Drug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: experience from a single UK renal unit

Nicholas Torpey1, Tim Barker2 and Calum Ross1

1Renal Unit and 2Department of Pathology, Norfolk and Norwich University Hospital, Norwich, UK

Correspondence and offprint requests to: Dr Nicholas Torpey, Yale University School of Medicine, BCMM Room 447, 295 Congress Avenue, New Haven, CT 06510, USA. Email: ntorpey{at}waitrose.com



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Acute tubulo-interstitial nephritis (TIN) is an important cause of acute renal failure, and is often caused by hypersensitivity to drugs. The aim of this study was to determine the aetiology of interstitial nephritis among an unselected cohort of patients, and to identify those drugs commonly implicated.

Methods. A single-centre retrospective analysis was carried out of renal biopsy results from 296 consecutive patients between 1995 and 1999.

Results. Acute TIN was identified in 24 (8.1%) biopsies. Eight out of 14 cases with presumed drug-related TIN could be attributed to the proton pump inhibitors omeprazole and lansoprazole. The two cases of lansoprazole-associated TIN are the first to be reported with this drug. The presentation and favourable response to treatment of these patients are described.

Conclusion. Drugs are the most common cause of interstitial nephritis in the population studied. Those drugs most commonly associated with interstitial nephritis were the proton pump inhibitors omeprazole and lansoprazole.

Keywords: acute tubulo-interstitial nephritis; drugs; proton pump inhibitors



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Tubulo-interstitial nephritis (TIN) is an important cause of reversible acute renal failure (ARF). Between 6 and 25% of patients undergoing renal biopsy for unexplained ARF will prove to have TIN [1,2]. The aetiology of at least half of all cases is attributed to medications [1,3,4]. Those most commonly implicated are antibiotics (penicillins, cephalosporins, sulfonamides and rifampicin) and non-steroidal anti-inflammatory drugs (NSAIDs), including at least one case with a cyclo-oxygenase-2 inhibitor [5], although cases of TIN have been linked to many prescribed and proprietary medications [4,6]. Some patients with drug-induced TIN, particularly when associated with penicillins, will develop symptoms of systemic inflammation with or without an allergic rash and a peripheral blood eosinophilia [7,8]. Many, however, will have no specific symptoms, and do not present until they have developed advanced renal failure. Nevertheless, early diagnosis is important since withdrawal of the precipitating drug, with or without corticosteroid treatment, usually leads to rapid recovery of renal function.

In this study, we report an association between TIN and the proton pump inhibitors (PPIs) omeprazole and lansoprazole in one-third of all biopsy-proven cases of TIN in a single centre over a 4.5 year period. The two cases attributed to lansoprazole are the first to be reported with this drug. PPIs are commonly prescribed in both hospital and community practice, and may be an under-recognized cause of TIN. A high index of suspicion and prompt testing of renal function is warranted in any patient who develops non-specific symptoms whilst taking PPIs.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Review of renal biopsy results
The Norfolk and Norwich Hospital provides renal services to a population of 750 000. The reports of all native renal biopsies carried out over a 4.5 year period were reviewed. All those in which interstitial inflammation featured in the final histopathological diagnosis were selected and the case notes obtained. Cases of primary TIN were identified based on histology showing interstitial oedema and a small cell interstitial infiltrate with or without monocytes, plasma cells, eosinophils, granuloma formation or tubulitis. Cases in which interstitial inflammation was secondary to urinary tract infection or obstruction, or which were associated with primary glomerular disease were excluded.

Data collection
The notes of those patients with a diagnosis of primary TIN were reviewed for the circumstances of their presentation, medical history, investigations, treatment and outcome. Specific details noted for each patient were: age at presentation; gender; all medications (with duration of treatment, where possible); investigations, including initial serum creatinine, urinalysis and culture of a mid-stream urine (MSU) specimen; post-diagnosis treatment; and serum creatinine measured at 3 and 6 months following diagnosis, and at the end of the 4.5 year study period. We did not measure or calculate creatinine clearance. In addition, each case history, examination findings and the results of further investigations [chest X-ray (CXR), serum angiotensin-converting enzyme (ACE), serum and urine protein electrophoresis, anti-nuclear antibody (ANA) and anti-neutrophil cytoplasmic antibody (ANCA)] were analysed to identify any systemic disease that might cause a secondary TIN.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Identification of cases of TIN
During the study period, the policy in our unit was to biopsy all patients with unexplained renal failure unless there was a specific contraindication to renal biopsy, or the patient withheld consent. The results of 296 renal biopsies were reviewed. Twenty-four of these (8.1%) had a final diagnosis of primary TIN. The notes of 23 patients were available, and the relevant details are summarized in Table 1. The mean age of these 23 patients was 63 years (range 16–88), 10 were male and all were Caucasian. Four patients presented as uraemic emergencies and required urgent dialysis. The mean serum creatinine at presentation of the remaining 19 was 413 µmol/l (range 200–800 µmol/l).


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Table 1. Details of the 23 patients with TIN

 
Causes of TIN
Table 2 lists the presumed aetiology of TIN in the 23 cases for which notes were available. One patient (MK1) had sarcoidosis (polyarthropathy, bilateral hilar lymphadenopathy on CXR, and granulomatous TIN on biopsy) and two (HB and KC) had a past history of anterior uveitis, suggesting a diagnosis of TIN/uveitis syndrome [9]. No cause could be identified in six patients, but 14 (60%) cases were associated with drug use (Table 2). Surprisingly, eight of these could be attributed to PPIs, six with omeprazole and two with lansoprazole. We did not observe a relationship between either the cause or severity of TIN and urinalysis, blood pressure or eosinophil count, although urinalysis and eosinophil count were not available for all patients. Serum ACE, ANA, ANCA and paraprotein studies were normal in the 19 patients for whom results were available. A comparison of the presumed aetiology of TIN in this study with three case series that enrolled patients between 1978 and 1993, before widespread prescribing of PPIs in the UK, is shown in Table 2.


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Table 2. Probable aetiology of TIN in this and three recent studies

 
PPI-associated TIN
The details of those patients with PPI-associated TIN are shown in Table 1. Duration of PPI treatment before presentation was between 2 weeks and 9 months. Neither the duration of PPI treatment nor urinalysis could be correlated with the severity of renal failure or the recovery of renal function with treatment. Only one patient had either a peripheral blood eosinophilia (CP) or a fever (BB), the latter associated with a coliform cystitis. No patient had a rash. Three patients (SH, PC and AS) were known to have normal serum creatinine before PPI treatment was started, two of whom (PC and AS) were diabetic. One patient (BB) had previously developed renal failure whilst taking omeprazole, with a peak serum creatinine of 353 µmol/l falling to 161 µmol/l on drug withdrawal. The episode of renal failure reported in this study occurred on inadvertent re-challenge with omeprazole. Two patients (BO and PC) were taking only PPIs, whilst the remaining six were taking on average an additional three medications. In three patients, these medications included other drugs reported to cause TIN; OF and BB were taking bendrofluazide, and WP was being treated for Helicobacter pylori with a regimen including omeprazole and amoxycillin. Two patients (BB and OF) had proven coliform urinary tract infections at the time TIN was diagnosed. Neither had evidence of ascending infection on their biopsy, and in both cases a Gram stain of the biopsy was negative.

Treatment
The treatment received by each patient is summarized in Table 1. Drugs implicated in the aetiology of TIN were withdrawn. In those three patients taking a PPI and in addition another drug associated with TIN, both were stopped. Treatment with oral corticosteroids was given to eight out of nine patients with TIN not associated with drugs, and 12 out of 14 with drug-associated TIN, including seven out of eight with PPI-associated TIN. Treatment was typically with 0.5 mg/kg body weight prednisolone continued until the serum creatinine stabilized, and then tapered to zero over 2–3 months. In addition, two patients with dialysis-dependent renal failure on presentation (JL and RM) were treated with three consecutive daily doses of 500 mg methylprednisolone administered intravenously. Haemodialysis was delivered as clinically indicated.

Outcome
Renal function was assessed according to clinical need. For the purposes of this retrospective analysis, we compared serum creatinine at presentation, 3 months (defined as the last result available before 3 month follow-up), 6 months (defined as the first available result after 6 months follow-up) and at the end of the study period (range 9–54 months, median 24 months) (Table 1 and Figure 1). Two diabetic patients (HM and TJ) remained dialysis dependent. The renal function of the remaining patients improved substantially. The mean serum creatinine of those patients not on dialysis fell from 416 µmol/l at presentation to 163 at 3 months, 146 at 6 months and 139 µmol/l at the end of the study. The outcome for those patients with drug-associated TIN was similar, both as a whole and in the PPI-associated group, with corresponding mean serum creatinine measurements of 427, 184, 159 and 152 µmol/l in the drug-associated group as a whole, and 411, 170, 147 and 144 µmol/l in the PPI group. The improvement of serum creatinine in all patients and in the PPI group is illustrated in Figure 1A and B. Renal function improved rapidly within the first 3 months of treatment, and then stabilized, or continued to improve further. The outcome of the three patients not treated with steroids did not differ substantially from the group as a whole (mean serum creatinine at presentation 404 µmol/l plus one dialysis-dependent patient, falling to 143 µmol/l).



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Fig. 1. Serum creatinine at presentation, 3 months, 6 months following biopsy, and at the end of the study (>=9 months). (A) All patients included in the study, and (B) those with PPI-associated TIN. Patients on dialysis were arbitrarily assigned a creatinine of 1000 µmol/l.

 
Of the four diabetic patients in this study, two (HM and TJ) had TIN of unknown origin that progressed to dialysis dependency during their initial hospitalization. The remaining two patients (AS and PC) had PPI-associated TIN. Both had clinic visits documenting normal serum creatinine and absence of proteinuria within 4 months of their presentation with TIN. Nevertheless, both patients had evidence of diabetic nephropathy on biopsy, with focal and segmental deposition of mesangial matrix and early nodule formation. The serum creatinine did not return to baseline in either patient despite PPI withdrawal and steroid treatment (Table 1).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The two important findings reported here are the association of TIN with PPI treatment in eight out of 23 (35%) of all patients presenting to a single renal unit with primary TIN, and the description of two cases of lansoprazole-associated TIN. Other notable points include the relatively high incidence of TIN in our population, the generally good prognosis and the apparently adverse effect of diabetes on outcome.

To our knowledge, the two cases of lansoprazole-associated TIN in our series are the first to be reported with this drug. However, there have been 19 case reports implicating omeprazole in the aetiology of drug-induced TIN [10,11]. An analysis of 18 of these cases by Myers [10] showed them to be very similar to our own, with an average age at diagnosis of 65.8 years (range 36–86), and an average duration of omeprazole treatment of 2.7 months (range 1 week–7 months). Importantly, only one of these 18 patients, and none of ours, presented with a fever, rash and eosinophilia. This classic triad was found frequently in patients with methicillin-induced TIN [7], but is now uncommon. In a survey of >150 case reports, Rossert identified one of these features in up to 50% of patients with non-methicillin-associated TIN, but all three in <5% [4]. Indeed, with the exception of NSAID-induced nephrotic syndrome, the majority of drugs now associated with TIN give rise to few specific symptoms, accounting in large part for the delayed presentation and advanced renal failure seen in many patients. Furthermore, drugs associated with TIN are in widespread use, emphasizing the need for a high index of suspicion for drug-associated TIN. This may be particularly the case with PPIs, which are prescribed with increasing frequency in both primary and secondary care and already account for at least 6% of primary care drug expenditure [12].

This series includes only patients with biopsy-proven TIN. One possible explanation for the unexpected number of PPI-associated cases is that these patients were more likely to be selected for renal biopsy than patients taking other medications more widely known to cause TIN. However, during the study period, the policy in our unit was to biopsy all patients with unexplained renal failure unless there was a medical contraindication to renal biopsy, or the patient was unable or unwilling to give informed consent. Consequently, we believe that the association of PPIs with TIN in this study population is real, and is an important cause of drug-induced TIN presenting as ARF.

Although we have identified eight patients with probable PPI-associated TIN, only two were taking PPIs alone; one omeprazole and one lansoprazole. Three of the remaining six were on medications not implicated in TIN, whilst three were taking other drugs possibly associated with TIN (one amoxycillin and two bendrofluazide). The combination of a PPI and amoxycillin is widely used as part of eradication therapy for H.pylori, and in this setting acute TIN could be attributed to either medication. Our patient reported that he had taken penicillin in the past without complications and, although not completely excluding amoxycillin as the likely cause, we have included this as a PPI-associated case. In contrast to the robust association between penicillins and TIN, bendrofluazide has been implicated in only one case of drug-associated TIN [13], and thiazide diuretics as a group in 14 [1318]. No case of thiazide-associated TIN was reported in three case series published between 1988 and 1993, which included 44 patients with drug-associated TIN [1,3,8]. Moreover, one of the patients taking both a PPI and bendrofluazide had developed renal impairment on two separate exposures to PPIs, further implicating the PPI as the causative drug. Consequently we believe that PPIs are a more likely cause of the TIN seen in these two patients. The patients in this study were taking on average 2.3 medications, and those with drug-associated TIN 2.7. Although this may cause difficulty in identifying the responsible drug, it is a reflection of modern medical practice, particularly the polypharmacy commonly observed in elderly populations.

The incidence of TIN in our study (8.1% of unselected biopsies) is similar to that described in a recent report from St Mary's Hospital, North London (7.9%) [19], although the causes of TIN were quite different. All of our patients were Caucasian and the majority had drug-associated TIN. In contrast, the ethnic origin of more than half of the patients diagnosed with TIN in the St Mary's study was Indian, and of these the majority had idiopathic TIN (see Table 2). Other studies from the UK have reported a much lower incidence of primary TIN; 2% in all biopsies performed between 1970 and 1986 at Guy's Hospital in London [20], and 2.2% in the UK MRC Glomerulonephritis Register [2], which began collecting data in 1978. In the latter study, primary TIN was more common in those patients aged over 60 (3% of all biopsies) than those under 60 (1.9%), in keeping with our own observations. Why both our study and the St Mary's study demonstrated such an increase in the incidence of TIN is not clear. It may be that each included a population at particular risk for TIN; a large Indian population in the St Mary's study, and a large elderly population in our own.

The outcome of patients in our series was broadly comparable with that reported elsewhere. In eight studies of drug-related TIN, 58% of those patients treated with steroids and 50% of untreated patients recovered normal renal function following drug withdrawal [3,7,8,13,2124]. All of these were small retrospective case series, and there remains no evidence to suggest that treatment with corticosteroids improves the long-term outcome of patients with drug-related TIN, although it may shorten the time to recovery from renal failure [3]. Those patients in this report that fared badly either had idiopathic TIN or were diabetic. Two patients (HM and TJ) with TIN of unknown cause had co-existing diabetes, whilst the remaining two diabetic patients (PC and AS) had PPI-associated TIN. All had diabetic nephropathy on biopsy. Although several studies have demonstrated a link between TIN of unknown aetiology and poor prognosis [1,19], an adverse effect of co-exisiting diabetic nephropathy has not been observed previously. Unfortunately, there were too few diabetic patients in our study to determine whether this association is robust.

This report suggests that the PPIs omeprazole and lansoprazole are an important cause of drug-associated TIN. The absence of prominent systemic symptoms in patients with PPI-associated TIN, and in many patients with TIN associated with other drugs, emphasizes the need for a high index of suspicion. Once the diagnosis is confirmed, withdrawal of the offending drug(s), with or without steroid treatment, usually permits a rapid improvement of renal function.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 31. 7.03
Accepted in revised form: 7. 1.04





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