NSAID Use and Multidimensional Assessment of Kidney Health

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PROJECT SUMMARY/ABSTRACT Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics for the treatment of acute and chronic pain, but their use is limited by concerns of potential nephrotoxicity. Though some cohort studies have associated NSAID-use with adverse kidney outcomes, the reported magnitudes of these associations are variable. Accurate assessment of kidney health risks among NSAID users remains difficult, in part due to the challenge of measuring NSAID exposure and the comparison of heterogenous populations in past cohort studies. As clinicians seek alternative options for effective pain management to stem the opioid epidemic, improved understanding of the impact of NSAID use on kidney health is urgently needed to inform approaches for safe prescribing. To this end, we propose analyzing the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) cohort, which recorded high-quality, standardized measures of NSAID use over time for each participant. Because NSAIDs are a mainstay of ankylosing spondylitis (AS) treatment, this population encompasses a range of NSAID exposure from very high intensity users to non-users over the course of up to 15 years of follow-up. These high-quality data thus allow rigorous investigation of dose and duration of NSAID exposure as possible drivers of kidney disease. Our proposed studies are a necessary step to better understanding of NSAID-associated kidney risk and to safer, evidence-based prescribing. Aim 1 will use the entire available PSOAS cohort to investigate the longitudinal association between NSAID exposure and kidney function. This Aim will improve upon past studies by (1) leveraging the granular and complete exposure data in PSOAS and (2) comparing estimated glomerular filtration rate (eGFR) by serum creatinine and cystatin C to determine the most sensitive indicator of kidney function decline in this population. Aim 1 will produce a high-quality estimate of the overall risk of NSAID- associated kidney function decline in this population and elucidate which doses, durations, and subject characteristics entail the highest risk of adverse outcomes. Aim 2 will focus on a subcohort of PSOAS participants based at UCSF and actively followed in the UCSF AS clinic to cross-sectionally measure urine biomarkers of tubulointerstitial function, injury, inflammation, and fibrosis. Aim 2 will characterize patterns of urine biomarkers corresponding to NSAID exposure. Results from this study will inform a longitudinal study of multidimensional kidney monitoring (GFR and tubulointerstitial health) to guide NSAID use that controls pain but minimizes kidney damage. These efforts can be extended to high-risk populations, including the elderly and patients with chronic kidney disease.