First name
Michelle
Middle name
R
Last name
Denburg

Title

Improving Blood Pressure Screening in Neonatal Follow-up Clinic: A Quality Improvement Initiative.

Year of Publication

2022

Number of Pages

e559

Date Published

06/2022

ISSN Number

2472-0054

Abstract

Introduction: The American Academy of Pediatrics recommends blood pressure screening at every health care encounter in children younger than 3 years if they have a history of prematurity or other neonatal complications requiring intensive care because these children have an increased risk for hypertension.

Methods: A multidisciplinary team conducted a quality improvement initiative to improve blood pressure screening at a single-center outpatient neonatal follow-up clinic. We developed a focused intervention program including a standardized blood pressure measurement protocol, staff training and education, and streamlined documentation. We conducted two Plan-Do-Study-Act cycles from November 2019 to January 2021. The outcome measure was the percentage of patients with a blood pressure measurement. Process measures included the percentage of medical assistants educated on the new protocol, percentage of patients 3 years, and younger old with the first blood pressure measurement taken from the right arm, and the percentage of patients 1 year and younger with 3 documented blood pressures. The balancing measure was staff satisfaction with time to obtain vital signs. We used statistical process control charts and Wilcoxon rank-sum test.

Results: At baseline, only 15.3% of patients had documented blood pressure. During the 10-month intervention period, there were 954 patient visits. Overall, blood pressure measurement increased to 54.7% with study interventions. The balancing measure was not negatively impacted.

Conclusions: After implementing a program of focused interventions, we substantially improved the frequency of blood pressure measurements and increased adherence to American Academy of Pediatrics screening guidelines. Improved blood pressure screening allows us to identify and evaluate at-risk infants after hospital discharge.

DOI

10.1097/pq9.0000000000000559

Alternate Title

Pediatr Qual Saf

PMID

35720869

Title

Vitamin D supplementation in children and young adults with persistent proteinuria secondary to glomerular disease.

Year of Publication

2022

Date Published

07/2022

ISSN Number

1432-198X

Abstract

BACKGROUND: Vitamin D deficiency is common in glomerular disease. Supplementation may be ineffective due to ongoing urinary losses of vitamin D binding protein. We sought to determine if daily cholecalciferol supplementation would increase vitamin D concentrations in children with glomerular disease and persistent proteinuria, without adverse effects.

METHODS: Eighteen participants at least 5 years of age with primary glomerular disease and urine protein:creatinine ratio ≥ 0.5 were enrolled from four pediatric nephrology practices to receive cholecalciferol supplementation: 4,000 IU or 2,000 IU per day for serum 25 hydroxyvitamin vitamin D (25OHD) concentrations < 20 ng/mL and 20 ng/mL to < 30 ng/mL, respectively. Measures of vitamin D and mineral metabolism were obtained at baseline and weeks 6 and 12. Multivariable generalized estimating equation (GEE) regression estimated mean percent changes in serum 25OHD concentration.

RESULTS: Median baseline 25OHD was 12.8 ng/mL (IQR 9.3, 18.9) and increased to 27.8 ng/mL (20.5, 36.0) at week 6 (p < 0.001) without further significant increase at week 12. A total of 31% of participants had a level ≥ 30 ng/mL at week 12. Supplementation was stopped in two participants at week 6 for mildly elevated calcium and phosphorus, respectively, with subsequent declines in 25OHD of > 20 ng/mL. In the adjusted GEE model, 25OHD was 102% (95% CI: 64, 141) and 96% (95% CI: 51, 140) higher versus baseline at weeks 6 and 12, respectively (p < 0.001).

CONCLUSION: Cholecalciferol supplementation in vitamin D deficient children with glomerular disease and persistent proteinuria safely increases 25OHD concentration. Ideal dosing to fully replete 25OHD concentrations in this population remains unknown.

CLINICAL TRIAL: NCT01835639. A higher resolution version of the Graphical abstract is available as Supplementary information.

DOI

10.1007/s00467-022-05660-9

Alternate Title

Pediatr Nephrol

PMID

35852656

Title

Validating a Computable Phenotype for Nephrotic Syndrome in Children and Adults Using PCORnet Data.

Year of Publication

2021

Number of Pages

1979-1986

Date Published

2021 Dec 30

ISSN Number

2641-7650

Abstract

<p><strong>Background: </strong>Primary nephrotic syndromes are rare diseases which can impede adequate sample size for observational patient-oriented research and clinical trial enrollment. A computable phenotype may be powerful in identifying patients with these diseases for research across multiple institutions.</p>

<p><strong>Methods: </strong>A comprehensive algorithm of inclusion and exclusion ICD-9 and ICD-10 codes to identify patients with primary nephrotic syndrome was developed. The algorithm was executed against the PCORnet CDM at three institutions from January 1, 2009 to January 1, 2018, where a random selection of 50 cases and 50 noncases (individuals not meeting case criteria seen within the same calendar year and within 5 years of age of a case) were reviewed by a nephrologist, for a total of 150 cases and 150 noncases reviewed. The classification accuracy (sensitivity, specificity, positive and negative predictive value, F1 score) of the computable phenotype was determined.</p>

<p><strong>Results: </strong>The algorithm identified a total of 2708 patients with nephrotic syndrome from 4,305,092 distinct patients in the CDM at all sites from 2009 to 2018. For all sites, the sensitivity, specificity, and area under the curve of the algorithm were 99% (95% CI, 97% to 99%), 79% (95% CI, 74% to 85%), and 0.9 (0.84 to 0.97), respectively. The most common causes of false positive classification were secondary FSGS (nine out of 39) and lupus nephritis (nine out of 39).</p>

<p><strong>Conclusion: </strong>This computable phenotype had good classification in identifying both children and adults with primary nephrotic syndrome utilizing only ICD-9 and ICD-10 codes, which are available across institutions in the United States. This may facilitate future screening and enrollment for research studies and enable comparative effectiveness research. Further refinements to the algorithm including use of laboratory data or addition of natural language processing may help better distinguish primary and secondary causes of nephrotic syndrome.</p>

DOI

10.34067/KID.0002892021

Alternate Title

Kidney360

PMID

35419531

Title

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

Year of Publication

2022

Date Published

2022 Mar 02

ISSN Number

1432-198X

Abstract

<p>Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).</p>

DOI

10.1007/s00467-022-05492-7

Alternate Title

Pediatr Nephrol

PMID

35237863

Title

Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology.

Year of Publication

2022

Number of Pages

375-386

Date Published

2022 Feb

ISSN Number

1533-3450

Abstract

<p><strong>BACKGROUND: </strong>Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN).</p>

<p><strong>METHODS: </strong>Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause.</p>

<p><strong>RESULTS: </strong>ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites.</p>

<p><strong>CONCLUSION: </strong>ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU.</p>

DOI

10.1681/ASN.2021040538

Alternate Title

J Am Soc Nephrol

PMID

35017168

Title

Using a Multi-Institutional Pediatric Learning Health System to Identify Systemic Lupus Erythematosus and Lupus Nephritis: Development and Validation of Computable Phenotypes.

Year of Publication

2021

Date Published

2021 Nov 03

ISSN Number

1555-905X

Abstract

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Performing adequately powered clinical trials in pediatric diseases, such as SLE, is challenging. Improved recruitment strategies are needed for identifying patients.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>Electronic health record algorithms were developed and tested to identify children with SLE both with and without lupus nephritis. We used single-center electronic health record data to develop computable phenotypes composed of diagnosis, medication, procedure, and utilization codes. These were evaluated iteratively against a manually assembled database of patients with SLE. The highest-performing phenotypes were then evaluated across institutions in PEDSnet, a national health care systems network of &gt;6.7 million children. Reviewers blinded to case status used standardized forms to review random samples of cases (=350) and noncases (=350).</p>

<p><strong>RESULTS: </strong>Final algorithms consisted of both utilization and diagnostic criteria. For both, utilization criteria included two or more in-person visits with nephrology or rheumatology and ≥60 days follow-up. SLE diagnostic criteria included absence of neonatal lupus, one or more hydroxychloroquine exposures, and either three or more qualifying diagnosis codes separated by ≥30 days or one or more diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 100% (95% confidence interval [95% CI], 99 to 100), specificity was 92% (95% CI, 88 to 94), positive predictive value was 91% (95% CI, 87 to 94), and negative predictive value was 100% (95% CI, 99 to 100). Lupus nephritis diagnostic criteria included either three or more qualifying lupus nephritis diagnosis codes (or SLE codes on the same day as glomerular/kidney codes) separated by ≥30 days or one or more SLE diagnosis codes and one or more kidney biopsy procedure codes. Sensitivity was 90% (95% CI, 85 to 94), specificity was 93% (95% CI, 89 to 97), positive predictive value was 94% (95% CI, 89 to 97), and negative predictive value was 90% (95% CI, 84 to 94). Algorithms identified 1508 children with SLE at PEDSnet institutions (537 with lupus nephritis), 809 of whom were seen in the past 12 months.</p>

<p><strong>CONCLUSIONS: </strong>Electronic health record-based algorithms for SLE and lupus nephritis demonstrated excellent classification accuracy across PEDSnet institutions.</p>

DOI

10.2215/CJN.07810621

Alternate Title

Clin J Am Soc Nephrol

PMID

34732529

Title

Early-Onset Kidney Stone Disease-Consequences and Opportunities.

Year of Publication

2021

Date Published

2021 Sep 07

ISSN Number

2168-6211

DOI

10.1001/jamapediatrics.2021.2966

Alternate Title

JAMA Pediatr

PMID

34491264

Title

Metabolite Biomarkers of CKD Progression in Children.

Year of Publication

2021

Number of Pages

1178-1189

Date Published

2021 Aug

ISSN Number

1555-905X

Abstract

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR.</p>

<p><strong>RESULTS: </strong>Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR &lt;60 ml/min per 1.73 m, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9).</p>

<p><strong>CONCLUSIONS: </strong>Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.</p>

DOI

10.2215/CJN.00220121

Alternate Title

Clin J Am Soc Nephrol

PMID

34362785

Title

Venous Thromboembolism in Pediatric Inflammatory Bowel Disease: A Case-Control Study.

Year of Publication

2021

Date Published

2021 Feb 16

ISSN Number

1536-4801

Abstract

<p><strong>OBJECTIVES: </strong>Inflammatory bowel disease (IBD) is associated with increased risk of venous thromboembolism (VTE). Despite this recognized risk, there are limited data and no anticoagulation guidelines for hospitalized pediatric IBD patients. The objectives of this study were to characterize pediatric IBD patients with VTE and determine risk factors.</p>

<p><strong>METHODS: </strong>This was a nested case-control study comparing hospitalized children with IBD diagnosed with VTE to those without VTE over a decade at a large referral center. Standard descriptive statistics were used to describe the VTE group. Multivariable conditional logistic regression was used to assess risk factors.</p>

<p><strong>RESULTS: </strong>Twenty-three cases were identified. Central venous catheter (CVC) presence (OR 77.9 (95% CI: 6.9, 880.6; p &lt; 0.001)) and steroid use (OR 12.7 (95% CI: 1.3, 126.4; p = 0.012)) were independent risk factors. Median age at VTE was 17 years (IQR 13.5, 18.2), and in 48% VTE was the indication for admission. Median duration of anticoagulation was 3.8 months (IQR 2.3, 7.6), and there were no major bleeding events for patients on anticoagulation. There were no patients with known sequelae from VTE, though 22% had severe VTE that required interventions.</p>

<p><strong>CONCLUSIONS: </strong>Pediatric patients with IBD are at risk for VTE, although the absolute risk remains relatively low. The safety and efficacy of pharmacologic thromboprophylaxis needs to be further evaluated in this population with attention to risk factors, such as steroid use and presence of CVC.</p>

<p>An infographic is available for this article at:http://links.lww.com/MPG/C232.</p&gt;

DOI

10.1097/MPG.0000000000003078

Alternate Title

J Pediatr Gastroenterol Nutr

PMID

33605670

Title

Acute Kidney Injury and Pediatric Bone Health.

Year of Publication

2020

Number of Pages

635628

Date Published

2020

ISSN Number

2296-2360

Abstract

<p>Acute kidney injury (AKI) has been associated with deleterious impacts on a variety of body systems. While AKI is often accompanied by dysregulation of mineral metabolism-including alterations in calcium, phosphate, vitamin D, parathyroid hormone, fibroblast growth factor 23, and klotho-its direct effects on the skeletal system of children and adolescents remain largely unexplored. In this review, the pathophysiology of dysregulated mineral metabolism in AKI and its potential effects on skeletal health are discussed, including data associating AKI with fracture risk.</p>

DOI

10.3389/fped.2020.635628

Alternate Title

Front Pediatr

PMID

33634055

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