Association of Non-steroidal Anti-Inflammatory Drugs With Kidney Health in Ambulatory Older Adults

Jonathan G. Amatruda, MD; Ronit Katz, DPhil; Carmen A. Peralta, MD, MAS; Michelle M. Estrella, MD, MHS; Harini Sarathy, MBBS, MHS; Linda F. Fried, MD, MPH; Anne B. Newman, MD, MPH; Chirag R. Parikh, MBBS, PhD; Joachim H. Ix, MD, MAS; Mark J. Sarnak, MD, MS; Michael G. Shlipak, MD, MPH

Disclosures

J Am Geriatr Soc. 2021;69(3):726-734. 

In This Article

Abstract and Introduction

Abstract

Background/Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) can cause kidney injury, especially in older adults. However, previously reported associations between NSAID use and kidney health outcomes are inconsistent and limited by reliance on serum creatinine-based GFR estimates. This analysis investigated the association of NSAID use with kidney damage in older adults using multiple kidney health measures.

Design: Cross-sectional and longitudinal analyses.

Setting: Multicenter, community-based cohort.

Participants: Two thousand nine hundred and ninty nine older adults in the Health ABC Study. A subcohort (n = 500) was randomly selected for additional biomarker measurements.

Exposure: Prescription and over-the-counter NSAID use ascertained by self-report.

Measurements: Baseline estimated glomerular filtration rate (eGFR) by cystatin C (cysC), urine albumin-to-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) were measured in 2,999 participants; alpha-1 microglobulin (α1m), neutrophil gelatinase-associated lipocalin (NGAL), propeptide type III procollagen (PIIINP), and uromodulin (UMOD) were measured in 500 participants. GFR was estimated three times over 10 years and expressed as percent change per year.

Results: Participants had a mean age of 74 years, 51% were female, and 41% African-American. No eGFR differences were detected between NSAID users (n = 655) and non-users (n = 2,344) at baseline (72 ml/min/1.73 m2 in both groups). Compared to non-users, NSAID users had lower adjusted odds of having ACR greater than 30 mg/g (0.67; 95% confidence interval (CI) = 0.51–0.89) and lower mean urine IL-18 concentration at baseline (−11%; 95% CI = −4% to −18%), but similar mean KIM-1 (5%; 95% CI = −5% to 14%). No significant differences in baseline concentrations of the remaining urine biomarkers were detected. NSAID users and non-users did not differ significantly in the rate of eGFR decline (−2.2% vs -2.3% per year).

Conclusion: Self-reported NSAID use was not associated with kidney dysfunction or injury based on multiple measures, raising the possibility of NSAID use without kidney harm in ambulatory older adults. More research is needed to define safe patterns of NSAID consumption.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used, especially in older adults, and the ongoing opioid epidemic has further highlighted the utility of NSAIDs as effective, non-addictive analgesics.[1–5] However, NSAID use is limited by their potential for adverse effects including cardiovascular toxicity, peptic ulcers, and nephrotoxicity.[6–8] NSAIDs can cause acute kidney injury (AKI), which if severe or prolonged may contribute to the development of chronic kidney disease (CKD), though there is little clarity on the magnitude of these risks and their variability across populations.[9–11] Despite concerns that older adults are at especially high risk of NSAID nephrotoxicity, their risk of long-term NSAID-associated kidney damage remains uncertain.[10,12,13] Partially due to these concerns, the American Geriatrics Society Beers Criteria label NSAIDs as potentially inappropriate for use in older adults.[14] Nonetheless, older adults suffer from a high burden of acute and chronic pain and might benefit if NSAIDs could be used safely in appropriate contexts.[15,16]

Most studies of NSAID nephrotoxicity have used serum creatinine (Cr) and estimated glomerular filtration rate (eGFR) to describe kidney function, but Cr has limited sensitivity and specificity for changes in kidney function and is biased by muscle mass.[17] Conversely, serum cystatin C (cysC) is unaffected by muscle mass and more accurately detects GFR changes in older persons.[18,19] Albuminuria, expressed clinically as the urine albumin-to-creatinine ratio (ACR), is an important measure of glomerular integrity and predicts poor outcomes for kidney and cardiovascular health as well as mortality.[20] However, Cr, cysC, and ACR may not detect damage to kidney tubules, the usual site of NSAID toxicity.[21] Therefore, to improve detection of NSAID-associated kidney injury, direct measures of kidney tubule health are also needed. Kidney tubule health broadly encompasses damage, representing cell injury and its physical consequences, as well as dysfunction, which refers to capacity for normal homeostatic mechanisms including biosynthesis, reabsorption, and secretion. Measures include biomarkers of tubule injury (kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and neutrophil gelatinase-associated lipocalin (NGAL)); tubulointerstitial fibrosis (propeptide type III procollagen (PIIINP)); proximal tubule resorptive function (alpha-1 microglobulin (α1m)); and tubule synthetic function (uromodulin (UMOD)). These investigational biomarkers are sensitive indicators of early kidney tubule damage in the setting of medication toxicity, including NSAID nephrotoxicity, and are also associated with long-term outcomes.[22–31] Importantly, they have been applied across the age spectrum and are associated with cardiovascular disease, heart failure, and mortality in older adults.[32–34]

The Health, Aging, and Body Composition (Health ABC) study offered a unique opportunity to evaluate associations of NSAID use with multiple measures of kidney health in a cohort of community-dwelling older adults. Specifically, we explored the association of NSAID use with measures of glomerular filtration, urine albumin, and biomarkers of kidney tubule health. We compared baseline kidney function and kidney tubule biomarkers among NSAID users and non-users and evaluated the association of NSAID use with longitudinal eGFR changes. We hypothesized that NSAID use would be associated with kidney damage and dysfunction at baseline and with faster eGFR decline over time.

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