Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population
Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, rec...
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| Published in | American journal of kidney diseases Vol. 81; no. 3; pp. 329 - 335 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.03.2023
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0272-6386 1523-6838 1523-6838 |
| DOI | 10.1053/j.ajkd.2022.08.014 |
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| Abstract | Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.
Cohort study.
12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.
CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.
Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.
Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.
The median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes.
Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.
We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease. |
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| AbstractList | Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.
Cohort study.
12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.
CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.
Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.
Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.
The median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes.
Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.
We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease. Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population. Cohort study. 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium. CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood. Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period. Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis. The median baseline eGFR was 84mL/min/1.73m . The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m , of age above or below 60 years, or with or without diabetes. Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants. We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease. Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.RATIONALE & OBJECTIVEClonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.Cohort study.STUDY DESIGNCohort study.12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.SETTING & PARTICIPANTS12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.EXPOSURECHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.OUTCOMERisk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.ANALYTICAL APPROACHCox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.The median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes.RESULTSThe median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes.Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.LIMITATIONSSmall number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.CONCLUSIONSWe report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease. |
| Author | Harris, Raymond C. Kestenbaum, Bryan Bick, Alexander G. Franceschini, Nora Vlasschaert, Caitlyn Robinson-Cohen, Cassianne Psaty, Bruce M. Lanktree, Matthew B. Natarajan, Pradeep Rauh, Michael J. Köttgen, Anna Shoemaker, Moore B. |
| AuthorAffiliation | 6 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA 11 Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany 10 Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA 12 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 3 Department of Medicine, Queen’s University, Kingston, ON 9 Department of Veterans Affairs, Nashville, TN 4 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON 1 Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA 8 Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt O’Brien Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, TN 2 Division of Genetic Medicine, Department of Medicine, Vand |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/36241009$$D View this record in MEDLINE/PubMed |
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| Keywords | mutation cancer driver genes whole-genome sequencing DNMT3A estimated glomerular filtration rate (eGFR) older adults TET2 renal function Albuminuria chronic kidney disease (CKD) eGFR decline clonal hematopoiesis of indeterminate potential (CHIP) |
| Language | English |
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| Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Authors’ Contributions: research idea and study design: BK, AB, CV, PN, CRC; data acquisition: AB, CRC, MS, BP, AK, PN, NF; data analysis/interpretation: BK, CRC, RH, AB, CV, MR, ML; statistical analysis: BK, CRC; supervision or mentorship: MR, ML, CRC. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. |
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| SubjectTerms | Albuminuria cancer driver genes chronic kidney disease (CKD) Clonal Hematopoiesis clonal hematopoiesis of indeterminate potential (CHIP) Cohort Studies Disease Progression DNMT3A eGFR decline estimated glomerular filtration rate (eGFR) Glomerular Filtration Rate Humans Kidney Kidney Failure, Chronic - epidemiology mutation older adults renal function Renal Insufficiency, Chronic - epidemiology TET2 whole-genome sequencing |
| Title | Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population |
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