Introduction

Acute kidney injury (AKI) results from renal hemodynamic alterations, leading to reduced renal perfusion, direct toxicity to the renal tubule cells (acute tubular necrosis), tubulointerstitial inflammation secondary to an allergic reaction (acute interstitial nephritis), nephrolithiasis, or glomerulonephritis.¹ AKI is specifically defined as:^2-4 at least a 0.3 mg/dL increase in serum creatinine within 48 hours, 1.5 times increase in serum creatinine from baseline, or urine volume less than 0.5 mL/kg/hr for 6 continuous hours.

Approximately 20% of AKI cases are drug-induced.¹ Proton pump inhibitors (PPIs) are known to cause AKI via acute interstitial nephritis (AIN), an idiopathic adverse drug reaction unrelated to dose. The mechanism of drug-induced AIN includes direct precipitation of the PPIs in the interstitial space and indirect precipitation where PPIs promote the release and precipitation of tissue-degradation products or cellular casts.^1,6,7 The majority of this pathogenesis is an Type 1 hypersensitivity reaction  supported by diffuse or focal infiltration of lymphocytes, eosinophils, and neutrophils into the interstitial space.  Proton pump inhibitors may bind to the basement membrane and act as a hapten, may mimic an antigen that is normally present in the basement membrane, may bind to the basement membrane inducing an antibody response, or may itself illicit and antibody response causing circulating immune complexes to deposit in the interstitial space.  All PPIs have been reported to cause AIN in tertiary databases and package inserts; these resources cite a world-wide review of PPIs performed in 2007 involving 60 reported cases as well as individually published reports.^9-12,19,20

Primary Literature

Due to the limited information in tertiary data bases, we conducted a PubMed search to include the terms: “acute kidney injury” and “acute interstitial nephritis” and “tubulonephritis” and “PPIs” and “Proton pump inhibitors,” and with each individual PPI. The search was conducted with and without medical subject headings (MeSH terms) and did not employ filters. The search identified three relevant observational studies and one meta-analysis.

A population-based cohort study of 290,592 patients who received treatment with a PPI (i.e., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; median exposure of 120 days) and an equal number of matched controls reported the incidence of AKI as 0.4% (13.49 per 1000 patient-years) versus 0.2% (5.46 per 1000 patient-years) with a hazard ratio 2.52 (95% CI, 2.27 to 2.79) for individuals on PPIs and matched controls, respectively.²³  Incidence of AIN was extremely rare (30 cases versus 10 cases, approximately 0.0% for each group): 0.32 versus 0.11 per 1000 patient-years with a hazard ratio 3.00 (95% CI, 1.47 to 6.14) in individuals on PPIs and matched controls respectively.  Data used in this study was abstracted from prescription drug databases, where Canadians older than 65 years have universal prescription drug coverage.  The study defined AKI as a median absolute increase in serum creatinine of 98 (interquartile range 43 to 200) mcmol/L above a recent serum creatinine performed within a median of 39 days of the preceding hospital admission.  Of 937 patients hospitalized with AKI related to PPI use, 59% were discharged with a new PPI prescription, potentially due to lack of recognition of this adverse effect. Forty-two (7.5%) of these patients who resumed PPI treatment upon discharge, were readmitted with AKI.

A nested case-control study assessed risk factors for 854 cases of new-onset acute or chronic kidney disease matched to 3,289 controls who did not experience new-onset kidney disease.²⁴The patient population was abstracted from an insurance database and included patients over the age of 18.  Exposure to OTC PPIs was not quantified.   Renal disease, as defined above was associated with PPI use with an odds ratio 2.04 (95% CI, 1.53 to 2.71, P < 0.001), after controlling for confounding variables, such as NSAID use, antibiotic use, diuretic use,  and certain disease states including: diabetes, hypertension, high cholesterol, myocardial infarction, congestive heart disease, peripheral vascular disease, and cerebrovascular disease.    

A retrospective case-control study involving new and prevalent users of PPI’s from the United Kingdom’s medical database, where 98% of the population is registered measured the outcomes of AIN and AKI associated with PPI use.²⁵ Patients were chosen based upon diagnostic code obtained from this database.  Patients excluded were: prior history of kidney transplant and individuals with the outcome of interest at baseline.  The primary outcome included 68 cases and 3347 controls of AIN in patients exposed to PPI’s and resulted in an adjusted odds ratio of 3.20 (95% CI, 0.8 to 12.79).  The secondary outcome measured 27,982 cases and 1,323,850 controls for AKI in patients exposed to PPIs and resulted in an odds ratio of 1.05 (95% CI, 0.97 to 1.14). 

A systematic review of articles published from 1970 to 2006, reported 64 cases of PPI-induced AIN, where AIN was diagnosed by renal biopsy in 59 of those cases.²⁶   The criteria for inclusion in the review was confirmed previous exposure to PPIs without initial AKI at baseline accompanied by the development of AKI or AIN as determined by biopsy, serum creatinine, or glomerular filtration rate.  They reported 47 cases of omeprazole-induced, six pantoprazole-induced, three esomeprazole-induced, two lansoprazole-induced, and two rabeprazole-induced AIN.  The mean age of patients was 78 years old (40% men, 60% women).  Mean exposure to PPI use before nephritis was 13 weeks within a range of 2 to 52 weeks.  The study’s assessment of the relationship between PPI use and AIN were classified as follows: 12 certain cases, 9 probable cases, 37 possible cases, 1 conditional case, and 1 with insufficient data when applying confounding variables.

Summary

• PPIs have been reported to cause AKI through AIN; this is largely based on a systematic review of the literature in 2007 presenting 60 cases of PPI-induced AIN, where medications were listed as the probable cause 60% of the time, greater than half of the cases (8 out of 14) were attributed to PPI use.^9,10
• A cohort study identified risk for AIN (hazard ratio 3.00 [95% CI, 1.47 to 6.14]) and AKI (hazard ratio 2.52 [95% CI, 2.27 to 2.79]) associated with PPIs.²³
• A nested case-control study of 854 patients associated renal disease with PPI use with an odds ratio of 2.04 (95% CI, 1.53 to 2.71, P < 0.001), after controlling for confounding variables.²⁴
• A systematic review of articles spanning 37 years reported 64 cases of PPI-induced AIN, where over 92% of cases demonstrated AIN on renal bioppsy.²⁶
• In a retrospective case-control study the measurements of the primary outcome AIN (n=68) and secondary outcome AKI (n=27,982) were reported in patients exposed to PPI use resulting in an odds ratio of 3.20 (95% CI, 0.8 to 12.79) and 1.05 (95% CI, 0.97 to 1.14) for AIN and AKI, respectively.²⁵
• None of the identified studies established risk factors associated with PPI-induced AIN or AKI. Studies did not account for nonprescription PPI use, and incidence rates were generally small.^23-26

References

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