparent treatment resistance.
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http://dx.doi.org/10.1007/s00467-019-04268-wDOI Listing
June 2020

Research Gaps in Primary Pediatric Hypertension.

Pediatrics 2019 05;143(5)

Office of Clinical Research Training and Medical Education, National Institutes of Health, Bethesda, Maryland.

Hypertension affects >40% of the US population and is a major contributor to cardiovascular-related morbidity and mortality. Although less common among children and adolescents, hypertension affects 1% to 5% of all youth. The 2017 Clinical Practice Guideline for the Diagnosis and Management of High Blood Pressure in Children and Adolescents provided updates and strategies regarding the diagnosis and management of hypertension in youth. Despite this important information, many gaps in knowledge remain, such as the etiology, prevalence, and trends of hypertension; the utility and practicality of ambulatory blood pressure monitoring; practical goals for lifestyle modification that are generalizable; the long-term end-organ impacts of hypertension in youth; and the long-term safety and efficacy of antihypertensive therapy in youth. The National Institute of Child Health and Human Development, in collaboration with the National Heart, Lung, and Blood Institute and the US Food and Drug Administration, sponsored a workshop of experts to discuss the current state of childhood primary hypertension. We highlight the results of that workshop and aim to (1) provide an overview of current practices related to the diagnosis, management, and treatment of primary pediatric hypertension; (2) identify related research gaps; and (3) propose ways to address existing research gaps.
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http://dx.doi.org/10.1542/peds.2018-3517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6564054PMC
May 2019

The Hypertensive Adolescent.

Authors:
Joseph T Flynn

Clin J Am Soc Nephrol 2019 07 24;14(7):1074-1076. Epub 2019 Apr 24.

Division of Nephrology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington

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http://dx.doi.org/10.2215/CJN.02800319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625625PMC
July 2019

Implications of the 2017 AAP Clinical Practice Guidelines for Management of Hypertension in Children and Adolescents: a Review.

Curr Hypertens Rep 2019 04 5;21(5):35. Epub 2019 Apr 5.

Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Purpose Of Review: To evaluate the impact of the 2017 American Academy of Pediatrics Clinical Practice Guideline (2017 AAP CPG) for Screening and Management of High Blood Pressure in Children and Adolescents.

Recent Findings: The 2017 AAP CPG had several significant changes compared to the 2004 Fourth Report. This review will focus on the emerging evidence from the first studies to apply the 2017 AAP CPG and the simplified table it contains on the overall prevalence of HTN and on recognition among children and adolescents at a higher cardiovascular risk. Recent evidence suggests that use of the 2017 AAP CPG will result in an overall increase in prevalence of HTN, particularly in youth who are obese or who have other cardiovascular risk factors. The change in prevalence likely differs based on sex, age, and height. The ability for the 2017 AAP CPG to detect an association with hypertension and target organ damage requires further study. Continued study is required to assess long-term implications of the 2017 AAP CPG with the goal of a more meaningful HTN definition in the young.
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http://dx.doi.org/10.1007/s11906-019-0943-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705594PMC
April 2019

KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline.

Am J Kidney Dis 2019 04;73(4):437-458

Department of Medicine, University of Utah, Salt Lake City, UT.

Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality and reduction of elevated blood pressure (BP) remains an important intervention for slowing kidney disease progression. Over the past decade, the most appropriate BP target for initiation and titration of BP-lowering medications has been an area of intense research and debate within the clinical community. In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) in conjunction with several other professional societies released new hypertension guidelines based on data from a systematic review of clinical trials and observational data. While many of the recommendations in the ACC/AHA hypertension guideline are relevant to nephrology practice, BP targets and management strategies for patients receiving dialysis are not discussed. This Kidney Disease Outcomes Quality Initiative (KDOQI) commentary focuses largely on recommendations from the ACC/AHA hypertension guidelines that are pertinent to individuals at risk of chronic kidney disease or with non-dialysis-dependent chronic kidney disease. This KDOQI commentary also includes a brief discussion of the consensus statement regarding hypertension diagnosis and management for adults receiving maintenance dialysis published by the European Renal and Cardiovascular Medicine Working Group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension. Overall, we support the vast majority of the ACC/AHA recommendations and highlight select areas in which best diagnosis and treatment options remain controversial.
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http://dx.doi.org/10.1053/j.ajkd.2019.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6740329PMC
April 2019