Kidney Week

Abstract: TH-OR01

Clonal Hematopoiesis of Indeterminate Potential Is Associated With a Higher Risk of Incident AKI

Session Information

• AKI Research: Prediction, Diagnosis, Recovery
  November 03, 2022 | Location: W230, Orange County Convention Center‚ West Building
  Abstract Time: 04:30 PM - 04:39 PM

Category: Acute Kidney Injury

• 101 AKI: Epidemiology‚ Risk Factors‚ and Prevention

Authors

• Vlasschaert, Caitlyn, Queen's University, Kingston, Ontario, Canada

Caitlyn Vlasschaert, MD, MS

• Bick, Alexander, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Alexander Bick,

• Rauh, Michael J., Queen's University, Kingston, Ontario, Canada

Michael J. Rauh,

• Lanktree, Matthew B., McMaster University, Hamilton, Ontario, Canada

Matthew B. Lanktree,

• Grams, Morgan, Johns Hopkins University, Baltimore, Maryland, United States

Morgan Grams,

• Psaty, Bruce M., University of Washington, Seattle, Washington, United States

Bruce M. Psaty,

• Kottgen, Anna, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany

Anna Kottgen,

• Franceschini, Nora, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States

Nora Franceschini,

• Kramer, Holly J., Loyola University Chicago, Chicago, Illinois, United States

Holly J. Kramer,

• Kestenbaum, Bryan R., University of Washington, Seattle, Washington, United States

Bryan R. Kestenbaum,

• Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Cassianne Robinson-Cohen,

Group or Team Name

• TOPMed Kidney Working Group

Background

Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related process wherein an acquired driver mutation in a hematopoietic stem cell produces a resilient clonal leukocyte population with dysregulated inflammatory signaling. The presence of CHIP has been associated with the progression of chronic kidney disease. We tested whether CHIP is a novel risk factor for acute kidney injury (AKI) in two community-based cohorts.

Methods

We evaluated participants from the Atherosclerosis Risk in Community (ARIC; N = 10,570) and Cardiovascular Health Study (CHS; N = 2,792). We identified somatic DNA mutations in peripheral leukocytes that met established criteria for CHIP using whole exome and whole genome data. AKI events were previously ascertained in both cohorts based on hospitalization codes with additional validation by manual chart review in CHS. We used proportional hazards regression to test associations of CHIP with AKI after adjustment for relevant confounders.

Results

CHIP was identified in 7.6% of ARIC participants (median age: 58) and 14.5% of CHS participants (median age: 72). The incidence rate of AKI was higher among persons with CHIP in both cohorts: 12.6 vs. 10.4 events per 1000 person-years in ARIC and 6.6 vs. 4.4 events per 1000 person-years in CHS. In a fixed-effects meta-analysis adjusted for age, age², sex, and baseline eGFR, the presence of CHIP was associated with an estimated 18% greater risk of AKI (HR 1.18, 95% CI: 1.02 – 1.37). The risk for AKI was greatest for mutations in driver genes other than DNMT3A (non-DNMT3A CHIP; HR 1.29, 95% CI: 1.07 – 1.55).

Conclusion

CHIP is associated with a greater risk of incident AKI in two large community-based cohorts. Non-DNMT3A CHIP mutations demonstrate the strongest associations with incident AKI. CHIP may therefore be a novel risk factor for AKI that could partially explain the strong age dependency of this condition. Future studies will elucidate which subtypes of CHIP pose the highest risk of kidney sequelae and in which scenarios emerging treatments for CHIP would be beneficial.

Funding

• Other NIH Support