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.

Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization

“…In another study that examined mortality risk stratification in CKD [19], the prevalence of CKD increased from 3 to 49% as age increased from 18-44 to 85-100 years. In the recent study by Chen et al [16], age was not a significant modifier of the association between APOL1 risk alleles and CKD progression. Our study differed from the AASK study in that we examined age in 5-year increments, instead of a binary variable with the cutoff at 55 years, which may have contributed to the difference in results.…”

“…Previous studies have alluded to the presence of other genetic and environmental factors that could contribute to the risk for CKD by interacting with APOL1 [7,15,16,17]. In a recent analysis of the African-American Study of Kidney Disease and Hypertension (AASK) [16], many sociodemographic (age >55 years, sex, education, income, etc.) and common clinical risk factors (systolic blood pressure, BMI, smoking, etc.)…”

“…Few previous studies on APOL1 included patients with diabetes [15,16]. In studies that did, a stronger association between APOL1 risk variants and renal decline has been shown in this subgroup [4].…”

Patterns of Kidney Function Decline Associated with APOL1 Genotypes: Results from AASK

“…eGFR was calculated using the AASK estimating equation: eGFR=3293(serum creatinine) 21.096 3(age) 20.294 3(0.736 for women). Probabilities of linearity and progression were estimated on the basis of the monthly slopes of eGFR trajectories approximated using a Bayesian smoothing technique (18).…”

“…Although the mechanisms by which the APOL1 risk variants influence kidney function remain unclear, these risk variants were reported to act synergistically with some environmental and genetic risk factors, such as higher levels of HIV viral load, hemostatic factors, and the glutathione-Stransferase-m1 null allele, and independent of other risk factors of CKD progression, including smoking and net endogenous acid production (11)(12)(13)21). Our study found that, among patients with CKD attributed to hypertension, those with the APOL1 high-risk genotype were more likely to experience a steady decline in eGFR.…”