■常染色体显性多囊肾病(ADPKD)是最常见的遗传性肾脏疾病,并导致成年后肾功能持续丧失。该疾病的可变病程使得有必要确定具有快速疾病进展的患者,这些患者将从靶向治疗和干预措施中受益最大。目前,基于磁共振成像的肾脏容积是最常用的工具。可以容易和定量确定的生物标志物,可以预测肾功能的丧失,尚未在临床实践中确立。糖蛋白Dickkopf3(DKK3)在应激时分泌于肾小管上皮细胞,并通过Wnt信号通路促进肾小管间质纤维化,最近被描述为评估肾功能丧失风险的生物标志物,但尚未对ADPKD进行调查。这项研究旨在初步了解DKK3是否确实可以改善未来ADPKD的结果预测。
■在AD(H)PKD注册的184名ADPKD患者和47名健康对照中,使用ELISA测定尿DKK3(uDKK3)水平。使用多元线性回归来检查这些值在结果预测中的潜力。
■ADPKD患者与对照组相比显示出明显更高的uDKK3值(平均1970±5287比112±134.7pg/mg肌酐)。此外,随着Mayo类的增加,uDKK3稳步增加(A/B1262±2315vsD/E类3104±7627pg/mg肌酐),ADPKD进展的最佳生物标志物。uDKK3也与估计的肾小球滤过率(eGFR)相关。与PKD2患者相比,PKD1突变患者的uDKK3水平更高(PKD1:2304±5119;PKD2:506.6±526.8pg/mg肌酐)。单变量线性回归显示uDKK3是未来eGFR斜率估计的显著预测因子。在多元线性回归中,这种效应在还包含高度调整的总肾脏体积和/或eGFR的模型中并不显著。然而,将copeptin水平和copeptin和uDKK3之间的相互作用项添加到模型中,导致所有这三个变量的显着预测价值和所有检查的模型的最高R2(〜0.5)。
■uDKK3与ADPKD患者的Mayo分类具有明显的相关性。uDKK3水平与肾功能相关,这可能表明uDKK3还预测了该集体中肾功能的不成比例的丧失。有趣的是,我们在我们的预测模型中发现了和肽素与uDKK3之间的相互作用,与以前的模型相比,包含两个变量及其相互作用项的最佳模型对eGFR斜率的方差有相当好的解释.考虑到这些分析中的患者数量有限,未来的研究将需要确认结果。尽管如此,uDKK3似乎是未来改善ADPKD结果预测的有吸引力的候选者。
UNASSIGNED: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, and leads to a steady loss of kidney function in adulthood. The variable course of the disease makes it necessary to identify the patients with rapid disease progression who will benefit the most from targeted therapies and interventions. Currently, magnetic resonance imaging-based volumetry of the kidney is the most commonly used tool for this purpose. Biomarkers that can be easily and quantitatively determined, which allow a prediction of the loss of kidney function, have not yet been established in clinical practice. The glycoprotein Dickkopf 3 (DKK3) which is secreted in the renal tubular epithelium upon stress and contributes to tubulointerstitial fibrosis via the Wnt signaling pathway, was recently described as a biomarker for estimating risk of kidney function loss, but has not been investigated for ADPKD. This study aimed to obtain a first insight into whether DKK3 may indeed improve outcome prediction in ADPKD in the future.
UNASSIGNED: In 184 ADPKD patients from the AD(H)PKD registry and 47 healthy controls, the urinary DKK3 (uDKK3) levels were determined using ELISA. Multiple linear regression was used to examine the potential of these values in outcome prediction.
UNASSIGNED: ADPKD patients showed significantly higher uDKK3 values compared with the controls (mean 1970 ± 5287 vs 112 ± 134.7 pg/mg creatinine). Furthermore, there was a steady increase in uDKK3 with an increase in the Mayo class (A/B 1262 ± 2315 vs class D/E 3104 ± 7627 pg/mg creatinine), the best-established biomarker of progression in ADPKD. uDKK3 also correlated with estimated glomerular filtration rate (eGFR). Patients with PKD1 mutations show higher uDKK3 levels compared with PKD2 patients (PKD1: 2304 ± 5119; PKD2: 506.6 ± 526.8 pg/mg creatinine). Univariate linear regression showed uDKK3 as a significant predictor of future eGFR slope estimation. In multiple linear regression this effect was not significant in models also containing height-adjusted total kidney volume and/or eGFR. However, adding both copeptin levels and the interaction term between copeptin and uDKK3 to the model resulted in a significant predictive value of all these three variables and the highest R2 of all models examined (∼0.5).
UNASSIGNED: uDKK3 shows a clear correlation with the Mayo classification in patients with ADPKD. uDKK3 levels correlated with kidney function, which could indicate that uDKK3 also predicts a disproportionate loss of renal function in this collective. Interestingly, we found an interaction between copeptin and uDKK3 in our prediction models and the best model containing both variables and their interaction term resulted in a fairly good explanation of variance in eGFR slope compared with previous models. Considering the limited number of patients in these analyses, future studies will be required to confirm the results. Nonetheless, uDKK3 appears to be an attractive candidate to improve outcome prediction of ADPKD in the future.