Faculty Bibliography

Background/Purpose: Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, associate with CKD in African Americans (AA) and are evolutionarily preserved due to improved infectious resistance. Interferons (IFN) in SLE, have been shown to increase APOL1 expression and RV toxicity in endothelial cells and podocytes. Though RV homozygotes with SLE nephritis demonstrate advanced renal progression, associations with renal histopathologies have not been validated in SLE.
Method(s): Herein, this cohort study tested the hypothesis that RV homozygosity (RV/RV) associates with specific clinical and biopsy features compared to reference allele (G0) homozygosity (G0/G0) or RV heterozygosity (RV/G0). Whole blood DNA for genotyping, kidney biopsy slides, and clinical reports from 77 AA SLE patients with biopsy-proven nephritis reviewed for: biopsy class, activity index (AI), chronicity index (CI) and clinical features across APOL1 genotype. RVattributed mitochondrial morphology, was assessed on electron microscopy (EM) images. Analysis was confirmed by two blinded pathologists. As proof of concept, primary endothelial cells across genotype were given IFN to over-express APOL1, and features on EM were compared.
Result(s): The G0/G0, RV/G0, and RV/RV groups comprised 35%, 52%, and 12% of the cohort. There were no genotype differences in SLE history or demographics. Compared to G0/G0, and RV/G0 groups, the RV/RV had higher urine protein to creatinine ratios (uPCR) and creatinine (Cr) at biopsy (mean uPCR: 2.5; 2.7; 4.3 mg/L p=0.06 and Cr: 1.3; 1.03; 2.3 mg/dL p=0.01 respectively). Adjusting for dsDNA, AI, CI, and percent sclerotic glomeruli, the RVs independently associated with proteinuria at biopsy (OR=2.1, p=0.05). Paradoxically, the G0/G0 and RV/G0 vs the RV/RV group displayed higher AI and CI with a trend toward higher dsDNAs at biopsy (G0/G0 or RV/G0: AI: 5.3/24; CI: 2.6/12 dsDNA: 447 vs RV/RV: AI: 1.2/24; CI: 1.3/12; dsDNA: 69, p=AI: 0.004; CI: 0.01; dsDNA: 0.1). In 30% of the RV/RV cases, the reading pathologist commented that clinical severity was out of proportion to the biopsy lesion. The RVassociated with ESRD in 7.9%, 3.9%, and 20% of the G0/ G0, RV/G0, and RV/RV cases (OR: 5.7; p=0.03). On EM, RVs associated with mitochondrial condensation (mitochondrial area: G0/G0: 0.17; RV/G0: 0.09; RV/RV: 0.06 mum²; p<0.01); this result was recapitulated in our cell culture model. IFNtreated endothelial cells increased APOL1 expression 18 fold across genotypes (p<0.01). Compared to G0/G0 and RV/G0 cells, RV/RV cells had mitochondrial areas: G0/G0: 0.08; RV/G0: 0.07; RV/RV: 0.04 mum²; (p<0.01).
Conclusion(s): In this SLE cohort, APOL1 RVs associated with poorer prognosticators, initial proteinuria and creatinine, and ultimately progressive nephritis. These features were paradoxically out of proportion to the SLE lesion on biopsy. The literature supports RV-conferred podocyte and endothelial cell mitochondrial defects owing to a mitophagy deficiency. As evidenced by EM images from both SLE patient biopsies and primary cell cultures, these genes may conferrer intrinsic renal pathology. Consequently, traditional scoring of histopathologic severity may underestimate injury that associates with RValleles

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) confers up to a 50-fold increased risk of cardiovascular disease (CVD), and African Americans with SLE experience accelerated damage accrual and doubled cardiovascular risk when compared to their European American counterparts. RECENT FINDINGS: Genome-wide association studies have identified a substantial signal at 22q13, now assigned to variation at apolipoprotein L1 (APOL1), which has associated with progressive nondiabetic nephropathy, cardiovascular disease, and many immune-associated renal diseases, including lupus nephritis. We contend that alterations in crucial APOL1 intracellular pathways may underpin associated disease states based on structure-functional differences between variant and ancestral forms. While ancestral APOL1 may be a key driver of autophagy, nonconserved primary structure changes result in a toxic gain of function with attenuation of autophagy and an unsupervised pore-forming feature. Thus, the divergent intracellular biological pathways of ancestral and variant APOL1 may explain a worsened prognosis as demonstrated in SLE.

OBJECTIVE: Atherosclerosis is exaggerated in African American (AA) systemic lupus erythematosus (SLE) patients, with doubled cardiovascular disease (CVD) risk compared to White patients. The extent to which common Apolipoprotein L1 (APOL1) risk alleles (RA) contribute to this trend is unknown. This retrospective cohort study assessed prevalent atherosclerotic disease across APOL1 genotypes in AA SLE patients. METHODS: One hundred thirteen AA SLE subjects were APOL1-genotyped and stratified as having: zero risk alleles, one risk allele, or two risk alleles. Chart review assessed CVD manifestations including abdominal aortic aneurysm, angina, carotid artery disease, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and vascular calcifications. Associations between the genotypes and a composite endpoint defined as one or more CVD manifestations were calculated using logistic regression. Symptomatic atherosclerotic disease, excluding incidental vascular calcifications, was also assessed. RESULTS: The 0-risk-allele, 1-risk-allele and 2-risk-allele groups, respectively, comprised 34%, 53%, and 13% of the cohort. Respectively, 13.2%, 41.7%, and 60.0% of the 0-risk allele, 1-risk-allele, and 2-risk-allele groups met the composite endpoint of atherosclerotic CVD (p = 0.001). Adjusting for risk factors-including smoking, ESRD, BMI >25 and hypertension-we observed an association between carrying one or more RA and atherosclerotic CVD (OR = 7.1; p = 0.002). For symptomatic disease, the OR was 3.5 (p = 0.02). In a time-to-event analysis, the proportion of subjects free from the composite primary endpoint, symptomatic atherosclerotic CVD, was higher in the 0-risk-allele group compared to the 1-risk-allele and 2-risk-allele groups (chi2 = 6.5; p = 0.04). CONCLUSIONS: Taken together, the APOL1 RAs associate with prevalent atherosclerotic CVD in this cohort of AA SLE patients, perhaps reflecting a potentiating effect of SLE on APOL1-related cardiovascular phenotypes.