Iio Kenichiro, Kabata Daijiro, Iio Rei, Shibamoto Shinichi, Watanabe Yuuki, Morita Masashi, Imai Yosuke, Hatanaka Masaki, Omori Hiroki, Isaka Yoshitaka
Department of Nephrology, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi Kawachinagano, Osaka, Japan.
Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
Immun Ageing. 2023 Feb 14;20(1):8. doi: 10.1186/s12979-023-00333-z.
Chronic kidney disease (CKD) is age-related disease, and decreased renal function is associated with the premature aging of T cells and increased incidence of other age-related diseases. However, the relationship between T cell senescence and CKD progression remains unclear. Here, we investigated the relationship between T cell senescence, as indicated by decreased thymic output and increased proportion of highly differentiated CD28 T cells, and CKD progression.
A total of 175 patients with non-dialysis-dependent CKD were enrolled in this study. Thymic output was assessed based on the CD45RACD31CD4 cell (recent thymic emigrant [RTE]) counts (RTEs) (/mm) and the proportion of RTE among CD4 T cells (RTE%). Highly differentiated T cells were assessed based on the proportion of CD28 cells among CD4 T cells (CD28/CD4) and CD28 cells among CD8 T cells (CD28/CD8). The primary outcome was estimated glomerular filtration rate (eGFR) decline of ≥40% or initiation of renal replacement therapy. The association between T cell senescence and renal outcomes was examined using Cox proportional hazards models and restricted cubic splines. The median age was 73 years, 33% were women, and the median eGFR was 26 mL/min/1.73 m. The median RTEs, RTE%, CD28/CD4, and CD28/CD8 were 97.5/mm, 16.2, 5.3, and 49.7%, respectively. After a median follow-up of 1.78 years, renal outcomes were observed in 71 patients. After adjusting for age, sex, eGFR, proteinuria, diabetes, and cytomegalovirus seropositivity, decreased RTEs, which corresponded to decreased thymic output, significantly and monotonically increased the risk of poor renal outcome (p = 0.04), and decreased RTE% and increased highly differentiated CD28/CD4 T cells also tended to monotonically increase the risk (p = 0.074 and p = 0.056, respectively), but not CD28/CD8 T cells.
Decreased thymic output in CKD patients, as well as increased highly differentiated CD4 T cells, predicted renal outcomes. Thus, the identification of patients prone to CKD progression using T cell senescence, particularly decreased RTE as a biomarker, may help to prevent progression to end-stage kidney disease.
慢性肾脏病（CKD）是一种与年龄相关的疾病，肾功能下降与T细胞过早衰老及其他与年龄相关疾病的发病率增加有关。然而，T细胞衰老与CKD进展之间的关系仍不清楚。在此，我们研究了以胸腺输出减少和高分化CD28⁻T细胞比例增加为指标的T细胞衰老与CKD进展之间的关系。
本研究共纳入175例非透析依赖性CKD患者。基于CD45RA⁺CD31⁺CD4⁺细胞（近期胸腺迁出细胞[RTE]）计数（/mm³）和RTE在CD4⁺T细胞中的比例（RTE%）评估胸腺输出。基于CD4⁺T细胞中CD28⁻细胞的比例（CD28⁻/CD4）和CD8⁺T细胞中CD28⁻细胞的比例（CD28⁻/CD8）评估高分化T细胞。主要结局为估计肾小球滤过率（eGFR）下降≥40%或开始肾脏替代治疗。使用Cox比例风险模型和受限立方样条检验T细胞衰老与肾脏结局之间的关联。中位年龄为73岁，33%为女性，中位eGFR为26 mL/min/1.73 m²。中位RTE计数、RTE%、CD28⁻/CD4和CD28⁻/CD8分别为97.5/mm³、16.2、5.3和49.7%。中位随访1.78年后，71例患者出现肾脏结局。在调整年龄、性别、eGFR、蛋白尿、糖尿病和巨细胞病毒血清学阳性后，与胸腺输出减少相对应的RTE计数下降显著且单调增加不良肾脏结局的风险（p = 0.04），RTE%下降和高分化CD28⁻/CD4⁺T细胞增加也倾向于单调增加风险（分别为p = 0.074和p = 0.056），但CD28⁻/CD8⁺T细胞无此情况。
CKD患者胸腺输出减少以及高分化CD4⁺T细胞增加可预测肾脏结局。因此，利用T细胞衰老，特别是将RTE计数下降作为生物标志物来识别易发生CKD进展的患者，可能有助于预防进展至终末期肾病。
