Biomarkers for acute interstitial nephritis in humans

人类急性间质性肾炎的生物标志物

• 批准号: 10402806
• 负责人: Dennis G. Moledina
• 金额: $ 61.09万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402806
• 关键词: Academic Medical Centers; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adrenal Cortex Hormones; Adult; Adverse event; Antibiotics; Area; Autoimmune Diseases; Biological Markers; Biopsy; Blinded; Characteristics; Chronic Kidney Failure; Clinical; Clinical Trials; Conflict (Psychology); Diagnosis; Diagnostic tests; Disease; Enrollment; Evaluation; Fibrosis; Future; Glomerular Filtration Rate; Goals; Hemorrhage; Histologic; Hospitals; Human; Image; Immune; Immune checkpoint inhibitor; Immune response; Inflammation; Injury to Kidney; Interleukin-9; Interstitial Nephritis; Kidney; Kidney Diseases; Leukocytes; Measurement; Mediating; Modeling; Monitor; Multicenter Studies; Observational Study; Outcome; Participant; Pathologist; Patient Care; Patients; Pharmaceutical Preparations; Plasma; Process; Proton Pump Inhibitors; ROC Curve; Recovery; Recovery of Function; Renal function; Resources; Risk; Sampling; Sarcoidosis; Schedule; Sensitivity and Specificity; Severities; Sjogren' s Syndrome; Specific qualifier value; Subgroup; Symptoms; TNF gene; Testing; Therapeutic immunosuppression; Time; Time Management; Treatment Side Effects; Urine; Withdrawal; acute care; adjudicate; adjudication; base; biobank; biomarker identification; clinical application; clinical biomarkers; clinical care; cohort; cytokine; diagnostic biomarker; eosinophil; experience; impression; improved; indexing; kidney biopsy; novel; patient subsets; predicting response; predictive marker; renal damage; response; standard of care; treatment effect

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.

摘要 急性间质性肾炎(AIN)是由免疫介导的肾损伤引起的，这种损伤是由使用 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 疾病(如干燥综合征和结节病)。AIN发作导致永久性肾脏 40%-60%的患者和AIN的损害是约2%的慢性肾脏疾病的原因，这 相当于50万至100万美国成年人。慢性阻塞性肺疾病患者的临床护理面临两大挑战 艾恩。首先，由于缺乏可靠的非侵入性生物标志物，AIN的诊断需要肾脏活检。活组织检查 由于出血风险，在一些患者中可能不可行，或者为了优化这种风险而推迟。这一延迟 在诊断中可能导致肾功能不完全恢复。第二，皮质类固醇治疗，目前 AIN治疗的标准护理，似乎并不是所有患者都受益，而是使他们面临 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 治疗方法目前尚不清楚。 这项提案的总体目标是验证尿液中白介素9和肿瘤坏死因子α作为 诊断AIN的生物标记物(目标1)和识别接受皮质类固醇治疗的患者亚组 受益(目标2)。在两家耶鲁附属医院对265名患者进行的研究中，我们表明 IL-9和肿瘤坏死因子-α的增殖产物(IL-9*肿瘤坏死因子-α)与AIN独立相关，并显示面积 受试者工作特征曲线[AUC]为0.79(95%CI，0.71，0.88)。将IL-9*肿瘤坏死因子-α添加到 临床医生活检前诊断AUC由0.62(0.53，0.71)增加到0.85(0.78，0.91)。我们还发现， 仅在确诊后6个月患者中使用皮质类固醇与较高的肾小球滤过率相关 尿液IL-9、肿瘤坏死因子-α升高(19.7ml/min/1.73m2)。这里我们提出了一个更大的、多中心的、观察性的 为验证这些发现而进行的研究。我们将在两个大型大学医疗中心招募580名患者 (耶鲁大学和约翰霍普金斯大学)，收集尿样进行生物标记物测量，并建立或 通过由三名肾脏病理学家领导的独立、盲目的裁决过程，AIN缺失。在目标1中， 我们将通过证明AUC的改善来验证IL-9*肿瘤坏死因子-α作为AIN的诊断生物标记物 与IL-9*肿瘤坏死因子-α的临床模型和临床医生的活检前印象。我们还将描述测试 两个预先指定的分界点的特征和区分关键亚组的测试准确性(药物与其他 和药物类别)。在目标2中，我们将验证IL-9*肿瘤坏死因子-α作为识别最多的患者亚群的生物标志物 使用临床处方的皮质类固醇后，可能会经历肾功能恢复。我们会跟踪观察病人 使用AIN进行长达六个月的治疗，以确定AIN后的肾功能。这项研究的结果将使 在发生永久性肾脏损害之前诊断AIN，在某些情况下不需要活检 患者，并确定免疫抑制治疗可能有益的患者亚组。