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 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 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 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.

Conclusions: 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.

Keywords: anemia; chronic inflammation; chronic renal insufficiency; clonal hematopoiesis; clone cells; cohort studies; hematopoiesis; macrophages.

Graphical abstract

Figure 1.

The prevalence of CHIP increases with age. Age distribution of CHIP carriers in the (A) Kingston and (B) CanPREDDICT cohorts. Each point represents a person, color-coded by the gene including a CHIP driver variant.

Figure 2.

CHIP is associated with worse baseline kidney function and progression of CKD. (A) The average baseline eGFR is lower in those with CHIP compared with those without CHIP (n=172) but not after adjusting for age and sex. (B) The 2-year KFRE scores are higher in those with CHIP in both cohorts, including after adjusting for age and sex. The 5-year KFRE scores are similarly higher in CHIP (29.1±4.4 versus 19.9±1.8), including after adjusting for baseline age and sex (P=0.01). (C) Survival curves for the composite outcome of 50% eGFR decline or ESKD by CHIP status adjusted for age, sex, and baseline eGFR over 5 years of follow-up (pooled cohorts; n=172; log-rank test P=0.01). Inset is a forest plot of the Cox proportional hazard ratio in each cohort independently and after meta-analysis, adjusted for age, sex, and baseline eGFR (n=172 total). (D) Iterative improvement in time-to-ESKD risk prediction. The best-fit model includes 2-year KFRE score, age, sex, baseline eGFR, and CHIP. The results for 5-year KFRE are similar and presented in Supplemental Figure 2B. Significant results are highlighted as follows: **P<0.01, *P<0.05.

Figure 3.

CHIP is associated with lower hemoglobin, higher MCV, and higher ferritin. (A) Hemoglobin values—averaged per person over yearly periods and shown with SEM—are significantly lower in those with CHIP throughout the follow-up period in the Kingston cohort. Baseline hemoglobin is significantly different in CanPREDDICT. Hemoglobin values are censored upon receipt of a kidney transplant. (B) The proportion of individuals prescribed ESA use was not significantly different among those with CHIP. (C) MCV was higher among those with CHIP (t test P<0.05). (D) Ferritin was higher among those with CHIP (t test P<0.01), whereas transferrin saturation was not different (n=87 for both). MCV, ferritin, and transferrin saturation were only available in the Kingston cohort.