Clinical features and HLA association of 5-aminosalicylate (5-ASA)-induced nephrotoxicity in inflammatory bowel disease

Graham A. Heap (Lead / Corresponding author), Kenji So, Mike Weedon, Naomi Edney, Claire Bewshea, Abhey Singh, Vito Annese, John Beckly, Dorien Buurman, Rakesh Chaudhary, Andrew T. Cole, Sheldon C. Cooper, Tom Creed, Fraser Cummings, Nanne K. de Boer, Renata D'Inca, Tawfique K. Daneshmend, Michael Delaney, Anjan Dhar, Natalie DirekzePaul Dunckley, Daniel R. Gaya, Richard Gearry, Steve Gore, Jonas Halfvarson, Ailsa L. Hart, Chris J. Hawkey, Frank Hoentjen, Tariq Iqbal, Peter Irving, Simon Lal, Ian Lawrence, Charlie W. Lees, Steve Lewis, Melanie Lockett, Stephen Mann, John C. Mansfield, Craig Mowat, Frank Muller, Charles Murray, Tim Orchard, Miles Parkes, Rosemary Phillips, Richard Pollok, Graham L. Radford-Smith, Shaji Sebastian, Sandip Sen, Tarek Shirazi, Mark S. Silverberg, Laurie Solomon, Giacomo C. Sturniolo, Mark Thomas, Mark Tremelling, Epameinondas V. Tsianos, David Watts, Sean Weaver, Emma Wesley, Arthur Holden, Richard D'Souza, Chris J. Mulgrew, Richard A. Oram, Rinse K. Weersma, Tariq Ahmad

    Research output: Contribution to journalArticlepeer-review

    78 Citations (Scopus)


    Background and Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients.

    Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, =50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls.

    Results: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixtyeight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1 × 10-7) with 5-ASAinduced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4 × 10-9, odds ratio 3.1).

    Conclusions: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

    Original languageEnglish
    Pages (from-to)149-158
    Number of pages10
    JournalJournal of Crohn's and Colitis
    Issue number2
    Publication statusPublished - 1 Feb 2016


    • 5-Aminosalicylates
    • Nephrotoxicity
    • Renal failure pharmacogenetics
    • Stratified medicine
    • Ulcerative colitis

    ASJC Scopus subject areas

    • General Medicine


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