Background: Non-steroid anti-inflammatory drug (NSAID) usage is associated with kidney injury. Rise in serum creatinine (sCr) often represents irreversible process. Thus to assess the early effects of regular NSAID use, we studied sensitive serum and urine biomarkers of kidney injury. Methods: In a protocol-based intervention study, 103 subjects were enrolled in 3 mutually exclusive groups. Group 1 included 37 healthy controls having minimal baseline NSAID exposure as per a definition, and group 2 had 41 spondyloarthritis (SpA) patients on regular NSAID therapy for >3 months. Group 3 included 25 SpA patients having minimal NSAID exposure at baseline. Blood and urine samples were collected from all the 3 groups at baseline. Furthermore, group 3 was started on 6-week regular NSAID therapy, and blood and urine samples were re-collected at 1, 6, and 12 weeks. Baseline normal kidney function as per the definition was ensured in all the subjects. Creatinine, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin-C, and microalbumin were measured in urine and serum samples to assess kidney injury. Results: Kidney injury biomarkers were 2-3-fold higher in SpA patients using regular NSAID therapy compared to healthy controls and SpA patients having minimal NSAID exposure (uKIM-1 and uNGAL p < 0.0001, sKIM-1 and sNGAL p = 0.001). There was no difference in sCr and estimated glomerular filtration rate using Cockcroft Gault equation between the groups. In SpA patients started on 6 weeks of regular NSAID (group 3), biomarker levels started rising at week 1 and showed a significant rise at week 6. The levels in the patients that stopped NSAID use at 6 weeks showed reversibility at 12 weeks. Conclusions: Regular NSAID use in SpA patients induces subclinical kidney injury represented by rise in biomarkers. These levels start rising as early as 7 days of regular NSAID use and are reversible on stopping the drug. (C) 2017 S. Karger AG, Basel