Clonal hematopoiesis of indeterminate potential (CHIP) is associated with acute kidney injury (AKI). This study investigates the link between CHIP and AKI, using large epidemiological datasets and mouse models. CHIP is a common hematological process, characterized by clonal expansion of hematopoietic stem cells after somatic genetic mutations. It affects 3.4% of the general population, increasing with age. While most CHIP cases do not progress to hematological malignancies, they are associated with a 40% increased risk of mortality due to non-hematological conditions. CHIP is linked to a pro-inflammatory phenotype in macrophages, contributing to various diseases. Epidemiological studies suggest a potential link between CHIP and chronic kidney disease. This study focuses on the association between CHIP and AKI. In the UK Biobank cohort, CHIP was associated with a 34% increased risk of AKI (HR 1.34, 95% CI 1.29–1.40). This association was stronger in cases requiring dialysis (HR 1.65, 95% CI 1.24–2.20). Non-DNMT3A CHIP variants were particularly associated with higher AKI risk. The risk was proportional to the allelic frequency of the variant. In the ASSESS-AKI cohort, non-DNMT3A CHIP and high FAV CHIP were linked to a greater risk of unresolved AKI. High FAV CHIP was also associated with end-stage renal failure or a 50% decline in eGFR at 5 years. Mouse models showed that Tet2-deficient hematopoietic stem cells led to more severe AKI and worse recovery. These mice exhibited increased inflammation, macrophage infiltration, and fibrosis. The study also showed that UUO in Tet2-deficient mice led to increased inflammation and fibrosis. The study is the first to show an epidemiological link between CHIP and AKI, and between CHIP and recovery after AKI. It also demonstrates a causal relationship between CHIP and AKI through experimental models. However, the study lacks therapeutic suggestions and the UUO model is not an AKI model. The study highlights CHIP as a new risk factor for AKI, with a causal link demonstrated in animals, favoring renal inflammation. This study opens up potential diagnostic and therapeutic perspectives.Clonal hematopoiesis of indeterminate potential (CHIP) is associated with acute kidney injury (AKI). This study investigates the link between CHIP and AKI, using large epidemiological datasets and mouse models. CHIP is a common hematological process, characterized by clonal expansion of hematopoietic stem cells after somatic genetic mutations. It affects 3.4% of the general population, increasing with age. While most CHIP cases do not progress to hematological malignancies, they are associated with a 40% increased risk of mortality due to non-hematological conditions. CHIP is linked to a pro-inflammatory phenotype in macrophages, contributing to various diseases. Epidemiological studies suggest a potential link between CHIP and chronic kidney disease. This study focuses on the association between CHIP and AKI. In the UK Biobank cohort, CHIP was associated with a 34% increased risk of AKI (HR 1.34, 95% CI 1.29–1.40). This association was stronger in cases requiring dialysis (HR 1.65, 95% CI 1.24–2.20). Non-DNMT3A CHIP variants were particularly associated with higher AKI risk. The risk was proportional to the allelic frequency of the variant. In the ASSESS-AKI cohort, non-DNMT3A CHIP and high FAV CHIP were linked to a greater risk of unresolved AKI. High FAV CHIP was also associated with end-stage renal failure or a 50% decline in eGFR at 5 years. Mouse models showed that Tet2-deficient hematopoietic stem cells led to more severe AKI and worse recovery. These mice exhibited increased inflammation, macrophage infiltration, and fibrosis. The study also showed that UUO in Tet2-deficient mice led to increased inflammation and fibrosis. The study is the first to show an epidemiological link between CHIP and AKI, and between CHIP and recovery after AKI. It also demonstrates a causal relationship between CHIP and AKI through experimental models. However, the study lacks therapeutic suggestions and the UUO model is not an AKI model. The study highlights CHIP as a new risk factor for AKI, with a causal link demonstrated in animals, favoring renal inflammation. This study opens up potential diagnostic and therapeutic perspectives.