Nephrology and Dialysis Unit, Bassini Hospital, Cinisello Balsamo, Milan, Italy.
PLoS One. 2013 Apr 4;8(4):e60089. doi: 10.1371/journal.pone.0060089. Print 2013.
Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease.
174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6-9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease.
Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline.
-374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.
慢性肾病（CKD）患者血液中晚期糖基化终产物（AGEs）水平升高。AGEs 通过与位于系膜细胞、内皮细胞和巨噬细胞膜上的受体（RAGE）结合来促进炎症。几个基因多态性影响 RAGE 的转录、表达和活性，包括 RAGE 基因启动子位置 -374 的胸腺嘧啶（T）被腺嘌呤（A）取代。我们的研究调查了 -374 T/A RAGE 多态性在受肾病心血管疾病影响的患者 CKD 进展中的作用。
研究了 174 名（119 名男性（68.4%），平均年龄 67.2±0.88 岁；55 名女性（31.6%）：平均年龄 65.4±1.50 岁）患有轻度至中度肾病心血管 CKD 的患者。每个患者前瞻性随访 84 个月，每 6-9 个月随访一次。研究的主要终点是血清肌酐浓度升高超过基础值的 50%或终末期肾病。
A/A 和 T/A 基因型携带者的白细胞介素 6（A/A 29.5±15.83；T/A 30.0±7.89，与 T/T 相比，p=0.01）和巨噬细胞趋化蛋白 1（A/A 347.1±39.87；T/A 411.8±48.41，与 T/T 相比，p=0.04）的血浆水平更高。与野生型患者相比，携带 A 等位基因的患者 CKD 进展更快（对数秩检验：卡方=6.84，p=0.03）。Cox 回归显示，-374 T/A RAGE 多态性（p=0.037）、白蛋白尿（p=0.01）和 LDL 胆固醇（p=0.038）与 CKD 进展直接相关。HDL 胆固醇（p=0.022）和 BMI（p=0.04）与 CKD 进展呈负相关。循环 RAGE 与肾功能下降之间无相关性。
-374 T/A RAGE 多态性可能与 CKD 进展和炎症有关。进一步的研究应该证实这一发现，并确定抑制 RAGE 下游信号是否有益于 CKD 的进展。
