Raptis Vassilios, Bakogiannis Constantinos, Loutradis Charalampos, Boutou Afroditi K, Sioulis Athanasios, Balaskas Elias, Zebekakis Pantelis, Sarafidis Pantelis A
Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Kidney Blood Press Res. 2018;43(3):744-754. doi: 10.1159/000489911. Epub 2018 May 22.
BACKGROUND/AIMS: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-β1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function.
Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-β1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques.
Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-β1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-β1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-β1 (OR 3.774, 95%CI 1.180-12.072, p=0.025).
ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-β1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.
背景/目的：常染色体显性多囊肾病（ADPKD）中肾脏疾病进展的病理生理学很大程度上尚不清楚。最近的证据表明，微血管功能障碍导致肾脏缺血，这是肾功能下降的另一条途径。本研究检测了肾功能正常或受损的ADPKD患者血清Fas配体（FasL）、血清肌生成抑制素和尿转化生长因子-β1（TGF-β1）水平及其与内皮功能障碍标志物的相关性。
78名参与者被纳入研究，分为三组：A组由26名肾功能受损的ADPKD患者组成（估算肾小球滤过率[eGFR]为45 - 70 ml/min/1.73m²），B组由26名肾功能正常的ADPKD患者组成（eGFR > 70 ml/min/1.73m²），C组由26名年龄和性别匹配且无肾脏疾病史的对照者组成。采用酶联免疫吸附测定（ELISA）技术检测血清FasL、肌生成抑制素以及尿TGF-β1水平，作为血管功能障碍、细胞凋亡和纤维化的生物标志物。
与B组（分别为9.6±1.28 ng/mL、3.06±0.35和2.09±0.37，所有比较p<0.001）或对照组（分别为6.59±1.17 ng/mL、2.18±0.45 ng/ml和1.58±0.21，所有比较p<0.001）相比，A组患者的FasL（13.12±1.69 ng/mL）、肌生成抑制素（4.62±0.59 ng/mL）和尿logTGF-β1（3.56±0.49 ng/24h）水平显著更高。尽管肾功能相似，但B组患者的所有标志物水平也高于对照组（p<0.001）。在ADKPD患者中，eGFR与FasL（r=-0.799，p<0.001）、肌生成抑制素（r=-0.856，p<0.001）和TGF-β1（r=-0.476，p<0.001）呈负相关，但这些标志物与不对称二甲基精氨酸（ADMA）呈正相关（分别为r=0.825；r=0.749；和r=0.599，p均<0.001）。多变量分析表明，FasL与高尿TGF-β1独立相关（比值比[OR] 3.774，95%置信区间[CI] 1.180 - 12.072，p = 0.025）。
肾功能中度正常的ADPKD患者的FasL、肌生成抑制素和尿TGF-β1水平高于对照组。这些结果表明，即使在ADPKD的早期阶段，内皮功能障碍和肾脏缺血之间可能存在与细胞凋亡和纤维化相关机制的相互作用。
