Clonal Hematopoiesis of Indeterminate Potential Associates with Severe AKI
Bibliographic record
Abstract
Background: Clonal hematopoiesis of indeterminate potential (CHIP) is the clonal expansion of hematopoietic stem cells due to somatic mutations like TET2 gene mutation, without evidence of hematologic malignancy or cytopenia. CHIP is associated with a pro-inflammatory state. The role of inflammation in acute kidney injury (AKI) among individuals with CHIP remains unclear. Methods: Bone marrow cells (BMC) were collected from recipient mice (CD45.1 isotype), Tet2-deficient and control mice (CD45.2 isotype). Lethally irradiated male recipient mice underwent retroorbital injection of 5 × 106 BMC, consisting of 80% recipient cells and 20% Tet2-deficient (Tet2-/-) or control (Tet2+/+) cells. Flow cytometry confirmed successful engraftment and clonal expansion of Tet2-deficient cells, and then the chimeric mice underwent unilateral kidney vascular clamping with contralateral nephrectomy (Unx-IRI). Renal function was assessed by BUN and creatinine levels, and kidney macrophages were isolated for analysis. Results: The chimeric mice with Tet2-/- BMC developed CHIP, indicated by flow cytometry of peripheral blood cells. Tet2-/- mice exhibited increased CD45.2 cells in the intrinsic myeloid kidney cell population. Following Unx-IRI, Tet2-/- mice had more severe kidney injury compared to control mice. Higher levels of tubule injury markers (KIM-1, NGAL) and more severe tubule injury were observed in Tet2-/- mice at 8 days after Unx-IRI. The kidneys of Tet2-/- mice displayed elevated expression of proinflammatory cytokines (Tnf, Il6, Il1b), chemokines (Ccl2, Ccl3), profibrotic genes (Tgfb, Ctgf, Acta2), and extracellular matrix-associated genes (Col1a1, Col3a1, Fn, Vim) compared to Tet2+/+ mice. Macrophages isolated from the kidneys of Tet2-/- mice exhibited increased expression of proinflammatory cytokines both before and after injury. Additionally, increased co-expression of NLRP3 inflammasome and IL-1β with CD68-positive macrophages was observed in kidneys only in the CD45.2 macrophages and not in the CD45.1 macrophages. Conclusions: This study demonstrates that CHIP is associated with an increased risk of severe AKI in this mouse model, potentially caused by enhanced infiltration of inflammatory cells into the kidneys and subsequent excessive production of proinflammatory cytokines and chemokines. Funding: NIDDK Support
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".