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. 2023 Mar 1;18(3):344-355.
doi: 10.2215/CJN.0000000000000069. Epub 2023 Feb 8.

Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes

Mahmoud Kallash  1 , Yujie Wang  2 , Abigail Smith  3 , Howard Trachtman  4 , Rasheed Gbadegesin  5 , Carla Nester  6 , Pietro Canetta  7 , Chen Wang  7 , Tracy E Hunley  8 , C John Sperati  9 , David Selewski  10 , Isabelle Ayoub  11 , Tarak Srivastava  12 , Amy K Mottl  13 , Jeffrey Kopp  14 , Brenda Gillespie  15 , Bruce Robinson  3 , Dhruti Chen  13 , Julia Steinke  16 , Katherine Twombley  10 , Kimberly Reidy  17 , Krzysztof Mucha  18   19 , Larry A Greenbaum  20 , Brooke Blazius  4 , Margaret Helmuth  3 , Peleg Yonatan  7 , Rulan S Parekh  21   22   23 , Susan Hogan  13 , Virginie Royal  24 , Vivette D'Agati  25 , Aftab Chishti  26 , Ronald Falk  13 , Ali Gharavi  7 , Lawrence Holzman  27 , Jon Klein  28 , William Smoyer  1 , Matthias Kretzler  29 , Debbie Gipson  4 , Jason M Kidd  30 ; CureGN*
Affiliations

Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes

Mahmoud Kallash et al. Clin J Am Soc Nephrol. .

Abstract

Background: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors.

Methods: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation.

Results: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups.

Conclusions: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function.

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Conflict of interest statement

I. Ayoub reports consultancy agreement with Aurinia Advisory Board, honoraria from Aurinia, and advisory or leadership roles for Lupus Foundation of America (not paid) and Aurinia (paid). B. Blazius reports ownership interest in Apple, Bank of America, Cisco, Delta, Deere, Disney, Ford, JP Morgan, Netflix, Pfizer, Qualcom, and Viatris. P. Canetta reports consultancy agreements with Chinook, Novartis, Otsuka, and Travere and research funding from Calliditas, Novartis, and Travere. D. Chen is part of Kidney Health Initiative APOL1 Group and reports research funding from Vertex Pharmaceuticals. A. Chishti reports ownership interest in Apple, Google, Microsoft, and Tesla. V. D'Agati reports serving on the Editorial Board of Kidney International. R. Falk reports research funding from Vertex Pharmaceutica and honoraria from other universities for presentations and from ASN for presentations at Board Review Course. R. Gbadegesin reports research funding from AstraZeneca, Goldfinch Biotech, Reata, and Travere and an advisory or leadership role for Alport Syndrome Foundation Advisory Board. A. Gharavi reports consultancy agreements with AstraZeneca Center for genomics research, Actio Biosciences, Goldfinch Bio, Novartis, and Travere; ownership interest in Actio; research funding from Natera and Renal Research Institute; honoraria from Alnylam and Sanofi; and serving on the Editorial Boards of JASN and Journal of Nephrology. D. Gipson reports research funding from Travere (to University of Michigan), Boehringer-Ingelheim, Goldfinch Bio, Novartis, and Reata; advisory boards/steering committees for AstraZeneca, Goldfinch Bio, Roche/Genentech, and Vertex; and other interests or relationships with Nephrotic Syndrome Patient Reported Outcome Consortium (public-private partnership, with Pfizer, GSK, Goldfinch Bio, NephCure Kidney International) and as Co-chair for National Kidney Foundation Improving Vaccinations in Kidney Disease Workshop. D. Gipson reports consultancy between University of Michigan and Vertex, AstraZeneca, Boehringer-Ingelheim, Goldfinch Bio, Roche, and Genentech; no individual consultancy agreements. L.A. Greenbaum reports consultancy agreements with Alexion, Arrowhead Pharmaceuticals, Aurinia, Cara Therapeutics, Natera, Novartis, Otsuka, and Roche; research funding from Abbvie, Advicenne, Alexion, Apellis, Aurinia, Otsuka, Reata Pharmaceuticals, Roche, and Vertex; an advisory or leadership role for Alexion; and DSMB payments from Alnylam, Akebia, Reata, Relypsa, Travere, and UCSD. M. Helmuth and A. Smith report employment with Arbor Research Collaborative for Health. S. Hogan reports honoraria from NIH/NIDDK (grant reviewer) and serving as a VA grant reviewer. L. Holzman reports employment with University of Pennsylvania, Department of Veterans Affairs; consultancy agreements with Arnold & Porter Kaye Scholer LLP; honoraria from NIH/NIDDK; patents or royalties from University of Michigan; advisory or leadership roles for Journal of Clinical Investigation, NephCure Kidney International, ASN, and JASN; and other interests or relationships with NephCure Kidney International. M. Kallash reports research funding from Duplex - Retrophin- PI. J.M. Kidd reports stock in multiple companies including Amazon, Apple, CVS, Delta Airlines, Dominion power, Ford, PNC, and Tesla as well as diversified mutual funds; Virginia Catalyst grant funding; honoraria from Boca Raton Regional Hospital; and serving as a member of American Society of Nephrology and National Kidney Foundation. J. Kopp reports an NIH patent. M. Kretzler reports sponsored research project as PI at U Michigan: NIH, JDRF, Chan Zuckerberg Initiative, amfAR, Angion, AstraZeneca, Boehringer-Ingelheim, Certa, Chinook, Elpidera, Gilead, Goldfinch, Ionis, Jansen, Lilly, Maze, Novo Nordisk, RenalytixAI, Regeneron, and Travere. M. Kretzler reports advisory or leadership roles for Council of NIH-National Center for Advancing Translational Sciences (NCATS), Advisory Board of Nephcure Kidney International, and Editorial Boards of JASN, Kidney Disease, and Kidney International. M. Kretzler reports consultancy as an employee of U Michigan for: Astellas, Boehringer Ingelheim, Certa, Janssen, Novo Nordisk, and Poxel. A.K. Mottl reports consultancy agreements with Bayer and Chinook; research funding from Alexion, Aurinia, Bayer, Calliditas, Duke Clinical Research Institute, Pfizer, and University of Pennsylvania; honoraria from UpToDate; and advisory or leadership roles for Bayer and Chinook. K. Mucha reports Patent No.: US 11029314 B2 (Mucha et al.) and serving as a Archivum Immunologiae et Therapiae Experimentalis Editorial Board member (2020–2022) and a Polish Society of Internal Medicine National Board Member 2016–2022. C. Nester reports honoriaria for serving on advisory boards for Alexion, Apellis, Biocryst, and Novartis; research funding from Retrophin - Pediatric Recruiting Site for the Duet Trial, Achillion—Site PI—C3G Trial, Alexion, Avacopan—Site PI—C3G Trial, Novartis—Site PI—C3G Trial, and Apellis—Site PI—C3G Trial. R.S. Parekh reports ownership interest in Synaptive-stock, Coramed-stock, and SpineFx; research funding from Canadian Institute of Health Research (CIHR), NIH, and Ontario Ministry; patents or royalties from IZI and SpineFx; serving as an Associate Editor of CJASN, a Board Member of Bishop Strachan School, and a Board Member of Conference of Independent Schools of Ontario; and an advisory or leadership role for ISN Council. R.S. Parekh's spouse reports patents or royalties from Coramed and serving as an officer of Coramed and SpineFx. Y. Peleg reports consultancy agreements with Aurinia Pharmaceuticals and KOL Insights at VMLY&R Health, honoraria from Aurinia Pharmaceuticals and KOL Insights at VMLY&R Health, and an advisory or leadership role for Aurinia Pharmaceuticals. K. Reidy reports research funding from Advicienne and Travere; advisory or leadership roles for AAP Executive committee, Neonatal Kidney Collaborative, and Frontiers; and other interests or relationships with Ruth Gottscho Kidney Foundation, NIH funding, and Preeclampsia Foundation funding. B. Robinson was an employee of Arbor Research Collaborative for Health, which administers the DOPPS Program, during the manuscript production period. Global support for the ongoing DOPPS Program is provided without restriction on publications by a variety of private industry, professional society, and public funders. For details see https://www.dopps.org/AboutUs/Support.aspx. B. Robinson has received consultancy fees or travel reimbursement in the last 3 years from AstraZeneca and Monogram Health, paid directly to his institution of employment, and from GlaxoSmithKline. B. Robinson reports serving on the Editorial Board of American Journal of Kidney Diseases and the Board of Directors of Kidney Health Initiative. V. Royal reports consultancy agreements with Vertex Pharmaceuticals and honoraria from Janssen. D. Selewski reports research funding from Travere Therapeutics, Inc. W.E. Smoyer reports consultancy agreements with Otsuka, Vertex, and Visterra; ownership interest in NephKey Therapeutics; research funding from Aurinia; honoraria from USC for CTSA External Advisory Committee and from UCLA for CTSA External Advisory Committee; royalties from UpToDate; and advisory or leadership roles as member of the Board of Directors of Pediatric Nephrology Research Consortium (PNRC), member of the Board of Directors of NephCure Kidney International (NKI), and a member of the Coordinating Committee of the Institute for the Advancement of Clinical Trials in Children (I-ACT). J. Sperati reports consultancy agreements with Alnylam Pharmaceuticals and Q32 Bio; research funding from Achillion Pharmaceuticals, Alnylam Pharmaceuticals, National Institutes of Health, and Novartis Pharmaceuticals; honoraria from Alexion Pharmaceuticals and Alnylam Pharmaceuticals; and advisory or leadership roles for Advances in Chronic Kidney Disease (Editorial Board), Current Hypertension Reports (Section Editor), American Board of Internal Medicine Nephrology Longitudinal Assessment Committee, and National Kidney Foundation Education Committee. T. Srivastava reports research funding from Apellis Pharmaceuticals, Bristol-Myer-Squib, Roche, and Travere; honoraria from Alnylam; an advisory or leadership role for Case Reports in Pediatrics; and other interests or relationships with UpToDate. J. Steinke reports serving on the Gift of Life Advisory Board. H. Trachtman reports employment with RenalStrategies LLC; consultancy agreements with Aclipse, Akebia, Alexion (inactive), Angion, Astellas (inactive), Bristol Meyers Squibb (inactive), Chemocentryx (DMSB), Complexa (inactive), Goldfinch Bio, Kaneka (inactive), Natera (RenaSight), Otsuka (DSMB Chair), Travere Therapeutics, and Walden; support for trial design from Travere Therapeutics and Goldfinch and Walden; support for clinical work from Alexion; honoraria for attendance at glomerular disease panels organized by Reata and Astellas; patents or royalties for design of EPPIK trial conducted by Travere Therapeutics, planned submission; advisory or leadership roles for DSMB RIVUR Trial (completed), DSMB bumetanide-seizure trial (completed), Chair of DSMB Otsuka trials of tolvaptan in children; DSMB for ANCA vasculitis for Chemocentryx (completed), Steering Committee for Abatacept Trial for BMS (completed), Steering Committee for DUPRO (DUPLEX and PROTECT trials for Travere Therapeutics, Steering Committee for Goldfinch Bio (Steering Committee), and MEDCAC committee member for KHI Board of Directors; serving on Editorial Boards for Glomerular Disease, Kidney360, and Pediatric Nephrology; and serves as a partner with NephCure Kidney International in efforts to promote pediatric participation in clinical trials for glomerular disease. K. Twombley reports consultancy agreements with Horizon; research funding from AHRQ, Kaneka, and NIDDK; and honoraria from American Academy of Pediatrics and American Board of Pediatrics. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Flow diagram of included patients. HSP, Henoch-Schonlein Purpura; IgA, IgA nephropathy; MCD, minimal change disease; MN, membranous nephropathy.
Figure 2
Figure 2
Sankey plot of FSGS therapy at biopsy, 0–6 months, and 6–12 months postbiopsy (N=552). At biopsy is defined as ±30 days of biopsy, at 6 months is defined as ±30 days of 6 months postbiopsy, and at 12 months is defined as ±30 days of 12 months postbiopsy. Ninety-eight patients are missing medication data. A Sankey plot separating treatment of patients with high-risk and low-risk APOL1 genotypes is included as Supplemental Figures 1 and 2. CNI, calcineurin inhibitor; CTX, cyclophosphamide; MMF, mycophenolate mofetil; RAASI, renin-angiotensin-aldosterone system inhibitor; RITUX, rituximab.
Figure 3
Figure 3
Adjusted eGFR progression by APOL1 categories using linear mixed model with random slopes and intercepts, N=575. P value represents the interaction between APOL1 and years after biopsy.
See this image and copyright information in PMC

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