Inaxaplin for Proteinuric Kidney Disease in Persons with Two
            <i>APOL1</i>
            Variants

Egbuna, Ogo; Zimmerman, Brandon; Manos, George C.; Fortier, Anne H.; Chirieac, Madalina C; Dakin, Leslie A; Friedman, David J.; Bramham, Kate; Barisoni, Laura; Falk, Ronald J.; Gipson, Debbie S.; Lipkowitz, Michael S.; Bunnage, Mark E.; Pollak, Martin R.; Altshuler, David; Chertow, Glenn M.

doi:10.1056/nejmoa2202396

Cited by 94 publications

(68 citation statements)

References 38 publications

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“…In a small clinical trial in patients with FSGS and APOL1 HR variants, a small molecule inhibitor of APOL1 ion conductance was reported to reduce proteinuria over 12 weeks of treatment. 36 The concordant effects of the p.N264K variant and pharmacologic interventions that act by the same mechanism 36 illustrate the value of identifying and characterizing genetic modifiers of disease and their potential effect in human populations as we accomplish in this study.…”

Section: Discussionmentioning

confidence: 94%

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

Hung,

Assimon,

Chen

et al. 2023

JASN

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Significance Statement African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 (APOL1) gene, termed G1/G2. A different APOL1 variant, p.N264K, reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1-mediated pore formation may be able to prevent and/or treat APOL1-associated kidney disease. Background African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. Methods We tested whether a different APOL1 variant, p.N264K, modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank (n=14,386) and National Institutes of Health All of Us (n=14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K. Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. Results In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K. In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K, was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. Conclusions APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

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Section: Discussionmentioning

confidence: 94%

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

Hung,

Assimon,

Chen

et al. 2023

JASN

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“…4 The utility of APOL1 genotype testing is under consideration in various clinical settings and APOL1 inhibition is under investigation in clinical trials. 5–7…”

Section: Introductionmentioning

confidence: 99%

APOL1 kidney risk variants in glomerular diseases modeled in transgenic mice

Yoshida

Latt

Santo

et al. 2023

Preprint

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APOL1 high-risk variants partially explain the high kidney disease prevalence among African ancestry individuals. Many mechanisms have been reported in cell culture models, but few have been demonstrated in mouse models. Here we characterize two models: (1) HIV-associated nephropathy (HIVAN) Tg26 mice crossed with bacterial artificial chromosome (BAC)/APOL1 transgenic mice and (2) interferon-g; administered to BAC/APOL1 mice. Both models showed exacerbated glomerular disease in APOL1-G1 compared to APOL1-G0 mice. HIVAN model glomerular bulk RNA-seq identified synergistic podocyte-damaging pathways activated by the APOL1-G1 allele and by HIV transgenes. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially-expressed genes as a function of APOL1 alleles. Eukaryotic Initiation factor-2 pathway was the most activated pathway in the interferon-g; model and the most deactivated pathway in the HIVAN model. HIVAN mouse model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis (FSGS) glomerular bulk RNA-seq data. Furthermore, single-nuclear RNA-seq data from interferon-g; mouse model podocytes (in vivo) showed similarity to human FSGS single-cell RNA-seq data from urine podocytes (ex vivo) and from human podocyte cell lines (in vitro) using bulk RNA-seq. These data highlight differences in the transcriptional effects of the APOL1-G1 risk variant in a model specific manner. Shared differentially expressed genes in podocytes in both mouse models suggest possible novel glomerular damage markers in APOL1 variant-induced diseases. Transcription factor Zbtb16 was downregulated in podocytes and endothelial cells in both models, possibly contributing to glucocorticoid-resistance. In summary, these findings in two mouse models suggest both shared and distinct therapeutic opportunities for APOL1 glomerulopathies.

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“…20,21 A recent 13-wk study of 13 individuals who had 2 APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria showed that daily inaxaplin reduced proteinuria by 48%. 22…”

Section: Discussionmentioning

confidence: 99%

Association of Recipient APOL1 Kidney Risk Alleles With Kidney Transplant Outcomes

Roy,

Morales-Alvarez,

Anis

et al. 2023

Transplantation

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Background. Kidney transplant survival in African American recipients is lower compared with non–African American transplant recipients. APOL1 risk alleles (RA) have been postulated as likely contributors. We examined the graft outcomes in kidney transplant recipients (KTRs) stratified by APOL1 RA status in a multicenter observational prospective study. Methods. The Renal Transplant Outcome Study recruited a cohort of incident KTRs at 3 transplant centers in the Philadelphia area from 1999–2004. KTRs were genotyped for APOL1 RA. Allograft and patient survival rates were compared by the presence and number of APOL1 RA. Results. Among 221 participants, approximately 43% carried 2 APOL1 RA. Recipients carrying 2 APOL1 RA demonstrated lower graft survival compared with recipients with only 1 or none of APOL1 RA at 1 y posttransplant, independently of other donor and recipient characteristics (adjusted hazard ratio 3.2 [95% confidence interval, 1.0-10.4], P = 0.05). There was no significant difference in overall survival or graft survival after 3 y posttransplantation. There was no difference in death by APOL1-risk status (P = 0.11). Conclusions. Recipients with 2 APOL1 high-risk alleles exhibited lower graft survival 1 y posttransplantation compared with recipients with only 1 or 0 APOL1 RA. Further research is required to study the combined role of the recipient and donor APOL1 genotypes in kidney transplantation.

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Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants

Cited by 94 publications

References 38 publications

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

APOL1 kidney risk variants in glomerular diseases modeled in transgenic mice

Association of Recipient APOL1 Kidney Risk Alleles With Kidney Transplant Outcomes

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