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.

Keywords: APOL1; FSGS; epidemiology; nephrotic syndrome; pediatrics.

FIGURE 1

Cascade plot describing age at disease onset (orange line), study entry (black dot) and time under study observation (black line). Each line represents one child, with the orange line displaying the age at disease onset to study entry, represented by a black point. Children with an FSGS diagnosis are represented by the solid line; children with non-FSGS diagnoses are represented by the discontinuous lines. The time under study observation is represented by the black line to the last study visit date. The median age at disease onset for each group is represented by the black diamond and corresponds to data presented in Table 2. CKiD, Chronic Kidney Disease in Children; NEPTUNE, Nephrotic Syndrome Study Network; LR, low risk; HR, high risk; FSGS, focal segmental glomerulosclerosis.

FIGURE 2

Graphical depiction of eGFR level at study entry (x-axis) and percent change per year (y-axis) by study and APOL1 risk status from linear mixed effects model (random intercepts and slopes). The black circles represent the point estimates with bars corresponding to the associated 95% confidence intervals. CKiD, Chronic Kidney Disease in Children; NEPTUNE, Nephrotic Syndrome Study Network; LR, low risk; HR, high risk; APOL1, apolipoprotein L1; eGFR, estimated glomerular filtration rate.