Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease

Area of Science:

• Genetics and Genomics
• Nephrology
• Hematology

Background:

• Age-related clonal hematopoiesis (CH), characterized by mosaic chromosome abnormalities and/or driver mutations, is increasingly recognized as a factor influencing age-related diseases.
• Chronic kidney disease (CKD) affects a significant portion of the aging population, and its underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the association between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD).
• To determine if CH, specifically myeloid CH, impacts the risk of adverse outcomes in individuals with CKD.

Main Methods:

• Analysis of UK Biobank data (n=190,487) to identify CH prevalence and its association with kidney function markers (eGFR.cys and eGFR.creat).
• Examination of specific mutations (e.g., TET2, JAK2) and mosaic chromosome abnormalities (mCA) in relation to CKD.
• Mendelian randomization analysis to explore potential causal relationships between CH and CKD.

Main Results:

• CH was identified in 2.9% of participants and was negatively associated with eGFR.cys, and specifically with CKD defined by eGFR.cys < 60.
• Myeloid CH was associated with lower eGFR.cys and, in participants without prior myeloid neoplasms or cardiovascular disease, significantly increased the risk of adverse outcomes in CKD (HR=1.6).
• Suggestive evidence for a causal link between CH and CKD was observed.

Conclusions:

• Age-related CH, particularly myeloid CH, is associated with CKD, especially when assessed using cystatin-C-based eGFR.
• Myeloid CH exacerbates adverse outcomes in individuals with CKD, highlighting the interplay between intrinsic (CH) and extrinsic factors in disease risk.
• These findings underscore the importance of considering CH in the comprehensive assessment of kidney disease risk and patient management.