Dataset Information

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

ABSTRACT: African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

SUBMITTER: Gupta Y

PROVIDER: S-EPMC10689833 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

Gupta Yask Y Friedman David J DJ McNulty Michelle T MT Khan Atlas A Lane Brandon B Wang Chen C Ke Juntao J Jin Gina G Wooden Benjamin B Knob Andrea L AL Lim Tze Y TY Appel Gerald B GB Huggins Kinsie K Liu Lili L Mitrotti Adele A Stangl Megan C MC Bomback Andrew A Westland Rik R Bodria Monica M Marasa Maddalena M Shang Ning N Cohen David J DJ Crew Russell J RJ Morello William W Canetta Pietro P Radhakrishnan Jai J Martino Jeremiah J Liu Qingxue Q Chung Wendy K WK Espinoza Angelica A Luo Yuan Y Wei Wei-Qi WQ Feng Qiping Q Weng Chunhua C Fang Yilu Y Kullo Iftikhar J IJ Naderian Mohammadreza M Limdi Nita N Irvin Marguerite R MR Tiwari Hemant H Mohan Sumit S Rao Maya M Dube Geoffrey K GK Chaudhary Ninad S NS Gutiérrez Orlando M OM Judd Suzanne E SE Cushman Mary M Lange Leslie A LA Lange Ethan M EM Bivona Daniel L DL Verbitsky Miguel M Winkler Cheryl A CA Kopp Jeffrey B JB Santoriello Dominick D Batal Ibrahim I Pinheiro Sérgio Veloso Brant SVB Oliveira Eduardo Araújo EA Simoes E Silva Ana Cristina AC Pisani Isabella I Fiaccadori Enrico E Lin Fangming F Gesualdo Loreto L Amoroso Antonio A Ghiggeri Gian Marco GM D'Agati Vivette D VD Magistroni Riccardo R Kenny Eimear E EE Loos Ruth J F RJF Montini Giovanni G Hildebrandt Friedhelm F Paul Dirk S DS Petrovski Slavé S Goldstein David B DB Kretzler Matthias M Gbadegesin Rasheed R Gharavi Ali G AG Kiryluk Krzysztof K Sampson Matthew G MG Pollak Martin R MR Sanna-Cherchi Simone S

Nature communications 20231130 1

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N ...[more]

PMID: 38036523

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Project description:Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

Project description:Rationale & objectiveRemission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival.Study designCohort analysis of clinical trial participants.Setting & participantsPatients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone.PredictorsReduction in proteinuria measured during 26 weeks after initiating treatment.OutcomesRepeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization.Analytical approachMultivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome.Results138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44).LimitationsLimited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years.ConclusionsThese findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Dataset Information

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

Publications

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

Similar Datasets

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