Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.
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Heap Graham A, So Kenji, Weedon Mike, Edney Naomi, Bewshea Claire, Singh Abhey, Annese Vito, Beckly John, Buurman Dorien, Chaudhary Rakesh, Cole Andrew T, Cooper Sheldon C, Creed Tom, Cummings Fraser, de Boer Nanne K, D'Inca Renata, D'Souza Richard, Daneshmend Tawfique K, Delaney Michael, Dhar Anjan, Direkze Natalie, Dunckley Paul, Gaya Daniel R, Gearry Richard, Gore Steve, Halfvarson Jonas, Hart Ailsa, Hawkey Chris J, Hoentjen Frank, Iqbal Tariq, Irving Peter, Lal Simon, Lawrance Ian, Lees Charlie W, Lockett Melanie, Mann Stephen, Mansfield John, Mowat Craig, Mulgrew Chris J, Muller Frank, Murray Charles, Oram Richard, Orchard Tim, Parkes Miles, Phillips Rosemary, Pollok Richard, Radford-Smith Graham, Sebastian Shaji, Sen Sandip, Shirazi Tarek, Silverberg Mark, Solomon Laurie, Sturniolo Giacomo C, Thomas Mark, Tremelling Mark, Tsianos Epameinondas V, Watts David, Weaver Sean, Weersma Rinse K, Wesley Emma, Holden Arthur, Ahmad Tariq
Аннотация
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. Sixty-eight 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-ASA-induced 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.