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 developm...