Clonal hematopoiesis of indeterminate potential and kidney disease

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is an acquired hematologic disorder that affects more than 10% of individuals aged 65 and older. Individuals with CHIP have acquired mutations in myeloid cancer-associated genes such as DNMT3A and TET2 in their hematopoietic stem cells (HSCs). White blood cells produced by CHIP-mutated HSCs are broadly pro-inflammatory, and having CHIP is linked with higher risks of premature death and chronic diseases affecting several organ systems. Work presented in this manuscript-based thesis focuses on the role of CHIP in kidney health and disease. The first chapter presents a small cohort-based study where we identified that, among individuals with chronic kidney disease, CHIP is associated with a two-fold increased risk of end-stage kidney disease independent of other risk factors over a 5-year follow-up period (hazard ratio 2.4, 95% confidence interval: 1.3–4.4). The second manuscript chapter presents a novel, practical approach for deriving individual-level CHIP calls in large population-sized cohorts, which involves applying variant identification algorithms to existing whole genome- or -exome sequencing data and subsequently tailoring sequence-based and population-based filtering strategies. We exemplify this approach using genomic data from over 500,000 individuals enrolled in the UK Biobank and the All of Us studies. The third chapter utilizes these large biobank-derived CHIP calls to glean insight into the role of interleukin (IL)-6 signaling in the cardiovascular risk associated with CHIP. The final chapter demonstrates that CHIP is associated with incident acute kidney injury (AKI) – especially severe AKI – in three population-based cohorts. We then show in two distinct mouse models that Tet2-CHIP is associated with more severe AKI, greater kidney infiltration of pro-inflammatory macrophages and neutrophils, and more post-AKI renal fibrosis. Altogether, this work establishes some of the first links between CHIP and both chronic and acute kidney injury.