Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression

Abstract

Background and objectives: Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications.

Design, setting, participants, & measurements: Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD).

Results: Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m(2), and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index ≥ 30 versus <30 kg/m(2); P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen ≥ 8 versus <8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction >0.05 for each).

Conclusions: Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.

Keywords: 25-hydroxyvitamin D2; AASK (African American Study of Kidney Disease and Hypertension); African Americans; apolipoprotein L1; blood pressure; body mass index; chronic; chronic kidney disease; fibroblast growth factor 23; genotype kidney failure; hypertension.

Figure 1.

Forest plot of the hazard for CKD progression (doubling of serum creatinine or ESRD) comparing APOL1 high– versus low–risk status stratified by sociodemographic and clinical factors. Models adjusted for age, sex, percentage of European ancestry, and baseline I¹²⁵ iothalamate GFR (iGFR). BMI, body mass index; 95% CI, 95% confidence interval; SBP, systolic BP.

Figure 2.

Forest plot of the hazard for CKD progression (doubling of serum creatinine or ESRD) comparing APOL1 high– versus low–risk status stratified by laboratory factors. Models adjusted for age, sex, percentage of European ancestry, and baseline I¹²⁵ iothalamate GFR (iGFR). ca-phos, calcium-phosphate; chol, cholesterol; 95% CI, 95% confidence interval; Hct, hematocrit; NEAP, net endogenous acid production; Phos, serum phosphorus; Urine Na⁺, 24-hour urine sodium; Urine K⁺, 24-hour urine potassium; UUN, 24-hour urine urea nitrogen.