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Clonal haematopoiesis, ageing and kidney disease

Nature Reviews Nephrology volume 20, pages 161–174 (2024)Cite this article

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Abstract

Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual’s circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing — more than 10% of individuals over 65 years of age are affected — and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease. Beyond its direct effect on the kidney, CHIP elevates the susceptibility of individuals to various conditions that can detrimentally affect the kidneys, including cardiovascular disease, obesity and insulin resistance, liver disease, gout, osteoporosis and certain autoimmune diseases. Aberrant pro-inflammatory signalling, telomere attrition and epigenetic ageing are potential causal pathophysiological pathways and mediators that underlie CHIP-related disease risk. Experimental animal models have shown that inhibition of inflammatory cytokine signalling can ameliorate many of the pathological effects of CHIP, and assessment of the efficacy and safety of this class of medications for human CHIP-associated pathology is ongoing.

Key points

  • Clonal haematopoiesis of indeterminate potential (CHIP) is a common, acquired condition wherein mutated white blood cells form an expanded clonal population in the blood and cause chronic organ damage through dysregulated inflammation.

  • CHIP has been associated with a greater risk of acute kidney injury (AKI) and impaired recovery from AKI in human population cohorts and in mouse models, as well as loss of kidney function in the general population and in those with chronic kidney disease.

  • In addition to its direct effects on the kidney, CHIP predisposes individuals to several conditions that impact kidney health, including cardiovascular disease, gout, osteoporosis and insulin resistance.

  • CHIP affects 10–20% of individuals aged 65 and older; other than age, risk factors include smoking, male sex, chronic inflammation, cytotoxic therapies and certain inherited genetic variants.

  • In preclinical models, cytokine blockade strategies mitigate many of the pathological effects of CHIP; these strategies are being evaluated in humans.

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Fig. 1: Subtypes of clonal haematopoiesis.
Fig. 2: The spectrum of clonal myeloid disease.
Fig. 3: CHIP mouse model systems.
Fig. 4: Conceptual model of the role of CHIP in kidney health.

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Authors and Affiliations

  1. Department of Medicine, Queen’s University, Kingston, Ontario, Canada

    Caitlyn Vlasschaert

  2. Department of Medicine and Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada

    Matthew B. Lanktree

  3. St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada

    Matthew B. Lanktree

  4. Population Health Research Institute, Hamilton, Ontario, Canada

    Matthew B. Lanktree

  5. Department of Pathology and Molecular Medicine, Kingston, Ontario, Canada

    Michael J. Rauh

  6. Division of Nephrology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Tanika N. Kelly

  7. Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Pradeep Natarajan

  8. Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Pradeep Natarajan

  9. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Pradeep Natarajan

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Contributions

C.V. researched data for the article and wrote the manuscript. P.N., C.V., M.B.L. and T.N.K. made substantial contributions to discussions of the content. All authors reviewed or edited the manuscript before submission.

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Correspondence to Pradeep Natarajan.

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Competing interests

P.N. reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in Preciseli and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. M.B.L. reports received speaking and advisory board fees from Bayer, Otsuka, Reata and Sanofi. The remaining authors declare no competing interests.

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Glossary

Passenger variants

Acquired genetic changes that accumulate in cells over time but are not expected to affect cell fitness or drive clonal expansion, in contrast to driver mutations.

Variant allele fraction

(VAF). The proportion of sequencing reads that contain the variant, which serves as an estimate of the fraction of cells that containing the variant (for autosomal chromosomes and X chromosomes in female individuals, VAF × 2 = the cell fraction).

VEXAS syndrome

First described in 2020, VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe, adult-onset autoinflammatory disease caused by acquired mutations in the ubiquitin ligase enzyme gene (UBA1) in circulating blood cells.

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Vlasschaert, C., Lanktree, M.B., Rauh, M.J. et al. Clonal haematopoiesis, ageing and kidney disease. Nat Rev Nephrol 20, 161–174 (2024). https://doi.org/10.1038/s41581-023-00778-x

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