Acute interstitial nephritis due to proton pump inhibitors

Introduction

Proton pump inhibitors (PPI) which are benzimidazole derivatives have made a significant impact on the treatment of acid peptic disease. Omeprazole was the first PPI to be introduced for clinic use in 1989. One of the most commonly prescribed drugs the world over, they are preceived as safe with low side-effect profile. Acute interstitial nephritis (AIN) is being increasingly recognized as a complication of PPIs. These drugs are widely prescribed and sold over the counter for specific as well as empiric indications in India. Physicians consider them as renally safe agents, but this view needs to be reconsidered in the light of recent evidences. We describe here the first case series of renal toxicity of PPI from India.

Case Reports

Case 1

Our first index case was a 49-year-old female who was on follow-up for hypothyroidism, bronchial asthma, and acid peptic disease. She was taking omeprazole, eltroxin, deriphyllin for 8 weeks before being admitted with complaints of dysphagia and heart burn for 4 days. Here was no fever, loin pain or skin rash. Blood pressure was 140/80 mmHg. On admission, dipstick urinalysis showed 1+ protein and with 4-6 WBCs/hpf. Blood urea was 45 mg/dl and serum creatinine 1.6 mg/dl. Oliguria developed after 48 h and renal failure worsened. Renal ultrasonogram showed enlarged kidneys with increased cortical echoes. In renal biopsy the glomeruli were normal, but interstitium showed diffuse and dense lymphocytic infiltrates covering >90% of the core [Figure 1].

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Figure 1

Renal biopsy showing dense interstitial mononuclear infiltrates. Glomeruli are normal

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Omeprazole was stopped. She was treated with 10 mg/kg of intravenous methyl prednisolone for 3 days followed by oral prednisolone 1 mg/kg tapered to 0.5 mg/kg over 3 months. Her renal parameters gradually improved, but she is left with residual renal impairment with serum creatinine of 1.6 mg % after 1 year.

Case 2

A 53-year-old female was admitted with a history of vomiting, loin pain for the 2 weeks and oliguria for 4 days. She was a known case of pulmonary tuberculosis who was receiving anti-tuberculosis therapy for the past 2 months. Pantoprazole was started for nausea 3 weeks ago. On examination, she appeared sick, febrile (100.5°F), tachypneic with a blood pressure of 130/80 mmHg. Blood urea was 76 mg/dl, serum creatinine 4.9 mg/dl and serum bicarbonate 14 mEq/L. She was started on daily hemodialysis for 4 days after which her general condition improved. Renal biopsy revealed AIN with dense lymphocyte and eosinophilic infiltrates in the interstitium [Figure 2]. PPI was stopped and she was started on oral corticosteroids for 8 weeks with continuation of anti-tuberculosis therapy. After 4 months her serum creatinine remained high at 1.6 mg/dl. Rifampicin induced AIN was considered unlikely given the temporal profile of events after start of pantoprazole and the fact that renal function rapidly recovered, after withdrawal of the latter with steroid therapy.

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Figure 2

Renal biopsy showing dense interstitial infiltrates with lymphocytes and scattered eosinophils. Some tubules show injury pattern

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Discussion

Every year millions of prescriptions are made out for PPI to treat dyspepsia and peptic ulcer disease. PPI-induced AIN is thought to be a common class effect. It is triggered by a hypersensitivity immune reaction to the drug or one of its metabolites. Ruffenach et al., published the first case report of AIN due to omeprazole in 1992.[1] Since, then reports have emanated from many national adverse drug registries. World Health Organization adverse drug reaction report included 498 cases as of July 2011.[2] A single-center retrospective analysis was carried out of renal biopsy results of 296 consecutive patients between 1995 and 1999 from UK. Acute tubulointerstitial nephritis (TIN) was identified in 24 (8.1%) biopsies. Eight out of 14 cases with presumed drug related AIN could be attributed to the PPI such as omeprazole and lansoprazole.[3] PPI induced AIN is a generally disease of the middle or older age, which mirrors the symptom of dyspepsia in the aged. Median age in our cases was 52.5±18 years. Male; female ratio is 1:3 whereas there is equal sex predilection in other series. Pantoprazole was the commonest PPI in our cases. Omeprazole and esomeprazole were consumed by one each of our cases. In Myer's series of omeprazole induced AIN the drug was taken for an average 2.7 months before the onset of renal involvement.[4] Our case series differs in that the PPI has been ingested for short period of 1-8 weeks before the onset of AIN. The signs and symptoms off PPI-induced AIN were non-specific such as nausea, vomiting, loin pain, or fever. These cases highlight the complexity of diagnosis of PPI induced AIN. As can be seen from the Table 1 PPIs are rarely prescribed singly. Co-prescription with drugs which themselves are linked to AIN such as penicillin, cephalosporine and non steroidal anti inflammatory drugs is common. In case 2, even though anti-tuberculosis therapy was started a few months earlier, the symptoms were of shorter duration. Rifampicin which is well-known to produce AIN was continued through the illness with subsequent renal recovery proving that this was not the cause of disease. None of our patients had fever, skin rash or joint pains. Rossert encountered these only in <5% of drug induced AIN.[5] Hence, without a renal biopsy correct diagnosis is likely to be missed.

Table 1 Clinical features, renal histopathology and follow-up

Inactive urinary sediment in the absence of significant hematuria or proteinuria should make one suspect AIN. None of these cases had eosinophilia. The severity of renal failure at presentation varied. Two of them had severe renal failure while the rest had mild to moderate renal failure. All of them showed almost uniform renal biopsy findings of extensive lymphoplasmacytic infiltrations involving the interstitium with sparing of the glomeruli. Eosinophils were seen in only two cases. Out of 18 renal biopsies reported by Geevasinga et al., classic picture of AIN with eosinophils emerged in 82%.[2]

We stopped the PPI in all cases and based on the severity of interstitial infiltrations either pulse methyl prednisolone or oral prednisolone was started. Hemodialysis was required in two cases of severe acute renal failure. Four patients in the Torpey's case series presented to emergency room with acute renal failure.[3] We continued prednisolone for a period of 8-12 weeks. In a series from New Zealand, 12 out of 14 cases of PPI induced AIN were left with permanent renal impairment.[6] In published case series, steroid therapy was required in many cases with good recovery of renal function.[78] At variance is a report from pharmacovigilance laboratory of Netherlands, wherein six out of seven cases recovered renal function once PPI was stopped.[9] Even with early management, two of our patients were left with significant renal impairment. Permanent dialysis dependency may be encountered especially in diabetics. Indian population may have racial predisposition to AIN as shown in a study.[10] Polymorphisms in hepatic and renal CYP450 microsomal enzyme system may underlie susceptibility to drug toxicity by increasing intra renal levels of the drug or its metabolites.[1112]

The implications of our findings are important both for the physicians and general public at large in India where over the counter prescriptions of drugs for upper gastrointestinal symptoms constitute second largest drug market share equivalent to 231 million US dollars.[13] Thus, even uncommon side-effects such as PPI induced AIN will be encountered regularly by the physicians given the sheer size of drug usage. Out-patients should be educated by the physicians to return if they develop loin pain and oliguria. On the other hand, PPI induced AIN should be considered in any in-patient who develops hospital acquired acute kidney injury.

Conclusion

PPI induced AIN is likely to be under recognized and undertreated in India. Its symptoms are non-specific. A high index of suspicion about this condition should prompt the physician to stop the drug, perform a renal biopsy if needed and start steroid therapy for halting a progressive renal disease.