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Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease
BD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK; Precision Medicine Exeter, University of Exeter, Exeter, UK .
Örebro University, School of Medicine, Örebro University, Sweden. Department of Gastroenterology.ORCID iD: 0000-0003-0122-7234
BD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK; Precision Medicine Exeter, University of Exeter, Exeter, UK .
Number of Authors: 63
2016 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no 2, 149-158 p.Article in journal (Refereed) Published
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Text
Abstract [en]

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. 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 x 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 x 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.

Place, publisher, year, edition, pages
Oxford University Press, 2016. Vol. 10, no 2, 149-158 p.
Keyword [en]
5-Aminosalicylates, nephrotoxicity, renal failure pharmacogenetics, stratified medicine, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-49368DOI: 10.1093/ecco-jcc/jjv219ISI: 000370276800006PubMedID: 26619893OAI: oai:DiVA.org:oru-49368DiVA: diva2:912448
Note

Funding Agencies:

International Serious Adverse Events Consortium (iSAEC)

Ferring Pharmaceuticals

Warner Chilcott UK

Crohn's and Colitis UK

Wellcome Trust WT097835MF

VIDI grant from the Netherlands Organization for Scientific Research (NWO) 016.136.308

NIHR Biomedical Research Centre awards

Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2017-10-17Bibliographically approved

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