Benetti Acaris, Ribeiro-Silva Joao Carlos, Gómez Luz M, Tavares Caio A M, Bensenor Isabela J, Lotufo Paulo A, Titan Silvia M O, Girardi Adriana C C
Laboratório de Genética e Cardiologia Molecular, Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clinicas HCFMUSP, Universidade de São Paulo, Avenida Dr. Enéas de Carvalho Aguiar, 44-Bloco II 10° Andar, São Paulo, SP, 05403-900, Brazil.
State University of New York (SUNY) Upstate Medical University, Syracuse, NY, USA.
Sci Rep. 2025 Jul 2;15(1):23190. doi: 10.1038/s41598-025-06395-x.
Experimental studies have shown that urinary dipeptidyl peptidase 4 (uDPP4), unlike serum DPP4 (sDPP4) activity, correlates with proteinuria, serum creatinine, and left ventricular (LV) hypertrophy in chronic kidney disease (CKD) models, suggesting a potential role for uDPP4 in CKD progression. This study examined the relationship of uDPP4 and sDPP4 activities with renal, cardiovascular, and metabolic markers, along with mortality and initiation of kidney replacement therapy (KRT) events in individuals with CKD. DPP4 activity was measured in the urine and serum of 426 participants from the Brazilian CKD cohort, PROGREDIR. Participants were stratified into tertiles based on uDPP4 and sDPP4 activities. Multivariable linear regression, Kaplan-Meier analysis, Cox hazards, and competing risk models (cause-specific and Fine-Gray) were used. uDPP4 activity was positively associated with albuminuria, urinary retinol-binding protein 4, LV mass, and type 2 diabetes but inversely associated with body mass index and use of renin-angiotensin system blockers. In contrast, sDPP4 activity correlated only with age and biological sex. Higher uDPP4 activity was associated with a higher incidence rate of all-cause mortality (p < 0.0001). Participants in the second and third uDPP4 activity tertiles had greater mortality risk compared to the lowest tertile (HR 2.03, 95% CI 1.36-3.04 and HR 2.48, 95% CI 1.67-3.67, respectively), even after controlling for potential confounders. No independent association was found between sDPP4 activity and mortality or initiation of KRT. These findings support uDPP4's involvement in CKD progression and its association with increased mortality risk in individuals with CKD.
实验研究表明，与血清二肽基肽酶4（sDPP4）活性不同，尿二肽基肽酶4（uDPP4）活性在慢性肾脏病（CKD）模型中与蛋白尿、血清肌酐及左心室（LV）肥厚相关，提示uDPP4在CKD进展中可能发挥作用。本研究探讨了uDPP4和sDPP4活性与CKD患者的肾脏、心血管及代谢标志物的关系，以及死亡率和开始肾脏替代治疗（KRT）事件。在巴西CKD队列研究PROGREDIR的426名参与者的尿液和血清中测量了DPP4活性。参与者根据uDPP4和sDPP4活性被分为三分位数。使用了多变量线性回归、Kaplan-Meier分析、Cox风险模型和竞争风险模型（病因特异性和Fine-Gray模型）。uDPP4活性与蛋白尿、尿视黄醇结合蛋白4、LV质量和2型糖尿病呈正相关，但与体重指数和肾素-血管紧张素系统阻滞剂的使用呈负相关。相比之下，sDPP4活性仅与年龄和生物学性别相关。较高的uDPP4活性与全因死亡率较高的发生率相关（p<0.0001）。与最低三分位数相比，uDPP4活性处于第二和第三三分位数的参与者死亡风险更高（HR分别为2.03，95%CI 1.36 - 3.04和HR 2.48，95%CI 1.67 - 3.67），即使在控制了潜在混杂因素之后。未发现sDPP4活性与死亡率或开始KRT之间存在独立关联。这些发现支持uDPP4参与CKD进展及其与CKD患者死亡风险增加的关联。
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