Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease

Heap, Graham A.; So, Kenji; Weedon, Michael N.; Edney, Naomi; Bewshea, Claire; Singh, Abhey; Annese, Vito; Beckly, John; Buurman, D. J.; Chaudhary, Rubina

doi:10.1093/ecco-jcc/jjv219

Cited by 96 publications

(77 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition to the lack of proven effectiveness of 5‐ASA in CD, treatment guidelines have addressed the potential for the rare and idiosyncratic 5‐ASA‐induced renal toxicity with suggestions for monitoring renal function in those at greater risk of impairment . While the exact mechanism of 5‐ASA‐related nephrotoxicity is still unclear, clinical reports include renal failure, interstitial nephritis and glomerulosclerosis as part of the pathophysiology . Clinical trials report 5‐ASA nephrotoxicity not to be dose‐ or treatment duration‐dependent, even though this was suggested by a retrospective case series .…”

Section: Discussionmentioning

confidence: 99%

No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study

Jairath

Hokkanen

Guizzetti

et al. 2019

Aliment Pharmacol Ther

View full text Add to dashboard Cite

Summary Background There is conflicting evidence about nephrotoxicity risk associated with 5‐aminosalicylates for treatment of IBD. Aims To determine population‐based temporal trends for 5‐aminosalicylates and estimated risk of nephrotoxicity associated with 5‐aminosalicylate use for ulcerative colitis (UC) and Crohn's disease (CD). Methods Retrospective cohort and nested case‐control study, using the Health Improvement Network primary care database linked to hospital discharge coding for patients in England, 1996‐2017. Nephrotoxicity risk analysis was a first recorded renal impairment diagnosis adjusted for key variables and was assessed between 2008 and 2017. Results A total of 35 601 patients with prevalent UC or CD were included. The proportion of patients prescribed 5‐aminosalicylates fell from 83% in 1996‐1999 to 71% in 2012‐2015 for UC patients and 64% to 45% for CD patients. Thirty per cent of patients had prolonged 5‐aminosalicylate use. Between 2008 and 2017, the incident rate of nephrotoxicity was similar and stable for UC (12.6/1000 person‐years) and CD (10.9/1000 person‐years) patients. Multivariate analysis showed no evidence for association between current prescription of 5‐aminosalicylate and nephrotoxicity in UC or CD patients, comparing ≤ 30 days prescription prior to index vs 31‐≤180 days. However, active disease, disease duration, concomitant cardiovascular disease or diabetes and nephrotoxic drug use were independently associated with development of nephrotoxicity in UC and CD. Conclusions Despite the paucity of evidence for their benefit, 5‐aminosalicylates were prescribed to approximately half of CD patients (30% prolonged therapy). Nephrotoxicity was rare in this patient cohort, and was not associated with 5‐aminosalicylate use, but rather with disease status, comorbidity and use of nephrotoxic drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study

Jairath

Hokkanen

Guizzetti

et al. 2019

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…5-ASA was the possible cause of interstitial nephritis in these cases. A genome-wide association study identified a suggestive association with 5-ASA-induced nephrotoxicity in the HLA region (p=4×10 −9 ; OR, 3.1), and 30% of cases recovered completely after drug withdrawal, with 15 out of 151 patients requiring permanent renal replacement therapy 16. Although the aetiology of UC is still not fully understood, increased and activated myeloid lineage leucocytes (granulocytes and monocytes) are potentially significant factors in the exacerbation and perpetuation of IBD because they release inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Interstitial nephritis associated with ulcerative colitis in monozygotic twins

Sato¹,

Umemura

Yamamoto

et al. 2017

BMJ Case Reports

View full text Add to dashboard Cite

Although renal impairment is a rare complication of ulcerative colitis (UC), interstitial nephritis can occur as an idiosyncratic reaction to 5-aminosalicylate (5-ASA) treatment for UC. Monozygotic twins developed UC at ages 49 and 51, and they were separately treated at different medical institutes. They did not know that they had the same disease and were treated with the same drug (5-ASA). During the course of 5-ASA treatment, renal impairment diagnosed as interstitial nephritis occurred in both. Granulocyte/monocyte adsorption was initiated, UC remission was achieved and renal function deterioration subsided in both. Drug or treatment responses may be concordant in monozygotic twins with UC. Careful review is important before treatment to avoid serious adverse events.

show abstract

“…However, a small portion of the applied aminosalicylates could also be absorbed in the small intestine. This part can cause adverse events such as kidney stones or in case of sulfasalazopyridine to be utilized for the treatment of rheumatoid arthritis [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

The Detergent Effect of Mesalazine Interferes with Phosphatidylcholine Binding to Mucin 2

2018

View full text Add to dashboard Cite

Objectives: Therapeutically applied delayed-release phosphatidylcholine (PC) revealed mucosa protection and clinical improvement of ulcerative colitis. However, a recent trial with simultaneous application of delayed-release PC and mesalazine showed lack of efficacy. It is hypothesized that mesalazine acts as detergent to prohibit PC integration into mucus as target compartment, thus preventing topical mucus protection. Methods: In vitro PC-binding studies with mucin 2 and intestinally differentiated CaCo2 cells as well as outcome analysis of a therapeutic trial with delayed-release PC and additional mesalazine. Results: Choline-containing phospholipids, in particular PC, bind to mucin 2 as main scaffold protein of intestinal mucus to establish a hydrophobic barrier towards microbiota in the intestinal lumen. PC also binds to the apical surface of polarized CaCo2 cells with membrane-anchored mucin 3. Mesalazine removes mucin-bound PC and, thus, reduces transepithelial resistance. A post hoc analysis of patients from a previous multicenter phase IIB trial with delayed-release PC revealed that those without mesalazine showed a PC dose-dependent outcome with regard to achievement of partial and complete remission (p < 0.05 for 1.6 and 3.2 g PC daily) whereas those treated simultaneously with mesalazine showed no PC dose dependency. Conclusion: Mesalazine solubilizes PC and, thus, prevents the protective action of therapeutically applied delayed-release PC within mucus.

show abstract

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease

Abstract: 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.

Cited by 96 publications

References 39 publications

No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study

No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study

Interstitial nephritis associated with ulcerative colitis in monozygotic twins

The Detergent Effect of Mesalazine Interferes with Phosphatidylcholine Binding to Mucin 2

Contact Info

Product

Resources

About