Ambinathan Jaya Prakash Nath, Sridhar Vikas S, Lytvyn Yuliya, Lovblom Leif Erik, Liu Hongyan, Bjornstad Petter, Perkins Bruce A, Lovshin Julie A, Cherney David Z I
Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
J Diabetes Complications. 2021 May;35(5):107880. doi: 10.1016/j.jdiacomp.2021.107880. Epub 2021 Feb 2.
The renin angiotensin aldosterone system (RAAS) is associated with renal disease and inflammation in a diabetes setting, however, little is known about the implicated mechanisms in individuals with long standing diabetes. Accordingly, our aim was to perform an observational study to quantify urinary excretion of inflammatory biomarkers in participants with long standing type 1 diabetes (T1D) (with and without diabetic kidney disease [DKD]) and controls, at baseline and in response to RAAS activation. GFR, ERPF, and 42 urine inflammatory biomarkers were measured in 74 participants with T1D for ≥50 years (21 with DKD and 44 without DKD [DKD resistors]) and 73 healthy controls. Additionally, inflammatory biomarkers were measured before and after an angiotensin II infusion (ANGII, 1 ng∙kg∙min). Significantly lower urinary excretion of cytokines (IL-18, IL-1RA, IL-8), chemokines (MCP1, RANTES) and growth factors (TGF-α, PDGFAA, PDGFBB, VEGF-A) was observed in participants with T1D at baseline compared to controls. Urinary IL-6 was higher in DKD than in DKD resistors in an exploratory analysis unadjusted for multiple comparisons. In T1D only, lower GFR correlated with greater excretion of proinflammatory biomarkers (IL-18, IP-10, & RANTES), growth factors (PDGF-AA & VEGFAA), and chemokines (eotaxin & MCP-1). ANGII increased 31 of 42 inflammatory biomarkers in T1D vs controls (p < 0.05), regardless of DKD resistor status. In conclusion, lower GFR and intra-renal RAAS activation were associated with increased inflammation even after longstanding T1D. The increased urinary IL-6 in patients with DKD requires further investigation to determine whether IL-6 is a candidate protective biomarker for prognostication or targeted therapy in DKD.
肾素血管紧张素醛固酮系统（RAAS）在糖尿病环境中与肾脏疾病及炎症相关，但对于长期患糖尿病个体的相关机制知之甚少。因此，我们的目的是开展一项观察性研究，以量化长期患1型糖尿病（T1D）（伴或不伴糖尿病肾病[DKD]）的参与者以及对照组在基线时和RAAS激活后的炎症生物标志物尿排泄量。对74名病程≥50年的T1D参与者（21名患有DKD，44名未患DKD[DKD抵抗者]）和73名健康对照者测量了肾小球滤过率（GFR）、有效肾血浆流量（ERPF）以及42种尿液炎症生物标志物。此外，在输注血管紧张素II（ANGII，1 ng∙kg∙min）前后测量了炎症生物标志物。与对照组相比，T1D参与者在基线时细胞因子（IL-18、IL-1RA、IL-8）、趋化因子（MCP1、RANTES）和生长因子（TGF-α、PDGFAA、PDGFBB、VEGF-A）的尿排泄量显著降低。在未经多重比较校正的探索性分析中，DKD患者的尿IL-6高于DKD抵抗者。仅在T1D患者中，较低的GFR与促炎生物标志物（IL-18、IP-10和RANTES）、生长因子（PDGF-AA和VEGFAA）以及趋化因子（嗜酸性粒细胞趋化蛋白和MCP-1）的排泄增加相关。与对照组相比，ANGII使T1D患者中42种炎症生物标志物中的31种增加（p < 0.05），无论其DKD抵抗者状态如何。总之，即使在长期患T1D后，较低的GFR和肾内RAAS激活仍与炎症增加相关。DKD患者尿IL-6升高需要进一步研究，以确定IL-6是否是DKD预后或靶向治疗的候选保护性生物标志物。
