背景:常染色体显性多囊肾病(ADPKD)是一种遗传性肾脏疾病,可能会进展为肾衰竭,占所有终末期肾病(ESKD)患者的5-10%。临床数据,以及分子遗传学和先进的成像技术提供了替代预后生物标志物来预测肾功能的快速下降,尽管如此,仍需要增强的评估ADPKD预后的工具.本研究的目的是分析参与ADPKD发病机制和肾纤维化发展的特异性microRNAs,评估其作为肾功能丧失预测因子的潜在作用。
方法:我们通过估计肾小球滤过率(eGFR)评估了32例ADPKD患者在T0和24个月随访(T1)后的不同肾脏疾病阶段的肾功能。患者分为两组:疾病进展迅速([RP],n15)和非快速疾病进展([NRP],n17),根据梅奥诊所的分类标准。在T0时,ADPKD患者接受血浆采样以定量分析h-miR-17-5p,h-miR-21-5p和h-miR-199a-5p微小RNA表达,使用定量逆转录酶-聚合酶链反应(qRT-PCR)方法和3T磁共振成像(MRI),使用先进的MRI成像协议,用于量化总肾脏体积(TKV),总灌注体积(TPV)和总纤维化体积(TFV)。
结果:在疾病进展迅速的ADPKD患者中,h-miR17-5p的表达更高(p<0.05)。h-miR-17-5p,h-miR-21-5p和h-mir-199-5p与eGFR斜率(mL/min/1.73m2/年)呈正相关且显着相关(p<0.05),但在T0和T1均与eGFR无关。总纤维化体积(cm3)和高度调整后的总纤维化体积(cm3/m)均与h-miR21-5p和h-miR199-5p呈显著正相关(p<0.05)。但不是总肾脏体积(cm3)和高度调整后的总肾脏体积(cm3/m)。
结论:我们研究的microRNAs与纤维化和肾损伤相关,提示它们作为生物标志物的可能作用,能够识别处于疾病进展高风险的ADPKD患者,无论肾功能程度如何,因此适合医学治疗,并可能有助于揭示膀胱形成的新分子机制。
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder that may progress to kidney failure, accounting for 5-10% of all patients with end-stage kidney disease (ESKD). Clinical data, as well as molecular genetics and advanced imaging techniques have provided surrogate prognostic biomarkers to predict rapid decline in kidney function, nonetheless enhanced tools for assessing prognosis for ADPKD are still needed. The aim of this study was to analyze specific microRNAs involved in the pathogenesis of ADPKD and in the development of renal fibrosis, evaluating their potential role as predictors of renal function loss.
METHODS: We evaluated kidney function by estimated glomerular filtration rate (eGFR) in 32 ADPKD patients in different stages of kidney disease at T0 and after a 24-month follow up (T1). Patients were divided into two groups: Rapid disease progression ([RP], n 15) and Non-rapid disease progression ([NRP], n 17), according to the Mayo Clinic classification criteria. At T0, ADPKD patients underwent plasma sampling for quantitative analysis of h-miR-17-5p, h-miR-21-5p and h-miR-199a-5p microRNA expression, using the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) method and a 3 T magnetic resonance imaging (MRI), using an advanced MRI imaging protocol, for the quantification of total kidney volume (TKV), total perfusion volume (TPV) and total fibrotic volume (TFV).
RESULTS: The expression of h-miR17-5p was higher (p < 0.05) in ADPKD patients with rapid disease progression. h-miR-17-5p, h-miR-21-5p and h-mir-199-5p showed a positive and significant correlation with the eGFR slope (mL/min/1.73 m2/year) (p < 0.05) but not with the eGFR at both T0 and T1. Both total fibrotic volume (cm3) and height-adjusted total fibrotic volume (cm3/m) were positively and significantly correlated to h-miR 21-5p and h-miR 199-5p (p < 0.05), but not to total kidney volume (cm3) and height-adjusted total kidney volume (cm3/m).
CONCLUSIONS: The microRNAs we studied were associated with fibrosis and renal damage, suggesting their possible role as biomarkers able to identify ADPKD patients at high risk of disease progression regardless of the degree of kidney function, and therefore suitable for medical therapy, and may help uncovering new molecular mechanisms underlying cystogenesis.