Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease

Abstract

We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10–4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10–8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10–5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.

Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes

“…Clonal hematopoiesis has been associated with increased risk of hematologic malignancy and cardiovascular disease, as well as other health outcomes including all-cause mortality, susceptibility to infection 3,4,25,26 . To test for expected as well as potentially novel associations, we performed cross-sectional association analyses across 4,871 traits (2,459 binary traits and 2,421 quantitative traits) available from the UK Biobank and curated as part of our efforts for the UKB Exome Sequencing Consortium.…”

Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential in Hematology and Cardiovascular Disease

“…Moreover, CHIP has recently been associated with chronic kidney disease (CKD) Population data of the UK biobank indicated a negative association with glomerular filtration rate estimated from cystatin-C. CHIP also increased the risk of adverse outcomes in CKD [ 95 ]. Detailed follow-up analysis of patients with kidney failure and CHIP showed a 2.2-fold increased risk of kidney failure, a higher baseline kidney failure risk score, and a higher likelihood to develop complications of CKD (including anemia) [ 96 ].…”

Combination strategies to promote sensitivity to cytarabine-induced replication stress in acute myeloid leukemia with and without DNMT3A mutations

“…Similar to other tissues such as esophagus and skin (56-60), age-related clonal expansion of HSCs is a common phenomenon, termed clonal hematopoiesis (CH) (61). While emergence of small clones defined by variant allele frequency (VAF) <2% without overt hematologic abnormalities is ubiquitous, presence of larger CH clones (VAF >10%) is associated with increased risk of blood malignancies (62)(63)(64)(65)(66)(67)(68) and other adverse outcomes ranging from atherosclerosis to cancer to chronic kidney disease (69)(70)(71)(72).…”