Department of Internal Medicine IV - Nephrology and Hypertension, Saarland University Medical Center, Homburg/Saar, Germany.
Nephrol Dial Transplant. 2021 Apr 26;36(5):761-767. doi: 10.1093/ndt/gfaa003.
Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/β-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications.
慢性肾脏病（CKD）是一个全球性的公共卫生问题，伴随着大量的合并症和预期寿命的降低。在这方面，进展性 CKD 导致的尿毒症可以被视为一种全身性疾病，对几乎所有的器官系统都有严重影响。因此，识别持续进展的 CKD 患者尤为重要，但这是具有挑战性的，因为 CKD 的个体病程很难预测。CKD 患者的进展模式包括 GFR 损失的线性和非线性轨迹，但肾功能也可以多年保持稳定。此外，在没有更高等级白蛋白尿（非蛋白尿性 CKD）的情况下，可能会发生大量的 GFR 下降，这使得白蛋白尿的测量在这些个体中对进展预测的可靠性降低。在本综述中，我们重点介绍了最近发现的糖蛋白 Dickkopf-3（DKK3），它是一种应激诱导的、肾小管上皮细胞衍生的、促纤维化分子。在实验性 CKD 模型中，DKK3 通过调节经典的 Wnt/β-catenin 信号通路促进肾间质纤维化。在临床研究中，尿 DKK3 水平升高可识别出短期 CKD 进展风险较高的患者，无论其肾脏病的病因、基线肾功能和白蛋白尿如何。此外，尿 DKK3 水平升高与心脏手术后急性肾损伤和随后肾功能丧失的风险增加相关。这些发现强调了 DKK3 作为肾脏损伤和短期肾脏病进展中肾小管细胞损伤的介质的作用，具有潜在的治疗意义。
