APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis

Abstract

Background The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. Methods In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light-or electron-microscopy traits measuring structural and cellular kidney changes. Results Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. Conclusions While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

Early recurrence of focal segmental glomerulosclerosis in a kidney transplant recipient withAPOL1one risk variant

“…APOL1 -associated FSGS is thought to be secondary to dose-dependent podocyte injury from the dominant toxic gain of function of the high risk APOL1 variants 12. Although APOL1- associated FSGS has been described mostly with two risk alleles, even a single risk allele is associated with cellular/tissue changes with some studies showing increased risk of chronic kidney disease with single G1 or G2 alleles 2 13–15…”

Precision medicine for focal segmental glomerulosclerosis

“…A total of 476 (73%) underwent genetic testing, of whom 87 (18%) were at high risk, and it was found that highrisk APOL1 genotypes were the primary factor associated with faster loss of kidney function [15]. A cohort study of 90 black patients with FSGS or MCDs showed that while APOL1-associated FSGS is associated with having two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in FSGS patients [16]. Expression of APOL1 risk variants in transgenic mouse models was found to increase susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction [17].…”

The Roles of Fatty Acids and Apolipoproteins in the Kidneys

“…Additionally, APOL1 is associated with recurrent FSGS after transplantation [ 194 ]. Recently, Zee et al showed that glomerular APOL1 expression or APOL1 risk alleles are associated with cellular/tissue changes in patients with FSGS [ 195 , 196 ]. ApoL2 is found mainly in the brain [ 197 ], but its function remains unknown in the kidneys.…”