Dataset Information

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

ABSTRACT: Background:Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. Methods:This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). Results:Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year). Conclusions:Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.

SUBMITTER: Ng DK

PROVIDER: S-EPMC5837652 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

Ng Derek K DK Robertson Catherine C CC Woroniecki Robert P RP Limou Sophie S Gillies Christopher E CE Reidy Kimberly J KJ Winkler Cheryl A CA Hingorani Sangeeta S Gibson Keisha L KL Hjorten Rebecca R Sethna Christine B CB Kopp Jeffrey B JB Moxey-Mims Marva M Furth Susan L SL Warady Bradley A BA Kretzler Matthias M Sedor John R JR Kaskel Frederick J FJ Sampson Matthew G MG

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20170601 6

<h4>Background</h4>Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known.<h4>Methods</h4>This study characterized 104 African-American childr ...[more]

PMID: 27190333

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Project description:BackgroundFew studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression.Study designProspective multicenter observational cohort study.Setting & participants496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study.PredictorsProteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia.OutcomesParametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR).Results398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow-ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally.LimitationsSmall number of events in glomerular patients and use of internal cross-validation.ConclusionsCharacterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD.

Project description:BackgroundTwo genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups. Yet, the majority of individuals with two APOL1 risk alleles [high-risk (HR) genotype] do not have renal disease. It is critical to identify environmental and secondary genetic influences that, when combined with these alleles, lead to kidney disease. In a recent study of black children with glomerular disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children Study (n = 104), we found that subjects with an HR genotype had a 4.6-fold increase in the odds of preterm birth as compared to those with a low risk (LR) genotype [odds ratio 4.6 (CI 1.4-15.5)]. There are known racial disparities in preterm birth, which itself is a known risk factor for chronic kidney disease and focal segmental glomerulosclerosis. Thus, we questioned whether an HR APOL1 genotype is associated with prematurity in the general African American population.MethodsWe analyzed two publically available genetic datasets of preterm birth in African Americans, including 867 infants and 519 mothers from the Gene Environment Association Studies (GENEVA) study of preterm delivery and 960 mothers from the Boston Medical Center genome-wide association study of preterm birth. We performed multivariable analyses testing for association between HR APOL1 and birth outcomes.ResultsIn both studies, there was no association between HR APOL1 in mothers and prematurity, gestational age or birthweight. Additionally, in the GENEVA study, we saw no association between infant HR APOL1 and prematurity, gestational age or birthweight.ConclusionFrom these data, we conclude that the previously observed association between HR APOL1 and prematurity is specific to those with glomerular disease, suggesting prematurity may act as an additional risk factor in APOL1-associated renal disease.

Project description:Rationale & objectiveTo identify differences in socioeconomic factors (SES) and subclinical cardiovascular disease (CVD) markers by race among Chronic Kidney Disease in Children (CKiD) participants and determine whether differences in CVD markers persist after adjusting for SES.Study designAnalysis of 3,103 visits with repeated measures from 628 children (497 White participants; 131 African American participants) enrolled in the CKiD study.Setting & participantsChildren with mild-moderate CKD with at least 1 cardiovascular (CV) parameter (ambulatory blood pressure, left ventricular mass index [LVMI], or lipid profile) measured.ExposureAfrican American race.OutcomesAmbulatory hypertension, LVMI, triglycerides, high-density lipoprotein cholesterol.Analytical approachDue to increased CV risks of glomerular disease, the analysis was stratified by CKD cause. Inverse probability weighting was used to adjust for SES (health insurance, household income, maternal education, food insecurity, abnormal birth history). Linear and logistic regression were used to evaluate association of race with CV markers.ResultsAfrican American children were disproportionately affected by adverse SES. African Americans with nonglomerular CKD had more instances of ambulatory hypertension and higher LVMI but more favorable lipid profiles. After adjustment for SES, age, and sex, the magnitude of differences in these CV markers was attenuated but remained statistically significant. Only LVMI differed by race in the glomerular CKD group, despite adjustment for SES.LimitationsStudy design limits causal inference.ConclusionAfrican American children with CKD are disproportionately affected by socioeconomic disadvantages compared with White children. The degree to which CV markers differ by race is influenced by disease etiology. African Americans with nonglomerular CKD have increased LVMI, more ambulatory hypertension, and favorable lipid profile, but attenuation in magnitude after adjustment for SES was observed. African Americans with glomerular CKD had increased LVMI, which persisted after SES adjustment. As many social determinants of health were not captured, future research should examine effects of systemic racism on CV health in this population.

Dataset Information

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

Publications

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

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