Non-SteroidAl Impact on Kidney Disease Study (NSAIDS)

非类固醇对肾脏疾病的影响研究 (NSAIDS)

• 批准号: 10655205
• 负责人: Michelle M Estrella
• 金额: $ 70.41万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655205
• 关键词: Absence of pain sensation; Adult; Adverse effects; Analgesics; Benign; Biological Markers; Blood; Chronic; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Collaborations; Creatinine; Development; Dimensions; Dose; Drug Exposure; Drug toxicity; Drug usage; Early Diagnosis; Elderly; Essential Drugs; Fibrosis; Fright; Fumarates; Future; Generations; Glomerular Filtration Rate; Goals; HIV Infections; Health; Hypertension; Incidence; Inflammation; Injury; Injury to Kidney; Kidney; Kidney Diseases; Learning; Measures; Monitor; Muscle; Non-Steroidal Anti-Inflammatory Agents; Opioid; Outcome; Pain; Pain management; Participant; Patients; Pattern; Persons; Pharmaceutical Preparations; Population; Prevalence; Proteins; Renal function; Renal tubule structure; Research; Risk; Risk Factors; Role; Safety; Serum; Severities; Site; Specificity; Spondylarthritis; Tenofovir; Time; Toxic effect; Tubular formation; United States; Urine; Work; chronic pain; chronic pain management; cohort; comorbidity; diagnostic panel; disorder risk; drug action; effective therapy; evidence base; experience; follow-up; high risk; high risk population; improved; insight; nephrotoxicity; novel; opioid epidemic; prognostication; renal artery; renal damage; risk mitigation; tool; treatment choice; vasoconstriction

ABSTRACT The prevalence of chronic pain among adults in the United States now exceeds 20% and is even higher among older adults and those with multiple comorbid conditions. As clinicians have increasingly learned to avoid opiates for chronic pain, non-steroidal anti-inflammatory drugs (NSAIDs) have an essential role as effective analgesics. Unfortunately, the threat of kidney toxicity from NSAIDs limits their use for pain control, and there are no options available to mitigate that risk during treatment. As a result, clinicians largely avoid using NSAIDs in persons who either have chronic kidney disease (CKD) or are at high risk for developing CKD, regardless of their severity of pain. The premise of this proposal is that NSAID effects on the kidneys can be monitored through a biomarker guided strategy, and that nephrotoxicity can be detected early among the subset who would experience deleterious impact on their kidneys. The primary objective of this proposal will be to build an NSAID Kidney Monitoring Panel from urine and blood biomarkers of kidney tubule health that will identify the specific sites of NSAID toxicity, distinguish NSAID-induced changes on the kidney, and forecast the impact on subsequent kidney function declines. Current monitoring for NSAID-related kidney toxicity still relies on serum creatinine (SCr), which is insensitive for early detection, lacks specificity for true kidney injury, and does not measure tubulointerstitial health, the major site of NSAID action and injury. Without a better strategy, clinicians will continue withholding NSAIDs from patients in chronic pain. Our research team has experience in deploying a broad panel of urine and blood biomarkers of kidney tubular function, injury and tubulointerstitial inflammation that enables both the sensitivity to detect early kidney damage and the specificity to distinguish patterns that are most consistent with a distinct medication effect. We will apply this strategy among two populations at high risk for developing NSAID nephrotoxicity. To best characterize the impact of high-dose NSAID use, we will evaluate the UCSF Axial Spondyloarthritis Cohort (Aim 1), as patients with this condition have few other treatment options and are also largely free of other kidney risk factors. Second, we will collaborate with the Chronic Renal Insufficiency Cohort (CRIC) to determine the effects of NSAID initiation and discontinuation on kidney health in this very high-risk group with moderate-to-severe CKD (Aim 2). In Aim 3, we will integrate the findings from each setting to determine the set of biomarkers that best captures chronic NSAID exposure, dynamic changes in longitudinal NSAID use, and risks for longitudinal kidney function trajectories. This research will unquestionably yield tremendous insights into the incidence and patterns of kidney tubulointerstitial injury from NSAID use in these two distinct populations. We are optimistic that our findings will guide future development of an NSAID Kidney Monitoring Panel that will improve the safe and effective treatment of pain across the spectrum of kidney disease risk.

抽象的 美国成年人慢性疼痛的患病率现已超过 20%，甚至更高 老年人和患有多种合并症的人。随着临床医生越来越多地学会 避免使用阿片类药物治疗慢性疼痛，非甾体类抗炎药 (NSAID) 在以下方面发挥着重要作用： 有效的镇痛药。不幸的是，非甾体抗炎药的肾毒性威胁限制了它们在控制疼痛方面的应用， 并且在治疗期间没有任何选择可以减轻这种风险。因此，临床医生基本上避免 患有慢性肾病 (CKD) 或罹患慢性肾病的高风险人群使用非甾体抗炎药 (NSAID) CKD，无论疼痛的严重程度如何。该提案的前提是 NSAID 对肾脏的影响可以 通过生物标志物指导策略进行监测，并且可以在早期发现肾毒性 会对肾脏造成有害影响的子集。该提案的主要目标是 根据肾小管健康的尿液和血液生物标志物建立 NSAID 肾脏监测小组，这将 识别 NSAID 毒性的具体部位，区分 NSAID 引起的肾脏变化，并预测 对后续肾功能下降的影响。 目前对 NSAID 相关肾毒性的监测仍然依赖于血清肌酐 (SCr)，这是 对早期检测不敏感，缺乏对真正肾损伤的特异性，并且不测量肾小管间质 健康，NSAID 作用和损伤的主要部位。如果没有更好的策略，临床医生将继续扣留 来自慢性疼痛患者的非甾体抗炎药。我们的研究团队在部署广泛的尿液样本方面拥有丰富的经验 以及肾小管功能、损伤和肾小管间质炎症的血液生物标志物，使 检测早期肾脏损伤的敏感性和区分最一致模式的特异性 具有明显的药效。我们将在两个发展高风险人群中应用这一策略 NSAID 肾毒性。为了最好地描述高剂量 NSAID 使用的影响，我们将评估 UCSF 中轴型脊柱关节炎队列（目标 1），因为患有这种疾病的患者几乎没有其他治疗选择，并且 也基本上没有其他肾脏危险因素。第二，我们将与慢性肾功能不全协会合作 队列（CRIC）确定 NSAID 开始和停止对肾脏健康的影响 患有中重度 CKD 的高危人群（目标 2）。在目标 3 中，我们将整合每个设置的结果 确定一组最能捕捉长期 NSAID 暴露、动态变化的生物标志物 纵向非甾体抗炎药的使用，以及纵向肾功能轨迹的风险。 毫无疑问，这项研究将对肾病的发病率和模式产生巨大的影响。 这两个不同人群中使用非甾体抗炎药导致的肾小管间质损伤。我们乐观地认为我们的发现将 指导 NSAID 肾脏监测小组的未来发展，以提高安全性和有效性 治疗各种肾脏疾病风险的疼痛。