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: 10624302
• 负责人: Dennis G. Moledina
• 金额: $ 60.62万
• 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/10624302
• 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; Diagnosis; Diagnostic tests; Disease; Enrollment; Evaluation; Fibrosis; Future; Glomerular Filtration Rate; Goals; Hemorrhage; Histologic; Hospitals; Human; Image; Immune; Immune checkpoint inhibitor; Immune response; Infiltration; 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; adjudication; 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.

概括 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（例如质子泵抑制剂、抗生素和免疫检查点抑制剂）或自身免疫性疾病 疾病（例如干燥综合征和结节病）。AIN 的发作会导致永久性肾病。 40-60% 的患者受到损害，AIN 是所有慢性肾病病例中约 2% 的原因，其中 相当于 0.5-100 万美国成年人。 患者的临床护理面临两大挑战。 首先，由于缺乏可靠的非侵入性生物标志物，AIN 诊断需要进行肾活检。 由于出血风险，某些患者可能无法进行治疗，或者为了优化这种风险而延迟治疗。 在诊断上有助于肾功能的不完全恢复 二、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： 然而，短期和长期不良事件的特征预示着对皮质类固醇的良好反应。 治疗方法目前未知。 该提案的总体目标是验证尿液白细胞介素 (IL)-9 和肿瘤坏死因子 (TNF)-α 用于诊断 AIN（目标 1）并确定接受皮质类固醇治疗的患者亚组的生物标志物 有益（目标 2） 在耶鲁大学附属医院对 265 名患者进行的一项研究中，我们表明 IL-9 和 TNF-α 的乘积 (IL-9*TNF-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）。 临床医生的活检前诊断将 AUC 从 0.62 (0.53, 0.71) 增加到 0.85 (0.78, 0.91)。 仅在患者中，诊断后 6 个月皮质类固醇的使用与较高的肾小球滤过率相关 尿液 IL-9*TNF-α 较高（19.7 ml/min/1.73m2）。在此，我们提出了一个更大的、多中心的、观察性的。 我们将在两个大型大学医疗中心招募 580 名患者进行研究来验证这些结果。 （耶鲁大学和约翰霍普金斯大学），收集尿液样本进行生物标志物测量，并确定存在或 在目标 1 中，通过由三名肾脏病理学家领导的独立、盲法裁决过程来确定不存在 AIN。 我们将通过证明 AIN AUC 的改善来验证 IL-9*TNF-α 作为 AIN 的诊断生物标志物 我们还将描述测试与 IL-9*TNF-α 的临床模型和临床医生的活检前印象。 两个预先指定的截止点的特征和区分关键亚组（药物与其他药物）的测试准确性 在目标 2 中，我们将验证 IL-9*TNF-α 作为生物标志物来识别最常见的患者亚组。 通过临床处方的皮质类固醇可能会出现肾功能恢复的情况，我们将跟踪患者。 进行长达六个月的 AIN 以确定 AIN 后的肾功能。本研究的结果将允许。 在发生永久性肾损伤之前诊断 AIN，在某些情况下无需进行活检 患者，并确定免疫抑制治疗可能有益的患者亚组。