Abstract

Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful.

Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes.

Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m² and/or urinary albumin-creatinine ratio ≥3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline.

Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27–2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16–1.69); myoglobin (OR 1.57, 95% CI 1.30–1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17–1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03–1.98]) but not after further adjustments for cardiovascular risk factors.

Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.

摘要

背景：糖尿病肾病（DKD）是终末期肾病的主要危险因素，并且是糖尿病患者心血管疾病的最重要危险因素之一。刻画病理生理基础过程的新标记可能是有用的。

目的：研究2型糖尿病中80种循环蛋白（通过邻近扩展测定法测定）与流行的DKD和主要的不良心血管事件（MACE）之间的关联。

方法：我们将来自两个队列的2型糖尿病患者随机分为三分之二的发现和三分之一的复制集（总计n  = 813，其中231个患者的DKD由估计的肾小球滤过率<60 mg / mL / 1.73 m定义）²和/或尿白蛋白-肌酐比值≥3 g / mol）。与DKD相关的蛋白质也被评估为基线时DKD患者发生重大心血管不良事件（MACE）的预测因子。

结果：在根据年龄，性别，心血管危险因素，血糖控制和糖尿病药物调整的模型中，四种蛋白质与DKD正相关：肾损伤分子1（KIM-1，每标准偏差增量的比值比[OR]为1.65， 95％置信区间[CI] 1.27–2.14）；生长分化因子15（GDF-15，或1.40，95％CI 1.16-1.69）；肌红蛋白（OR 1.57，95％CI 1.30-1.91）和基质金属蛋白酶10（MMP-10，OR 1.43，95％CI 1.17-1.74）。在调整了基线年龄，性别，微量白蛋白尿和肾功能后，GDF-15患者中的GDF-15与MACE风险显着相关，并且（在7年的随访中有59次MACE事件，每标准差的危险比增加1.43 [95] ％CI 1.03–1.98]），但在进一步调整心血管危险因素后没有。

结论：我们的蛋白质组学方法证实并扩展了先前2型糖尿病患者较高的GDF-15循环水平与微血管和大血管疾病的关联。我们的数据鼓励其他研究评估我们的发现的临床效用。