Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial

Abstract

Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.

Keywords: FSGS; cyclosporin; genetic renal disease.

Figure 1.

Interaction between APOL1 genotype and treatment response. Randomized treatment with cyclosporin (CSA) or mycophenolate mofetil combined with oral pulse dexamethasone (MMF) was associated with remissions scored as one to six. Each of 94 (total) subjects is depicted as a circle, with open circles denoting those with zero or one APOL1 risk alleles (RAs) and closed circles denoting those with two APOL1 RAs. Analysis for interaction between treatment and genotype using two-way ANOVA yielded a nonsignificant P value (P=0.45), suggesting that the presence or absence of the APOL1 risk genotype was not associated with differential responses to these medications.

Figure 2.

Renal survival analysis. Renal survival, assessed from FSGS onset to dialysis or kidney transplant and censored for death with kidney function, was significantly shorter for individuals with two APOL1 risk alleles (RAs) compared with others. Analysis includes all 94 subjects.