Paper Details

ABSTRACT

Chronic kidney disease (CKD) is frequently observed in patients with myeloid malignancies, but it is generally considered a comorbidity rather than an active modifier of hematopoiesis. We hypothesized that renal injury directly reprograms hematopoietic stem and progenitor cells (HSPCs), alters their supporting bone marrow (BM) niche, and promotes inflammatory communication between the BM and kidney.

Analysis of more than 502,000 participants in the UK Biobank showed that patients with myeloproliferative neoplasms (MPNs) had an increased prevalence and future risk of CKD, providing clinical evidence for a bidirectional relationship between renal and myeloid disease. To define the underlying mechanism, we induced aristolochic acid nephropathy in wild-type mice and in JAK2V617F and TET2-deficient models of MPN and clonal hematopoiesis. We combined flow cytometry, single-cell transcriptomics, spatial transcriptomics, stromal trajectory analysis, and transplantation assays to assess hematopoietic, niche, and immune alterations.

CKD reduced the frequency of BM LSK (Lineage^- Sca1⁺ c-Kit⁺) cells by 37%, predominantly through loss of multipotent progenitors, with an additional reduction in long-term hematopoietic stem cells (LT-HSCs). This phenotype was reproduced in JAK2V617F and TET2-deficient mice, demonstrating that CKD disrupts the stem and progenitor compartment across distinct hematopoietic backgrounds. However, the functional response depends on disease context. Under steady-state hematopoiesis, CKD promoted HSC quiescence and reduced proliferation, whereas in JAK2V617F and TET2-deficient hematopoiesis it increased proliferation and reduced quiescence. Thus, the same renal injury suppresses normal hematopoiesis but promotes aberrant cycling in malignant or clonally altered stem cells. Importantly, re-transplantation of c-Kit-positive cells from CKD donors into non-uremic recipients reproduced the stem cell defect. The reduction was most pronounced within the LT-HSC compartment and persisted in the absence of ongoing renal injury, demonstrating that CKD induces durable, cell-intrinsic reprogramming of hematopoietic stem cells.

CKD also profoundly remodeled the HSPC-supportive niche. HSPC-support programs were reduced in osteogenic-primed CXCL12-abundant reticular (CAR) cells and osteolineage cells, while they increased in adipogenic-primed CAR cells. Trajectory analysis revealed enhanced differentiation of adipogenic-primed CAR cells toward an osteogenic fate, yet the resulting osteogenic populations showed impaired hematopoietic support. This maladaptive stromal transition coincided with marked urinary calcium loss, potentially linking CKD-associated mineral dysregulation to altered BM stromal function.

In JAK2V617F mice, severe renal injury was accompanied by reduced glomerular filtration and increased creatinine and blood urea nitrogen. Nevertheless, JAK2V617F-driven, erythropoietin-independent erythropoiesis maintained normal hemoglobin levels, whereas CKD caused anemia in all other genotypes. These findings suggest that JAK2V617F can conceal the hematologic manifestation of CKD despite ongoing renal, stem cell, and niche injury. Among BM immune populations, basophils were the most consistently altered by CKD. Within the BM, basophils acquired an immature, less inflammatory state characterized by reduced chemokine expression and suppression of TNF/NF-κB, interferon, and IL-6/JAK/STAT3 signaling. In contrast, kidney-infiltrating basophils displayed a strongly pro-inflammatory phenotype. This response was present in CKD alone but was markedly amplified by JAK2V617F, revealing spatially opposing basophil states within the BM and injured kidney.

Together, these findings establish CKD as an active regulator of hematopoietic stem cells and their niche rather than a passive consequence of myeloid disease. CKD suppresses normal HSC function, promotes aberrant activity in malignant hematopoiesis, induces maladaptive stromal remodeling, and generates a kidney-directed inflammatory basophil phenotype. These data define a mechanistic bone marrow–kidney axis and nominate basophils as potential mediators and therapeutic targets within this inter-organ disease circuit.