#3155 apol1 genotype is a major determinant of lupus nephritis severity in patients of african ancestry

Abstract Background and Aims Two polymorphisms of APOL1 gene, G1 and G2, exclusively found among patients of African ancestry, have been associated with chronic kidney disease (CKD) and end-stage kidney disease (ESKD)1. These high-risk polymorphisms have also been associated with collapsing glomerulopathy in various diseases. We aimed to evaluate the impact of APOL1 G1 and G2 polymorphisms on the clinical and pathological course LN which is already known to be more severe among patients of African ancestry2. Method We included patients from 6 hospitals in Paris and Marseille in France, between January 2017 and March 2020, with biopsy-proven LN, African ancestry and age >18 years at the time of inclusion. We excluded those with HIV infection. The data were retrospectively collected at LN diagnosis, 1 year after diagnosis and at last follow-up. APOL1 genotyping was performed and we divided patients in 2 groups: the high-risk genotype (HRG) group with 2 risk alleles and the low risk genotype (LRG) group with 1 or 0 risk allele. All patients signed a consent form for the genetic analysis and protocol approval was obtained from the ethic committee CERAPHP (Comité d'Ethique de la Recherche AP-HP Centre), registration number 00011928. Results Ninety-nine patients were included in the study, 13 in the HRG group and 86 in the LRG group. The median duration between LN diagnosis and inclusion in the study was 9.6 years [4.9-16.9]. At LN diagnosis, clinical and biological characteristics were similar except for kidney function that was lower in the HRG group compared to the LRG group with a median serum creatinine of 131μmol/L [69-687] versus 66μmol/L [52-133] (p = 0.0085). Patients in the HRG group were more likely to have a serum creatinine above 200 μmol/L compared to the LRG group (45.5% versus 10.5%, p = 0.0096, OR 7.1[1.8-28.6]), and required acute haemodialysis more frequently (30.8% versus 1.3% respectively, p = 0.0012, OR 34.7[3.5-345.1]). Collapsing glomerulopathy was more frequent in the HRG group (45.5% of patients, versus 4.5%, OR 17.5[3.3-91.9], p = 0.001). No significant difference was observed in the proportion of kidney response at 12 months, however, patients in the HRG group were more likely to develop CKD (33.3% versus 4.9%, OR 9.6[2.0-46.1]). Median follow-up from LN diagnosis to the end of study, ESKD or last follow-up was 7.9 years [3.4-13.3] and was similar between the 2 groups. At last follow-up, median eGFR was 22mL/min/1.73m2 [10-98] vs 99mL/min/1.73m2 [55-118] respectively, p = 0.0189. Survival without ESKD was poorer in the HRG group than in the LRG group with a hazard ratio (HR) of 5.0[1.6-15.8], p = 0.006, even after adjusting with the kidney response at 12 months (adjusted HR 6.24[1.8-21.6], p = 0.004) (Figure 1). Conclusion APOL1 genotype affects LN prognosis, resulting in a worse kidney function at diagnosis, development of collapsing glomerulopathy and higher risk of subsequent ESKD. Kidney survival remained significantly lower in the HRG group, after adjustment for kidney response at 12 months, suggesting that the prognosis of LN is heavily driven by APOL1 genotype regardless of the kidney response. APOL1 inhibitors are currently being developed, and could be used in the next future, for HRG patients with primary or secondary forms of collapsing glomerulopathy.