Association of Clonal Hematopoiesis of Indeterminate Potential with Worse Kidney Function and Anemia in Two Cohorts of Patients with Advanced Chronic Kidney Disease

Abstract

Background Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in chronic kidney disease (CKD) is unknown. Methods We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m2. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. Results At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP had a lower eGFR and were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE) compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or endstage kidney disease (ESKD) over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. Conclusion In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.

Clonal Hematopoiesis and CKD Progression

“…Altogether, Vlasschaert et al 7 add a new and provocative dataset to the growing corpus on the association of CHIP with nonmalignant diseases. In line with the findings presented here, a recent analysis of the UK Biobank also reported lower eGFR among individuals with CHIP and an association between CHIP and adverse outcomes in CKD 6 . Similar to the UK Biobank analysis, the data presented by Vlasschaert et al 6 raises several key questions that should be explored further in epidemiologic datasets and experimental models.…”

A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout

“…Indeed, IGF1R and IRS1 are central to insulin signalling, are co-localized eQTLs, and have been implicated in the training mechanism 96 . CHIP also associates with heart failure 97–99 and deteriorating kidney function 100 and may link the etiologies of gout and co-morbid cardiorenal conditions via an inflammatory state. Supporting a role for the NLRP3-inflammasome, TET2 -CHIP has been implicated in heart failure through the NLRP3-inflammasome and IL-1β 101 .…”

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome

“…Furthermore, CHIP has also been associated with an adverse clinical progression of heart failure, a leading cause of hospitalization for elderly individuals [7,9]. Beyond heart disease, some CHIP mutations have been suggested to contribute to the development and progression of a variety of conditions prevalent in the elderly, such as osteoporosis, chronic obstructive pulmonary disease, chronic kidney disease, or insulin resistance [11][12][13][14]. However, despite the accumulating evidence supporting the clinical relevance of CHIP in normal aging, its potential contribution to the pathophysiology of accelerated aging syndromes remains unexplored.…”