Chen Teresa K, Estrella Michelle M, Katz Ronit, Sarnak Mark J, Grams Morgan E, Cushman Mary, Levitan Emily B, Parikh Chirag R, Kimmel Paul L, Bonventre Joseph V, Coca Steven G, Gutiérrez Orlando M, Ix Joachim H, Shlipak Michael G
Kidney Health Research Collaborative and Department of Medicine, University of.
Department of Obstetrics & Gynecology, University of Washington, Seattle, WA.
Clin J Am Soc Nephrol. 2024 Dec 1;19(12):1585-1593. doi: 10.2215/CJN.0000000000000544. Epub 2024 Sep 20.
In diabetes and CKD, creatinine- and cystatin C–based eGFR has a strong inverse correlation with plasma TNF receptor 1, TNF receptor 2, and soluble urokinase-type plasminogen activator receptor. Higher plasma soluble TNF receptors 1 and 2 and soluble urokinase-type plasminogen activator receptor were each individually associated with mortality, independent of baseline kidney measures.
Several plasma biomarkers of kidney health have been associated with CKD progression in persons with diabetes, but their associations with mortality risk have been largely unexplored.
In a random sample of 594 participants with diabetes and creatinine-based eGFR <60 ml/min per 1.73 m from the REGARDS cohort study, Cox proportional hazards regression was used to determine hazard ratios of mortality by plasma concentrations of soluble TNF receptors 1 and 2 (TNFR1 and TNFR2), soluble urokinase-type plasminogen activator receptor (suPAR), kidney injury molecule 1 (KIM-1), chitinase 3–like 1 (YKL-40), and monocyte chemotactic protein 1 (MCP-1). Covariates included sociodemographic and clinical factors, urine albumin-to-creatinine ratio (UACR), and creatinine- and cystatin C–based eGFR (eGFRcr-cys).
At baseline, the mean age was 70 years, 47% were male, 53% self-identified as Black, mean±SD eGFRcr-cys was 41±13 ml/min per 1.73 m, and median (interquartile range) UACR was 32 (9–224) mg/g. Correlations with eGFRcr-cys were stronger for TNFR1, TNFR2, and suPAR (=−0.72 to −0.76) than for KIM-1, YKL-40, and MCP-1 (=−0.10 to −0.40). With a median follow-up of 7 years, 332 participants died. In models adjusted for sociodemographic and clinical factors, each SD higher baseline concentration of plasma TNFR1 (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.20 to 1.38), TNFR2 (HR, 1.61; 95% CI, 1.42 to 1.82), suPAR (HR, 1.33; 95% CI, 1.22 to 1.44), KIM-1 (HR, 1.20; 95% CI, 1.08 to 1.33), and YKL-40 (HR, 1.23; 95% CI, 1.11 to 1.38) was associated with higher risk of all-cause mortality, whereas MCP-1 was not. Upon further adjustment for baseline eGFRcr-cys and UACR, only the associations for TNFR1 (HR, 1.16; 95% CI, 1.04 to 1.29), TNFR2 (HR, 1.34; 95% CI, 1.12 to 1.60), and suPAR (HR, 1.23; 95% CI, 1.11 to 1.36) persisted.
Among adults with diabetes and CKD, higher plasma TNFR1, TNFR2, and suPAR were associated with all-cause mortality, independent of baseline kidney function.
在糖尿病和慢性肾脏病（CKD）患者中，基于肌酐和胱抑素C的估算肾小球滤过率（eGFR）与血浆肿瘤坏死因子受体1（TNF受体1）、肿瘤坏死因子受体2（TNF受体2）及可溶性尿激酶型纤溶酶原激活物受体呈强负相关。较高的血浆可溶性TNF受体1、TNF受体2及可溶性尿激酶型纤溶酶原激活物受体各自均与死亡率独立相关，与基线肾脏指标无关。
几种肾脏健康的血浆生物标志物已被证实与糖尿病患者的CKD进展相关，但它们与死亡风险的关联在很大程度上尚未得到充分研究。
在REGARDS队列研究中随机抽取594例糖尿病患者，其基于肌酐的eGFR<60ml/（min·1.73m²），采用Cox比例风险回归分析，以确定可溶性TNF受体1和2（TNFR1和TNFR2）、可溶性尿激酶型纤溶酶原激活物受体（suPAR）、肾损伤分子1（KIM-1）、几丁质酶3样蛋白1（YKL-40）及单核细胞趋化蛋白1（MCP-1）的血浆浓度与死亡率的风险比。协变量包括社会人口统计学和临床因素、尿白蛋白与肌酐比值（UACR）以及基于肌酐和胱抑素C的eGFR（eGFRcr-cys）。
基线时，平均年龄为70岁，47%为男性，53%自我认定为黑人，eGFRcr-cys的均值±标准差为41±13ml/（min·1.73m²），UACR的中位数（四分位间距）为32（9 - 224）mg/g。TNFR1、TNFR2和suPAR与eGFRcr-cys的相关性（r=-0.72至-0.76）强于KIM-1、YKL-40和MCP-1（r=-0.10至-0.40）。中位随访7年，332例参与者死亡。在对社会人口统计学和临床因素进行校正的模型中，血浆TNFR1（风险比[HR]，1.28；95%置信区间[CI]，1.20至1.38）、TNFR2（HR，1.61；95%CI，1.42至1.82）、suPAR（HR，1.33；95%CI，1.22至1.44）、KIM-1（HR，1.20；95%CI，1.08至1.33）及YKL-40（HR，1.23；95%CI，1.11至1.38）的基线浓度每升高1个标准差，均与全因死亡风险增加相关，而MCP-1则不然。在进一步校正基线eGFRcr-cys和UACR后，仅TNFR1（HR，1.16；95%CI，1.04至1.29）、TNFR2（HR，1.34；95%CI，1.12至1.60）和suPAR（HR，1.23；95%CI，1.11至1.36）的相关性仍然存在。
在患有糖尿病和CKD的成年人中，较高的血浆TNFR1、TNFR2和suPAR与全因死亡率独立相关，与基线肾功能无关。
