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Proton pump inhibitors and acute interstitial nephritis

BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4412 (Published 22 September 2010) Cite this as: BMJ 2010;341:c4412
  1. S Ray, gastroenterology registrar1,
  2. M Delaney, consultant nephrologist2,
  3. A F Muller, consultant physician and gastroenterologist1
  1. 1Department of Gastroenterology, Kent and Canterbury Hospital, East Kent University Hospitals NHS Foundation Trust, Canterbury CT1 3NG
  2. 2Renal Medicine, Kent and Canterbury Hospital, East Kent University Hospitals NHS Foundation Trust, Canterbury CT1 3NG
  1. Correspondence to: A F Muller andrew.muller{at}ekht.nhs.uk
  • Accepted 30 July 2010

Proton pump inhibitors are an important iatrogenic cause of acute kidney injury

Since the introduction of omeprazole in 1989, proton pump inhibitors (PPIs) have become one of the most widely prescribed classes of drugs. A community database of patients who have had any renal function tests in our region shows a prescription rate of 8% (C Farmer, personal communication, 2010). Proton pump inhibitors are associated with a range of side effects including hip fracture, Clostridium difficile infection, and hypomagnesaemia.1 2 3 Sporadic case series have implicated them as a potential cause of acute interstitial nephritis leading to acute kidney injury.4 5 6

In southeast England during 2007 and 2008, we examined 210 kidney biopsies and found six cases of acute interstitial nephritis that were strongly associated with PPIs either by temporal association with the injury or response to stopping the drugs. These patients had biopsies because renal function was declining, the cause was uncertain, and screening for acute kidney injury was negative. The table summarises five of the six cases of acute interstitial nephritis associated with PPIs (one patient did not consent to be included), and we present two of the cases.

Acute interstitial nephritis related to proton pump inhibitors (PPI)

View this table:

Case 1

A 70 year old woman was referred by her general practitioner in April 2008 with deteriorating kidney function. She presented with malaise and tiredness. Her medical history included hypertension. She was taking lisinopril (for 15 years), domperidone, and omeprazole. She had not used antibiotic or non-steroidal anti-inflammatory drugs (NSAIDs) recently. Omeprazole was first prescribed in December 2007.

Physical examination, including blood pressure, was normal. Urinalysis confirmed a trace of blood and protein. Screening for acute kidney injury (antinuclear antibodies, antineutrophil cytoplasmic antibodies, complement factors, C3 and C4, and serum and urine electrophoresis) was negative. Proteinuria (urinary protein:creatinine ratio) was 15 mg/mmol (normal range 3-14 mg/mmol). Kidney function was assessed by plasma creatinine (µmol/l) and estimated glomerular filtration rate (table; patient 1). An ultrasound scan showed normal sized, non-obstructed kidneys.

Kidney biopsy confirmed normal glomeruli and patchy tubulo-interstitial lymphocytic infiltrates. An allergic-type drug reaction was diagnosed. In view of the temporal association of omeprazole ingestion and acute kidney injury, the omeprazole was stopped. Lisinopril and domperidone were continued. She was treated with oral prednisolone at 30 mg daily for four weeks and tapered to cessation at three months. Kidney function improved but it did not return to pre-PPI levels.

Case 2

A 60 year old woman was referred by her general practitioner with chronic kidney disease stage 4 in February 2008. She gave a two month history of fatigue and thirst. Her medical treatment consisted of betahistine, citalopram, omeprazole, and tramadol. She had no history of recent antibiotic or NSAID use. Omeprazole was first prescribed in February 2005 for gastritis and used intermittently until January 2007, and then consistently until presentation. Kidney function was normal during November 2006, but at presentation the creatinine concentration was 196 µmol/l (eGFR 23 ml/min/1.73m2). Physical examination was unremarkable and urinalysis confirmed 1+ protein and a trace of blood. Screen for acute kidney injury was negative. Proteinuria measured by protein:creatinine ratio was 108 mg/mmol (normal range 3-14 mg/mmol), equivalent to approximately 1 g/day. Proteinuria in the non-nephrotic range supported a non-glomerular aetiology. Kidney function results are summarised in the table (patient 2). Ultrasound scan was normal.

Renal biopsy confirmed normal glomeruli and focal lymphocytic tubulitis consistent with an acute tubulointerstitial nephritis. Omeprazole was discontinued on 19 March 2008 and prednisolone was started at 30 mg daily, tapered for four months, and then discontinued. Kidney function improved but did not return to normal.

Discussion

About 15% of patients admitted to hospital with acute kidney injury will eventually be diagnosed with acute interstitial nephritis.7 Most cases are due to an idiosyncratic reaction to certain drugs, including penicillins and NSAIDs. Since the first case report of acute interstitial nephritis provoked by proton pump inhibitors was published in 1992,8 all drugs in the PPI class have been associated with reports of acute kidney injury.5 6 8 9 10 11 The mechanism of renal injury is not fully understood but is thought to involve an immune component. In vitro lymphocyte stimulation tests show response to selected drugs and rapid return of disease on inadvertent rechallenge.12 The standard treatment involves withdrawing the drug and steroids (depending on the degree of acute kidney injury and clinical assessment).

In the cases presented, the deterioration in kidney function was temporally associated with treatment with PPIs, stopping PPIs led to an improvement in kidney function, and the biopsy findings were consistent with an allergic-type acute tubulointerstitial nephritis. Although these findings are insufficient to show causation, due to possible confounding factors (such as the use of other drugs), our data combined with other case reports are highly suggestive. In our renal unit, PPIs were the leading likely cause of biopsy proved acute interstitial nephritis,13 which is a common cause of acute kidney injury. After PPIs were stopped, kidney function improved considerably, consistent with the case reports in the literature. The development of chronic kidney disease after acute kidney injury has long term detrimental effects on health, including increased cardiovascular disease. Delays in making the diagnosis are important because this may affect prognosis.

The incidence of acute interstitial nephritis related to PPIs remains uncertain, but it is thought to be relatively uncommon. During a 22 month period, we identified six cases of acute interstitial nephritis associated with PPIs, proved by biopsy, in a renal centre serving a population of 1.1 million people.13 An earlier study in the United Kingdom reported eight cases in a four year period.7 Analysis of the Medicines and Healthcare products Regulatory Agency reporting scheme in the UK (www.mhra.gov.uk/Onlineservices/Medicines/Druganalysisprints/index.htm) found 74 cases of acute interstitial nephritis related to PPIs between 1992 and December 2009. The condition is likely to be considerably under-reported because of a lack of awareness of the condition, the non-specific nature of the symptoms, and attributing decline in kidney function to other conditions.

Although the incidence of acute kidney injury induced by proton pump inhibitors is likely to be low (even accounting for under-reporting), it is important to consider it in the differential diagnosis of kidney disease. Acute interstitial nephritis induced by PPIs is an iatrogenic cause of kidney injury that can be wholly or partially reversed in most patients, avoiding the development of chronic kidney disease and its deleterious sequelae.

The relative infrequency of kidney function testing and the non-specific symptoms of this condition suggest that a high index of suspicion is needed. If a decline in renal function is noted, PPIs should be considered as a cause and stopped. They can often be replaced with lifestyle measures, antacids, and ranitidine (which is very rarely associated with acute interstitial nephritis.14) PPIs are not without risks and should always be appropriately prescribed.

Notes

Cite this as: BMJ 2010;341:c4412

Footnotes

  • Contributors: SR reviewed the results of all renal biopsies in the study period and the notes of those identified with interstitial nephritis and drafted the paper. MD and AFM devised the study protocol, reviewed all of the results, and contributed to the final version of the paper. AFM is guarantor.

  • Funding: No additional funding.

  • Competing interests: All authors have completed the unified competing interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organisation for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Patient consent obtained.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

References

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