Identification of Acute Kidney Injury Subphenotypes with Differing Molecular Signatures and Responses to Vasopressin Therapy
Identification of Acute Kidney Injury Subphenotypes with Differing Molecular Signatures and Responses to Vasopressin Therapy
复制标题
DOI：
10.1164/rccm.201807-1346oc
复制
发表时间：
2019-04-01
影响因子：
24.7
通讯作者：
Wurfel, Mark M.
中科院分区：
文献类型：
--
作者：
Bhatraju, Pavan K.;Zelnick, Leila R.;Wurfel, Mark M.
依据：目前，对于急性肾损伤（阿基），尚无安全有效的药物干预措施。原因之一可能是异质性存在于阿基人群中，从而阻碍了对特定病理生理学途径和治疗靶点的鉴定目的：本研究的目的是鉴定和测试阿基亚表型是否具有预后和治疗意义。第一、在两个患有阿基的危重患者群体（发现[n = 794]和复制[n = 425]）中独立地应用潜在分类分析方法。其次，开发了一种简约的分类模型来识别阿基亚表型。第三，将分类模型应用于VASST（加压素和脓毒性休克试验; n = 271）中的阿基患者，并确定治疗反应的差异。在所有三个人群中，阿基定义使用血清肌酐和尿output. Measures和主要结果：两个亚表型潜在类分析模型有最好的适合在发现（P = 0.004）和复制（P = 0.004）阿基组。与阿基亚表型1（AKI-SP1）相比，阿基亚表型2（AKI-SP2）的7天肾功能不恢复和28天死亡的风险更大。阿基亚表型区分临床结局差的风险优于肾脏疾病：改善阿基的全球结局阶段。包括内皮功能障碍和炎症标志物的三变量模型准确地确定了亚表型成员资格（C-统计量0.92）。在VASST中，与去甲肾上腺素相比，血管加压素与AKI-SP1中90天死亡率的改善相关（分别为27%和46%; P = 0.02），但AKI-SP2无显著差异（分别为45%和49%; P = 0.99），相互作用的P值为0.05。该分析确定了两种分子上不同的阿基亚表型，具有不同的临床结局和对加压素治疗的反应。阿基亚表型的鉴定可以改善风险预测，并可能有助于临床试验中的预测富集。
Rationale: Currently, no safe and effective pharmacologic interventions exist for acute kidney injury (AKI). One reason maybe that heterogeneity exists within the AKI population, thereby hampering the identification of specific pathophysiologic pathways and therapeutic targets.Objective: The aim of this study was to identify and test whether AKI subphenotypes have prognostic and therapeutic implications.Methods: First, latent lass analysis methodology was applied independently in two critically ill populations (discovery [n = 794] and replication [n = 425]) with AKI. Second, a parsimonious classification model was developed to identify AKI subphenotypes. Third, the classification model was applied to patients with AKI in VASST (Vasopressin and Septic Shock Trial; n = 271), and differences in treatment response were determined. In all three populations, AKI was defined using serum creatinine and urine output.Measurements and Main Results: A two-subphenotype latent class analysis model had the best fit in both the discovery (P = 0.004) and replication (P = 0.004) AKI groups. The risk of 7-day renal nonrecovery and 28-day mortality was greater with AKI subphenotype 2 (AKI-SP2) relative to AKI subphenotype 1 (AKI-SP1). The AKI subphenotypes discriminated risk for poor clinical outcomes better than the Kidney Disease: Improving Global Outcomes stages of AKI. A three-variable model that included markers of endothelial dysfunction and inflammation accurately determined subphenotype membership (C-statistic 0.92). In VASST, vasopressin compared with norepinephrine was associated with improved 90-day mortality in AKI-SP1 (27% vs. 46%, respectively; P = 0.02), but no significant difference was observed in AKI-SP2 (45% vs. 49%, respectively; P = 0.99) and the P value for interaction was 0.05.Conclusions: This analysis identified two molecularly distinct AKI subphenotypes with different clinical outcomes and responses to vasopressin therapy. Identification of AKI subphenotypes could improve risk prognostication and may be useful for predictive enrichment in clinical trials.