最近的全基因组分析揭示了体细胞造血干细胞突变随着衰老而积累。克隆扩增，称为不确定潜能克隆造血 (CHIP)，是血液癌的一种癌前状态。它被定义为缺乏血液肿瘤的明确形态学证据并且外周血中出现≥2%的突变等位基因分数。在 CHIP 中，最常见突变的基因是表观遗传调节因子，例如 DNMT3A、TET2 和 ASXL1。 CHIP 会诱发炎症。研究表明，CHIP 不仅与血液恶性肿瘤有关，还与动脉粥样硬化、心血管疾病和慢性肝病等非恶性疾病有关。此外，最近的几项大型临床试验表明，CHIP也是发展为慢性肾脏病（CKD）的危险因素。在这篇综述文章中，我们根据最近的基础和临床研究提出了有关 CHIP 和 CHIP 相关肾脏疾病的新发现。 CHIP 中肾损伤的可能机制被认为是由于骨髓细胞和淋巴细胞系的克隆扩张所致。在骨髓细胞系中，突变的巨噬细胞增加炎症细胞因子水平并诱导慢性炎症。它导致肾脏和巨噬细胞 klotho 水平的表观遗传下调。在淋巴细胞系中，CHIP 可能与肾意义单克隆丙种球蛋白病 (MGRS) 相关。它描述了任何不符合癌症标准但产生肾毒性单克隆免疫球蛋白、导致肾损伤或疾病的 B 细胞或浆细胞克隆性疾病。 MGRS 会导致老年 CKD 患者中常见的 M 蛋白相关肾病。在管理老年 CKD 患者时，考虑血液系统恶性肿瘤、心血管疾病和代谢紊乱等 CHIP 相关并发症非常重要。目前尚无针对 CHIP 和 CHIP 相关 CKD 的既定疗法。然而，最近的研究支持开发有效的 CHIP 疗法，例如阻止异常 HSC 的扩增和抑制慢性炎症。此外，针对肾脏和巨噬细胞中 Klotho 表观遗传调控的药物可能是肾脏中 CHIP 的治疗靶点。版权所有 © 2023 Ogura 和 Mimura。

Accumulation of somatic hematopoietic stem cell mutations with aging has been revealed by the recent genome-wide analysis. Clonal expansion, known as clonal hematopoiesis of indeterminate potential (CHIP), is a premalignant condition of hematological cancers. It is defined as the absence of definitive morphological evidence of a hematological neoplasm and occurrence of ≥2% of mutant allele fraction in the peripheral blood. In CHIP, the most frequently mutated genes are epigenetic regulators such as DNMT3A, TET2, and ASXL1. CHIP induces inflammation. CHIP is shown to be associated with not only hematological malignancy but also non-malignant disorders such as atherosclerosis, cardiovascular diseases and chronic liver disease. In addition, recent several large clinical trials have shown that CHIP is also the risk factor for developing chronic kidney disease (CKD). In this review article, we proposed novel findings about CHIP and CHIP related kidney disease based on the recent basic and clinical research. The possible mechanism of the kidney injury in CHIP is supposed to be due to the clonal expansion in both myeloid and lymphoid cell lines. In myeloid cell lines, the mutated macrophages increase the inflammatory cytokine level and induce chronic inflammation. It leads to epigenetic downregulation of kidney and macrophage klotho level. In lymphoid cell lines, CHIP might be related to monoclonal gammopathy of renal significance (MGRS). It describes any B cell or plasma cell clonal disorder that does not fulfill the criteria for cancer yet produces a nephrotoxic monoclonal immunoglobulin that leads to kidney injury or disease. MGRS causes M-protein related nephropathy frequently observed among aged CKD patients. It is important to consider the CHIP-related complications such as hematological malignancy, cardiovascular diseases and metabolic disorders in managing the elderly CKD patients. There are no established therapies for CHIP and CHIP-related CKD yet. However, recent studies have supported the development of effective CHIP therapies, such as blocking the expansion of aberrant HSCs and inhibiting chronic inflammation. In addition, drugs targeting the epigenetic regulation of Klotho in the kidney and macrophages might be therapeutic targets of CHIP in the kidney.Copyright © 2023 Ogura and Mimura.