Effects of Apolipoprotein L1 Mutation G1 and G2 on Renal Outcomes in Pediatrics Patients with Sickle Cell Disease

Background

Sickle Cell Disease (SCD) is an inherited hemoglobinopathy caused by a β-globin mutation resulting in hemoglobin S (HbS), which polymerizes under low oxygen conditions, and leads to red blood cell sickling, hemolysis, anemia and vaso-occlusion. A common and serious complication of SCD is sickle cell nephropathy (SCN); driven by recurrent sickling within the renal microcirculation, chronic medullary hypoxia, ischemia leading to tubular dysfunction and papillary necrosis. Over time, SCN may progress to CKD, chronic kidney disease, often characterized by glomerular hyperfiltration and albuminuria. Variants in the apolipoprotein L1 (APOL1) gene, specifically G1 and G2 risk alleles, are known to increase susceptibility to CKD and may further modify renal risk in patients with SCD.

Methods

This retrospective study evaluated whether pediatric patients with SCD who carry APOL1 G1 and/or G2 risk variants develop SCN at an earlier age or demonstrate worse renal outcomes compared with those without these variants. The study also examined whether APOL1 risk status modifies the renal effects of disease-modifying therapies, including hydroxyurea and chronic transfusion therapy. Data was collected from 148 pediatric and young adult patients with SCD (ages 3-24) followed at St. Christopher’s Children’s Hospital in Philadelphia, Pennsylvania. The cohort included 85 female patients and 63 male patients, with 119 patients identifying as African American. Clinical data included routine vital signs, laboratory studies, including glomerular filtration rate (eGFR), as well as APOL1 genotyping categorized as no risk (wild-type), heterozygous (low risk), or homozygous (high risk). Treatment exposure was categorized as hydroxyurea, chronic transfusion therapy , or neither.

Results

Mean GFR was compared across APOL1 risk groups using analysis of variance (ANOVA). No statistically significant differences in mean eGFR were observed between APOL1 risk categories (p = 0.767), a finding that contrasts with prior reports suggesting increased renal risk associated with APOL1 variants. Analysis of covariance (ACNOVA) was subsequently performed to evaluate potential interactions between APOL 1 risk status and treatment modality (hydroxyurea or chronic transfusion therapy). No significant modifying effect of APOL1 variants on treatment-associated renal outcome was identified (all p-values>0.05)

Conclusions

In a single-center retrospective cohort, APOL1 G1 and G2 risk variants were not associated with differences in renal function as measured by eGFR, nor did they appear to modify the renal effects of hydroxyurea or chronic transfusion therapy. This negative findings may reflect small sample size, heterogeneity in age and disease severity, and relatively short follow-up. Larger, longitudinal studies are needed to better define the role of APOL1 risk alleles in the development and progression of sickle cell nephropathy. Improved understanding of APOL1-associated renal risk may ultimately support earlier identification of high-risk patients and enable more individualized strategies for renal surveillance and prevention in SCD.

APOL 1 eGFR by Risk Level

eGFR vs Risk Level for Patients treated with Chronic Transfusions

eGFR vs Risk Level for Patients treated with Hydroxyurea