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Gembillo G, Sessa C, Santoro D. Advances in the pathophysiology and treatment of focal segmental glomerulosclerosis: The importance of a timely and tailored approach. World J Nephrol 2025; 14. [DOI: 10.5527/wjn.v14.i2.103039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/14/2025] [Accepted: 01/21/2025] [Indexed: 04/09/2025] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that significantly contributes to chronic kidney disease and end-stage renal disease. Its incidence is rising globally, necessitating timely and personalized management strategies. This paper aims to provide an updated overview of the pathophysiology, diagnosis, and therapeutic strategies for FSGS, emphasizing the importance of early interventions and tailored treatments. This editorial synthesizes key findings from recent literature to highlight advancements in understanding and managing FSGS. Emerging evidence supports the role of targeted therapies and personalized approaches in improving outcomes for FSGS patients. Advances include novel biomarkers, genetic testing, and innovative therapeutics such as transient receptor potential ion channel blockers and antisense oligonucleotides for apolipoprotein 1-related FSGS. Effective management of FSGS requires a combination of timely diagnosis, evidence-based therapeutic strategies, and ongoing research to optimize patient outcomes and address gaps in the current understanding of the disease.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, AOU "G. Martino", University of Messina, Messina 98125, Sicilia, Italy
| | - Concetto Sessa
- Unit of Nephrology and Dialysis, P.O. Maggiore "Nino Baglieri", Ragusa 97100, Sicilia, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, AOU "G. Martino", University of Messina, Messina 98125, Sicilia, Italy
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2
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Pollak MR, Friedman DJ. APOL1-associated kidney disease: modulators of the genotype-phenotype relationship. Curr Opin Nephrol Hypertens 2025; 34:191-198. [PMID: 40047214 DOI: 10.1097/mnh.0000000000001068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
PURPOSE OF REVIEW Apolipoprotein-L1 (APOL1) G1 and G2 risk variants, found in people of recent west sub-Saharan African ancestry, dramatically increase the likelihood of kidney disease, yet the incomplete penetrance an diverse clinical manifestations underscore the need to understand the molecular and environmental factors that modulate APOL1-mediated toxicity. RECENT FINDINGS Recent studies confirm that risk variants exert a toxic gain-of-function effect, exacerbated by inflammatory triggers such as HIV infection and COVID-19. Epigenetic mechanisms and microRNA pathways further modulate APOL1 expression, influencing disease penetrance. Multiple models have clarified how subcellular localization, signal peptide processing, and interactions with the endoplasmic reticulum may contribute to pathogenesis. Therapeutic advances include inhibitors targeting APOL1 ion channel activity and strategies that block key inflammatory signaling pathways. SUMMARY These findings highlight a multifaceted disease process driven by both the intrinsic toxic potential of APOL1 variants and numerous extrinsic triggers. Understanding this complex interplay will be pivotal for risk stratification and the development of precision therapies, potentially improving outcomes for populations disproportionately affected by APOL1-associated kidney disease.
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Affiliation(s)
- Martin R Pollak
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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Byun JH, Lebeau PF, Trink J, Uppal N, Lanktree MB, Krepinsky JC, Austin RC. Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease. Nat Rev Nephrol 2025; 21:299-313. [PMID: 39988577 DOI: 10.1038/s41581-025-00938-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2025] [Indexed: 02/25/2025]
Abstract
The endoplasmic reticulum (ER) has crucial roles in metabolically active cells, including protein translation, protein folding and quality control, lipid biosynthesis, and calcium homeostasis. Adverse metabolic conditions or pathogenic genetic variants that cause misfolding and accumulation of proteins within the ER of kidney cells initiate an injurious process known as ER stress that contributes to kidney disease and its cardiovascular complications. Initiation of ER stress activates the unfolded protein response (UPR), a cellular defence mechanism that functions to restore ER homeostasis. However, severe or chronic ER stress rewires the UPR to activate deleterious pathways that exacerbate inflammation, apoptosis and fibrosis, resulting in kidney injury. This insidious crosstalk between ER stress, UPR activation, oxidative stress and inflammation forms a vicious cycle that drives kidney disease and vascular damage. Furthermore, genetic variants that disrupt protein-folding mechanisms trigger ER stress, as evidenced in autosomal-dominant tubulointerstitial kidney disease and Fabry disease. Emerging therapeutic strategies that enhance protein-folding capacity and reduce the burden of ER stress have shown promising results in kidney diseases. Thus, integrating knowledge of how genetic variants cause protein misfolding and ER stress into clinical practice will enhance treatment strategies and potentially improve outcomes for various kidney diseases and their vascular complications.
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Affiliation(s)
- Jae Hyun Byun
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada
- Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Paul F Lebeau
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada
| | - Jackie Trink
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada
| | - Nikhil Uppal
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine and Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- Population Health Research Institute, Hamilton, Ontario, Canada
| | - Matthew B Lanktree
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine and Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- Population Health Research Institute, Hamilton, Ontario, Canada
| | - Joan C Krepinsky
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada
| | - Richard C Austin
- Division of Nephrology, Department of Medicine, The Research Institute of St Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada.
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.
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Skitchenko R, Modrusan Z, Loboda A, Kopp JB, Winkler CA, Sergushichev A, Gupta N, Stevens C, Daly MJ, Shaw A, Artomov M. CR1 variants contribute to FSGS susceptibility across multiple populations. iScience 2025; 28:112234. [PMID: 40241753 PMCID: PMC12003020 DOI: 10.1016/j.isci.2025.112234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 11/25/2024] [Accepted: 03/13/2025] [Indexed: 04/18/2025] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome, with an annual incidence of 24 cases per million among African-Americans and 5 per million among European-Americans in the United States. It ranks as the second most common glomerular disease in Europe and Latin America and the fifth in Asia. We conducted a case-control study involving 726 FSGS cases and 13,994 controls from diverse ethnic backgrounds, using panel sequencing of ∼2,500 podocyte-expressed genes. Rare variant association tests confirmed known risk genes (KANK1, COLAPOL1) and identified a significant association with the CR1 gene. The CR1 variant rs17047661, which encodes the Sl1/Sl2 (R1601G) allele, was previously linked to cerebral malaria protection and is now identified as a risk variant for FSGS. This highlights an evolutionary trade-off between infectious disease resistance and kidney disease susceptibility, emphasizing the role of adaptive immunity in FSGS pathogenesis and potential therapeutic targets.
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Affiliation(s)
- Rostislav Skitchenko
- ITMO University, St. Petersburg, Russia
- Almazov National Medical Research Centre, St. Petersburg, Russia
| | - Zora Modrusan
- Research Biology, Genentech Inc., San Francisco, CA, USA
| | - Alexander Loboda
- ITMO University, St. Petersburg, Russia
- Almazov National Medical Research Centre, St. Petersburg, Russia
- Broad Institute, Cambridge, MA, USA
| | - Jeffrey B. Kopp
- Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
| | - Cheryl A. Winkler
- Molecular Genetic Epidemiology Studies Section, National Cancer Institute (NCI), Frederick, MD, USA
| | | | | | | | - Mark J. Daly
- Broad Institute, Cambridge, MA, USA
- Massachusetts General Hospital, Boston, MA, USA
- Institute for Molecular Medicine Finland, Helsinki, Finland
| | - Andrey Shaw
- Research Biology, Genentech Inc., San Francisco, CA, USA
| | - Mykyta Artomov
- Broad Institute, Cambridge, MA, USA
- Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
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Mejia SM, Fischman CJ, Sise ME. Kidney disease in patients with HIV. Curr Opin HIV AIDS 2025:01222929-990000000-00154. [PMID: 40184511 DOI: 10.1097/coh.0000000000000941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2025]
Abstract
PURPOSE OF REVIEW With the advent of antiretroviral therapy, people with HIV (PWH) are living longer and are at risk of developing age-related comorbid illnesses, such as chronic kidney disease (CKD). The purpose of this review article is to summarize recent advances in the diagnosis and management of kidney disease in PWH, and ultimately inform clinical practice. RECENT FINDINGS Individuals of West African descent are often genetically predisposed to develop CKD. Among carriers of the APOL-1 risk variant, Na+/K+ transport has been identified as the proximal driver in APOL-1-mediated pathogenesis. The use of urine biomarkers in CKD diagnosis among PWH has been supported and is comparable to the general population. Additionally, novel CKD therapies, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists can potentially offer significant clinical benefit to PWH with CKD. SUMMARY Despite being an underrepresented group in clinical trials, recent research findings have broadened our understanding of kidney disease in PWH. Given that PWH experience an increased risk of developing CKD, early detection and management is vital in improving quality of life and overall healthcare outcomes.
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Affiliation(s)
- Sherley M Mejia
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Clara J Fischman
- Renal-Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Meghan E Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
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Zahr RS, Kang G, Zhang X, Rashkin SR, Kovesdy CP, Takemoto C, Weiss M, Lebensburger J, Ataga KI, Saraf SL. Development of Polygenic Risk Score for Persistent Albuminuria in Children and Adults With Sickle Cell Anemia. Am J Hematol 2025. [PMID: 40186439 DOI: 10.1002/ajh.27678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 03/09/2025] [Accepted: 03/16/2025] [Indexed: 04/07/2025]
Abstract
Albuminuria is associated with high-risk apolipoprotein-L1 variants (APOL1 G1/G2) in patients with sickle cell anemia (SCA). However, this gene variant does not account for all chronic kidney disease (CKD) risk. We hypothesized that we could develop a polygenic risk score (PRS) for CKD in SCA, combining APOL1 G1/G2 with other candidate genes that modify SCA severity and further stratify patients into risk categories based on this risk score. Variants in APOL1, HMOX1 (rs743811), BCL11A (rs1424407), and α-thalassemia (α-3.7) were identified in children with SCA enrolled in the Sickle Cell Clinical Research and Intervention Program longitudinal cohort (SCCRIP). We individually tested the association of these variants with persistent albuminuria, tested a three-variant PRS (PRS-3) (APOL1, BCL11A (rs1424407), and α-3.7), and developed a four-variant PRS (PRS-4) after adding HMOX1 (rs743811) to PRS-3 using the summation of high-risk alleles. An adult SCA cohort from the University of Illinois, Chicago (UIC), was used for validation. Persistent albuminuria was defined as having a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g on at least 2 of 3 consecutive measurements. In both cohorts, APOL1 risk variants increased the risk while α-thalassemia protected against persistent albuminuria. PRS-4 was significantly associated with persistent albuminuria (SCCRIP: p = 0.004; UIC: p = 0.00016). When stratifying patients into three and four risk categories based on the PRS, 58% and 86% of the high-risk (PRS-3) and 54% and 89% of very high-risk (PRS-4) categories developed persistent albuminuria cases in the SCCRIP and UIC cohorts, respectively. A PRS may identify high-risk SCA patients for albuminuria. Applying this PRS to guide the early implementation of disease modifiers and renoprotective therapies may help reduce the burden of SCA-related CKD. Trial Registration: NCT02098863.
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Affiliation(s)
- Rima S Zahr
- Department of Paediatric Nephrology and Hypertension, UTHSC, Memphis, Tennessee, USA
| | - Guolian Kang
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Xu Zhang
- Department of Haematology and Oncology, Sickle Cell Center, UIC, Chicago, Illinois, USA
| | - Sara R Rashkin
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | | | - Clifford Takemoto
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Mitch Weiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | | | | | - Santosh L Saraf
- Department of Haematology and Oncology, Sickle Cell Center, UIC, Chicago, Illinois, USA
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Maslyennikov Y, Bărar AA, Rusu CC, Potra AR, Tirinescu D, Ticala M, Urs A, Pralea IE, Iuga CA, Moldovan DT, Kacso IM. The Spectrum of Minimal Change Disease/Focal Segmental Glomerulosclerosis: From Pathogenesis to Proteomic Biomarker Research. Int J Mol Sci 2025; 26:2450. [PMID: 40141093 PMCID: PMC11941885 DOI: 10.3390/ijms26062450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Podocyte injury plays a central role in both focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Pathogenic mechanisms are diverse and incompletely understood, partially overlap between FSGS and MCD, and are not reflected by kidney biopsy. In order to optimize the current variable response to treatment, personalized management should rely on pathogenesis. One promising approach involves identifying biomarkers associated with specific pathogenic pathways. With the advancement of technology, proteomic studies could be a valuable tool to improve knowledge in this area and define valid biomarkers, as they have in other areas of glomerular disease. This work attempts to cover and discuss the main mechanisms of podocyte injury, followed by a review of the recent literature on proteomic biomarker studies in podocytopathies. Most of these studies have been conducted on biofluids, while tissue proteomic studies applied to podocytopathies remain limited. While we recognize the importance of non-invasive biofluid biomarkers, we propose a sequential approach for their development: tissue proteomics could first identify proteins with increased expression that may reflect underlying disease mechanisms; subsequently, the validation of these proteins in urine or plasma could pave the way to a diagnostic and prognostic biomarker-based approach.
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Affiliation(s)
- Yuriy Maslyennikov
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Andrada Alina Bărar
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Crina Claudia Rusu
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Alina Ramona Potra
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Dacian Tirinescu
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Maria Ticala
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Alexandra Urs
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Ioana Ecaterina Pralea
- Department of Personalized Medicine and Rare Diseases, MedFuture—Research Centre for Biomedical Research, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (I.E.P.); (C.A.I.)
| | - Cristina Adela Iuga
- Department of Personalized Medicine and Rare Diseases, MedFuture—Research Centre for Biomedical Research, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (I.E.P.); (C.A.I.)
- Department of Drug Analysis, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Diana Tania Moldovan
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Ina Maria Kacso
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
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Sheehy S, Friedman D, Liu C, Lunetta KL, Zirpoli G, Palmer JR. Association between Apolipoprotein L1 genetic variants and risk of preeclampsia and preterm birth among U.S. Black women. Eur J Obstet Gynecol Reprod Biol X 2025; 25:100365. [PMID: 39895997 PMCID: PMC11783058 DOI: 10.1016/j.eurox.2025.100365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/02/2025] [Accepted: 01/06/2025] [Indexed: 02/04/2025] Open
Abstract
Background Preeclampsia and preterm birth disproportionally affects Black women, but the current understanding of genetic predisposition to preeclampsia and preterm birth is rudimentary. It has been hypothesized that carriers of high-risk genetic variants in the apolipoprotein L1 gene (APOL1) may have an increased risk of preeclampsia and preterm birth. These genetic variants are found only among individuals of recent African ancestry. Previous studies have been small and have yielded inconsistent results. Objective To examine whether APOL1 genetic variants are associated with risk of preeclampsia or preterm birth. Study design We conducted a retrospective case-control study of 6616 Black women from the Black Women's Health Study, a cohort of self-identified Black women in the U.S. Genotype data on APOL1 risk alleles for this case control study were obtained through new genotyping and existing genetic data from a prior case control study of breast cancer using the Illumina Infinium Global Diversity Array or Multi Ethnic Genotyping Array. Primary analyses evaluated risk based on a recessive model, comparing women who carried two APOL1 risk alleles to women who carried zero or one risk allele. We used multivariable logistic regression models to examine associations among 1473 participants with a history of preeclampsia (cases) and 5143 parous women who had not experienced preeclampsia (controls), and among 1296 participants who had a history of preterm birth and 5320 without such history. Results The odds ratio (OR) of preeclampsia for two APOL1 risk alleles vs. zero or one risk allele was 0.99 (95 % confidence interval (CI): 0.74, 1.32) after adjustment for principal components, genotype platform, and age in 1995. For preterm birth, the comparable multivariable OR was 1.04 (95 % CI: 0.86, 1.25). Conclusions This large prospective study from a general population of Black women found no evidence of an association of APOL1 genotype with risk of either preeclampsia or preterm birth.
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Affiliation(s)
| | | | - Chunyu Liu
- Department of Biostatistics, Boston University School of Public Health, USA
| | - Kathryn L. Lunetta
- Department of Biostatistics, Boston University School of Public Health, USA
| | - Gary Zirpoli
- Slone Epidemiology Center, Boston University, USA
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Tassiopoulos KK, Wu K, Wu Z, Overton ET, Palella FJ, Wyatt C, Kalayjian RC, Bruggeman LA. APOL1 Genotype and HIV Infection: 20-Year Outcomes for CKD, Cardiovascular Disease, and Hypertension. Kidney Int Rep 2025; 10:855-865. [PMID: 40225368 PMCID: PMC11993672 DOI: 10.1016/j.ekir.2024.12.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/10/2024] [Accepted: 12/16/2024] [Indexed: 04/15/2025] Open
Abstract
Introduction APOL1 variant alleles substantially increase the risk for chronic kidney disease (CKD) in Black individuals, especially in the setting of HIV infection; however, their impact on hypertension and cardiovascular disease (CVD) is unclear. Methods Black persons with HIV (n = 1194) followed in the AIDS Clinical Trials Group (ACTG) observational studies A5001 and A5322 were genotyped for APOL1 risk alleles. Cox proportional hazard models were used to assess associations between APOL1 genotype and incident CKD, CVD, and hypertension, and linear mixed effects models were used to examine associations with longitudinal estimated glomerular filtration rate (eGFR) and proteinuria. Plasma HIV-1 viral suppression was evaluated as an effect modifier. Results APOL1 genotype was associated with CKD, but not with hypertension or CVD, although CVD events were infrequent in this relatively young cohort. Annual rates of eGFR decline and proteinuria were greater among persons with APOL1 risk alleles, including a detrimental effect of 1 APOL1 risk allele, which only became evident in the second decade of follow-up. Sustained HIV-1 viral suppression did not alter the association between incident CKD and APOL1 genotype; however, it was associated with a slower rate of eGFR decline and less proteinuria in participants with at least 1 APOL1 risk allele, including individuals with eGFRs above the CKD threshold throughout follow-up. Conclusion Among treated persons with HIV, APOL1 risk alleles were associated with CKD and eGFR decline, including an effect of 1 APOL1 risk allele which took longer to manifest and was greater in individuals who did not achieve sustained viral suppression. Conversely, no association between APOL1 risk alleles and incident hypertension or CVD was detected.
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Affiliation(s)
| | - Kunling Wu
- Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Zhenzhen Wu
- Department of Inflammation & Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Edgar T. Overton
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
- ViiV Healthcare Medical Affairs, Durham, North Carolina, USA
| | - Frank J. Palella
- Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Christina Wyatt
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Robert C. Kalayjian
- Division of Infectious Diseases, Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Leslie A. Bruggeman
- Department of Inflammation & Immunity, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Kidney Medicine, Cleveland Clinic, Cleveland, Ohio, USA
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10
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Zanoni F, Obayemi JE, Gandla D, Castellano G, Keating BJ. Emerging role of genetics in kidney transplantation. Kidney Int 2025; 107:424-433. [PMID: 39710162 DOI: 10.1016/j.kint.2024.09.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 09/16/2024] [Accepted: 09/25/2024] [Indexed: 12/24/2024]
Abstract
The advent of more affordable genomic analytical pipelines has facilitated the expansion of genetic studies in kidney transplantation. Advances in genetic sequencing have allowed for a greater understanding of the genetic basis of chronic kidney disease, which has helped to guide transplant management and address issues related to living donation in specific disease settings. Recent efforts have shown significant effects of genetic ancestry and donor APOL1 risk genotypes in determining worse allograft outcomes and increased donation risks. Genetic studies in kidney transplantation outcomes have started to assess the effects of donor and recipient genetics in primary disease recurrence and transplant-related comorbidities, while genome-wide donor-recipient genetic incompatibilities have been shown to represent an important determinant of alloimmunity. Future large-scale comprehensive studies will shed light on the clinical utility of integrative genomics in the kidney transplantation setting.
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Affiliation(s)
- Francesca Zanoni
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Transplantation, Department of Surgery, New York University Langone Health, Grossman School of Medicine, New York, New York, USA
| | - Joy E Obayemi
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA; Comprehensive Transplant Center, Department of Surgery, Northwestern University, Chicago Illinois, USA
| | - Divya Gandla
- Division of Transplantation, Department of Surgery, New York University Langone Health, Grossman School of Medicine, New York, New York, USA
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Science and Community Health, University of Milan, Milan, Italy
| | - Brendan J Keating
- Institute of Systems Genetics, New York University Langone Health, Grossman School of Medicine, New York, New York, USA.
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11
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Yeboah EK, Seshan SV, Pariya F, Khan S, Azhar M, Salifu M, Saggi S. Collapsing Focal Segmental Glomerulosclerosis With Concurrent IgG4 Nephropathy. Cureus 2025; 17:e81031. [PMID: 40264599 PMCID: PMC12013533 DOI: 10.7759/cureus.81031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Accepted: 03/22/2025] [Indexed: 04/24/2025] Open
Abstract
A 41-year-old male with a history of chronic kidney disease, hypertension, and psoriasis was referred to the nephrologist for worsening kidney function associated with nephrotic range proteinuria. The patient had no symptoms, but the initial workup showed elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), positive double-stranded DNA antibody(anti-DsDNA) but normal complement levels, normal antinuclear antibody (ANA) and negative beta-glycoprotein-1 IgG, IgM, and IgA. Further, the workup revealed the patient had elevated total immunoglobulin as well as elevated IgG subsets 2, 3, and 4. He was also found to have a high variant of apolipoprotein L1 (APOL1). A renal biopsy revealed diffuse active, subacute, and chronic interstitial inflammation, plasma cell-rich (25% IgG4 positive), confirming IgG4-related tubulointerstitial nephritis with concomitant IgG4 dominant, PLA2R negative membranous glomerulonephritis. There was also a severe podocytopathy in the form of diffuse segmental/global collapsing glomerulopathy with sclerosing changes as well as global glomerulosclerosis, extensive tubular atrophy with mild interstitial changes suggestive of a variant of focal segmental glomerulosclerosis (FSGS). A diagnosis of APOL-1 collapsing glomerulopathy with IgG4 nephropathy was made based on clinical and pathological findings. The patient's kidney function stabilized, and IgG4 levels returned to normal after the patient was initiated on 60 mg daily prednisolone. The steroid was tapered off and the patient was started on mycophenolate mofetil 1000 mg twice daily. To our knowledge, this is the first reported case of IgG4-related kidney disease with concurrent severe APOL1-associated collapsing glomerulopathy.
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Affiliation(s)
- Eugene K Yeboah
- Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Surya V Seshan
- Pathology and Laboratory Medicine, Weil Cornell Medicine, New York, USA
| | - Fnu Pariya
- Nephrology, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Sulayman Khan
- Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Muhammad Azhar
- Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Moro Salifu
- Nephrology, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Subodh Saggi
- Nephrology, State University of New York Downstate Medical Center, Brooklyn, USA
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12
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Ray PE. Progression of HIV-1 CKDs: Viral Load Versus APOL1 Risk Alleles. Kidney Int Rep 2025; 10:657-659. [PMID: 40225366 PMCID: PMC11993681 DOI: 10.1016/j.ekir.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025] Open
Affiliation(s)
- Patricio E. Ray
- Child Health Research Center and Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
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13
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Zhu Y, Xu G. Advances in Focal Segmental Glomerulosclerosis Treatment From the Perspective of the Newest Mechanisms of Podocyte Injury. Drug Des Devel Ther 2025; 19:857-875. [PMID: 39935575 PMCID: PMC11812565 DOI: 10.2147/dddt.s498457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/19/2024] [Indexed: 02/13/2025] Open
Abstract
Podocyte injury was widely recognized as a fundamental mechanism driving the progression of focal segmental glomerulosclerosis (FSGS). Recent research has therefore focused on the development of targeted therapies aimed at disrupting specific pathogenic signaling cascades within podocytes, resulting in noteworthy advancements. The role of mechanisms such as alterations in the actin cytoskeleton, oxidative stress, mitochondrial dysfunction, and inadequate autophagy within the microenvironment of podocyte injury have garnered increasing attention. Corresponding targeted medications such as Abatacept, chemokine receptor (CCR) inhibitors, CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), adenosine monophosphate-activated protein kinase (AMPK) activators, and Adalimumab are currently under investigation. Notably, some medications such as Rituximab and Sparsentan, may simultaneously target multiple downstream mechanisms, Furthermore, exploring molecular strategies for established medications and developing novel treatments guided by biomarkers such as Anti-CD40 antibody, blood microRNA, urinary microRNA, and tumor necrosis factor-alpha (TNF-α) may provide additional therapeutic avenues for patients with FSGS.
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Affiliation(s)
- Yan Zhu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
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14
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Simeone CA, McNulty MT, Gupta Y, Genovese G, Sampson MG, Sanna-Cherchi S, Friedman DJ, Pollak MR. The APOL1 p.N264K variant is co-inherited with the G2 kidney disease risk variant through a proximity recombination event. G3 (BETHESDA, MD.) 2025; 15:jkae290. [PMID: 39658338 PMCID: PMC11797048 DOI: 10.1093/g3journal/jkae290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/18/2024] [Accepted: 11/21/2024] [Indexed: 12/12/2024]
Abstract
Black Americans are 3-4 times more likely to develop nondiabetic kidney disease than other populations. Exclusively found in people of recent African (AFR) ancestry, risk variants in Apolipoprotein L1 (APOL1) termed G1 and G2 contribute significantly to this increased susceptibility. Our group and others showed that a missense variant in APOL1, rs73885316 (p.N264K, "M1"), is remarkably protective against APOL1 kidney disease when co-inherited with the G2 risk allele. Since the distance between the M1 and G2 variants is only 367 base pairs, we initially suspected that 2 independent mutation events occurred to create non-risk M1-G0 and M1-G2 haplotypes. Here, we examined APOL1 haplotypes in individuals of AFR ancestry from the 1000 Genomes Project, the Nephrotic Syndrome Study Network (NEPTUNE), and an ancient individual from the Allen Ancient Genome Diversity Project to determine how the M1-G2 haplotype arose. We demonstrate that M1 most likely first appeared on a non-risk G0 haplotype, and that a subsequent recombination event bypassed strong recombination hotspots flanking APOL1 and occurred between p.N388Y389del on a G2 haplotype and M1 on a G0 haplotype to create the M1-G2 haplotype. Observing a recombination event within a small region between clinically relevant loci emphasizes the importance of studying the entire haplotype repertoire of a disease gene and the impact of haplotype backgrounds in disease susceptibility.
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Affiliation(s)
- Christopher A Simeone
- Harvard Medical School, Boston, MA 02215, USA
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Michelle T McNulty
- Division of Pediatric Nephrology, Boston Children's Hospital, Boston, MA 02215, USA
- Kidney Disease Initiative and Medical and Population Genetics Program, Broad Institute, Cambridge, MA 02142, USA
| | - Yask Gupta
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York City, NY 10032, USA
| | - Giulio Genovese
- Harvard Medical School, Boston, MA 02215, USA
- Stanley Center, Broad Institute of MIT and Harvard, Boston, MA 02215, USA
| | - Matthew G Sampson
- Harvard Medical School, Boston, MA 02215, USA
- Division of Pediatric Nephrology, Boston Children's Hospital, Boston, MA 02215, USA
- Kidney Disease Initiative and Medical and Population Genetics Program, Broad Institute, Cambridge, MA 02142, USA
- Division of Nephrology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Simone Sanna-Cherchi
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, Columbia University, New York City, NY 10032, USA
| | - David J Friedman
- Harvard Medical School, Boston, MA 02215, USA
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Martin R Pollak
- Harvard Medical School, Boston, MA 02215, USA
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
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15
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Singhal PC, Skorecki K. APOL1 Dynamics in Diabetic Kidney Disease and Hypertension. Biomolecules 2025; 15:205. [PMID: 40001508 PMCID: PMC11853202 DOI: 10.3390/biom15020205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
APOL1 Renal Risk Variants (APOL1RRVs, G1, and G2) are known to be toxic to glomerular podocytes and causally associated with an enhanced prevalence and progression of many different etiologies of chronic kidney disease (CKD), leading to the delineation of a new disease designation of APOL1-Mediated Kidney Disease (AMKD). Notably, APOL1RRVs have not consistently been shown to increase the prevalence or severity of diabetic kidney disease (DKD) progression, which is the most common cause of End-Stage Kidney Disease (ESKD). While this apparent discrepancy seems perplexing, its clarification should provide important mechanistic and therapeutic insights. Activation of the Renin-Angiotensin System (RAS) plays a critical role in the development and progression of DKD. Recent in vitro and in vivo studies also demonstrated that RAS activation contributes to kidney cell injury in AMKD experimental models. Both high glucose, as well as APOL1RRVs escalate the podocyte expression of miR193a, a known mediator of glomerulosclerosis, including idiopathic Focal Segmental Glomerular Sclerosis (FSGS) and DKD. We propose that either the RAS and/or miR193a levels in the diabetic milieu are already maximally conducive to kidney target cell injury and, therefore, are agnostic to further injury in response to APOL1RRVs. Similarly, the contributory role of hypertension (which is frequently reported as the second most common cause of ESKD) in the progression of AMKD remains a controversial issue. Since several clinical reports have shown that controlling hypertension does not consistently slow the progression of AMKD, this has led to a formulation wherein APOL1-RRVs primarily lead to kidney injury with accompanying hypertension. Notably, half a decade later, the notion that hypertension is not a cause but rather a consequence of kidney injury was contested by investigators analyzing the Mount Sinai BioMe repository, a comprehensive clinical and genetic database including participants with APOL1RRVs. These investigators observed that hypertension predated the observed decline in GFR in individuals with APOL1RRVs by ten years. In the present study, we discuss the mechanistic forces that may underpin the gaps in these clinical manifestations, which did not allow the temporal association of hypertension with AMKD to be translated into causation and may also dissociate DKD and AMKD. We have hypothesized models that need to be validated in future experimental studies.
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Affiliation(s)
- Pravin C. Singhal
- Department of Medicine, Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA
| | - Karl Skorecki
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel;
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3525433, Israel
- Department of Nephrology, Rambam Health Care Campus, Haifa 3109601, Israel
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16
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Gbadegesin RA, Ulasi I, Ajayi S, Raji Y, Olanrewaju T, Osafo C, Ademola AD, Asinobi A, Winkler CA, Burke D, Arogundade F, Ekem I, Plange-Rhule J, Mamven M, Matekole M, Amodu O, Cooper R, Antwi S, Adeyemo AA, Ilori TO, Adabayeri V, Nyarko A, Ghansah A, Amira T, Solarin A, Awobusuyi O, Kimmel PL, Brosius FC, Makusidi M, Odenigbo U, Kretzler M, Hodgin JB, Pollak MR, Boima V, Freedman BI, Palmer ND, Collins B, Phadnis M, Smith J, Agwai CI, Okoye O, Abdu A, Wilson J, Williams W, Salako BL, Parekh RS, Tayo B, Adu D, Ojo A. APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans. N Engl J Med 2025; 392:228-238. [PMID: 39465900 PMCID: PMC11735277 DOI: 10.1056/nejmoa2404211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
BACKGROUND Apolipoprotein L1 gene (APOL1) variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans, a major group in the Black population. METHODS We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease. We analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex. RESULTS Among 8355 participants (4712 with CKD stages 2 through 5, 866 with glomerular diseases, and 2777 with no kidney disease), the prevalence of monoallelic APOL1 variants was 43.0% and that of biallelic APOL1 variants was 29.7%. Participants with two APOL1 risk alleles had higher odds of having CKD than those with one risk allele or no risk alleles (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.11 to 1.40), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.84; 95% CI, 1.30 to 2.61). Participants with one APOL1 risk allele had higher odds of having CKD than those with no risk alleles (adjusted odds ratio, 1.18; 95% CI, 1.04 to 1.33), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.61; 95% CI, 1.04 to 2.48). The inclusion of covariates did not modify the association of monoallelic and biallelic APOL1 variants with CKD or focal segmental glomerulosclerosis. CONCLUSIONS In this study, monoallelic APOL1 variants were associated with 18% higher odds of CKD and 61% higher odds of focal segmental glomerulosclerosis; biallelic APOL1 variants were associated with 25% higher odds of CKD and 84% higher odds of focal segmental glomerulosclerosis. (Funded by the National Human Genome Research Institute and others.).
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Affiliation(s)
- Rasheed A. Gbadegesin
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina. USA
| | - Ifeoma Ulasi
- Department of Medicine, University of Nigeria, Enugu State, Nigeria
| | - Samuel Ajayi
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Yemi Raji
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Charlotte Osafo
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Adebowale D. Ademola
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Adanze Asinobi
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Cheryl A. Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - David Burke
- Departments of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Fatiu Arogundade
- Department of Medicine, Obafemi Awolowo University, Ile- Ife, Nigeria
| | - Ivy Ekem
- Department of Medicine, University of Cape Coast, Cape Coast, Ghana
| | | | - Manmak Mamven
- Department of Medicine, University of Abuja, Abuja, Nigeria
| | - Michael Matekole
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Olukemi Amodu
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Richard Cooper
- Parkinson School of Health Sciences and Public Health, Loyola University, Chicago. USA
| | - Sampson Antwi
- Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Adebowale A. Adeyemo
- Centre for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Titilayo O. Ilori
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Victoria Adabayeri
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Alexander Nyarko
- Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana
| | - Anita Ghansah
- Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana
| | - Toyin Amira
- Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Adaobi Solarin
- Department of Medicine, College of Medicine, Lagos State University, Lagos, Nigeria
| | - Olugbenga Awobusuyi
- Department of Medicine, College of Medicine, Lagos State University, Lagos, Nigeria
| | - Paul L. Kimmel
- Division of Kidney, Urologic and Digestive Disease, NIDDK, NIH, Bethesda, USA
| | - Frank Chip Brosius
- Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Muhammad Makusidi
- Department of Medicine, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
| | - Uzoma Odenigbo
- Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria
| | - Matthias Kretzler
- Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jeffrey B. Hodgin
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Martin R. Pollak
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Vincent Boima
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Barry I. Freedman
- Department of Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Nicholette D. Palmer
- Department of Biochemistry, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Bernard Collins
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - Milind Phadnis
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jill Smith
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Celia I. Agwai
- Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ogochukwu Okoye
- Delta State University Teaching Hospital, Oghara, Delta state, Nigeria
| | - Aliyu Abdu
- Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria
| | - Jillian Wilson
- Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Winfred Williams
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Babatunde L. Salako
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Rulan S. Parekh
- Department of Medicine and Pediatrics, Women’s College Hospital, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
| | - Bamidele Tayo
- Parkinson School of Health Sciences and Public Health, Loyola University, Chicago. USA
| | - Dwomoa Adu
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Akinlolu Ojo
- Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
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17
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Zimmerman B, Dakin LA, Fortier A, Nanou E, Blasio A, Mann J, Miller H, Fletcher M, Wang T, Nanthakumar S, McCarthy G, Matar C, Matsye P, Wang G, Snyder P, Daniel K, Swamy H, Sullivan K, Bright F, Powers A, Gagnon KJ, Lu F, Paula S, Khare-Pandit S, Henry L, Hamel M, Denis F, Nicolas O, Hariparsad N, Kumar S, Proctor J, Senter T, Furey B, Bunnage ME. Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease. Nat Commun 2025; 16:167. [PMID: 39747090 PMCID: PMC11696124 DOI: 10.1038/s41467-024-55408-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
Chronic kidney disease affects ~10% of people worldwide and there are no disease modifying therapeutics that address the underlying cause of any form of kidney disease. Genome wide association studies have identified the G1 and G2 variants in the apolipoprotein L1 (APOL1) gene as major contributors to a subtype of proteinuric kidney disease now referred to as APOL1-mediated kidney disease (AMKD). We hypothesized that inhibition of APOL1 could have therapeutic potential for this genetically-defined form of kidney disease. Here we describe the development of preclinical assays and the discovery of potent and specific APOL1 inhibitors with drug-like properties. We provide evidence that APOL1 channel activity drives podocyte injury and that inhibition of this activity stops APOL1-mediated cell death and kidney damage in a transgenic mouse model. These preclinical data, combined with clinical data from our previously published phase 2 proof-of-concept study, support the potential of APOL1 channel inhibition for the treatment of AMKD.
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Affiliation(s)
| | | | - Anne Fortier
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | - Angelo Blasio
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - James Mann
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - Howard Miller
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | | | | | | | - Caline Matar
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - Prachi Matsye
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - Guanyu Wang
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | - Kevin Daniel
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - Harsha Swamy
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | | | - Audrey Powers
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | - Fan Lu
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - Steven Paula
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | - Larry Henry
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | - Martine Hamel
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
| | | | | | | | | | | | | | - Brinley Furey
- Vertex Pharmaceuticals Incorporated, Boston, MA, USA
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18
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Altintas MM, Agarwal S, Sudhini Y, Zhu K, Wei C, Reiser J. Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders. ANNUAL REVIEW OF PATHOLOGY 2025; 20:329-353. [PMID: 39854184 PMCID: PMC11875227 DOI: 10.1146/annurev-pathol-051220-092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.
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Affiliation(s)
- Mehmet M Altintas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | | | - Yashwanth Sudhini
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ke Zhu
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Changli Wei
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Jochen Reiser
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
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19
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Tumlin J, Rovin B, Anders HJ, Mysler EF, Jayne DR, Takeuchi T, Lindholm C, Weiss G, Sorrentino A, Woollard K, Ferrari N. Targeting the Type I Interferon Pathway in Glomerular Kidney Disease: Rationale and Therapeutic Opportunities. Kidney Int Rep 2025; 10:29-39. [PMID: 39810777 PMCID: PMC11725820 DOI: 10.1016/j.ekir.2024.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 01/16/2025] Open
Abstract
Type I interferons (IFNs) are immunostimulatory molecules that can activate the innate and adaptive immune systems. In cases of immune dysfunction, prolonged activation of the type I IFN pathway has been correlated with kidney tissue damage in a wide range of kidney disorders, such as lupus nephritis (LN) and focal segmental glomerulosclerosis (FSGS). Genetic mutations, such as APOL1 risk variants in conjunction with elevated type I IFN expression, are also associated with higher rates of chronic kidney disease in patients with LN and collapsing FSGS. Long-term activation of the type I IFN pathway can result in chronic inflammation, leading to kidney tissue damage, cell death, and decline in organ function. Thus, therapeutic strategies targeting type I IFN could provide clinical benefits to patients with immune dysregulation who are at risk of developing impaired kidney function. Here, we present a critical review of type I IFN signaling, the consequences of chronically elevated type I IFN expression, and therapeutic strategies targeting type I IFN signaling in the context of kidney disease.
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Affiliation(s)
- James Tumlin
- NephroNet Clinical Trials Consortium, Buford, Georgia, USA
| | - Brad Rovin
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | | | - Tsutomu Takeuchi
- Department of Rheumatology and Applied Immunology, Saitama Medical University and Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, Japan
| | | | - Gudrun Weiss
- Global Medical Affairs, Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Alessandro Sorrentino
- Global Medical Affairs, Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Kevin Woollard
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Nicola Ferrari
- Translational Science and Experimental Medicine, Early R&I, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Munis MA, Chen Q, Hill TM, Zhuo M, Schachter AD, Bhandari SK, Hever A, Harrison TN, Fernandes AW, Sim JJ. Incidence and Proportion of Primary Focal Segmental Glomerulosclerosis (FSGS) among a Racially and Ethnically Diverse Adult Patient Population between 2010 and 2021. Clin J Am Soc Nephrol 2024; 20:01277230-990000000-00479. [PMID: 39392691 PMCID: PMC11835197 DOI: 10.2215/cjn.0000000590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/07/2024] [Indexed: 10/13/2024]
Abstract
Key Points Primary FSGS is a rare immune mediated glomerulopathy that accounted for 16.6% for all FSGS reported biopsies among a diverse patient population. From 2010 to 2021, the standardized incidence of primary FSGS was estimated at 1.7 cases per 100,000 patient-years. The highest incidence of primary FSGS was observed among Black (3.2) and Asian (2.7 cases per 100,000 patient-years) people. Background Focal segmental glomerulosclerosis (FSGS) refers to a pattern of glomerular injury but also includes primary FSGS which is considered as an immune-mediated glomerulopathy. We sought to determine the incidence of primary FSGS and proportion of patients with FSGS who have primary FSGS among a large diverse patient population in the United States. Methods A cross-sectional study (2010–2021) was performed within an integrated health system in patients (age 18 or older) with biopsy-proven FSGS. Among biopsies with FSGS as the first diagnosis on pathology report, chart reviews were performed to determine primary FSGS, defined as podocyte foot process effacement ≥80% on electron microscopy. The proportion of patients with primary FSGS and annual incidence rate (IR) (per 100,000 patient-years) were calculated. Standardized IR were determined by age, sex, and race and ethnicity based on US population structure of the 5-year (2018–2022) American Community Survey estimates. Results We identified 3838 patients with FSGS reported on biopsy. Among 1502 with FSGS as the principal diagnosis, 637 met criteria for primary FSGS (mean [SD] age 55.5 years [17.9], 56.5% male, 35.6% Hispanic, 28.7% White, 17.9% Asian/Pacific Islander, and 16.0% Black). The mean standardized IR (confidence interval) of primary FSGS was 1.7 (0.9 to 2.5) per 100,000 patient-years during the study period. The standardized annual IR ranged from 1.3 to 2.4 per 100,000 patient-years. IR (per 100,000 patient-years) were highest among Black (3.2), Asian (2.7), and Pacific Islander (2.8) patients. Conclusions Primary FSGS accounted for 16.6% of biopsy-proven FSGS. Primary FSGS is a likely a rare disease with incidence highest among Black, Asian, and Pacific Islander people. More precise identification of primary FSGS may facilitate work to improve understanding of this glomerulopathy and improve kidney outcomes.
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Affiliation(s)
- Mercedes A. Munis
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - Qiaoling Chen
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - T. Matthew Hill
- Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
| | - Min Zhuo
- Visterra Inc., Waltham, Massachusetts
| | | | - Simran K. Bhandari
- Department of Internal Medicine, Downey Medical Center, Downey, California
| | - Aviv Hever
- Department of Pathology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
| | - Teresa N. Harrison
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - Ancilla W. Fernandes
- Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
| | - John J. Sim
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
- Division of Nephrology and Hypertension, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
- Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California
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Kumar V, Kaur P, Ayasolla K, Jha A, Wiqas A, Vashistha H, Saleem MA, Popik W, Malhotra A, Gebeshuber CA, Skorecki K, Singhal PC. APOL1 Modulates Renin-Angiotensin System. Biomolecules 2024; 14:1575. [PMID: 39766282 PMCID: PMC11674849 DOI: 10.3390/biom14121575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/21/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
Patients carrying APOL1 risk alleles (G1 and G2) have a higher risk of developing Focal Segmental Glomerulosclerosis (FSGS); we hypothesized that escalated levels of miR193a contribute to kidney injury by activating renin-angiotensin system (RAS) in the APOL1 milieus. Differentiated podocytes (DPDs) stably expressing vector (V/DPD), G0 (G0/DPDs), G1 (G1/DPDs), and G2 (G2/DPDs) were evaluated for renin, Vitamin D receptor (VDR), and podocyte molecular markers (PDMMs, including WT1, Podocalyxin, Nephrin, and Cluster of Differentiation [CD]2 associated protein [AP]). G0/DPDs displayed attenuated renin but an enhanced expression of VDR and Wilms Tumor [WT]1, including other PDMMs; in contrast, G1/DPDs and G2/DPDs exhibited enhanced expression of renin but decreased expression of VDR and WT1, as well as other PDMMs (at both the protein and mRNA levels). G1/DPDs and G2/DPDs also showed increased mRNA expression for Angiotensinogen and Angiotensin II Type 1 (AT1R) and 2 (AT2R) receptors. Protein concentrations of Brain Acid-Soluble Protein [BASP]1, Enhancer of Zeste Homolog [EZH]2, Histone Deacetylase [HDAC]1, and Histone 3 Lysine27 trimethylated [H3K27me3] in WT1-IP (immunoprecipitated proteins with WT1 antibody) fractions were significantly higher in G0/DPDs vs. G1/DPD and G2/DPDs. Moreover, DPD-silenced BASP1 displayed an increased expression of renin. Notably, VDR agonist-treated DPDs showed escalated levels of VDR and a higher expression of PDMMs, but an attenuated expression of renin. Human Embryonic Kidney (HEK) cells transfected with increasing APOL1(G0) plasmid concentrations showed a corresponding reduction in renin mRNA expression. Bioinformatics studies predicted the miR193a target sites in the VDR 3'UTR (untranslated region), and the luciferase assay confirmed the predicted sites. As expected, podocytes transfected with miR193a plasmid displayed a reduced VDR and an enhanced expression of renin. Renal cortical section immunolabeling in miR193a transgenic (Tr) mice showed renin-expressing podocytes. Kidney tissue extracts from miR193aTr mice also showed reduced expression of VDR and PDMMs, but enhanced expression of Renin. Blood Ang II levels were higher in miR193aTr, APOLG1, and APOL1G1/G2 mice when compared to control mice. Based on these findings, miR193a regulates the activation of RAS and podocyte molecular markers through modulation of VDR and WT1 in the APOL1 milieu.
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Affiliation(s)
- Vinod Kumar
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
- Department of Nephrology and Dermatology, Postgraduate Institute for Medical Research, Chandigarh 160012, India
| | - Prabhjot Kaur
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
- Department of Nephrology and Dermatology, Postgraduate Institute for Medical Research, Chandigarh 160012, India
| | - Kameshwar Ayasolla
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
| | - Alok Jha
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
| | - Amen Wiqas
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
| | - Himanshu Vashistha
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
| | - Moin A. Saleem
- Department of Pediatrics, Bristol School of Medicine, University of Bristol, Bristol BS8 1UD, UK;
| | - Waldemar Popik
- Center for AIDS Health Disparity, Meharry Medical College, Nashville, TN 37208, USA;
| | - Ashwani Malhotra
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
| | | | - Karl Skorecki
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel;
| | - Pravin C. Singhal
- Department of Medicine and Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA; (V.K.); (P.K.); (K.A.); (A.J.); (A.W.); (H.V.); (A.M.)
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Ray PE, Li J, Das J, Xu L, Yu J, Han Z. Pathogenesis of HIV-associated nephropathy in children and adolescents: taking a hard look 40 years later in the era of gene-environment interactions. Am J Physiol Renal Physiol 2024; 327:F1049-F1066. [PMID: 39323389 PMCID: PMC11687833 DOI: 10.1152/ajprenal.00208.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/16/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024] Open
Abstract
HIV-associated nephropathy (HIVAN) is a kidney disease that affects mainly people of African ancestry with a high HIV-1 viral load. New antiretroviral therapies (ART) have been highly efficient in preventing and improving the outcome of HIVAN. However, providing chronic ART to children and adolescents living with HIV (CALWH) remains a significant challenge all over the world. More than 2.5 million CALWH, including those living in Sub-Saharan Africa, continue to be at high risk of developing HIVAN. Much of our understanding of the pathogenesis of HIVAN is based on studies conducted in transgenic mice and adults with HIVAN. However, CALWH may experience different health outcomes, risk factors, and susceptibilities to HIVAN in comparison to adults. This article reviews the progress made over the last 40 years in understanding the pathogenesis of HIVAN in CALWH, focusing on how the HIV virus, alongside genetic and environmental factors, contributes to the development of this disease. The landmark discovery that two risk alleles of the apolipoprotein-1 (APOL1) gene play a critical role in HIVAN has significantly advanced our understanding of the disease's pathogenesis. However, we still need to understand why renal inflammation persists despite ART and determine whether the kidney may harbor HIV reservoirs that need to be eliminated to cure HIV permanently. For these reasons, we emphasize reviewing how HIV-1 infects renal cells, affects their growth and regeneration, and discussing how inflammatory cytokines and APOL1 affect the outcome of childhood HIVAN.
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Affiliation(s)
- Patricio E Ray
- Department of Pediatrics and Child Health Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Jinliang Li
- Children's National Hospital, Washington, District of Columbia, United States
| | - Jharna Das
- Children's National Hospital, Washington, District of Columbia, United States
| | - Lian Xu
- Children's National Hospital, Washington, District of Columbia, United States
| | - Jing Yu
- Department of Pediatrics and Child Health Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Zhe Han
- Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
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23
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Muthya A, Ekinci EI, Lecamwasam A. What is the spectrum of kidney pathology associated with COVID-19? Intern Med J 2024; 54:1935-1943. [PMID: 39485035 PMCID: PMC11610687 DOI: 10.1111/imj.16540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 08/20/2024] [Indexed: 11/03/2024]
Abstract
Kidney involvement occurs in almost one third of patients hospitalised with coronavirus disease 2019 (COVID-19) and is associated with increased disease severity. This review aims to outline the spectrum of kidney pathology involved in COVID-19. Literature was reviewed systematically on the databases Medline OVID and Scopus in search of case reports, case series, cohort studies and autopsy studies of patients with COVID-19 who underwent kidney biopsies. Studies were published between August 2020 and November 2021. Fourteen studies consisting of 159 patients were included in this review. Acute tubular necrosis is the most common pathology followed by collapsing glomerulopathy, occurring in 40.1% and 28.9% of patients respectively. Of the 46 patients with collapsing glomerulopathy, 44 were of African descent with high-risk apolipoprotein L1 genotypes. Less common glomerular diseases include membranous nephropathy, secondary focal segmental glomerulosclerosis, minimal change disease and primary focal segmental glomerulosclerosis occurring in 5%, 4.4%, 3.1% and 2.5% of patients respectively. Glomerulonephritis occurred in a minority of patients. Direct viral infection has not been found as a definitive aetiology. Acute kidney injury occurs frequently in hospitalised COVID-19 patients and is associated with increased morbidity and mortality. The mechanisms underpinning acute kidney injury are multifactorial. Acute tubular necrosis is the most common. Collapsing glomerulopathy is the most common glomerular injury and is strongly linked to apolipoprotein L1 genotypes. Improved understanding of COVID-19-related kidney pathologies can guide treatment to improve patient outcomes and reduce progression of chronic kidney disease. The longitudinal impact of COVID-19-related kidney disease requires further research.
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Affiliation(s)
- Ankita Muthya
- Department of MedicineUniversity of MelbourneMelbourneVictoriaAustralia
| | - Elif I. Ekinci
- Department of MedicineUniversity of MelbourneMelbourneVictoriaAustralia
- Department of EndocrinologyAustin HealthMelbourneVictoriaAustralia
| | - Ashani Lecamwasam
- Department of MedicineUniversity of MelbourneMelbourneVictoriaAustralia
- Department of EndocrinologyAustin HealthMelbourneVictoriaAustralia
- Department of NephrologyNorthern HealthMelbourneVictoriaAustralia
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24
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Gonzalez-Vicente A, Crawford DC, Bush WS, Wu Z, Bruggeman LA, Nair V, Eichinger F, Wessely O, Kretzler M, O'Toole JF, Sedor JR. Analysis of Glomerular Transcriptomes from Nephrotic Patients Suggest APOL1 Risk Variants Impact Parietal Epithelial Cells. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.11.05.24316766. [PMID: 39830251 PMCID: PMC11741451 DOI: 10.1101/2024.11.05.24316766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
The disproportionate risk for idiopathic proteinuric podocytopathies in Black people is explained, in part, by the presence of two risk alleles (G1 or G2) in the APOL1 gene. The pathogenic mechanisms responsible for this genetic association remain incompletely understood. We analyzed glomerular RNASeq transcriptomes from patients with idiopathic nephrotic syndrome of which 72 had inferred African ancestry (AA) and 152 did not (noAA). Using gene coexpression networks we found a significant association between APOL1 risk allele number and the coexpression metamodule 2 (MM2), even after adjustment for eGFR and proteinuria at biopsy. Unadjusted Kaplan-Meier curves showed that unlike noAA, AA with the highest tertile of MM2 gene activation scores were less likely to achieve complete remission (p≤0.014). Characteristic direction (ChDir) identified a signature of 1481 genes, which separated patients with APOL1 risk alleles from those homozygous for reference APOL1 . Only in AA, the tertile with the highest activation scores of these 1481 genes was less likely to achieve complete remission (p≤0.022) and showed a trend to faster progression to the composite event of kidney failure or loss of 40% eGFR (p≤0.099). The MM2 and ChDir genes significantly overlapped and were both enriched for Epithelial Mesenchymal Transition and inflammation terms. Finally, MM2 significantly overlapped with a parietal epithelial cell (PEC)-identity gene signature but not with a podocyte identity signature. Podocytes expressing variant APOL1s may generate inflammatory signals that activate PECs by paracrine mechanisms contributing to APOL1 nephropathy.
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25
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Sever S, Reiser J. Treatment of Podocytopathies: Risky Business and Our Personal Journey. J Am Soc Nephrol 2024; 35:1600-1602. [PMID: 39484859 PMCID: PMC11543009 DOI: 10.1681/asn.0000000000000415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024] Open
Affiliation(s)
- Sanja Sever
- Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts
| | - Jochen Reiser
- The University of Texas Medical Branch at Galveston, Galveston, Texas
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26
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Yu P, Jin X, Huang W, Wang J, Zhang S, Ren L, Zhang H, Shi S. Characterization of immortalized human podocytes infected with lentivirus as an in vitro model of viral infection-associated podocytopathy. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2024; 13:204-214. [PMID: 39583339 PMCID: PMC11578807 DOI: 10.62347/bbcx1142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/25/2024] [Indexed: 11/26/2024]
Abstract
A large number of studies have shown the association of kidney disease with viral infections in the body. Viral infections cause kidney injury in two manners, the systemic inflammation (cytokine storm) and the direct infection of kidney cells. Concerning direct viral infection of podocytes, the mechanism underlying virus-induced podocyte injury remains largely unknown and requires effective experimental models to facilitate its study. Here, we performed molecular characterization of immortalized human podocyte cell line (HPC) infected with lentivirus by RNA-seq. Bioinformatics analysis revealed a strong innate immune response in the cells, including interferon production and signaling. Meanwhile, activations of ferroptosis pathway and TNF-alpha signaling were also found, consistent with an impaired viability of the cells. Lentiviral infection also upregulated expression of APOL1 as observed in patients with HIV associated nephropathy (HIVAN) and diabetic nephropathy (DN). Interestingly, when the lentiviral infected cells were treated with Adriamycin (ADR), the ADR-associated signaling pathways were not interfered and remained activated as that in the cells treated with ADR only, suggesting that the virus and ADR have distinct mechanisms in damaging podocytes. Thus, the lentivirus-infected HPC cells represent a useful in vitro model of viral infection-associated podocytopathy.
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Affiliation(s)
- Peng Yu
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Xi Jin
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Weijun Huang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Jingjing Wang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Sipang Zhang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Lu Ren
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Haitao Zhang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
| | - Shaolin Shi
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu, China
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Zhang DY, Levin MG, Duda JT, Landry LG, Witschey WR, Damrauer SM, Ritchie MD, Rader DJ. Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles. JCI Insight 2024; 9:e181238. [PMID: 39163132 PMCID: PMC11466179 DOI: 10.1172/jci.insight.181238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).
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Affiliation(s)
| | - Michael G. Levin
- Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Jeffrey T. Duda
- Penn Image Computing and Science Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Walter R. Witschey
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Scott M. Damrauer
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
- Department of Surgery, University of Pennsylvania, and
| | - Marylyn D. Ritchie
- Department of Genetics
- Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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28
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Olabisi OA, Barrett NJ, Lucas A, Smith M, Bethea K, Soldano K, Croall S, Sadeghpour A, Chakraborty H, Wolf M. Design and Rationale of the Phase 2 Baricitinib Study in Apolipoprotein L1-Mediated Kidney Disease (JUSTICE). Kidney Int Rep 2024; 9:2677-2684. [PMID: 39291185 PMCID: PMC11403079 DOI: 10.1016/j.ekir.2024.06.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/06/2024] [Accepted: 06/17/2024] [Indexed: 09/19/2024] Open
Abstract
Introduction Individuals of recent West African ancestry develop focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (HTN-ESKD) at 4 times the rate of White Americans. Two protein-coding variants of the Apolipoprotein L1 (APOL1) gene, G1 and G2, explain 50% to 70% of the excess risk of HTN-ESKD and FSGS among this group. Increased expression of G1 and G2 in the kidney, mediated by Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling, drive pathogenesis of these kidney diseases. Baricitinib is an orally active inhibitor of JAK1/2 that blocks APOL1 synthesis. The Janus kinase-STAT Inhibition to Reduce APOL1-Associated Kidney Disease (JUSTICE) trial is evaluating the antiproteinuric efficacy and safety of baricitinib in patients with APOL1-associated FSGS and HTN-attributed chronic kidney disease (HTN-CKD). Methods JUSTICE is a single-center, randomized, double-blind, placebo-controlled, pilot phase 2 trial of baricitinib in patients with proteinuria, APOL1-associated FSGS or APOL1-associated HTN-CKD without diabetes. A total of 75 African American patients with APOL1-associated CKD, including 25 with FSGS and 50 with HTN-CKD, aged 18 to 70 years will be randomized 2:1 to daily treatment with baricitinib or placebo, respectively. Results The primary efficacy end point will be percent change in urine albumin-to-creatinine ratio (UACR) from baseline to end of month 6. The primary safety end point will be incidence of clinically significant decreases in hemoglobin of ≥ 1g/dl. Conclusion The phase 2 JUSTICE study will characterize the antiproteinuric efficacy and safety of JAK1/2 inhibition with baricitinib in patients with APOL1-associated FSGS and APOL1-associated HTN-CKD.
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Affiliation(s)
- Opeyemi A Olabisi
- Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Nadine J Barrett
- Atrium Health/Wake Forest Comprehensive Cancer Center and Maya Angelo Center for Health Equity, Wake Forest School of Medicine, Wake Forest, North Carolina, USA
- Department of Social Science and Health Policy, Division of Population Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
- Maya Angelo Center for Health Equity, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Anika Lucas
- Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Maurice Smith
- Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Kenisha Bethea
- Duke Clinical and Translational Science Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Karen Soldano
- Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Stephanie Croall
- Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Azita Sadeghpour
- Duke Precision Medicine Program, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Myles Wolf
- Division of Nephrology, Duke University School of Medicine, Durham, North Carolina, USA
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
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29
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Vivante A. Genetics of Chronic Kidney Disease. N Engl J Med 2024; 391:627-639. [PMID: 39141855 DOI: 10.1056/nejmra2308577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Affiliation(s)
- Asaf Vivante
- From the Department of Pediatrics and the Pediatric Nephrology Unit, Edmond and Lily Safra Children's Hospital, and the Nephro-Genetics Clinic and Genetic Kidney Disease Research Laboratory, Sheba Medical Center, Tel Hashomer, and the Faculty of Medicine, Tel Aviv University, Tel Aviv - all in Israel
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30
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Yoshida T, Latt KZ, Santo BA, Shrivastav S, Zhao Y, Fenaroli P, Chung JY, Hewitt SM, Tutino VM, Sarder P, Rosenberg AZ, Winkler CA, Kopp JB. Single-Cell Transcriptional Signatures of Glomerular Disease in Transgenic Mice with APOL1 Variants. J Am Soc Nephrol 2024; 35:1058-1075. [PMID: 38709562 PMCID: PMC11377807 DOI: 10.1681/asn.0000000000000370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/26/2024] [Indexed: 05/08/2024] Open
Abstract
Key Points Apolipoprotein L1 (APOL1)-G1 induced kidney disease in the two APOL1 transgenic mouse models, HIV-associated nephropathy and IFN-γ administration. Glomerular single-nuclear RNA-sequencing identified genes differentially expressed among mice with APOL1-G1 and G0 variants at single-cell resolution. Background Apolipoprotein L1 (APOL1 ) high-risk variants contribute to kidney disease among individuals with African ancestry. We sought to describe cell-specific APOL1 variant–induced pathways using two mouse models. Methods We characterized bacterial artificial chromosome/APOL1 transgenic mice crossed with HIV-associated nephropathy (HIVAN) Tg26 mice and bacterial artificial chromosome/APOL1 transgenic mice given IFN-γ . Results Both mouse models showed more severe glomerular disease in APOL1-G1 compared with APOL1-G0 mice. Synergistic podocyte-damaging pathways activated by APOL1-G1 and by the HIV transgene were identified by glomerular bulk RNA sequencing (RNA-seq) of HIVAN model. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially expressed genes as a function of APOL1 alleles. Shared activated pathways, for example, mammalian target of rapamycin, and differentially expressed genes, for example, Ccn2 , in podocytes in both models suggest novel markers of APOL1-associated kidney disease. HIVAN mouse-model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis glomerular RNA-seq data. Differential effects of the APOL1 -G1 variant on the eukaryotic initiation factor 2 pathway highlighted differences between the two models. Conclusions These findings in two mouse models demonstrated both shared and distinct cell type–specific transcriptomic signatures induced by APOL1 variants. These findings suggest novel therapeutic opportunities for APOL1 glomerulopathies.
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Affiliation(s)
- Teruhiko Yoshida
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland
| | - Khun Zaw Latt
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland
| | - Briana A. Santo
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Shashi Shrivastav
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland
| | - Yongmei Zhao
- Frederick National Laboratory for Cancer Research, NCI, NIH, Frederick, Maryland
| | - Paride Fenaroli
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
- S.C. Nefrologia e Dialisi, AUSL-IRCCS, Reggio Emilia, Italy
| | | | | | - Vincent M. Tutino
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Pinaki Sarder
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York
- College of Medicine, University of Florida, Gainesville, Florida
| | - Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Cheryl A. Winkler
- Frederick National Laboratory for Cancer Research, NCI, NIH, Frederick, Maryland
| | - Jeffrey B. Kopp
- Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland
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Pelchen-Matthews A, Mocroft A, Ryom L, Ross MJ, Sharma S, Coca S, Achhra A, Cornell E, Tracy R, Phillips A, Alonso MM, Toulomi G, Agan BK, Medland N, Wyatt CM. Long-term impact of immediate versus deferred antiretroviral therapy on kidney health in people with HIV. Kidney Int 2024; 106:136-144. [PMID: 38697479 PMCID: PMC11193627 DOI: 10.1016/j.kint.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/20/2024] [Accepted: 04/01/2024] [Indexed: 05/05/2024]
Abstract
People with human immunodeficiency virus (HIV) are at risk for chronic kidney disease (CKD) due to HIV and antiretroviral therapy (ART) nephrotoxicity. Immediate ART initiation reduces mortality and is now the standard of care, but the long-term impact of prolonged ART exposure on CKD is unknown. To evaluate this, the Strategic Timing of Antiretroviral Treatment (START) trial randomized 4,684 ART-naïve adults with CD4 cell count under 500 cells/mm3 to immediate versus deferred ART. We previously reported a small but statistically significantly greater decline in estimated glomerular filtration rate (eGFR) over a median of 2.1 years in participants randomized to deferred versus immediate ART. Here, we compare the incidence of CKD events and changes in eGFR and urine albumin/creatinine ratio (UACR) in participants randomized to immediate versus deferred ART during extended follow-up. Over a median of 9.3 years, eight participants experienced kidney failure or kidney-related death, three in the immediate and five in the deferred ART arms, respectively. Over a median of five years of more comprehensive follow-up, the annual rate of eGFR decline was 1.19 mL/min/1.73m2/year, with no significant difference between treatment arms (difference deferred - immediate arm 0.055; 95% confidence interval -0.106, 0.217 mL/min/1.73m2). Results were similar in models adjusted for baseline covariates associated with CKD, including UACR and APOL1 genotype. Similarly, there was no significant difference between treatment arms in incidence of confirmed UACR 30 mg/g or more (odds ratio 1.13; 95% confidence interval 0.85, 1.51). Thus, our findings provide the most definitive evidence to date in support of the long-term safety of early ART with respect to kidney health.
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Affiliation(s)
- Annegret Pelchen-Matthews
- Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK
| | - Amanda Mocroft
- Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK; CHIP, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lene Ryom
- CHIP, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases 144, Hvidovre University Hospital, Copenhagen, Denmark
| | - Michael J Ross
- Department of Medicine, Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Shweta Sharma
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Steven Coca
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Amit Achhra
- Department of Medicine, Division of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA
| | - Elaine Cornell
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA
| | - Russell Tracy
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA
| | - Andrew Phillips
- Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK
| | - Marta Montero Alonso
- Infectious Diseases Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Giota Toulomi
- Department of Hygiene, Epidemiology & Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Brian K Agan
- Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA
| | - Nicholas Medland
- Kirby Institute, University of New South Wales, Sydney, Australia
| | - Christina M Wyatt
- Department of Medicine, Division of Nephrology, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
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Fisher M, Ross M, DiFranza L, Reidy K. An Update on Viral Infection-Associated Collapsing Glomerulopathy. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:317-325. [PMID: 39084757 PMCID: PMC11296492 DOI: 10.1053/j.akdh.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 11/14/2023] [Accepted: 12/14/2023] [Indexed: 08/02/2024]
Abstract
The COVID-19 era has been a reminder to clinicians around the world of the important role that viral infections play in promoting glomerular disease. Several viral infections including human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, cytomegalovirus, and parvovirus B19 can cause podocyte injury and present with a collapsing glomerulopathy (CG) variant of focal segmental glomerulosclerosis or minimal change disease. CG associated with COVID-19 has been termed COVID-19-associated nephropathy due to its striking resemblance to HIV-associated nephropathy. Host susceptibility is a major determinant of viral infection-associated CG, and the presence of two APOL1 risk variants explains most of the racial predilection to viral-associated CG observed in individuals of African ancestry. Interactions between APOL1 risk variants, viral genes, and the systemic inflammatory response to viral infection all contribute to kidney injury. This review will summarize our current knowledge of viral infection-associated CG, focusing primarily on the clinical presentation, histological features, mechanisms, and disease course of HIV-associated nephropathy and COVID-19-associated nephropathy.
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Affiliation(s)
- Molly Fisher
- Division of Nephrology, Albert Einstein College of Medicine, Montefiore Health System, Bronx, NY.
| | - Michael Ross
- Division of Nephrology, Albert Einstein College of Medicine, Montefiore Health System, Bronx, NY; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Lanny DiFranza
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Health System, Bronx, NY
| | - Kimberly Reidy
- Division of Pediatric Nephrology, The Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY
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Caparali EB, De Gregorio V, Barua M. Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:309-316. [PMID: 39084756 DOI: 10.1053/j.akdh.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 08/02/2024]
Abstract
The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.
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Affiliation(s)
- Emine Bilge Caparali
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vanessa De Gregorio
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Moumita Barua
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
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Tabachnikov O, Skorecki K, Kruzel-Davila E. APOL1 nephropathy - a population genetics success story. Curr Opin Nephrol Hypertens 2024; 33:447-455. [PMID: 38415700 PMCID: PMC11139250 DOI: 10.1097/mnh.0000000000000977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
PURPOSE OF REVIEW More than a decade ago, apolipoprotein L1 ( APOL1 ) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased risk for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending to the development and clinical testing of genomically precise small molecule therapy accompanied by emergence of RNA medicine platforms and clinical testing within just over a decade. RECENT FINDINGS Given the plethora of excellent prior review articles, we will focus on new findings regarding unresolved questions relating mechanism of cell injury with mode of inheritance, regulation and modulation of APOL1 activity, modifiers and triggers for APOL1 kidney risk penetrance, the pleiotropic spectrum of APOL1 related disease beyond the kidney - all within the context of relevance to therapeutic advances. SUMMARY Notwithstanding remaining controversies and uncertainties, promising genomically precise therapies targeted at APOL1 mRNA using antisense oligonucleotides (ASO), inhibitors of APOL1 expression, and small molecules that specifically bind and inhibit APOL1 cation flux are emerging, many already at the clinical trial stage. These therapies hold great promise for mitigating APOL1 kidney injury and possibly other systemic phenotypes as well. A challenge will be to develop guidelines for appropriate use in susceptible individuals who will derive the greatest benefit.
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Affiliation(s)
- Orly Tabachnikov
- Department of Nephrology, Rambam Healthcare Campus, Haifa, Israel
| | - Karl Skorecki
- Department of Nephrology, Rambam Healthcare Campus, Haifa, Israel
- Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion—Israel Institute of Technology, Haifa, Israel
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Etty Kruzel-Davila
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
- Department of Nephrology, Galilee Medical Center, Nahariya, Israel
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Itoku A, Isaac J, Wilson S, Reidy K, Kaskel F. APOL1 Nephropathy Risk Variants Through the Life Course: A Review. Am J Kidney Dis 2024; 84:102-110. [PMID: 38341125 DOI: 10.1053/j.ajkd.2023.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/26/2023] [Accepted: 12/05/2023] [Indexed: 02/12/2024]
Abstract
Two variant alleles of the gene apolipoprotein L1 (APOL1), known as risk variants (RVs), are a major contributor to kidney disease burden in those of African descent. The APOL1 protein contributes to innate immunity and may protect against Trypanosoma, HIV, Salmonella, and leishmaniasis. However, the effects of carrying 1 or more RVs contribute to a variety of disease processes starting as early as in utero and can be exacerbated by other factors (or "second hits"). Indeed, these genetic variations interact with environmental exposures, infections, and systemic disease to modify health outcomes across the life span. This review focuses on APOL1-associated diseases through the life-course perspective and discusses how early exposure to second hits can impact long-term outcomes. APOL1-related kidney disease typically presents in adolescents to young adults, and individuals harboring RVs are more likely to progress to kidney failure than are those with kidney disease who lack APOL-1 RVs. Ongoing research is aimed at elucidating the association of APOL1 RV effects with adverse donor and recipient kidney transplant outcomes. Unfortunately, there is currently no established treatment for APOL1-associated nephropathy. Long-term research is needed to evaluate the risk and protective factors associated with APOL1 RVs at different stages of life.
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Affiliation(s)
- Ai Itoku
- Division of Pediatric Nephrology, Children's Hospital at Montefiore, Bronx, New York
| | - Jaya Isaac
- Division of Pediatric Nephrology, Children's Hospital at Montefiore, Bronx, New York
| | - Scott Wilson
- Albert Einstein College of Medicine, Bronx, New York.
| | - Kimberly Reidy
- Division of Pediatric Nephrology, Children's Hospital at Montefiore, Bronx, New York
| | - Frederick Kaskel
- Division of Pediatric Nephrology, Children's Hospital at Montefiore, Bronx, New York
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36
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Tory K. The dominant findings of a recessive man: from Mendel's kid pea to kidney. Pediatr Nephrol 2024; 39:2049-2059. [PMID: 38051388 PMCID: PMC11147900 DOI: 10.1007/s00467-023-06238-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/07/2023] [Accepted: 11/15/2023] [Indexed: 12/07/2023]
Abstract
The research of Mendel, born two centuries ago, still has many direct implications for our everyday clinical work. He introduced the terms "dominant" and "recessive" characters and determined their 3:1 ratio in the offspring of heterozygous "hybrid" plants. This distribution allowed calculation of the number of the phenotype-determining "elements," i.e., the alleles, and has been used ever since to prove the monogenic origin of a disorder. The Mendelian inheritance of monogenic kidney disorders is still of great help in distinguishing them from those with multifactorial origin in clinical practice. Inheritance of most monogenic kidney disorders fits to Mendel's observations: the equal contribution of the two parents and the complete penetrance or the direct correlation between the frequency of the recessive character and the degree of inbreeding. Nevertheless, beyond the truth of these basic concepts, several observations have expanded their genetic characteristics. The extreme genetic heterogeneity, the pleiotropy of the causal genes and the role of modifiers in ciliopathies, the digenic inheritance and parental imprinting in some tubulopathies, and the incomplete penetrance and eventual interallelic interactions in podocytopathies, reflect this expansion. For all these reasons, the transmission pattern in a natural setting may depend not only on the "character" but also on the causal gene and the variant. Mendel's passion for research combined with his modest personality and meticulous approach can still serve as an example in the work required to understand the non-Mendelian universe of genetics.
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Affiliation(s)
- Kálmán Tory
- MTA-SE Lendület Nephrogenetic Laboratory, Hungarian Academy of Sciences, Budapest, Hungary.
- Pediatric Center, MTA Center of Excellence, Semmelweis University, Budapest, Hungary.
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Abdulhamid A, Shepherd BE, Wudil UJ, Van Wyk C, Dankishiya FS, Hussaini N, Wester CW, Aliyu MH. Sickle cell trait, APOL1 risk allele status and chronic kidney disease among ART-experienced adults living with HIV in northern Nigeria. Int J STD AIDS 2024:9564624241262397. [PMID: 38915133 DOI: 10.1177/09564624241262397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
BACKGROUND We sought to determine the prevalence of sickle cell trait (SCT) and apolipoprotein-1 (APOL1) risk variants in people living with HIV (PLWH) in Nigeria, and to establish if SCT and APOL1 high-risk status correlate with estimated glomerular filtration rate (eGFR) and/or prevalent chronic kidney disease (CKD). METHODS Baseline demographic and clinical data were obtained during three cross-sectional visits. CKD was defined as having an eGFR<60 mL/min/1.73 m2. We collected urine specimens to determine urine albumin-creatine ratio and blood samples for sickle cell genotyping, APOL1 testing, and for creatinine/cystatin C assessment. The associations between SCT, APOL1 genotype, and eGFR/CKD stages/CKD were investigated using linear/ordinal logistic/logistic regression models, respectively. RESULTS Of 2443 participants, 599 (24.5%) had SCT, and 2291 (93.8%) had a low-risk APOL1 genotype (0 or 1 risk variant), while 152 (6.2%) had high-risk genotype (2 allele copies). In total, 108 participants (4.4%) were diagnosed with CKD. In adjusted analyses, SCT was associated with lower eGFR (adjusted mean difference [aMD]= -2.33, 95% CI -4.25, -0.42), but not with worse CKD stages, or increased odds of developing CKD. Participants with the APOL1 high risk genotype were more likely to have lower eGFR (aMD= -5.45, 95% CI -8.87, -2.03), to develop CKD (adjusted odds ratio [aOR] = 1.97, 95% CI: 1.03, 3.75), and to be in worse CKD stages (aOR = 1.60, 95% CI: 1.12, 2.29) than those with the low-risk genotype. There was no evidence of interaction between SCT and APOL1 genotype on eGFR or risk of CKD. CONCLUSION Our findings highlight the multifaceted interplay of genetic factors in the pathogenesis of CKD in PLWH.
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Affiliation(s)
- Abdurrahman Abdulhamid
- Department of Statistics, School of Technology, Kano State Polytechnic, Kano, Nigeria
- Department of Mathematical Sciences, Bayero University, Kano, Nigeria
| | - Bryan E Shepherd
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Usman J Wudil
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chelsea Van Wyk
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Nafiu Hussaini
- Department of Mathematical Sciences, Bayero University, Kano, Nigeria
| | - C William Wester
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Muktar H Aliyu
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN, USA
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Doshi MD, Li L, Naik AS, Thomas CP. APOL1 Kidney Risk Variants and Long-Term Kidney Function in Healthy Middle-Aged Black Individuals: The Atherosclerosis Risk in Communities (ARIC) Study. Kidney Med 2024; 6:100828. [PMID: 38799783 PMCID: PMC11127222 DOI: 10.1016/j.xkme.2024.100828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024] Open
Abstract
Rationale & Objective The effect of apolipoprotein L1(APOL1) genotype on future risk of kidney disease among middle-aged individuals with good kidney function is not well established. Study Design Longitudinal cohort study. Setting & Participants In total, 5,886 healthy individuals (45-64 years old) enrolled in the Atherosclerosis Risk in Communities study with creatinine-based estimated glomerular filtration rate ≥ 80 mL/min who would be suitable kidney donors. Exposures Race and APOL1 genotype. Outcomes Creatinine- and cystatin C-based estimated glomerular filtration rate (eGFRcr-cys) using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2021 equation, urinary albumin-creatinine ratio (UACR), proportion with chronic kidney disease (CKD) 3a or worse, end-stage kidney disease (ESKD), and death. Analytical Approach Participants grouped based on race and APOL1 genotype. Compared eGFRcr-cys and UACR across groups. Multinomial logistic regression models were used compare odds of CKD. Kaplan-Meier survival curves were created to compare rates of ESKD and death at last follow-up. Results There were 5,075 Whites (86%), 701 Blacks carrying the low-risk APOL1 genotype (12%), and 110 Blacks carrying the high-risk APOL1 genotype (2%). The mean age at baseline was 53 ± 6 years. At 10 years, White participants had lower eGFRcr-cys than low-risk and high-risk groups (89 ± 16 vs 91 ± 16 and 92 ± 15 mL/min/1.73 m2, respectively; P < 0.001). At 25 years, White participants continued to have lower eGFRcr-cys than the low-risk group (70 ± 18 vs 72 ± 19 mL/min/1.73 m2; P < 0.001) but not compared with the high-risk APOL1 genotype (67±23 mL/min/1.73 m2). There was no difference in UACR among groups at 10 and 25 years (P = 0.87 and 0.91, respectively). The odds of developing CKD stage 3a or worse were not different between low-risk and high-risk APOL1 group in both unadjusted and adjusted models (P = 0.26 and P = 0.39, respectively). At last follow-up, <5% developed ESKD, and 45% of individuals either died or reached ESKD with no difference in outcomes between the groups. Limitations Low ascertainment because of death and long follow-up. Conclusions Among middle-aged individuals, APOL1 genotype does not appear to be a major driver of future risk of kidney disease.
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Affiliation(s)
- Mona D. Doshi
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI
| | - Lihua Li
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Abhijit S. Naik
- Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI
| | - Christie P. Thomas
- Department of Medicine and the Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA
- Division of Nephrology, Department of Medicine, Iowa City, IA
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Bonilla M, Efe O, Selvaskandan H, Lerma EV, Wiegley N. A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations. Kidney Med 2024; 6:100826. [PMID: 38765809 PMCID: PMC11099322 DOI: 10.1016/j.xkme.2024.100826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) defines a distinct histologic pattern observed in kidney tissue that is linked to several distinct underlying causes, all converging on the common factor of podocyte injury. It presents a considerable challenge in terms of classification because of its varied underlying causes and the limited correlation between histopathology and clinical outcomes. Critically, precise nomenclature is key to describe and delineate the pathogenesis, subsequently guiding the selection of suitable and precision therapies. A proposed pathomechanism-based approach has been suggested for FSGS classification. This approach differentiates among primary, secondary, genetic, and undetermined causes, aiming to provide clarity. Genetic FSGS from monogenic mutations can emerge during childhood or adulthood, and it is advisable to conduct genetic testing in cases in which there is a family history of chronic kidney disease, nephrotic syndrome, or resistance to treatment. Genome-wide association studies have identified several genetic risk variants, such as those in apolipoprotein L1 (APOL1), that play a role in the development of FSGS. Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS.
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Affiliation(s)
- Marco Bonilla
- Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL
| | - Orhan Efe
- Division of Nephrology, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Haresh Selvaskandan
- IgA Mayer Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
| | - Edgar V. Lerma
- Section of Nephrology, University of Illinois at Chicago/Advocate Christ Medical Center, Oak Lawn, IL
| | - Nasim Wiegley
- University of California Davis School of Medicine, Division of Nephrology, Sacramento, CA
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McCutcheon K, Nqebelele U, Murray L, Thomas TS, Mpanya D, Tsabedze N. Cardiac and Renal Comorbidities in Aging People Living With HIV. Circ Res 2024; 134:1636-1660. [PMID: 38781295 PMCID: PMC11122746 DOI: 10.1161/circresaha.124.323948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Contemporary World Health Organization data indicates that ≈39 million people are living with the human immunodeficiency virus. Of these, 24 million have been reported to have successfully accessed combination antiretroviral therapy. In 1996, the World Health Organization endorsed the widespread use of combination antiretroviral therapy, transforming human immunodeficiency virus infection from being a life-threatening disease to a chronic illness characterized by multiple comorbidities. The increased access to combination antiretroviral therapy has translated to people living with human immunodeficiency virus (PLWH) no longer having a reduced life expectancy. Although aging as a biological process increases exposure to oxidative stress and subsequent systemic inflammation, this effect is likely enhanced in PLWH as they age. This narrative review engages the intricate interplay between human immunodeficiency virus associated chronic inflammation, combination antiretroviral therapy, and cardiac and renal comorbidities development in aging PLWH. We examine the evolving demographic profile of PLWH, emphasizing the increasing prevalence of aging individuals within this population. A central focus of the review discusses the pathophysiological mechanisms that underpin the heightened susceptibility of PLWH to renal and cardiac diseases as they age.
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Affiliation(s)
| | - Unati Nqebelele
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, Western Cape, South Africa (U.N.)
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Western Cape, South Africa (U.N.)
| | - Lyle Murray
- Division of Infectious Diseases, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand and the Charlotte Maxeke Johannesburg Academic Hospital, South Africa (L.M.)
| | - Teressa Sumy Thomas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand and the Chris Hani Baragwanath Academic Hospital, Johannesburg, Gauteng, South Africa (T.S.T.)
| | - Dineo Mpanya
- Division of Cardiology, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa (D.M., N.T.)
| | - Nqoba Tsabedze
- Division of Cardiology, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa (D.M., N.T.)
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41
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Hopper T, Olabisi OA. APOL1-Mediated Kidney Disease. JAMA 2024; 331:1668-1669. [PMID: 38662391 PMCID: PMC11462457 DOI: 10.1001/jama.2024.2667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
This JAMA Insights reviews the origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease, and discusses recommendations for screening and management.
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Affiliation(s)
- Timothy Hopper
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Opeyemi A Olabisi
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina
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42
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Labarque V, Okocha EC. Systematic Review of Genetic Modifiers Associated with the Development and/or Progression of Nephropathy in Patients with Sickle Cell Disease. Int J Mol Sci 2024; 25:5427. [PMID: 38791464 PMCID: PMC11121490 DOI: 10.3390/ijms25105427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/05/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the effect of genetic modifiers on SCN were eligible. Twenty-eight studies (fair-to-good quality) were included: one genome-wide association study, twenty-six case-control studies, and one article combining both approaches. APOL1 was significantly associated with albuminuria and hyperfiltration in children and with worse glomerular filtration in adults. On the other hand, alpha-thalassemia protected patients against albuminuria and hyperfiltration, while BCL11A variants were protective against albuminuria alone. The HMOX1 long GT-tandem repeat polymorphism led to a lower glomerular filtration rate. No modifiers for the risk of hyposthenuria were identified. A genome-wide association approach identified three new loci for proteinuria (CRYL1, VWF, and ADAMTS7) and nine loci were linked with eGFR (PKD1L2, TOR2A, CUBN, AGGF1, CYP4B1, CD163, LRP1B, linc02288, and FPGT-TNNI3K/TNNI3K). In conclusion, this systematic review supports the role of genetic modifiers in influencing the risk and progression of SCN. Incorporating and expanding this knowledge is crucial to improving the management and clinical outcomes of patients at risk.
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Affiliation(s)
- Veerle Labarque
- Department of Pediatric Hemato-Oncology, University Hospitals Leuven, 3000 Leuven, Belgium
- Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium
| | - Emmanuel Chide Okocha
- Haematology Department, Faculty of Basic Clinical Sciences, College of Health Sciences, Nnamdi Azikiwe University, Nnewi PMB 5025, Anambra State, Nigeria
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Breeze CE, Lin BM, Winkler CA, Franceschini N. African ancestry-derived APOL1 risk genotypes show proximal epigenetic associations. BMC Genomics 2024; 25:452. [PMID: 38714935 PMCID: PMC11077761 DOI: 10.1186/s12864-024-10226-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 03/14/2024] [Indexed: 05/12/2024] Open
Abstract
Apolipoprotein L1 (APOL1) coding variants, termed G1 and G2, are established genetic risk factors for a growing spectrum of diseases, including kidney disease, in individuals of African ancestry. Evidence suggests that the risk variants, which show a recessive mode of inheritance, lead to toxic gain-of-function changes of the APOL1 protein. Disease occurrence and presentation vary, likely due to modifiers or second hits. To understand the role of the epigenetic landscape in relation to APOL1 risk variants, we performed methylation quantitative trait locus (meQTL) analysis to identify differentially methylated CpGs influenced by APOL1 risk variants in 611 African American individuals. We identified five CpGs that were significantly associated with APOL1 risk alleles in discovery and replication studies, and one CpG-APOL1 association was independent of other genomic variants. Our study highlights proximal DNA methylation alterations that may help explain the variable disease risk and clinical manifestation of APOL1 variants.
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Affiliation(s)
- Charles E Breeze
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Bridget M Lin
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
| | - Cheryl A Winkler
- Cancer Innovation Laboratory, National Cancer Institute, National Institutes of Health, Basic Research Program, Frederick National Laboratory, Frederick, MD, USA
| | - Nora Franceschini
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
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Zhu JY, Fu Y, van de Leemput J, Yu Y, Li J, Ray PE, Han Z. HIV-1 Nef acts in synergy with APOL1-G1 to induce nephrocyte cell death in a new Drosophila model of HIV-related kidney diseases. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.08.584069. [PMID: 38496548 PMCID: PMC10942446 DOI: 10.1101/2024.03.08.584069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Background: People carrying two APOL1 risk alleles (RA) G1 or G2 are at greater risk of developing HIV-associated nephropathy (HIVAN). Studies in transgenic mice showed that the expression of HIV-1 genes in podocytes, and nef in particular, led to HIVAN. However, it remains unclear whether APOL1-RA and HIV-1 Nef interact to induce podocyte cell death. Method: We generated transgenic (Tg) flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. Results: We found that HIV-1 Nef acts in synergy with APOL1-G1 resulting in nephrocyte structural and functional defects. Specifically, HIV-1 Nef itself can induce endoplasmic reticulum (ER) stress without affecting autophagy. Furthermore, Nef exacerbates the organelle acidification defects and autophagy reduction induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating ER stress, triggering nephrocyte dysfunction and ultimately cell death. Conclusions: Using a new Drosophila model of HIV-1-related kidney diseases, we identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high relevance between Drosophila nephrocytes and human podocytes, this finding suggests ER stress as a new therapeutic target for HIV-1 and APOL1-associated nephropathies.
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45
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Diana NE, Naicker S. The changing landscape of HIV-associated kidney disease. Nat Rev Nephrol 2024; 20:330-346. [PMID: 38273026 DOI: 10.1038/s41581-023-00801-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2023] [Indexed: 01/27/2024]
Abstract
The HIV epidemic has devastated millions of people globally, with approximately 40 million deaths since its start. The availability of antiretroviral therapy (ART) has transformed the prognosis of millions of individuals infected with HIV such that a diagnosis of HIV infection no longer automatically confers death. However, morbidity and mortality remain substantial among people living with HIV. HIV can directly infect the kidney to cause HIV-associated nephropathy (HIVAN) - a disease characterized by podocyte and tubular damage and associated with an increased risk of kidney failure. The reports of HIVAN occurring primarily in those of African ancestry led to the discovery of its association with APOL1 risk alleles. The advent of ART has led to a substantial decrease in the prevalence of HIVAN; however, reports have emerged of an increase in the prevalence of other kidney pathology, such as focal segmental glomerulosclerosis and pathological conditions associated with co-morbidities of ageing, such as hypertension and diabetes mellitus. Early initiation of ART also results in a longer cumulative exposure to medications, increasing the likelihood of nephrotoxicity. A substantial body of literature supports the use of kidney transplantation in people living with HIV, demonstrating significant survival benefits compared with that of people undergoing chronic dialysis, and similar long-term allograft and patient survival compared with that of HIV-negative kidney transplant recipients.
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Affiliation(s)
- Nina E Diana
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
| | - Saraladevi Naicker
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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46
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Duret LC, Hamidouche T, Steers NJ, Pons C, Soubeiran N, Buret D, Gilson E, Gharavi AG, D'Agati VD, Shkreli M. Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy. Kidney Int 2024; 105:980-996. [PMID: 38423182 DOI: 10.1016/j.kint.2024.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/16/2023] [Accepted: 02/02/2024] [Indexed: 03/02/2024]
Abstract
Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-β functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
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Affiliation(s)
- Lou C Duret
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Tynhinane Hamidouche
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Nicholas J Steers
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Catherine Pons
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Nicolas Soubeiran
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Delphine Buret
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Eric Gilson
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France; International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/INSERM/Nice University, Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Huangpu, Shanghai, PR China; Department of Genetics, CHU Nice, Nice, France
| | - Ali G Gharavi
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
| | - Marina Shkreli
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France.
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47
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Chandran S, Stock PG, Roll GR. Expanding Access to Organ Transplant for People Living With HIV: Can Policy Catch Up to Outcomes Data? Transplantation 2024; 108:874-883. [PMID: 37723620 DOI: 10.1097/tp.0000000000004794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2023]
Abstract
Advances in antiretroviral and immunosuppressive regimens have improved outcomes following solid organ transplantation in people living with HIV (PLWH). The HIV Organ Policy and Equity Act was conceived to reduce the discard of HIV-positive organs and improve access to transplant for PLWH. Nevertheless, PLWH continue to experience disproportionately low rates of transplant. This overview examines the hurdles to transplantation in PLWH with end-organ disease, the potential and realized impact of the HIV Organ Policy and Equity Act, and changes that could permit expanded access to organ transplant in this population.
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Affiliation(s)
- Sindhu Chandran
- Department of Medicine, University of California-San Francisco (UCSF), San Francisco, CA
| | - Peter G Stock
- Department of Surgery, University of California-San Francisco (UCSF), San Francisco, CA
| | - Garrett R Roll
- Department of Surgery, University of California-San Francisco (UCSF), San Francisco, CA
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48
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Mirioglu S, Daniel-Fischer L, Berke I, Ahmad SH, Bajema IM, Bruchfeld A, Fernandez-Juarez GM, Floege J, Frangou E, Goumenos D, Griffith M, Moran SM, van Kooten C, Steiger S, Stevens KI, Turkmen K, Willcocks LC, Kronbichler A. Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group. Nephrol Dial Transplant 2024; 39:569-580. [PMID: 38341276 PMCID: PMC11024823 DOI: 10.1093/ndt/gfae025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Indexed: 02/12/2024] Open
Abstract
The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.
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Affiliation(s)
- Safak Mirioglu
- Division of Nephrology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Lisa Daniel-Fischer
- Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Ilay Berke
- Division of Nephrology, Marmara University School of Medicine, Istanbul, Turkey
| | - Syed Hasan Ahmad
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Ingeborg M Bajema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Annette Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden
| | | | - Jürgen Floege
- Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleni Frangou
- Department of Nephrology, Limassol General Hospital, Limassol, Cyprus; University of Nicosia Medical School, Nicosia, Cyprus
| | - Dimitrios Goumenos
- Department of Nephrology and Renal Transplantation, Patras University Hospital, Patras, Greece
| | - Megan Griffith
- Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom
| | - Sarah M Moran
- Cork University Hospital, University College Cork, Cork, Ireland
| | - Cees van Kooten
- Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefanie Steiger
- Division of Nephrology, Department of Internal Medicine IV, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Kate I Stevens
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kultigin Turkmen
- Division of Nephrology, Department of Internal Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Lisa C Willcocks
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
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49
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Randle RK, Amara VR, Popik W. IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions. Int J Mol Sci 2024; 25:3324. [PMID: 38542298 PMCID: PMC10970439 DOI: 10.3390/ijms25063324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/28/2024] [Accepted: 03/13/2024] [Indexed: 04/04/2024] Open
Abstract
Genetic variants in the protein-coding regions of APOL1 are associated with an increased risk and progression of chronic kidney disease (CKD) in African Americans. Hypoxia exacerbates CKD progression by stabilizing HIF-1α, which induces APOL1 transcription in kidney podocytes. However, the contribution of additional mediators to regulating APOL1 expression under hypoxia in podocytes is unknown. Here, we report that a transient accumulation of HIF-1α in hypoxia is sufficient to upregulate APOL1 expression in podocytes through a cGAS/STING/IRF3-independent pathway. Notably, IFI16 ablation impedes hypoxia-driven APOL1 expression despite the nuclear accumulation of HIF-1α. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1α. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer/promoter region, showing increased HIF-1α binding to HREs located in the APOL1 gene enhancer. Luciferase reporter assays confirm the role of these HREs in transcriptional activation. Chromatin immunoprecipitation (ChIP)-qPCR assays demonstrate that IFI16 is not recruited to HREs, and IFI16 deletion reduces HIF-1α binding to APOL1 HREs. RT-qPCR analysis indicates that IFI16 selectively affects APOL1 expression, with a negligible impact on other hypoxia-responsive genes in podocytes. These findings highlight the unique contribution of IFI16 to hypoxia-driven APOL1 gene expression and suggest alternative IFI16-dependent mechanisms regulating APOL1 gene expression under hypoxic conditions.
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Affiliation(s)
- Richaundra K. Randle
- Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA;
- Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA;
| | - Venkateswara Rao Amara
- Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA;
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur 844102, Bihar, India
| | - Waldemar Popik
- Center for AIDS Health Disparities Research, Meharry Medical College, Nashville, TN 37208, USA;
- Department of Internal Medicine, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
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50
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Adamson WE, Noyes H, Johnson P, Cooper A, Monckton DG, Ogunsola J, Beckett-Hill G, Sullivan M, Mark P, Parekh RS, MacLeod A. Phenome-wide analysis reveals epistatic associations between APOL1 variants and chronic kidney disease and multiple other disorders. EBioMedicine 2024; 101:105000. [PMID: 38360481 PMCID: PMC10944146 DOI: 10.1016/j.ebiom.2024.105000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 01/21/2024] [Accepted: 01/23/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND APOL1 variants G1 and G2 are common in populations with recent African ancestry. They are associated with protection from African sleeping sickness, however homozygosity or compound heterozygosity for these variants is associated with chronic kidney disease (CKD) and related conditions. What is not clear is the extent of associations with non-kidney-related disorders, and whether there are clusters of diseases associated with individual APOL1 genotypes. METHODS Using a cohort of 7462 UK Biobank participants with recent African ancestry, we conducted a phenome-wide association study investigating associations between individual APOL1 genotypes and conditions identified by the International Classification of Disease phenotypes. FINDINGS We identified 27 potential associations between individual APOL1 genotypes and a diverse range of conditions. G1/G2 compound heterozygotes were specifically associated with 26 of these conditions (all deleteriously), with an over-representation of infectious diseases (including hospitalisation and death resulting from COVID-19). The analysis also exposed complexities in the relationship between APOL1 and CKD that are not evident when risk variants are grouped together: G1 homozygosity, G2 homozygosity, and G1/G2 compound heterozygosity were each shown to be associated with distinct CKD phenotypes. The multi-locus nature of the G1/G2 genotype means that its associations would go undetected in a standard genome-wide association study. INTERPRETATION Our findings have implications for understanding health risks and better-targeted detection, intervention, and therapeutic strategies, particularly in populations where APOL1 G1 and G2 are common such as in sub-Saharan Africa and its diaspora. FUNDING This study was funded by the Wellcome Trust (209511/Z/17/Z) and H3Africa (H3A/18/004).
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Affiliation(s)
- Walt E Adamson
- School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, United Kingdom; Wellcome Centre for Integrative Parasitology, University of Glasgow, United Kingdom; TrypanoGEN+ Research Group, Uganda, Member of the H3Africa Consortium, South Africa.
| | - Harry Noyes
- TrypanoGEN+ Research Group, Uganda, Member of the H3Africa Consortium, South Africa; Centre for Genomic Research, University of Liverpool, United Kingdom
| | - Paul Johnson
- School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, United Kingdom
| | - Anneli Cooper
- School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, United Kingdom; Wellcome Centre for Integrative Parasitology, University of Glasgow, United Kingdom
| | - Darren G Monckton
- School of Molecular Biosciences, University of Glasgow, United Kingdom
| | - John Ogunsola
- School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, United Kingdom; Wellcome Centre for Integrative Parasitology, University of Glasgow, United Kingdom
| | - Georgia Beckett-Hill
- School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, United Kingdom
| | - Michael Sullivan
- School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom
| | - Patrick Mark
- School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom
| | - Rulan S Parekh
- Women's College Hospital, Hospital for Sick Children and University of Toronto, Canada
| | - Annette MacLeod
- School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, United Kingdom; Wellcome Centre for Integrative Parasitology, University of Glasgow, United Kingdom; TrypanoGEN+ Research Group, Uganda, Member of the H3Africa Consortium, South Africa.
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