Kidney Disease Progression in Membranous Nephropathy among Black Participants with High-Risk APOL1 Genotype.

BACKGROUND: Disparity in CKD progression among Black individuals persists in glomerular diseases. Genetic variants in the apolipoprotein L1 ( APOL1 ) gene in the Black population contribute to kidney disease, but the influence in membranous nephropathy remains unknown. METHODS: Longitudinally followed participants enrolled in the Glomerular Disease Collaborative Network or Cure Glomerulonephropathy Network were included if they had DNA or genotyping available for APOL1 (Black participants with membranous nephropathy) or had membranous nephropathy but were not Black. eGFR slopes were estimated using linear mixed-effects models with random effects and adjusting for covariates and interaction terms of covariates. Fisher exact test, Kruskal-Wallis test, and Kaplan-Meier curves with log-rank tests were used to compare groups. RESULTS: Among 118 Black membranous nephropathy participants, 16 (14%) had high-risk APOL1 genotype (two risk alleles) and 102 (86%) had low-risk APOL1 genotype (zero or one risk alleles, n =53 and n =49, respectively). High-risk APOL1 membranous nephropathy participants were notably younger at disease onset than low-risk APOL1 and membranous nephropathy participants that were not Black ( n =572). eGFR at disease onset was not different between groups, although eGFR decline (slope) was steeper in participants with high-risk APOL1 genotype (-16±2 [±SE] ml/min per 1.73 m 2 per year) compared with low-risk APOL1 genotype (-4±0.8 ml/min per 1.73 m 2 per year) or membranous nephropathy participants that did not identify themselves as Black (-2.0±0.4 ml/min per 1.73 m 2 per year) ( P <0.0001). Time to kidney failure was faster in the high-risk APOL1 genotype than low-risk APOL1 genotype or membranous nephropathy participants that were not Black. CONCLUSIONS: The prevalence of high-risk APOL1 variant among Black membranous nephropathy participants is comparable with the general Black population (10%-15%), yet the high-risk genotype was associated with worse eGFR decline and faster time to kidney failure compared with low-risk genotype and participants that were not Black.

PRTN3 variant correlates with increased autoantigen levels and relapse risk in PR3-ANCA versus MPO-ANCA disease.

A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.