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The Longitudinal Effect of APOL1 Risk Alleles on Sickle Cell Anemia-Associated Kidney Function
Sara R Rashkin1, Guolian Kang2, Clifford M Takemoto1
1Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Insights
APOL1 risk variants accelerate kidney function decline in sickle cell anemia (SCA) patients after age 10. Early genetic risk assessment and kidney monitoring are crucial for managing SCA-related kidney disease.
Area of Science:
- Nephrology
- Genetics
- Hematology
Background:
- Sickle cell anemia (SCA) is a leading cause of kidney disease, morbidity, and mortality.
- APOL1 G1/G2 risk variants are associated with kidney disease in individuals of African ancestry.
- Longitudinal effects of APOL1 variants in pediatric and young adult SCA patients are understudied.
Purpose of the Study:
- To investigate the association between APOL1 risk variants and kidney function trajectory in young individuals with SCA.
- To determine if APOL1 variants influence the rate of estimated glomerular filtration rate (eGFR) decline over time.
- To identify early indicators of accelerated kidney injury in SCA patients.
Main Methods:
- Analysis of 494 individuals (ages 1-25) from the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort.
- Longitudinal assessment of kidney function, including eGFR and hyperfiltration.
- Statistical modeling to evaluate the association of APOL1 G1/G2 alleles with kidney function parameters before and after age 10.
Main Results:
- Before age 10, APOL1 G1/G2 alleles showed no significant association with CKD, hyperfiltration, or eGFR.
- After age 10, APOL1 G1/G2 variants were linked to higher baseline eGFR, a steeper eGFR decline, and increased odds of accelerated eGFR loss.
- Individuals with hyperfiltration before age 10 or APOL1 risk alleles had a significantly higher risk of accelerated eGFR decline.
Conclusions:
- APOL1 risk variants significantly impact kidney function decline in SCA patients, particularly after age 10.
- Early identification of APOL1 risk alleles and renal surveillance can help predict and manage progressive kidney injury in SCA.
- Genetic risk stratification may improve outcomes for SCA patients at risk of chronic kidney disease.
Abstract:
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 (βAPOL1 = 0.098; PAPOL1 = 0.016), a steeper downward slope of eGFR over time (βAPOL1xAge = -0.014; PAPOL1xAge = 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.
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