Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA.
Department of Medicine, St. Elizabeth's Hospital, Boston, MA.
Hepatology. 2019 Feb;69(2):729-741. doi: 10.1002/hep.30230. Epub 2019 Jan 4.
Acute kidney injury in decompensated cirrhosis has limited therapeutic options, and novel mechanistic targets are urgently needed. Angiopoietin-2 is a context-specific antagonist of Tie2, a receptor that signals vascular quiescence. Considering the prominence of vascular destabilization in decompensated cirrhosis, we evaluated Angiopoietin-2 to predict clinical outcomes. Serum Angiopoietin-2 was measured serially in a prospective cohort of hospitalized patients with decompensated cirrhosis and acute kidney injury. Clinical characteristics and outcomes were examined over a 90-day period and analyzed according to Angiopoietin-2 levels. Primary outcome was 90-day mortality. Our study included 191 inpatients (median Angiopoietin-2 level 18.2 [interquartile range 11.8, 26.5] ng/mL). Median Model for End-Stage Liver Disease (MELD) score was 23 [17, 30] and 90-day mortality was 41%. Increased Angiopoietin-2 levels were associated with increased mortality (died 21.9 [13.9, 30.3] ng/mL vs. alive 15.2 [9.8, 23.0] ng/mL; P < 0.001), higher Acute Kidney Injury Network stage (stage I 13.4 [9.8, 20.1] ng/mL vs. stage II 20.0 [14.1, 26.2] ng/mL vs. stage III 21.9 [13.0, 29.5] ng/mL; P = 0.002), and need for renal replacement therapy (16.5 [11.3, 23.6] ng/mL vs. 25.1 [13.3, 30.3] ng/mL; P = 0.005). The association between Angiopoietin-2 and mortality was significant in unadjusted and adjusted Cox regression models (P ≤ 0.001 for all models), and improved discrimination for mortality when added to MELD score (integrated discrimination increment 0.067; P = 0.001). Conclusion: Angiopoietin-2 was associated with mortality and other clinically relevant outcomes in a cohort of patients with decompensated cirrhosis with acute kidney injury. Further experimental study of Angiopoietin/Tie2 signaling is warranted to explore its potential mechanistic and therapeutic role in this population.
代偿性肝硬化并发急性肾损伤的治疗选择有限，迫切需要新的机制靶点。血管生成素-2 是 Tie2 的一种特定于背景的拮抗剂，Tie2 是一种信号血管静止的受体。鉴于失代偿性肝硬化中血管不稳定的突出表现，我们评估了血管生成素-2 以预测临床结果。对一组住院失代偿性肝硬化合并急性肾损伤的患者进行前瞻性队列研究，连续测量血清血管生成素-2 水平。在 90 天的时间内检查临床特征和结局，并根据血管生成素-2 水平进行分析。主要结局是 90 天死亡率。我们的研究纳入了 191 名住院患者（中位血管生成素-2 水平为 18.2[11.8，26.5]ng/ml）。中位终末期肝病模型评分 23[17，30]，90 天死亡率为 41%。血管生成素-2 水平升高与死亡率增加相关（死亡 21.9[13.9，30.3]ng/ml 与存活 15.2[9.8，23.0]ng/ml；P<0.001），急性肾损伤网络分期更高（I 期 13.4[9.8，20.1]ng/ml 与 II 期 20.0[14.1，26.2]ng/ml 与 III 期 21.9[13.0，29.5]ng/ml；P=0.002），需要肾脏替代治疗（16.5[11.3，23.6]ng/ml 与 25.1[13.3，30.3]ng/ml；P=0.005）。血管生成素-2 与死亡率的相关性在未调整和调整后的 Cox 回归模型中均具有统计学意义（所有模型 P≤0.001），并且当加入 MELD 评分时，对死亡率的区分度有所提高（综合判别增量 0.067；P=0.001）。结论：在一组失代偿性肝硬化合并急性肾损伤的患者中，血管生成素-2 与死亡率和其他临床相关结局相关。需要进一步的实验研究来探索血管生成素/Tie2 信号在该人群中的潜在机制和治疗作用。
