Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain.
Cardiovasc Diabetol. 2024 Aug 24;23(1):314. doi: 10.1186/s12933-024-02393-x.
Diabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD).
In this open-label, randomized controlled, prospective single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA.
Patients treated with PTF presented a better evolution of CIMT, increased KL mRNA levels in peripheral blood cells (PBCs) and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in PBCs. Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R = 0.24, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.103 (P = 0.001) and 0.001 (P = 0.005), respectively].
PTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs.
The study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009-016595-77). The validation date was 2010-03-09.
糖尿病肾病（DKD）与心血管疾病（CVD）风险增加相关。己酮可可碱（PTF）是一种非选择性磷酸二酯酶抑制剂，具有抗炎、抗增殖和抗纤维化作用，在临床试验和荟萃分析中均显示出对肾脏有益。本研究旨在研究 PTF 对糖尿病合并中重度慢性肾脏病（CKD）患者亚临床动脉粥样硬化（SA）进展的影响。
在这项开放标签、随机对照、前瞻性单中心试点研究中，102 例 2 型糖尿病合并 CKD 患者被分配到 PTF 组、阿司匹林组或对照组，随访 18 个月。我们还测定了颈动脉内膜中层厚度（CIMT）和踝臂指数（ABI）的变化，并确定了炎症标志物和 Klotho（KL）水平的变化，KL 是一种与维持心血管健康有关的蛋白，及其与 SA 进展的关系。
接受 PTF 治疗的患者 CIMT 改善较好，外周血单个核细胞（PBC）中 KL mRNA 水平升高，炎症状态减轻。CIMT 值的进展与血清和 PBCs 中 KL mRNA 表达水平的变化呈负相关。多元回归分析表明，PTF 治疗和 PBCs 中 KL mRNA 表达的变化，以及 HDL 的变化，是 CIMT 进展的独立决定因素（调整后的 R²=0.24，P<0.001），独立于传统危险因素。此外，这两个变量都是 CIMT 恶化的保护因素[比值比：0.103（P=0.001）和 0.001（P=0.005）]。
PTF 通过降低 CIMT 变化来减轻 SA 进展，这一有益作用与 PBCs 中 KL 基因表达有关。
研究方案代码为 PTF-AA-TR-2009，该试验在欧洲药品管理局临床试验注册处（EudraCT #2009-016595-77）注册。验证日期为 2010 年 3 月 9 日。
