Non-SteroidAl Impact on Kidney Disease Study (NSAIDS)

摘要 美国成年人慢性疼痛的患病率现在超过20%，甚至更高 老年人和患有多种共病的人。随着临床医生越来越多地学会 避免阿片类药物治疗慢性疼痛，非甾体抗炎药（NSAID）具有重要作用， 有效的止痛药。不幸的是，NSAID的肾毒性威胁限制了它们用于疼痛控制， 并且在治疗期间没有可用于减轻该风险的选项。因此，临床医生在很大程度上避免了 在患有慢性肾脏疾病（CKD）或处于发展高风险的人中使用NSAID CKD，无论疼痛的严重程度如何。这项建议的前提是，NSAID对肾脏的影响， 通过生物标志物指导的策略进行监测，并且可以在患者中早期检测到肾毒性。 这些人会对他们的肾脏产生有害影响。本提案的主要目标是 建立一个非甾体抗炎药肾脏监测小组从尿液和血液生物标志物的肾小管健康， 确定NSAID毒性的具体部位，区分NSAID诱导的肾脏变化，并预测 影响后续肾功能下降。 目前对NSAID相关肾毒性的监测仍然依赖于血清肌酐（SCr）， 对早期检测不敏感，对真正的肾损伤缺乏特异性，并且不能测量肾小管间质 健康，NSAID作用和损伤的主要部位。如果没有更好的策略，临床医生将继续保留 慢性疼痛患者的NSAID。我们的研究团队有经验部署一个广泛的小组尿液 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， 检测早期肾损伤的灵敏度和区分最一致模式的特异性 具有明显的药物作用。我们将在两个高风险人群中应用这种策略， NSAID肾毒性。为了更好地描述高剂量NSAID使用的影响，我们将评估UCSF 轴性脊柱关节炎队列（Aim 1），因为患有这种疾病的患者几乎没有其他治疗选择， 也基本上没有其他肾脏风险因素。其次，我们将与慢性肾功能不全合作 队列（CRIC），以确定NSAID开始和停止对肾脏健康的影响， 中重度CKD高危人群（目标2）。在目标3中，我们将整合每种环境的研究结果 为了确定最能捕捉慢性NSAID暴露的一组生物标志物， 纵向NSAID使用和纵向肾功能轨迹的风险。 这项研究无疑将对肾脏疾病的发病率和模式产生巨大的影响。 在这两个不同的人群中使用NSAID引起的肾小管间质损伤。我们乐观地认为，我们的发现将 指导未来开发NSAID肾脏监测小组，以提高安全性和有效性 治疗肾脏疾病风险范围内的疼痛。

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.