Publications by authors named "Larry A Greenbaum"

112 Publications

Improving data quality in observational research studies: Report of the Cure Glomerulonephropathy (CureGN) network.

Contemp Clin Trials Commun 2021 Jun 17;22:100749. Epub 2021 Feb 17.

NYU Langone Health, Department of Pediatrics, Division of Nephrology, New York, NY, USA.

Background: High data quality is of crucial importance to the integrity of research projects. In the conduct of multi-center observational cohort studies with increasing types and quantities of data, maintaining data quality is challenging, with few published guidelines.

Methods: The Cure Glomerulonephropathy (CureGN) Network has established numerous quality control procedures to manage the 70 participating sites in the United States, Canada, and Europe. This effort is supported and guided by the activities of several committees, including Data Quality, Recruitment and Retention, and Central Review, that work in tandem with the Data Coordinating Center to monitor the study. We have implemented coordinator training and feedback channels, data queries of questionable or missing data, and developed performance metrics for recruitment, retention, visit completion, data entry, recording of patient-reported outcomes, collection, shipping and accessing of biological samples and pathology materials, and processing, cataloging and accessing genetic data and materials.

Results: We describe the development of data queries and site Report Cards, and their use in monitoring and encouraging excellence in site performance. We demonstrate improvements in data quality and completeness over 4 years after implementing these activities. We describe quality initiatives addressing specific challenges in collecting and cataloging whole slide images and other kidney pathology data, and novel methods of data quality assessment.

Conclusions: This paper reports the CureGN experience in optimizing data quality and underscores the importance of general and study-specific data quality initiatives to maintain excellence in the research measures of a multi-center observational study.
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http://dx.doi.org/10.1016/j.conctc.2021.100749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039553PMC
June 2021

The dietary management of potassium in children with CKD stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

Pediatr Nephrol 2021 Mar 17. Epub 2021 Mar 17.

University Hospital Ghent, Ghent, Belgium.

Dyskalemias are often seen in children with chronic kidney disease (CKD). While hyperkalemia is common, with an increasing prevalence as glomerular filtration rate declines, hypokalemia may also occur, particularly in children with renal tubular disorders and those on intensive dialysis regimens. Dietary assessment and adjustment of potassium intake is critically important in children with CKD as hyperkalemia can be life-threatening. Manipulation of dietary potassium can be challenging as it may affect the intake of other nutrients and reduce palatability. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, has developed clinical practice recommendations (CPRs) for the dietary management of potassium in children with CKD stages 2-5 and on dialysis (CKD2-5D). We describe the assessment of dietary potassium intake, requirements for potassium in healthy children, and the dietary management of hypo- and hyperkalemia in children with CKD2-5D. Common potassium containing foods are described and approaches to adjusting potassium intake that can be incorporated into everyday practice discussed. Given the poor quality of evidence available, a Delphi survey was conducted to seek consensus from international experts. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs, based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT.
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http://dx.doi.org/10.1007/s00467-021-04923-1DOI Listing
March 2021

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

Pediatr Nephrol 2021 Mar 1. Epub 2021 Mar 1.

Division of Pediatric Nephrology, Boston Children's Hospital, Enders 509 (Mail Stop BCH3100), 300 Longwood Ave, Boston, MA, 02115, USA.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging.

Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes.

Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features.

Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
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http://dx.doi.org/10.1007/s00467-021-04990-4DOI Listing
March 2021

Grip Strength in Adults and Children with Cystinosis.

Kidney Int Rep 2021 Feb 24;6(2):389-395. Epub 2020 Nov 24.

Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, Georgia, USA.

Introduction: Chronic kidney disease (CKD) is associated with impaired muscle strength. Patients with cystinosis have an increased risk for impaired muscle strength because of early development of CKD and cystinosis-induced myopathy. This study assesses muscle strength in patients with cystinosis and investigates risk factors of decreased muscle strength.

Methods: Adult and pediatric patients were recruited from Cystinosis Research Network conferences and a large pediatric nephrology clinic between 2017 and 2019. Patients and caregivers completed questionnaires on demographic characteristics, disease course, daily physical activity, and neuromuscular symptoms. Grip strength was assessed using a dynameter and calculated z-scores for age and sex were assessed for associations with patient characteristics.

Results: We included 76 patients with a mean grip strength z-score of -2.1 (SD, 1.1), which was lower than seen in patients with CKD without cystinosis. Male sex and delayed cysteamine initiation were independently associated with impaired grip strength. Among adults, a low level of physical activity was associated with lower grip strength z score, but no association was found in children. A third of the patients reported neuromuscular symptoms, with swallowing issues associated with lower grip strength. There was no significant correlation between eGFR and grip strength z-score.

Conclusion: Patients with cystinosis have impaired muscle strength compared with healthy control subjects and patients with CKD. This impairment is greater in male patients and in patients with late initiation of cysteamine therapy and is associated with lower physical activity. Further studies investigating the effect of different types of physical activities, optimizing cysteamine therapy, and other interventions are needed.
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http://dx.doi.org/10.1016/j.ekir.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879123PMC
February 2021

Assessment of nutritional status in children with kidney diseases-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

Pediatr Nephrol 2021 Apr 14;36(4):995-1010. Epub 2020 Dec 14.

Children's Mercy Kansas City, Kansas City, MO, USA.

In children with kidney diseases, an assessment of the child's growth and nutritional status is important to guide the dietary prescription. No single metric can comprehensively describe the nutrition status; therefore, a series of indices and tools are required for evaluation. The Pediatric Renal Nutrition Taskforce (PRNT) is an international team of pediatric renal dietitians and pediatric nephrologists who develop clinical practice recommendations (CPRs) for the nutritional management of children with kidney diseases. Herein, we present CPRs for nutritional assessment, including measurement of anthropometric and biochemical parameters and evaluation of dietary intake. The statements have been graded using the American Academy of Pediatrics grading matrix. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs based on the clinical judgment of the treating physician and dietitian. Audit and research recommendations are provided. The CPRs will be periodically audited and updated by the PRNT.
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http://dx.doi.org/10.1007/s00467-020-04852-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910229PMC
April 2021

The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment.

Kidney Int 2020 Dec 8. Epub 2020 Dec 8.

Division of Pediatric Nephrology, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2-3 weeks to every 4-8 weeks depending on bodyweight. Here, we evaluated the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x10/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome.
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http://dx.doi.org/10.1016/j.kint.2020.10.046DOI Listing
December 2020

Impact of autoimmune cytopenias on severity of childhood-onset systemic lupus erythematosus: A single-center retrospective cohort study.

Lupus 2021 Jan 27;30(1):109-117. Epub 2020 Oct 27.

Department of Pediatrics, Division of Pediatric Rheumatology, Emory University School of Medicine and Children's Healthcare of Atlanta, Georgia, USA.

Objective: To assess whether children with autoimmune cytopenias prior to or at diagnosis of systemic lupus erythematosus (cSLE), differ phenotypically from other cSLE patients; and have a lower risk and severity of lupus nephritis (LN) as observed in prior adult studies. To assess the effect of prior immune therapy for autoimmune cytopenias on 2-year risk of LN.

Methods: This was a retrospective cohort study of incident cSLE cases. We included patients aged less than 17 years at diagnosis. We excluded patients with LN at cSLE diagnosis. Our follow-up period was 2 years. We defined autoimmune cytopenias as either autoimmune hemolytic anemia, immune thrombocytopenia or Evan's syndrome.

Results: Forty-three (33%) of the 130 patients had autoimmune cytopenias before or at cSLE diagnosis. Those with autoimmune cytopenias had significantly more neuropsychiatric symptoms and higher mean ESR but less arthritis, malar rash and myositis versus those without autoimmune cytopenias. They had lower 2-year incidence proportion of LN compared to other cSLE patients (7% vs 15%). Of the 16 patients who developed LN, those with autoimmune cytopenias had mostly class V (2 of 3 patients) versus mostly class III and IV in those without autoimmune cytopenias (6 of 12 patients). None of the 13 patients pre-treated for autoimmune cytopenias developed LN.

Conclusion: Patients with autoimmune cytopenias before or at cSLE diagnosis have intriguing differences from other cSLE patients. They may represent a unique sub-type of cSLE patients and should be further explored.
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http://dx.doi.org/10.1177/0961203320969806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769889PMC
January 2021

Safety and efficacy of sucroferric oxyhydroxide in pediatric patients with chronic kidney disease.

Pediatr Nephrol 2021 May 27;36(5):1233-1244. Epub 2020 Oct 27.

Children's National Hospital, The George Washington University, Washington, DC, USA.

Background: Pediatric patients with advanced chronic kidney disease (CKD) are often prescribed oral phosphate binders (PBs) for the management of hyperphosphatemia. However, available PBs have limitations, including unfavorable tolerability and safety.

Methods: This phase 3, multicenter, randomized, open-label study investigated safety and efficacy of sucroferric oxyhydroxide (SFOH) in pediatric and adolescent subjects with CKD and hyperphosphatemia. Subjects were randomized to SFOH or calcium acetate (CaAc) for a 10-week dose titration (stage 1), followed by a 24-week safety extension (stage 2). Primary efficacy endpoint was change in serum phosphorus from baseline to the end of stage 1 in the SFOH group. Safety endpoints included treatment-emergent adverse events (TEAEs).

Results: Eighty-five subjects (2-18 years) were randomized and treated (SFOH, n = 66; CaAc, n = 19). Serum phosphorus reduction from baseline to the end of stage 1 in the overall SFOH group (least squares [LS] mean ± standard error [SE]) was - 0.488 ± 0.186 mg/dL; p = 0.011 (post hoc analysis). Significant reductions in serum phosphorus were observed in subjects aged ≥ 12 to ≤ 18 years (LS mean ± SE - 0.460 ± 0.195 mg/dL; p = 0.024) and subjects with serum phosphorus above age-related normal ranges at baseline (LS mean ± SE - 0.942 ± 0.246 mg/dL; p = 0.005). Similar proportions of subjects reported ≥ 1 TEAE in the SFOH (75.8%) and CaAc (73.7%) groups. Withdrawal due to TEAEs was more common with CaAc (31.6%) than with SFOH (18.2%).

Conclusions: SFOH effectively managed serum phosphorus in pediatric patients with a low pill burden and a safety profile consistent with that reported in adult patients.
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http://dx.doi.org/10.1007/s00467-020-04805-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009783PMC
May 2021

Infection-Related Acute Care Events among Patients with Glomerular Disease.

Clin J Am Soc Nephrol 2020 Dec 20;15(12):1749-1761. Epub 2020 Oct 20.

Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, North Carolina.

Background And Objectives: Infections contribute to patient morbidity and mortality in glomerular disease. We sought to describe the incidence of, and identify risk factors for, infection-related acute care events among Cure Glomerulonephropathy Network (CureGN) study participants.

Design, Setting, Participants, & Measurements: CureGN is a prospective, multicenter, cohort study of children and adults with biopsy sample-proven minimal change disease, FSGS, membranous nephropathy, or IgA nephropathy/vasculitis. Risk factors for time to first infection-related acute care events (hospitalization or emergency department visit) were identified using multivariable Cox proportional hazards regression.

Results: Of 1741 participants (43% female, 41% <18 years, 68% White), 163 (9%) experienced infection-related acute care events over a median follow-up of 17 months (interquartile range, 9-26 months). Unadjusted incidence rates of infection-related acute care events were 13.2 and 6.2 events per 100 person-years among pediatric and adult participants, respectively. Among participants with versus without corticosteroid exposure at enrollment, unadjusted incidence rates were 50.6 and 28.6 per 100 person-years, respectively, during the first year of follow-up (adjusted hazard ratio for time to first infection, 1.31; 95% CI, 0.89 to 1.93), and 4.1 and 1.1 per 100 person-years, respectively, after 1 year of follow-up (hazard ratio, 2.99; 95% CI, 1.54 to 5.79). Hypoalbuminemia combined with nephrotic-range proteinuria (serum albumin ≤2.5 g/dl and urinary protein-creatinine ratio >3.5 mg/mg), compared with serum albumin >2.5 g/dl and urinary protein-creatinine ratio ≤3.5 mg/mg, was associated with higher risk of time to first infection (adjusted hazard ratio, 2.49; 95% CI, 1.51 to 4.12).

Conclusions: Among CureGN participants, infection-related acute care events were common and associated with younger age, corticosteroid exposure, and hypoalbuminemia with proteinuria.
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http://dx.doi.org/10.2215/CJN.05900420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769021PMC
December 2020

The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab.

Pediatr Nephrol 2021 Apr 13;36(4):889-898. Epub 2020 Oct 13.

Division of Pediatric Nephrology, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disease associated with poor outcomes if untreated. Ravulizumab, a long-acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for the treatment of aHUS. Here, we report outcomes from a pediatric patient cohort from the ravulizumab clinical trial (NCT03131219) who were switched from chronic eculizumab to ravulizumab treatment.

Methods: Ten patients received a loading dose of ravulizumab on Day 1, followed by maintenance doses administered initially on Day 15, and then, every 4-8 weeks thereafter, depending on body weight. All patients completed the initial evaluation period of 26 weeks and entered the extension period.

Results: No patients required dialysis at any point throughout the study. The median estimated glomerular filtration rate values remained stable during the trial: 99.8 mL/min/1.73m at baseline, 93.5 mL/min/1.73m at 26 weeks, and 104 mL/min/1.73m at 52 weeks. At last available follow-up, all patients were in the same chronic kidney disease stage as recorded at baseline. Hematologic variables (platelets, lactate dehydrogenase, and hemoglobin) also remained stable throughout the initial evaluation period and up to the last available follow-up. All patients experienced adverse events; the most common were upper respiratory tract infection (40%) and oropharyngeal pain (30%). There were no meningococcal infections reported, no deaths occurred, and no patients discontinued during the study.

Conclusions: Overall, treatment with ravulizumab in pediatric patients with aHUS who were previously treated with eculizumab resulted in stable kidney and hematologic parameters, with no unexpected safety concerns when administered every 4-8 weeks.

Trial Registration: Trial identifiers: Trial ID: ALXN1210-aHUS-312 Clinical trials.gov : NCT03131219 EudraCT number: 2016-002499-29 Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04774-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910247PMC
April 2021

The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network.

Clin Kidney J 2020 Aug 5;13(4):597-606. Epub 2019 Aug 5.

Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.

Background: Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS).

Methods: FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied.

Results: There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P = 0.02) and mobility (-4.2, P = 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P = 0.009) and anxiety (-2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P  0.03).

Conclusions: PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.
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http://dx.doi.org/10.1093/ckj/sfz092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467600PMC
August 2020

Functional Assessment of Fatigue and Other Patient-Reported Outcomes in Patients Enrolled in the Global aHUS Registry.

Kidney Int Rep 2020 Aug 19;5(8):1161-1171. Epub 2020 May 19.

The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a progressive and potentially life-threatening disease characterized by complement-mediated thrombotic microangiopathy. Patients with aHUS may experience fatigue, which can negatively impact their lives, but there is a knowledge gap regarding disease burden in these patients.

Methods: In this longitudinal study, patients with aHUS from the Global aHUS Registry who completed patient-reported outcome assessments (Functional Assessment of Chronic Illness Therapy-Fatigue scale [FACIT-Fatigue], general health status, and work status) at ≥2 time points were assessed relative to treatment status: (i) never treated with eculizumab; (ii) on eculizumab at registry enrollment and continued therapy; and (iii) started eculizumab after registry enrollment.

Results: Patients who started eculizumab after the baseline visit ( = 23) exhibited improvements in fatigue (nearly 75% achieved clinically meaningful improvement), improved general health status (55%), and 25% to 30% rate reduction in symptoms of fatigue, weakness, irritability, nausea/vomiting, and swelling at last follow-up. Among patients already on eculizumab at registry enrollment ( = 295) and those never treated ( = 233), these parameters changed minimally relative to the baseline. Emergency room visits and hospital admissions were similar between groups. The number of health care provider visits and work days missed were higher in patients who started eculizumab after registry enrollment.

Conclusion: These real-world findings confirm the detrimental effects of aHUS on patients' daily lives, including high levels of fatigue and impairments in general health status. The results suggest clinically meaningful improvement in fatigue, other patient-reported outcomes, and symptoms with eculizumab initiation after enrollment into the aHUS registry.
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http://dx.doi.org/10.1016/j.ekir.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403628PMC
August 2020

Timing of patient-reported renal replacement therapy planning discussions by disease severity among children and young adults with chronic kidney disease.

Pediatr Nephrol 2020 10 3;35(10):1925-1933. Epub 2020 May 3.

Department of Pediatrics, Division of Nephrology, University of New Mexico Children's Hospital, Albuquerque, NM, USA.

Background: Preparing children with chronic kidney disease (CKD) for renal replacement therapy (RRT) begins with a discussion about transplant and dialysis, but its typical timing in the course of CKD management is unclear. We aimed to describe participant-reported RRT planning discussions by CKD stage, clinical and sociodemographic characteristics, in the Chronic Kidney Disease in Children (CKiD) cohort.

Methods: Participants responded to the question "In the past year, have you discussed renal replacement therapy with your doctor or healthcare provider?" at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measure logistic models estimated the proportion discussing RRT by stage, with modification by sex, age, race, socioeconomic status, and CKD diagnosis (glomerular vs. non-glomerular).

Results: A total of 721 CKiD participants (median age = 12, 62% boys) contributed 2856 person-visits. Proportions of person-visits reporting RRT discussions increased as CKD severity increased (10% at the lowest disease stage and 87% at the highest disease stage). After controlling for CKD risk stage, rates of RRT discussions did not differ by sex, age, race, and socioeconomic status.

Conclusions: Despite participant-reported RRT discussions being strongly associated with CKD severity, a substantial proportion with advanced CKD reported no discussion. While recall bias may lead to underreporting, it is still meaningful that some participants with severe CKD did not report or remember discussing RRT. Initiating RRT discussions early in the CKD course should be encouraged to foster comprehensive preparation and to align RRT selection for optimal health and patient preferences.
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http://dx.doi.org/10.1007/s00467-020-04542-2DOI Listing
October 2020

Nocturnal hypertension and left ventricular hypertrophy in pediatric renal transplant recipients in South India.

Pediatr Transplant 2020 06 22;24(4):e13710. Epub 2020 Apr 22.

Division of Pediatric Nephrology, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA.

HTN after renal transplantation is associated with cardiovascular morbidity. ABPM allows diagnosis of masked HTN and isolated nocturnal HTN. Longitudinal ABPM data in children post-transplant are limited. ABPM was performed in children post-transplant and repeated in 6-12 months. BP indices were used to determine the prevalence of masked HTN, masked uncontrolled HTN (masked HTN in patients on antihypertensive medications), and isolated nocturnal HTN. Linear regression determined the association between LVMI and ABPM indices. Thirty children underwent a baseline ABPM. Ambulatory HTN was present in 25 (83%). Masked HTN was present in 18 (60%) and isolated nocturnal HTN in 13 (43%). Nocturnal ambulatory BP was higher than corresponding daytime BPs (P < .001 for systolic and diastolic) and 25 (83%) had a blunted nocturnal dip. Prednisone dose predicted nocturnal DBP index and DBP load (r  = .40, P = .024 and r  = .178, P = .02). ABPM was repeated in 18 patients within 11 (±3) months. BP indices decreased with time, but nocturnal BPs remained higher than daytime (P < .001 for SBP and DBP). Blunted nocturnal dip did not improve. LVH was present in 12 (57%). LVMI was directly related to the nocturnal SBP index (r  = .377, P = .003) and nocturnal DBP index (r  = .493, P < .001). We found no association between LVMI and daytime BP indices. The prevalence of masked HTN, isolated nocturnal HTN, and blunted nocturnal dip was high in children with kidney transplants. Nocturnal BP predicted LVMI. Ambulatory BP improved on longitudinal follow-up, but the pattern of isolated nocturnal HTN persisted.
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http://dx.doi.org/10.1111/petr.13710DOI Listing
June 2020

Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome.

Kidney Int Rep 2020 Apr 5;5(4):414-425. Epub 2019 Dec 5.

Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.

Introduction: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome.

Methods: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time.

Results: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m per year ( < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression ( = 0.74;  < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m per year per log decrease in uEGF/Cr;  < 0.001).

Conclusion: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome.
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http://dx.doi.org/10.1016/j.ekir.2019.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136430PMC
April 2020

A dual efficacy-implementation trial of a novel mobile application for childhood nephrotic syndrome management: the UrApp for childhood nephrotic syndrome management pilot study protocol (UrApp pilot study).

BMC Nephrol 2020 04 9;21(1):125. Epub 2020 Apr 9.

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

Background: Idiopathic nephrotic syndrome has a relapsing-remitting course in the majority of pediatric patients, demanding vigilant monitoring and self-management. A novel, expert-designed, user-informed mobile application (app), UrApp©, was created to support management tasks, including home urine protein monitoring.

Methods: The UrApp Pilot Study (ClinicalTrials.gov, NCT04075656) is a randomized trial comparing UrApp-supported nephrotic syndrome management with standard-of-care with parallel process evaluation of the intervention delivery. Sixty caregivers of children with newly diagnosed, steroid-sensitive nephrotic syndrome will be randomized 1:1 to UrApp-supported care or standard-of-care. Follow-up will be 1 year, with primary outcomes of adherence to urine monitoring and medications assessed at 6 and 12 months. Secondary outcomes at 6 and 12 months include self-efficacy, quality-of-life, hospitalizations and delayed relapse diagnoses. A mixed-methods approach will evaluate UrApp engagement, use retention, features used, user perceptions, and contextual barriers and facilitators of UrApp use. User behavior will be assessed for relationships to the primary and secondary outcomes. A Stakeholder Committee of volunteer trial participants, clinicians, and engineers will examine the trial results and design a pragmatic UrApp-enhanced nephrotic syndrome intervention with potential for wide implementation. The final UrApp intervention will be tested in a user-centered hybrid effectiveness-implementation trial designed with stakeholder input.

Discussion: The UrApp Pilot Study examines the efficacy of a novel app designed specifically for nephrotic syndrome. The protocol involves dual efficacy and process evaluation aims to increase efficiency and incorporates the stakeholders' perspective in formative assessment to inform intervention redesign and the design of a future user-centered trial.

Trial Registration: ClinicalTrials.gov, NCT04075656. Registered on September 2, 2019, https://clinicaltrials.gov/ct2/show/NCT04075656.
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http://dx.doi.org/10.1186/s12882-020-01778-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146890PMC
April 2020

Sex and Glomerular Filtration Rate Trajectories in Children.

Clin J Am Soc Nephrol 2020 03 28;15(3):320-329. Epub 2020 Feb 28.

Department of Pediatric Nephrology, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France;

Background And Objectives: Differences in CKD progression by sex have been hypothesized to explain disparities in access to kidney transplantation in children. This study aims to identify distinct trajectories of eGFR decline and to investigate the association of sex with eGFR decline.

Design, Setting, Participants, & Measurements: We used data from the CKD in Children study. Latent class mixed models were used to identify eGFR trajectories and patient characteristics were compared between trajectories. Progression was studied to two outcomes: ESKD (dialysis or transplantation) and a combined outcome of ESKD or 50% eGFR decline from baseline, using multivariable parametric failure time models.

Results: Among 888 patients, 613 with nonglomerular and 275 with glomerular diseases, we observed four and two distinct GFR trajectories, respectively. Among patients with nonglomerular diseases, there was a higher proportion of males in the group with a low baseline GFR. This group had an increased risk of ESKD or 50% GFR decline, despite a similar absolute decline in GFR. Eight patients with nonglomerular diseases, mostly males with obstructive uropathies, had a more rapid absolute GFR decline. However, the association between male sex and rapid absolute GFR decline was NS after adjustment for age, baseline GFR, and proteinuria. Among patients with glomerular diseases, a subgroup including mostly females with systemic immunologic diseases or crescentic GN had a rapid absolute GFR decline.

Conclusions: This study identifies different trajectories of CKD progression in children and found a faster progression of CKD in females in patients with glomerular diseases, but no significant sex difference in patients with nonglomerular diseases. The differences in progression seem likely explained by sex differences in the underlying primary kidney disease and in baseline GFR rather than by a direct effect of sex on progression.
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http://dx.doi.org/10.2215/CJN.08420719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057295PMC
March 2020

Diagnosis, Treatment, and Outcomes in Children With Congenital Nephrogenic Diabetes Insipidus: A Pediatric Nephrology Research Consortium Study.

Front Pediatr 2019 21;7:550. Epub 2020 Jan 21.

Department of Nephrology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, United States.

Congenital or primary nephrogenic diabetes insipidus (NDI) is a rare genetic disorder that severely impairs renal concentrating ability, resulting in massive polyuria. There is limited information about prognosis or evidence guiding the management of these patients, either in the high-risk period after diagnosis, or long-term. We describe the clinical presentation, genetic etiology, treatment and renal outcomes in a large group of children <21 years with NDI. A multi-center retrospective chart review. We report on 66 subjects from 16 centers. They were mainly male (89%) and white (67%). Median age at diagnosis was 4.2 months interquartile range (IQR 1.1, 9.8). A desmopressin acetate loading test was administered to 46% of children at a median age of 4.8 months (IQR 2.8, 7.6); only 15% had a water restriction test. Genetic testing or a known family history was present in 70% of the patients; out of those genetically tested, 89 and 11% had mutations in and , respectively. No positive family history or genetic testing was available for 30%. The most common treatments were thiazide diuretics (74%), potassium-sparing diuretics (67%) and non-steroidal anti-inflammatory drugs (42%). At the time of first treatment, 70 and 71% of children were below -2 standard deviations (SD) for weight and height, respectively. At last follow-up, median age was 72.3 months (IQR 40.9, 137.2) and the percentage below -2 SD improved to 29% and 38% for weight and height, respectively. Adverse outcomes included inpatient hospitalizations (61%), urologic complications (37%), and chronic kidney disease (CKD) stage 2 or higher in 23%. We found the majority of patients were treated with thiazides with either a potassium sparing diuretic and/or NSAIDs. Hospitalizations, urologic complications, short stature, and CKD were common. Prospective trials to evaluate different treatment strategies are needed to attempt to improve outcomes.
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http://dx.doi.org/10.3389/fped.2019.00550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985429PMC
January 2020

Grip strength in children with chronic kidney disease.

Pediatr Nephrol 2020 05 13;35(5):891-899. Epub 2020 Jan 13.

Department of Pediatrics, Emory School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: The relationship between muscle strength and chronic kidney disease (CKD) in children is unknown. This study aims to quantify the association between grip strength (GS) and kidney function and to explore factors associated with grip strength in children and adolescents with CKD.

Methods: We included 411 children (699 GS assessments) of the Chronic Kidney Disease in Children (CKiD) study. They were matched by age, sex, and height to a healthy control from the National Health and Nutrition Examination Survey to quantify the relationship between GS and CKD. Linear mixed models were used to identify factors associated with GS among CKD patients.

Results: Median GS z-score was - 0.72 (IQR - 1.39, 0.11) among CKD patients with CKD stages 2 through 5 having significantly lower GS than CKD stage 1. Compared with healthy controls, CKiD participants had a decreased GS z-score (- 0.53 SD lower, 95% CI - 0.67 to - 0.39) independent of race/ethnicity and body mass index. Factors associated with reduced GS included longer duration of CKD, pre-pubertal status, delayed puberty, neuropsychiatric comorbidities, need of feeding support, need for alkali therapy, and hemoglobin level. Decreased GS was also associated with both a lower frequency and intensity of physical activity.

Conclusions: CKD is associated with impaired muscle strength in children independent of growth retardation and BMI. Exposure to CKD for a prolonged time is associated with impaired muscle strength. Potential mediators of the impact of CKD on muscle strength include growth retardation, acidosis, poor nutritional status, and low physical activity. Additional studies are needed to assess the efficacy of interventions targeted at these risk factors.
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http://dx.doi.org/10.1007/s00467-019-04461-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313477PMC
May 2020

Risk Behaviors in Teens with Chronic Kidney Disease: A Study from the Midwest Pediatric Nephrology Consortium.

Int J Nephrol 2019 4;2019:7828406. Epub 2019 Dec 4.

Department of Pediatrics, Wright State University, Dayton, OH, USA.

Introduction: There is a paucity of information about risk behaviors in adolescents with chronic kidney disease (CKD). We designed this study to assess the prevalence of risk behaviors among teens with CKD in the United States and to investigate any associations between risk behavior and patient or disease characteristics.

Methods: After informed consent, adolescents with CKD completed an anonymous, confidential, electronic web-based questionnaire to measure risk behaviors within five domains: sex, teen driving, alcohol and tobacco consumption, illicit drug use, and depression-related risk behavior. The reference group was composed of age-, gender-, and race-matched US high school students.

Results: When compared with controls, teens with CKD showed significantly lower prevalence of risk behaviors, except for similar use of alcohol or illicit substances during sex (22.5% vs. 20.8%, =0.71), feeling depressed for ≥2 weeks (24.3% vs. 29.1%, =0.07), and suicide attempt resulting in injury needing medical attention (36.4% vs. 32.5%, =0.78). Furthermore, the CKD group had low risk perception of cigarettes (28%), alcohol (34%), marijuana (50%), and illicit prescription drug (28%). Use of two or more substances was significantly associated with depression and suicidal attempts ( < 0.05) among teens with CKD.

Conclusions: Teens with CKD showed significantly lower prevalence of risk behaviors than controls. Certain patient characteristics were associated with increased risk behaviors among the CKD group. These data are somewhat reassuring, but children with CKD still need routine assessment of and counselling about risk behaviors.
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http://dx.doi.org/10.1155/2019/7828406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914908PMC
December 2019

Restless Legs Syndrome in Chronic Kidney Disease: Is Iron or Inflammatory Status To Blame?

J Clin Sleep Med 2019 11;15(11):1629-1634

Division of Pulmonology, Allergy, Cystic Fibrosis and Sleep Medicine, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia.

Study Objectives: Restless legs syndrome (RLS) is increased in pediatric chronic kidney disease (CKD). In adults without CKD, central nervous system iron deficiency is involved in RLS pathogenesis and a low serum ferritin levels is consequently an indication for initiation of iron therapy. However, children with CKD are at risk for iron deficiency and inflammation, which raises serum ferritin. We examined the role of iron deficiency and inflammation in RLS in pediatric CKD.

Methods: This cross-sectional study examined RLS prevalence in three groups of pediatric patients with CKD: nontransplant, nondialysis CKD (estimated GFR < 60 mL/min/1.73 m²) (n = 27); renal transplant recipients (n = 65); and dialysis (n = 32). RLS was diagnosed using a validated questionnaire. Serum ferritin < 100 ng/mL or transferrin saturation < 20% defined iron deficiency. Serum high sensitivity C-reactive protein ≥ 1 mg/L defined inflammation.

Results: Among 124 patients, RLS prevalence was 15.3%; this did not differ across groups. There was no significant difference in RLS prevalence between those with and without iron deficiency, defined by either reduced ferritin or transferrin. Median ferritin levels in patients with RLS tended to be higher than in those without RLS (51.2 versus 40.1 ng/mL; P = .08). Inflammation (elevated CRP) also did not differ significantly by RLS status (57.9% [with RLS] versus 41.2% [without RLS], P = .18).

Conclusions: Neither ferritin nor inflammation differentiated pediatric patients with CKD with and without RLS. This study suggests that the factors mediating the pathogenesis and, potentially, treatment, of RLS in pediatric CKD may be different from non-CKD populations.
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http://dx.doi.org/10.5664/jcsm.8028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853406PMC
November 2019

Text Messaging for Disease Monitoring in Childhood Nephrotic Syndrome.

Kidney Int Rep 2019 Aug 7;4(8):1066-1074. Epub 2019 May 7.

Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.

Introduction: There is limited information on effective disease monitoring for prompt interventions in childhood nephrotic syndrome. We examined the feasibility and effectiveness of a novel text messaging system (SMS) for disease monitoring in a multicenter, prospective study.

Methods: A total of 127 patients <19 years with incident nephrotic syndrome were enrolled in the ongoing Nephrotic Syndrome Study Network between June 2015 and March 2018. Text messages soliciting home urine protein results, symptoms, and medication adherence were sent to a designated caregiver ( = 116) or adolescent patient ( = 3). Participants responded by texting. Feasibility of SMS was assessed by SMS adoption, retention, and engagement, and concordance between participant-reported results and laboratory/clinician assessments. The number of disease relapses and time-to-remission data captured by SMS were compared with data collected by conventional visits.

Results: A total of 119 of 127 (94%) patients agreed to SMS monitoring. Retention rate was 94%, with a median follow-up of 360 days (interquartile range [IQR] 353-362). Overall engagement was high, with a median response rate of 87% (IQR, 68-97). Concordance between SMS-captured home urine protein results and edema status with same-day in-person study visit was excellent (kappa values 0.88 and 0.92, respectively). SMS detected a total of 108 relapse events compared with 41 events captured by scheduled visits. Median time to remission after enrollment was 22 days as captured by SMS versus 50 days as captured by scheduled visits.

Conclusion: SMS was well accepted by caregivers and adolescent patients and reliably captured nephrotic syndrome disease activity between clinic visits. Additional studies are needed to explore the impact of SMS on disease outcomes.
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http://dx.doi.org/10.1016/j.ekir.2019.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698307PMC
August 2019

Development of a novel mobile application to detect urine protein for nephrotic syndrome disease monitoring.

BMC Med Inform Decis Mak 2019 05 30;19(1):105. Epub 2019 May 30.

Division of Pediatric Nephrology, Emory University, 2015 Uppergate Drive NE, Atlanta, GA, 30322-1015, USA.

Background: Home monitoring of urine protein is a critical component of disease management in childhood nephrotic syndrome. We describe the development of a novel mobile application, UrApp - Nephrotic Syndrome Manager, to aid disease monitoring.

Methods: UrApp was iteratively developed by a panel of two pediatric nephrologists and three research engineers from May 2017 to October 2018 for Apple iPhones. App features were devised by this expert panel to support urine monitoring and other home care tasks. Each feature and user-app interface element was systematically reviewed by the panel and iteratively redesigned to remove anticipated use issues. The app prototype was then refined based on two rounds of usability testing and semi-structured user interviews with a total of 20 caregivers and adolescent patients. The analytic function of UrApp in providing a camera read of the urine test strip was compared to a standard urinalysis machine using 88 patient urine samples and three iPhones, model versions 6S and 7. Exact agreement and weighted kappa were calculated between the UrApp and urinalysis machine reads.

Results: The final UrApp features include: camera read of a urine test strip; analysis of urine protein trends and alerts for new disease relapse/remission; transmission of urine protein results to providers; education materials; and medication reminders. During the second round of UrApp usability testing, all users were able to perform each of the functions without error and all perceived UrApp to be helpful and indicated that they would use UrApp. UrApp camera results had 97% exact agreement and an overall weighted kappa value of 0.91 (95% CI, 0.85-0.97) compared with standard urinalysis machine interpretation.

Conclusions: UrApp was specifically designed to support patients and families living with nephrotic syndrome by supporting disease monitoring and home management tasks. The technically innovative feature that makes this possible is the use of a smartphone camera to read the urine test strip. This novel tool has the potential to improve disease monitoring and reduce management burden.
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http://dx.doi.org/10.1186/s12911-019-0822-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543567PMC
May 2019

Renal allograft loss due to renal vascular thrombosis in the US pediatric renal transplantation.

Pediatr Nephrol 2019 09 26;34(9):1545-1555. Epub 2019 May 26.

Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.

Background: Renal vascular thrombosis (RVT) is a major cause of early allograft loss in the first year following pediatric kidney transplantation. We examined recent trends in allograft loss due to RVT and identified associated risk factors.

Methods: We identified 14,640 kidney-only transplants performed between 1995 and 2014 with follow-up until June 30, 2016, in 13,758 pediatric patients aged < 19 years from the US Renal Data System. We examined the 1-year incidence of allograft loss due to RVT by year of transplant, and plotted the trend over time. Cox proportional hazards models were used to investigate the relationship between year of transplant as well as recipient, donor, and transplant characteristics with allograft loss due to RVT.

Results: The incidence of allograft loss due to RVT consistently declined among pediatric kidney transplant performed between 1995 and 2014. Among transplants performed between 1995 and 2004, 128/7542 (1.7%) allografts were lost due to RVT compared to 53/7098 (0.8%) among transplants performed between 2005 and 2014; average 1-year cumulative incidence was 1.5% (95% CI, 1.3-1.9%) and 0.6% (95% CI, 0.5-0.8%), respectively. Increased risk for allograft loss due to RVT was associated with en bloc kidney transplantation (HR, 3.42; 95% CI 1.38-8.43) and cold ischemia time ≥ 12 h (HR, 1.78; 95% CI, 1.15-2.76). Interestingly, these risk factors were more prevalent in the latter decade.

Conclusions: The incidence of allograft loss due to RVT significantly and continuously declined among pediatric kidney transplants performed between 1995 and 2014. The causes for this improvement are unclear in the present analysis.
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http://dx.doi.org/10.1007/s00467-019-04264-0DOI Listing
September 2019

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study.

Clin Kidney J 2019 Apr 16;12(2):196-205. Epub 2018 May 16.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Methods: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated.

Results: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment.

Conclusions: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.
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http://dx.doi.org/10.1093/ckj/sfy035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452204PMC
April 2019

Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study.

BMC Nephrol 2019 04 10;20(1):125. Epub 2019 Apr 10.

Division of Pediatric Nephrology, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Drive NE, Atlanta, GA, 30322, USA.

Background: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab.

Methods: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events.

Results: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported.

Conclusions: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes.

Trial Registration: ClinicalTrials.gov NCT01522170 , January 31, 2012.
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http://dx.doi.org/10.1186/s12882-019-1314-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456946PMC
April 2019

Association between BMI changes and mortality risk in children with end-stage renal disease.

Pediatr Nephrol 2019 09 8;34(9):1557-1563. Epub 2019 Apr 8.

Department of Pediatrics, Division of Pediatric Nephrology, University of California San Francisco, San Francisco, CA, USA.

Background: Few studies have examined how changes in BMI [body mass index] over time associate with risk of adverse outcomes in children receiving renal replacement therapy [RRT]. The objective of this study was to examine the association between annualized changes in BMI and the risk of death in children treated with RRT.

Methods: We performed a retrospective cohort study of 1182 pediatric dialysis and transplant patients in the Pediatric Growth and Development Special Study of the United States Renal Data System. Quintiles of annualized change in BMI z-score (with cutoffs of - 0.50, - 0.13, 0.09, 0.57) were used as the primary predictor, with the middle quintile (- 0.13 to 0.09) serving as the reference category. Cox models were used to examine the association between exposure and death, with time of analysis starting from the second BMI measurement.

Results: Median follow-up time to death or censoring was 6 years. Median age was 14.6 years, and 61% of children had a functional graft at cohort entry. There was a U-shaped association between BMI change and mortality risk: a large decline in annualized BMI z-score change (> - 0.50) was associated with an increased risk of death (adjusted hazard ratio [aHR] 1.54 (95% CI 1.17-2.03), p = 0.002). A large increase in annualized BMI z-score change (> 0.57) was also associated with an increased risk of death (aHR 1.44 (95% CI 1.07-1.92), p = 0.02). No interaction was noted between annualized BMI change and initial treatment modality (dialysis or transplant, p = 0.15).

Conclusions: Maintenance of a stable BMI in pediatric patients receiving RRT may be associated with improved survival.
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http://dx.doi.org/10.1007/s00467-019-04249-zDOI Listing
September 2019

Kidney biopsy findings in children with sickle cell disease: a Midwest Pediatric Nephrology Consortium study.

Pediatr Nephrol 2019 08 3;34(8):1435-1445. Epub 2019 Apr 3.

Department of Pediatrics, Division of Nephrology, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: Renal damage is a progressive complication of sickle cell disease (SCD). Microalbuminuria is common in children with SCD, while a smaller number of children have more severe renal manifestations necessitating kidney biopsy. There is limited information on renal biopsy findings in children with SCD and subsequent management and outcome.

Methods: This is a multicenter retrospective analysis of renal biopsy findings and clinical outcomes in children and adolescents with SCD. We included children and adolescents (age ≤ 20 years) with SCD who had a kidney biopsy performed at a pediatric nephrology unit. The clinical indication for biopsy, biopsy findings, subsequent treatments, and outcomes were analyzed.

Results: Thirty-six SCD patients (ages 4-19 years) were identified from 14 centers with a median follow-up of 2.6 years (0.4-10.4 years). The indications for biopsy were proteinuria (92%) and elevated creatinine (30%). All biopsies had abnormal findings, including mesangial hypercellularity (75%), focal segmental glomerulosclerosis (30%), membranoproliferative glomerulonephritis (16%), and thrombotic microangiopathy (2%). There was increased use of hydroxyurea, angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers following renal biopsy. At last follow-up, 3 patients were deceased, 2 developed insulin-dependent diabetes mellitus, 6 initiated chronic hemodialysis, 1 received a bone marrow transplant, and 1 received a kidney transplant.

Conclusions: Renal biopsies, while not commonly performed in children with SCD, were universally abnormal. Outcomes were poor in this cohort of patients despite a variety of post-biopsy interventions. Effective early intervention to prevent chronic kidney disease (CKD) is needed to reduce morbidity and mortality in children with SCD.
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http://dx.doi.org/10.1007/s00467-019-04237-3DOI Listing
August 2019