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.

Evolution of the primate trypanolytic factor APOL1

“…In humans, APOL1 circulates in blood in the 5-μg/mL range and does not differ between WT and trypanolytic variants (38). Based on both in vitro and in vivo data, we conclude that the protective capacity of APOL1 variants against T. b. rhodesiense is baboon > K4 > G2 > G1 > WT and that it is governed, in part, by their affinity for binding to SRA at a physiological pH range (pH 6.1-4.5) found within endosomes and lysosomes of the parasite.…”

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

“…Because of the elevated risks for cardiovascular disease (CVD) and heart failure (HF) among people with chronic kidney disease compared with the general population,15 investigation of the cardiovascular risk of individuals who carry the APOL1 high‐risk variants is an issue of active study. Apolipoprotein L1 (Apol1) has been localized to endothelial and vascular smooth muscle cells within the kidney16, 17 and is also known to circulate in plasma with high‐density lipoprotein particles,18, 19 suggesting a potential role of the APOL1 risk variants in CVD. Studies to date on this topic, however, have been conflicting.…”

The Apolipoprotein L1 Gene and Cardiovascular Disease

“…Circulating APOL1 protein concentration does not appear to be dependent on APOL1 renal-risk variant genotypes. 7,38 APOL1 messenger RNA and protein have been detected in vascular cells, which supports the potential for a local vascular effect as with nephropathy risk. 39,40 If APOL1 renal-risk alleles exhibit opposing effects on CVD and nephropathy risk, an effect supported by AA-DHS, treatments that improve renal outcomes might have the potential to aggravate CVD.…”