Plasma apolipoprotein L1 levels do not correlate with CKD

Abstract

Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to <60 ml/min per 1.73 m(2) (eGFR<60 cohort) or protein-to-creatinine ratios became >3.5 g/g (nephrotic proteinuria cohort). Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR<60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR<60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.

Figure 1.

APOL1 plasma levels did not correlate with eGFR or proteinuria. Scatter plots of APOL1 plasma levels relative to (A) eGFR or (B) UP/Cr in all participants (cases and controls combined). Linear regression trend lines are shown; Pearson correlation coefficients (r) and P values are presented in key.

Figure 2.

APOL1 plasma levels did not associate with APOL1 genotype. Box whisker plot associating APOL1 genotype with APOL1 plasma levels in cases and controls stratified by number of risk alleles. Boxes denote interquartile range with a median line; outliers are indicated with filled circles outside range whiskers. Statistical analyses for genotype comparisons are presented in Supplemental Table 3.

Figure 3.

APOL1 plasma levels did not correlate with sTNFR2 levels. Scatter plot of APOL1 plasma levels relative to sTNFR2 levels in all cases and controls. See Table 4 for correlations with other cytokines. Linear regression trend lines are shown; Pearson correlation coefficients (r) and P values are presented in key.

Figure 4.

APOL1 risk alleles associated with CKD in the eGFR<60 cohort but not the nephrotic range proteinuria cohort. Forest plots of risk factors for CKD. Odds ratios, 95% confidence intervals (95% CIs), and P values for the associations between CKD in the (A) eGFR<60 cohort and (B) nephrotic proteinuria cohort. The associations with APOL1 genotype and CKD is depicted in a univariate conditional logistic regression model (univariate), or with comorbid conditions and tenofovir exposure estimated from a single multivariable conditional logistic regression model that included each of these covariates (model 1). These covariates also were included in separate multivariable models that tested associations with the individual cytokines (model 2). Odds ratios for risk alleles shown in model 2 are for sTNFR2 (see Supplemental Table 4 for odds ratios with other cytokines). Only cytokines with significant associations are shown. The complete results of all univariate and multivariate analyses are presented in Supplemental Tables 4 and 5. *Because of the small number of patients with diabetes (n=9 cases and n=1 control), association was determined by Fisher exact test and diabetes was not included in the model. NS, not significant.

Figure 5.

APOL1 risk alleles associated with eGFR decline but not with changes in proteinuria. (A) Longitudinal changes in eGFR in all cases (combined eGFR<60 and nephrotic proteinuria cohorts); slopes in ml/min per year. (B) Longitudinal changes in UP/Cr ratios in all cases; slopes in g/g per year. Controls did not change over time (see matching criteria in Concise Methods section). Graphical data are time point means with SEM bars. Slopes were determined for each participant and are presented in the legend as a mean slope (interquartile range) and P values versus no risk alleles. Below each graph are the numbers of participants with available data (n) per each time point for no, one, or two risk alleles.