Crohn’s disease (CD) and ulcerative colitis (UC) are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract, affecting 400 patients per 100,000 population in Europe and North America. Collectively the Inflammatory bowel diseases (IBD) represent an important cause of morbidity in young people, and a significant burden to healthcare resources. In the UK direct annual healthcare costs associated with the care of patients with IBD total £720 million1.
5-aminosalicylate induced nephrotoxicity
5-aminosalicylate drugs (5-ASA) are the most frequently prescribed class of drug to induce and maintain remission in patients with mild-to-moderately active IBD. The use of these drugs as long-term maintenance therapy inevitably leads to prolonged drug exposure and therefore toxicity is an important consideration.
Nephrotoxicity is a serious but rare idiosyncratic complication of 5-ASA therapy2. Whilst the incidence is low, the morbidity and costs to the health economy are high with a significant proportion of patients developing end stage renal failure. Nephrotoxicity most frequently takes the form of a severe progressive interstitial nephritis. Whilst the precise underlying pathogenic mechanisms are yet to be elucidated, a delayed cell-mediated response, resembling that described for non-steroidal anti-inflammatory drugs seems likely3.
The precise incidence of 5-ASA induced nephrotoxicity is uncertain as cases are rare and confounding factors common. Such factors include the concomitant use of other nephrotoxic drugs (e.g. NSAIDs to manage associated joint disease), and the occurrence of other, rare IBD associated renal manifestations, which cannot always be readily distinguished. These include tubular proteinuria related to IBD inflammatory activity4, renal stone disease, amyloidosis, membranous glomerulonephritis, rapidly progressive glomersulonephritis and IgA nephropathy5. Data from clinical trials of 5-ASA drugs, in which serum creatinine has been regularly monitored, suggest a mean annual nephrotoxicity risk of 0.26% (0.13% – 0.5%)2. In contrast data from a detailed postal questionnaire sent to all UK gastroenterologists and renal physicians estimates an incidence of 1/4000 patient years6.
Nephrotoxicity is reported most often within the first 12 months of drug exposure, but may be delayed for many years. Symptoms and signs may be mild and non-specific which may delay detection for many months. For these reasons regular monitoring of renal function for the duration of therapy is recommended, although it is not known if the serum creatinine gives sufficient warning of developing nephrotoxicity. Furthermore the benefit and cost-effectiveness of this approach has not been demonstrated. Timely recognition of renal impairment and prompt withdrawal of 5-ASA treatment is crucial to maximize chances of renal recovery. Failure to detect 5-aminosalicyalte nephrotoxicity early is an increasing cause of medical litigation.
IBD genetics at the forefront of complex disease genetics
The last 4 years have seen tremendous progress in the identification of Inflammatory bowel disease susceptibility genes. Using genome wide association scans (GWAS) more than 90 IBD risk loci have been identified including at least 28 association signals shared between Crohn’s disease and ulcerative colitis. The UK and international IBD Genetics consortia have been central to these discovery efforts7-11. This exciting progress has provided major pathogenic insights but has not yet translated to the clinic for patient benefit. With the exception of TPMT genotyping to identify patients at risk of myelosuppression with thiopurines, no loci are used in IBD clinical practice12.
Genetic contribution to adverse drug reactions
Recent studies have demonstrated that the same unbiased GWAS technology can be successfully employed to identify genetic factors that determine adverse drug reactions, promising a safe individualized therapeutic strategy for patients. Importantly these studies have confirmed that rare side effects may be determined by large effect variants and can be identified using a relatively small number of rigorously characterized cases. Thus the HLA class II allele HLA-B*5701 genotype has been shown to be a major determinant of flucloxacillin-induced cholestatic hepatitis with an odds ratio of 80 using a cohort of only 51 patients13. This same HLA allele was earlier found to associate with Abacavir hypersensitivity14, a finding that has translated into clinical practice to reduce the burden of this serious adverse reaction in a cost effective manner15 – in Europe HLA-B*5701 testing is now mandatory before prescribing Abacavir.
1. Bassi A, Dodd S, Williamson P, Bodger K. Cost of illness of inflammatory bowel disease in the UK: a single centre retrospective study. Gut 2004;53:1471-8.
2. Gisbert JP, Gonzalez-Lama Y, Mate J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2007;13:629-38.
3. Popoola J, Muller AF, Pollock L, O’Donnell P, Carmichael P, Stevens P. Late onset interstitial nephritis associated with mesalazine treatment. BMJ 1998;317:795-7.
4. Poulou AC, Goumas KE, Dandakis DC, Tyrmpas I, Panagiotaki M, Georgouli A, Soutos DC, Archimandritis A. Microproteinuria in patients with inflammatory bowel disease: is it associated with the disease activity or the treatment with 5-aminosalicylic acid? World J Gastroenterol 2006;12:739-46.
5. Corrigan G, Stevens PE. Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther 2000;14:1-6.
6. Muller AF, Stevens PE, McIntyre AS, Ellison H, Logan RF. Experience of 5-aminosalicylate nephrotoxicity in the United Kingdom. Aliment Pharmacol Ther 2005;21:1217-24.
7. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield JC, Cardon L, Mathew CG. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 2007;39:830-2.
8. Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 2008;40:710-2.
9. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008;40:955-62.
10. Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M. Investigation of Crohn’s disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 2009;136:523-9 e3.
11. Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H, Drummond H, Nimmo ER, Massey D, Blaszczyk K, Elliott T, Cotterill L, Dallal H, Lobo AJ, Mowat C, Sanderson JD, Jewell DP, Newman WG, Edwards C, Ahmad T, Mansfield JC, Satsangi J, Parkes M, Mathew CG, Donnelly P, Peltonen L, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Craddock N, Deloukas P, Duncanson A, Jankowski J, Markus HS, McCarthy MI, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Samani N, Trembath RC, Viswanathan AC, Wood N, Spencer CC, Bellenguez C, Davison D, Freeman C, Strange A, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Perez ML, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, Attwood AP, Stephens J, Sambrook J, Ouwehand WH, McArdle WL, Ring SM, Strachan DP. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 2009;41:1330-4.
12. Ahmad T, Tamboli CP, Jewell D, Colombel JF. Clinical relevance of advances in genetics and pharmacogenetics of IBD. Gastroenterology 2004;126:1533-49.
13. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816-9.
14. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-32.
15. Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 2004;14:335-42.