Biomarkers for acute interstitial nephritis in humans

总结 急性间质性肾炎（AIN）是由免疫介导的肾损伤引起的， 药物（如质子泵抑制剂，抗生素和免疫检查点抑制剂）或自身免疫性 疾病（如干燥综合征和结节病）。AIN发作导致永久性肾脏 在40-60%的患者中，AIN是约2%的慢性肾病病例的原因， 相当于50 - 100万美国成年人。有两个主要的挑战，在临床护理的病人， 奈恩.首先，由于缺乏可靠的非侵入性生物标志物，AIN诊断需要肾活检。活检 由于出血风险，在某些患者中可能不可行，或者为了优化该风险而延迟。该延迟 在诊断中有助于肾功能的不完全恢复。其次，皮质类固醇治疗，目前 AIN治疗的护理标准似乎并不能使所有患者受益，同时使他们面临以下风险： 短期和长期不良事件。然而，预测对皮质类固醇有良好反应的特征 治疗目前尚不清楚。 本提案的总体目标是验证尿白细胞介素（IL）-9和肿瘤坏死因子（TNF）-α作为 诊断AIN的生物标志物（目的1），并确定接受皮质类固醇治疗的患者亚组 有益（目标2）。在一项对耶鲁大学附属医院的265名患者进行的研究中，我们发现， IL-9和TNF-α的乘积（IL-9*TNF-α）与AIN独立相关，并显示面积 在受试者工作特征曲线[AUC]下为0.79（95% CI，0.71，0.88）。将IL-9*TNF-α添加至 临床医生的活检前诊断将AUC从0.62（0.53，0.71）增加至0.85（0.78，0.91）。我们还发现 皮质类固醇的使用与诊断后6个月的肾小球滤过率升高相关， 尿IL-9*TNF-α增高（19.7ml/min/1.73m2）。在这里，我们提出了一个更大的，多中心的，观察性的， 研究证实了这些发现。我们将在两个大型大学医学中心招募580名患者 (Yale和约翰霍普金斯），收集尿液样品用于生物标志物测量，并建立存在或 通过由三名肾脏病理学家领导的独立、设盲裁定过程，确定不存在AIN。在目标1中， 我们将通过证实AIN的AUC改善来验证IL-9*TNF-α作为AIN的诊断生物标志物 IL-9*TNF-α在临床模型和临床医生的活检前印象上的作用。我们还将描述测试 两个预先规定的临界值的特征和区分关键亚组（药物与其他）的测试准确性 和药物类别）。在目标2中，我们将验证IL-9*TNF-α作为生物标志物，以识别最常见的患者亚组， 使用临床处方的皮质类固醇后可能出现肾功能恢复。我们将跟踪患者 持续6个月，以确定AIN后的肾功能。这项研究的结果将允许 在发生永久性肾损伤之前诊断AIN，在某些情况下无需活检。 患者，并确定免疫抑制治疗可能有益的患者亚组。

SUMMARY Acute interstitial nephritis (AIN) results from an immune-mediated kidney injury, which is triggered by use of medications (such as proton pump inhibitors, antibiotics, and immune checkpoint inhibitors) or by autoimmune diseases (such as Sjogren’s syndrome and sarcoidosis). An episode of AIN results in permanent kidney damage in 40-60% of patients and AIN is the cause of about 2% of all cases of chronic kidney disease, which is equivalent to 0.5-1 million U.S. adults. There are two major challenges in the clinical care of patients with AIN. First, due to lack of a reliable non-invasive biomarker, AIN diagnosis requires a kidney biopsy. Biopsy may not be feasible in some patients due to bleeding risk or is delayed in order to optimize this risk. This delay in diagnosis contributes to incomplete recovery of kidney function. Second, corticosteroid therapy, the current standard of care for AIN treatment, does not appear to benefit all patients while exposing them to the risk of short- and long-term adverse events. However, characteristics predicting a favorable response to corticosteroid therapy are currently unknown. The overall goal of this proposal is to validate urine interleukin (IL)-9 and tumor necrosis factor (TNF)-α as biomarkers to diagnose AIN (aim 1) and to identify the subgroup of patients in whom corticosteroid therapy is beneficial (aim 2). In a study of 265 patients conducted at two Yale-affiliate hospitals, we showed that the multiplication product of IL-9 and TNF-α (IL-9*TNF-α) was independently associated with AIN and showed area under receiver operating characteristic curve [AUC] of 0.79 (95% CI, 0.71, 0.88). Addition of IL-9*TNF-α to the clinician’s pre-biopsy diagnosis increased AUC from 0.62 (0.53, 0.71) to 0.85 (0.78, 0.91). We also found that corticosteroid use was associated with higher glomerular filtration rate 6-months after diagnosis only in patients with higher urine IL-9*TNF-α (by 19.7 ml/min/1.73m2). Here we propose a larger, multicenter, observational study to validate these findings. We will enroll a cohort of 580 patients at two large university medical centers (Yale and Johns Hopkins), collect urine samples for biomarker measurement, and establish presence or absence of AIN through an independent, blinded adjudication process led by three renal pathologists. In aim 1, we will validate IL-9*TNF-α as a diagnostic biomarker for AIN by demonstrating improvement in AUC for AIN with IL-9*TNF-α over a clinical model and clinician’s prebiopsy impression. We will also describe test characteristics at two pre-specified cut-offs and test accuracy in differentiating key sub-groups (drug vs. other and by drug classes). In aim 2, we will validate IL-9*TNF-α as a biomarker to identify subgroup of patients most likely to experience kidney function recovery with clinically-prescribed corticosteroids. We will follow patients with AIN for up to six months to determine kidney function after AIN. Results from this study will allow diagnosis of AIN before occurrence of permanent kidney damage, eliminate the need for a biopsy in some patients, and identify the subgroup of patients in whom immunosuppressive therapy could be beneficial.