The Longitudinal Effect of <scp> <i>APOL1</i> </scp> Risk Alleles on Sickle Cell Anemia‐Associated Kidney Function

Progressive kidney injury is a major cause of morbidity and mortality in sickle cell anemia (SCA). The high risk APOL1 G1/G2 variants contribute to the development of kidney disease in individuals of African ancestry, including those with SCA. However, few studies have evaluated the longitudinal effect of APOL1 variants in children and young adults. We analyzed the association of APOL1 risk variants with kidney function in 494 individuals aged 1 to 25 in the Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study (clinicaltrials.gov #NCT02098863). Before age 10, APOL1 G1/G2 alleles were not associated with time to CKD (hazard ratio [HR] = 1.87; p = 0.14), hyperfiltration (HR = 0.96; p = 0.88), or continuous eGFR (β = -0.0090; p = 0.71). However, after age 10, APOL1 G1/G2 variants were associated with higher baseline eGFR (β_APOL1 = 0.098; P_APOL1 = 0.016), a steeper downward slope of eGFR over time (β_APOL1xAge = -0.014; P_APOL1xAge = 1.60 × 10^-10), and increased odds of having an accelerated rate of eGFR decline (individual-specific eGFR slopes in the most negative tertile; odds ratio [OR] = 2.18; p = 0.040). Among 111 individuals with measurements before and after 10 years of age, those with hyperfiltration before age 10 or APOL1 risk alleles were at increased risk of having an accelerated rate of eGFR decline (OR = 2.96; p = 0.019). These findings support the hypothesis that genetic risk stratification and early renal surveillance can help identify patients most at risk for the progression of kidney injury. Trial Registration: Clinicaltrials.gov #NCT02098863.