Published: 10 June 2015

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Keeping it Renal: Drug-Induced Acute Interstitial Nephritis

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Prescriber Update 36(2): 26-27
June 2015

Background

Acute interstitial nephritis (AIN) is the third most common cause of acute kidney injury (AKI) after prerenal AKI and acute tubular necrosis¹. Over two-thirds of AIN cases are drug-induced and infection-related AIN accounts for 5% to 10% of cases².

Medicines that can cause AIN

Antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) are most frequently associated with drug-induced AIN². The role of proton pump inhibitors (PPIs) has also been highlighted more recently³. Medicines most commonly associated with AIN are shown in Table 1.

Table 1: Medicines associated with acute interstitial nephritis¹

Medicine class	Examples
Antibiotics	β-lactam antibiotics*, fluoroquinolones*, rifampicin*, sulphur-based medicines*, vancomycin, minocycline, ethambutol, erythromycin, chloramphenicol
Analgesics	non-steroidal anti-inflammatory drugs* (eg, diclofenac), selective COX-2 inhibitors (eg, celecoxib)
Gastrointestinal medicines	proton pump inhibitors* (eg, omeprazole), h2-receptor antagonists (eg, ranitidine)
Antiviral medicines	aciclovir, abacavir, indinavir, atazanavir
Antiepileptic medicines	phenytoin*, phenobarbital, carbamazepine
Other medicines	allopurinol*, 5-aminosalicylates* (eg, mesalazine, sulfasalazine), captopril, interferon, ciclosporin, anti-angiogenesis medicines (tyrosine kinase inhibitors [eg, sunitinib]), diuretics (eg, furosemide)

*most common causative medicines

The average time period between starting the medicine and the appearance of renal manifestations is 10 days⁴. However, this time period can be as short as one day after some antibiotics or as long as several months with NSAIDs⁴.

For PPIs, the interval is most commonly 10 to11 weeks but this can vary between one week and nine months².

Clinical Features

Clinical suspicion of AIN in patients with AKI usually relies on:²

• the presence of general symptoms
  • test
  • malaise
  • anorexia
  • nausea
  • arthralgia
• hypersensitivity reactions
  • low grade fever
  • skin rash
  • eosinophilia
• urinalysis findings typical of AIN
  • microhaematuria
  • non-nephrotic proteinuria (some patients with NSAID-related AIN can present complete nephrotic syndrome)
  • leucocyturia.

Sterile pyuria and leucocyte casts are important clues for the diagnosis of AIN in patients with AKI². An important number of cases have an oligosymptomatic presentation; the classical triad of rash, fever and eosinophilia are less commonly observed than was initially reported².

The absence of hypersensitivity reactions and normal urinary sediment are important features to distinguish acute tubular necrosis from AIN². AIN is difficult to diagnose. Ultimately, kidney biopsy is needed to confirm the diagnosis².

Treatment

Rapid identification and withdrawal of the suspect medicine is the mainstay of treatment².

Early treatment with corticosteroids (within the first five days) can reduce the amount of tubulointerstitial fibrosis that develops and avoid incomplete recovery of renal function^1,2. However, the use of corticosteroids is still controversial and further studies are required to confirm their place in the treatment of drug-induced AIN².

New Zealand Cases

The Centre for Adverse Reactions Monitoring (CARM) has received 189 case reports of AIN. However, some cases involve more than one suspect medicine.

The most common medicines reported were omeprazole, diclofenac, flucloxacillin and amoxicillin-containing medicines.

Average onset time of AIN following medicine initiation varied from within a few days to more than one year. This is consistent with onset times reported in the literature.

The suspect medicine was withdrawn in 170 of the 189 cases. Of these 170 cases, there was definite improvement in 108 and the result not known in 50. It is not known if treatment with corticosteroids occurred in any of the reported cases.

Healthcare professionals are encouraged to report any adverse events to medicines, including drug-induced AIN, to CARM. Reports may be submitted on paper or electronically (https://nzphvc.otago.ac.nz/report/).

References

1. Perazella M. 2014. Diagnosing drug-induced AIN in the hospitalized patient: a challenge for the clinician. Clinical Nephrology 81(6): 381–388.
2. Praga M, Sevillano A, Auñon P, et al. 2014. Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrology, Dialysis, Transplantation doi: 10.1093/ndt/gfu326 (accessed 1 April 2015).
3. Medsafe. 2011. Proton pump inhibitors and interstitial nephritis. Prescriber Update 32(3): 25. URL: www.medsafe.govt.nz/profs/PUArticles/ProtonPumpSept2011.htm (accessed 19 May 2015).
4. Praga M, González E. 2010. Acute interstitial nephritis. Kidney International 77(11): 956–961.