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. 2024 Oct;20(10):6960-6971.
doi: 10.1002/alz.14182. Epub 2024 Aug 8.

Clonal hematopoiesis of indeterminate potential is associated with reduced risk of cognitive impairment in patients with chronic kidney disease

Cissy Xiao  1 , Manjula Kurella Tamura  2 , Yang Pan  1 , Varun Rao  1 , Celestin Missikpode  1 , Caitlyn Vlasschaert  3 , Tetsushi Nakao  4 , Xiao Sun  1 , Changwei Li  5 , Zhijie Huang  5 , Amanda Anderson  6 , Md Mesbah Uddin  4 , Do-Kyun Kim  7 , Jonathan Taliercio  8 , Rajat Deo  9 , Zeenat Bhat  10 , Dawei Xie  11 , Panduranga Rao  10 , Jing Chen  5 , James P Lash  1 , Jiang He  5 , Pradeep Natarajan  4 , James E Hixson  7 , Kristine Yaffe  12 , Tanika N Kelly  1 ; CRIC Study Investigators
Affiliations

Clonal hematopoiesis of indeterminate potential is associated with reduced risk of cognitive impairment in patients with chronic kidney disease

Cissy Xiao et al. Alzheimers Dement. 2024 Oct.

Abstract

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown.

Methods: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean.

Results: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted hazard ratio [HR] [95% confidence interval {CI}] = 0.44 [0.26, 0.76], p = 0.003) and executive function (adjusted HR [95% CI] = 0.60 [0.37, 0.97], p = 0.04). There were no significant associations between CHIP and impairment in global cognition or verbal memory.

Discussion: CHIP was associated with lower risks of impairment in attention and executive function among CKD patients.

Highlights: Our study is the first to examine the role of CHIP in cognitive decline in CKD. CHIP markedly decreased the risk of impairment in attention and executive function. CHIP was not associated with impairment in global cognition or verbal memory.

Keywords: CHIP; attention; chronic kidney disease; clonal hematopoiesis of indeterminate potential; cognitive impairment; executive function; trail making tests.

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Conflict of interest statement

M.K.T. is the deputy editor for the Journal of the American Society of Nephrology, receives support from the American Society of Nephrology, and serves on the board of the American Federation of Aging Research. A.A. received presentation honoraria to speak at a Kidney Precision Medicine Project (KPMP) Steering Committee meeting. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co‐founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. L.D. receives consulting fees from Merck and AstraZeneca, payments from Mass General Brigham, American Society of Nephrology, Washington University, University of Colorado, University of Washington, participates on the board of Alucent Biomedical, CSL Behring, Vertex, Cara Therapeutics, and serves as the deputy editor of the American Journal of Kidney Diseases. The other authors do not have any conflicts of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Flowchart showing analytic cohorts for each cognitive test. CRIC, chronic renal insufficiency cohort; 3MS, Modified Mini‐Mental State Examination.
FIGURE 2
FIGURE 2
Frequency and count (n) of top CHIP driver genes and clone size among those with CHIP (N = 556).
FIGURE 3
FIGURE 3
Kaplan–Meier curves displaying the probability of remaining free from cognitive impairment over time based on CHIP status. The number of participants still at risk of cognitive impairment is shown above the x‐axis. (A) Modified Mini‐Mental State Examination. (B) Trail Making Test A. (C) Trail Making Test B. (D) Buschke Selective Reminding Test.
FIGURE 4
FIGURE 4
Forest plots displaying the associations between CHIP and incident cognitive impairment, overall and according to sex and race. Model 1 adjusted for age, sex, race and ethnicity, education, and CRIC clinical center. Model 2 adjusted for covariates in model 1, estimated glomerular filtration rate, urine protein to creatinine ratio, and cardiovascular disease. Model 3 adjusted for covariates in model 2 and APOE genotype. (A) Modified Mini‐Mental State Examination. (B) Trail Making Test A. (C) Trail Making Test B. (D) Buschke Selective Reminding Test.
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