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

Area of Science:

• Nephrology
• Genetics
• Pathology

Background:

• The G1 and G2 alleles of apolipoprotein L1 (APOL1) are prevalent in the Black population and are associated with an elevated risk of focal segmental glomerulosclerosis (FSGS).
• The precise molecular mechanisms connecting APOL1 risk variants to FSGS remain unclear, compounded by the absence of APOL1 in laboratory animals, hindering pathobiological studies.

Purpose of the Study:

• To investigate the tissue-based consequences of APOL1 risk variants and gene expression in Black patients with FSGS and minimal change disease (MCD).
• To identify correlations between APOL1 risk alleles or glomerular APOL1 mRNA expression and kidney biopsy morphologic traits.

Main Methods:

• Analysis of kidney biopsy traits from 90 Black patients (58% pediatric onset) with FSGS or MCD within the Nephrotic Syndrome Study Network.
• Testing associations between APOL1 risk alleles/mRNA expression and 83 light- or electron-microscopy determined kidney structural and cellular changes.

Main Results:

• In FSGS patients, APOL1 risk variants significantly correlated with reduced mesangial hypercellularity, decreased cytoskeleton condensation, and increased tubular microcysts under both recessive and dominant models.
• No significant correlations were found in the minimal change disease (MCD) cohort.
• Glomerular APOL1 expression in FSGS patients did not correlate with morphologic features, independent of risk alleles.

Conclusions:

• Both one and two APOL1 risk alleles are associated with cellular/tissue changes in FSGS patients, extending beyond the presence of two risk alleles.
• The limited discovery of tissue differences and lack of significant findings in MCD may indicate a need for increased statistical power or the application of machine learning methods for more sensitive detection of APOL1-associated changes.