Susan F. Massengill

Management of Childhood Onset Nephrotic Syndrome

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Childrens Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a childrens primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

Self-Management and Transition Readiness Assessment: Development, Reliability, and Factor Structure of the STARx Questionnaire

INTRODUCTION The Self-Management and Transition to Adulthood with Rx=Treatment (STARx) Questionnaire was developed to collect information on self-management and health care transition (HCT) skills, via self-report, in a broad population of adolescents and young adults (AYAs) with chronic conditions. METHODS Over several iterations, the STARx questionnaire was created with AYA, family, and health provider input. The development and pilot testing of the STARx Questionnaire took place with the assistance of 1219 AYAs with different chronic health conditions, in multiple institutions and settings over three phases: item development, pilot testing, reliability and factor structuring. RESULTS The three development phases resulted in a final version of the STARx Questionnaire. The exploratory factor analysis of the third version of the 18-item STARx identified six factors that accounted for about 65% of the variance: Medication management, Provider communication, Engagement during appointments, Disease knowledge, Adult health responsibilities, and Resource utilization. Reliability estimates revealed good internal consistency and temporal stability, with the alpha coefficient for the overall scale being .80. The STARx was developmentally sensitive, with older patients scoring significantly higher on nearly every factor than younger patients. CONCLUSION The STARx Questionnaire is a reliable, self-report tool with adequate internal consistency, temporal stability, and a strong, multidimensional factor structure. It provides another assessment strategy to measure self-management and transition skills in AYAs with chronic conditions.

Progression of Pediatric CKD of Nonglomerular Origin in the CKiD Cohort

BACKGROUND AND OBJECTIVES Congenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Urine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study. RESULTS A total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m(2) (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m(2) per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m(2) per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m(2) per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria. CONCLUSIONS Baseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.

Self-Management and Transition Readiness Assessment: Concurrent, Predictive and Discriminant Validation of the STARx Questionnaire

INTRODUCTION The STARx Questionnaire was designed with patient and provider input, to measure self-management and transition skills in adolescents and young adults (AYA) with chronic health conditions. With proven reliability and an empirically-based factor structure, the self-report STARx Questionnaire requires further validation to demonstrate its clinical and research utility. In this study we examine the concurrent, predictive, and discriminant validity of the STARx Questionnaire. METHODS To examine concurrent validity, the STARx Questionnaire was compared to two other published transition readiness tools. Predictive validity was examined using linear regressions between the STARx Total Score and literacy, medication adherence, quality of life, and health services use. Discriminant validity was examined by comparing the performance of three chronic illness conditions on the STARx Total Score and associated subscales. RESULTS The STARx Questionnaire and its subscales positively correlated with the scores for both transition readiness tools reflecting strong concurrent validity. The STARx Questionnaire also correlated positively with the literacy, self-efficacy, and adherence measures indicating strong predictive validity; however, it did not correlate with either quality of life or health care utilization. The performance of AYA across three different clinical conditions was not significant, indicating the clinical utility of this HCT tool for a variety of chronic health conditions. CONCLUSION The strong validity of the STARx Questionnaire, in tandem with its strong reliability, indicated adequate psychometric properties for this generic self-report measure. These strong psychometric properties should contribute to the STARx being a viable measure of health care transition for both research and clinical purposes.

Antiphospholipid antibodies in pediatric lupus nephritis

Antiphospholipid antibodies (aPL) of various isotypes are known to occur in systemic lupus erythematosus (SLE), but the significance of this finding in the pediatric population remains unclear. Our aim was to determine whether children with lupus nephritis have an increased risk of thrombosis and whether antiphosphatidylserine (APS) or antiphosphatidylinositol (API) antibodies were predictive of thrombotic complications. Thirty-six children (27 girls/9 boys; 44% black) with SLE nephritis (WHO II, 1; WHO III, 7; WHO IV, 21; WHO V, 7) were evaluated for antiphosphatidylserine, antiphosphatidylinositol, and anticardiolipin immunoglobulin (Ig) G and IgM isotypes, using a modified solid-phase enzyme-linked immunoassay (ELISA). Twenty-four patients (67%) had at least one positive aPL. Longitudinal data on 26 patients showed fluctuations in the degree of positivity. Eight patients experienced thrombotic complications, with equal distribution between arterial and venous events. Other clinical manifestations included thrombocytopenia in seven patients (19%), hemolytic anemia (44%), lupus anticoagulant (6%) and false-positive Venereal Disease Research Laboratory (VDRL) test results (11%). Comparisons between those with and without a thrombotic event showed no detectable difference in the incidence of aPL positivity between the two groups. We conclude that neither APS, API, nor anticardiolipin (ACL) activity was predictive of thrombotic complications in our subset of patients with lupus nephritis.

Infantile systemic lupus erythematosus with onset simulating congenital nephrotic syndrome

Abstract Two white female infants were seen with congenital nephrotic syndrome at age 6 weeks and 3 months, respectively. Both had hypocomplementemia, elevated antinuclear antibody and anti-double-stranded DNA titers, and diffuse proliferative glomerulonephritis with positive immunofluorescence in their initial renal biopsy samples. Although uncommon, infantile systemic lupus erythematosus should be considered in the evaluation of congenital nephrotic syndrome. (J P EDIATR 1994;124:27-31)

Medication Treatment Complexity and Adherence in Children with CKD

BACKGROUND AND OBJECTIVES The complexity of CKD management in children is increased by the number of comorbid conditions. This study assessed the prevalence of comorbidities in pediatric CKD and the frequency with which multiple comorbidities present together by assessing prevalent medication use by CKD stage and diagnosis and their association with clinical or sociodemographic factors. The association between number and frequency of dosing of medications prescribed and self-report of nonadherence was also assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this cross-sectional analysis of the Chronic Kidney Disease in Children study, medication use at study entry grouped by indication was examined by CKD stage, diagnosis, age, race, ethnicity, income, and CKD duration. Multivariate adjusted predictors of medication use and clustering were examined. Nonadherence was assessed by self-report of missed medications in the past 7 days. RESULTS The 558 eligible participants had a median age of 11 years and median GFR of 44 ml/min per 1.73 m(2); 62% of participants were male and 78% had nonglomerular kidney disease. The number of medications for treatment of CKD comorbidities increased with advanced CKD stage (2.5-fold for stages IV versus II; P<0.001) and glomerular disease (1.4-fold versus nonglomerular; P<0.001). Three distinct medication clusters were identified that corresponded to treatment of glomerular disease, advanced renal tubular dysfunction, and proteinuric complications, respectively. Nonadherence was associated with increased medication dosing frequency (administration >2 times/d; P<0.001) but not the number of medications. CONCLUSIONS Medical therapy for children with CKD is complex and is affected by glomerular diagnosis, CKD stage, and medication frequency. The need for CKD-related medication treatment cannot be easily predicted by CKD staging alone. Poorer adherence was associated with increased medication frequency, but not with the number of medical problems needing treatment. Consolidating medical treatment and reducing medication frequency may improve adherence rates in children with CKD.

Chronic Kidney Disease in Children and Adolescents

1. Susan F. Massengill, MD* 2. Maria Ferris, MD, MPH, PhD† 1. *Director, Pediatric Nephrology, Levine Children’s Hospital, Adjunct Associate Professor of Pediatrics, University of North Carolina School of Medicine, Charlotte, NC. 2. †Director, Pediatric Dialysis and Transplant Programs, UNC Kidney Center, Founder and Director, The UNC Children’s Hospital TRxANSITION Program, University of North Carolina at Chapel Hill, Chapel Hill, NC. * Abbreviations: 1,25(OH)2 D: : 1,25-dihydroxyvitamin D ACE: : angiotensin-converting enzyme CKD: : chronic kidney disease CKiD: : Chronic Kidney Disease in Children CVD: : cardiovascular disease eGFR: : estimated glomerular filtration rate ESKD: : end-stage kidney disease GFR: : glomerular filtration rate HCT: : health care transition MBD: : metabolic bone disease Chronic kidney disease (CKD) is a devastating diagnosis with many co-morbidities, increasing the risk of mortality 30 to 150 times that of the general pediatric population. Recognition of at-risk children can lead to earlier screening and risk reduction. Primary care clinicians are often unaware of the comorbid conditions and long-term consequences of CKD, particularly with respect to cardiovascular disease, nutrition and growth, neurocognitive development, and burden of disease. After completing this article, readers should be able to: 1. Be aware of the life course of CKD and its co-morbidities. 2. Recall the risk factors and complications of pediatric CKD. 3. Discuss measures to prevent or delay the progression of pediatric CKD. 4. Optimize the communication between the primary care clinician and nephrologist in treating children, adolescents, and young adults with CKD. A 13-month-old toddler new to your practice presents for his 1-year health maintenance visit with poor growth and developmental delay. He is just now sitting without support and appears to have occasional leg pain. He is pale, weighs 7.9 kg, and has a normal blood pressure. The results of laboratory studies are remarkable for anemia (hemoglobin, 9 g/dL [90 g/L]), profound acidosis (carbon dioxide, 12 mEq/L [12 mmol/L]), azotemia (urea nitrogen, 117 mg/dL [41.8 mmol/L]; creatinine, 2.44 mg/dL [216 μmol/L]), and profound hypocalcemia (calcium, 5.6 mg/dL [1.40 mmol/L]), prompting further evaluation where hypocalcemia was confirmed. Urinalysis revealed a specific gravity of 1.005 and proteinuria (1+). Renal ultrasonography revealed bilateral renal hypoplasia. Renal replacement therapy was initiated with peritoneal dialysis, and the patient is on the renal transplantation waiting list. A previously healthy, 14-year-old, African American girl presents with a 3-month history of facial …

Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD

Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of β-oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD. Among participants, 110 were men (51.4%), 64 were black (29.9%), and 150 were white (70.1%), and the mean (SD) age was 60 (16) years old. We measured plasma lipids and acylcarnitines using liquid chromatography-mass spectrometry. Overall, we identified 330 different lipids across 17 different classes. Compared with earlier stages, stage 5 CKD associated with a higher abundance of saturated C16-C20 free fatty acids (FFAs) and long polyunsaturated complex lipids. Long-chain-to-intermediate-chain acylcarnitine ratio, a marker of efficiency of β-oxidation, exhibited a graded decrease from stage 2 to 5 CKD (P<0.001). Additionally, multiple linear regression revealed that the long-chain-to-intermediate-chain acylcarnitine ratio inversely associated with polyunsaturated long complex lipid subclasses and the C16-C20 FFAs but directly associated with short complex lipids with fewer double bonds. We conclude that increased abundance of saturated C16-C20 FFAs coupled with impaired β-oxidation of FFAs and inverse partitioning into complex lipids may be mechanisms underpinning lipid metabolism changes that typify advancing CKD.

Depressive Symptoms in Children with Chronic Kidney Disease

OBJECTIVE To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL). STUDY DESIGN Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Childrens Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy. RESULTS A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P < .05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate. CONCLUSION Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease.