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P609. 5-Aminosalicylate (5-ASA) induced nephrotoxicity in inflammatory bowel disease

K. So1, C. Bewshea2, G. Heap1, A. Muller3, M. Delaney4, T. Daneshmend1, C. Mulgrew5, R. D'Souza5, J. Kwan5, P. Irving6, T. Orchard7, A. Hart8, E. Tsianos9, V. Annese10, M. Silverberg11, G. Watermeyer12, D. Renata13, G. Radford-Smith14, R. Gearry15, R. Oram5, IIBDGC16, R. Russell17, D. Wilson18, M. Parkes19, J. Satsangi20, R. Weersma21, I. Lawrance22, A. Holden23, C. Lees20, T. Ahmad1, 1Royal Devon and Exeter Hospital, Gastroenterology, Exeter, United Kingdom, 2Royal Devon and Exeter Hospital, IBD Pharmacogenetics Research, Exeter, United Kingdom, 3Kent and Canterbury Hospital, Gastroenterology, Canterbury, United Kingdom, 4Kent and Canterbury Hospital, Renal Medicine, Canterbury, United Kingdom, 5Royal Devon and Exeter Hospital, Renal Medicine, Exeter, United Kingdom, 6Guy's and St Thomas' Hospital, Gastroenterology, London, United Kingdom, 7St Mary's Hospital, Gastroenterology, London, United Kingdom, 8St Mark's Hospital, Gastroenterology, London, United Kingdom, 9University of Ioannina, Gastroenterology, Ioannina, Greece, 10Azienda Ospedaliero Universitaria (AOU), Gastroenterology, Careggi, Italy, 11Mount Sinai Hospital, Gastroenterology, Toronto, Canada, 12Groote Schuur Hospital, Gastroenterology, Cape Town, South Africa, 13University Hospital Padua, Gastroenterology, Padua, Italy, 14Royal Brisbane and Women's Hospital, Gastroenterology, Brisbane, Australia, 15University of Otago, Gastroenterology, Christchurch, United Kingdom, 16Wellcome Trust Sanger Institute, United Kingdom, 17Yorkhill Hospital, Gastroenterology, Glasgow, United Kingdom, 18University of Edinburgh, Paediatric Gastroenterology, Edinburgh, United Kingdom, 19Addenbrooke's Hospital, Gastroenterology, Cambridge, United Kingdom, 20Western General Hospital, Gastroenterology, Edinburgh, United Kingdom, 21University Medical Center, Gastroenterology, Groningen, Netherlands, 22Fremantle Hospital, Gastroenterology, Fremantle, Australia, 23International Serious Adverse Event Consortium, Chicago, United States

Background

Nephrotoxicity is a rare idiosyncratic reaction to 5-ASA therapy. The exact pathogenic mechanisms are unknown but it is commonly characterised by progressive interstitial nephritis. This study aims to a) describe the clinical features of this complication b) explore the underlying mechanisms and c) identify clinically useful predictive genetic markers so that these drugs can be avoided, or monitoring intensified, in high-risk patients. Here we report the clinical features.

Methods

Patients were recruited from 185 (130 UK) international sites and DNA extracted. Inclusion criteria comprise normal renal function prior to commencing 5-ASA + ≥50% rise in creatinine + medical opinion implicating 5-ASA justifies drug withdrawal. An adjudication panel of expert gastroenterologists and nephrologists assessed causality from detailed case report forms. Patients were assigned “definite” (requires positive rechallenge), “probable”, “possible” or “unlikely” cases of 5-ASA nephrotoxicity using the validated Liverpool Adverse Drug Reaction Causality Assessment Tool.

Results

156 (44.5% Crohn's disease, 71.9% male) patients have been recruited to date. These include 4 definite, 105 probable, 20 possible, 3 unlikely cases and 13 to be adjudicated. One patient with microscopic colitis was excluded. The side effect was seen with all aminosalicylates (mesalazine, balsalazide, olsalazine and sulfasalazine). 5-ASA nephrotoxicity occurred at a median age of 38.2 years (range 7.7–87.7). 78.6% of patients were white British. Two patients had a confirmed family history of 5-ASA-induced renal impairment. 75% of cases were detected by routine blood monitoring. The interval between 5-ASA introduction and first abnormal blood test was 0.2–521.3 months with 22.4% occurring in the first 12 months. The mean peak creatinine recorded was 296.8 micromol/litre (range 112–1726). A renal biopsy was performed in 46.9% cases. 81.1% had a ≥20% recovery in peak creatinine on drug withdrawal; of these the mean time to best-recovered renal function was 2 months (range 0.1–252.8) months). Seventeen patients required renal replacement therapy (15 transplantation).

Conclusion

This is the largest most detailed study of 5-ASA induced nephrotoxicity. Whilst the incidence is low, the morbidity is high with 12% of patients requiring renal replacement therapy. Early recognition is important as drug withdrawal leads to recovery in only 81.1% of patients. Genome-wide association sequencing (GWAS) will be performed in February 2013.