| Abstract|| |
Proton-pump inhibitors (PPIs) are the most effective therapy for gastric acid- related diseases. They are generally well tolerated with rare, often self-limiting adverse reactions. On the other hand, there is growing concern regarding the increased public access and inappropriate PPI use. This review aims to give a critical appraisal of current literature and to analyze a possible relationship between renal disorders and PPI use. A plethora of observational pharmacoepidemiological studies link PPI therapy to the development of acute interstitial nephritis (AIN). Most of these studies show a higher risk for acute kidney injury, de novo chronic kidney disease, and end-stage renal disease. However, current evidence is inadequate to establish a causal relationship between PPI use and many of the proposed renal syndromes. Residual confounding and bias related to study design and the over extrapolation of quantitatively small treatment effects contributed to the unnecessary controversy about PPI safety. Undoubtedly, PPI use may rarely induce AIN. Given the worldwide use of PPIs, the number of patients with biopsy- proven AIN is extremely small. However, more research is required to explore the underlying pathophysiological mechanisms and possible differences between commercially available PPIs regarding adverse renal effects. Till then, the PPIs should be used in the lowest effective dose, and inappropriate use should be avoided.
|How to cite this article:|
Schiffl H, Al-Nemnem E, Lang SM. Proton-pump inhibitors and chronic kidney disease: Hidden consequences of an inappropriate drug use?. Saudi J Kidney Dis Transpl 2020;31:312-9
|How to cite this URL:|
Schiffl H, Al-Nemnem E, Lang SM. Proton-pump inhibitors and chronic kidney disease: Hidden consequences of an inappropriate drug use?. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 5];31:312-9. Available from: https://www.sjkdt.org/text.asp?2020/31/2/312/284005
| Introduction|| |
Proton-pump inhibitors (PPIs) are one of the most widely used medications worldwide, both in the ambulatory and the inpatient clinical setting.,,, Approved indications for PPI therapy include the treatment of gastroesophageal reflux disease, eradication of Helicobacter pylori infection in combination with antibiotics, therapy of peptic ulcers and dyspepsia, prevention and treatment of nonsteroidal anti- inflammatory drug-induced ulcers, and the management of pathologic hypersecretory conditions (including the Zollinger-Ellison syndrome).,,
The effectiveness and favorable safety profile led to the overuse and misuse of PPIs., Estimates of the extent of inappropriate use vary grossly in the international literature (11%-84%).
In the ambulatory care setting, PPIs are often prescribed for inappropriate diagnoses and maintained rather than tapered or discontinued according to guidelines. High levels of self- medication with over-the-counter drugs for heartburn or abdominal symptoms, which are not necessarily related to gastric acid, sustain the overuse of PPIs in the outpatient setting. PPI overuse in hospitalized patients is often a result of inappropriate stress ulcer prophylaxis and the failure to discontinue these drugs before hospital discharge.,
The overuse of PPIs exposes patients to potentially serious, sometimes irreversible adverse drug effects. PPI use has been linked to acute and chronic diseases through numerous pharmacoepidemiologic studies.,, This review aims to evaluate the current evidence to help physicians and health-care providers to critically appraise the plethora of publications and guide them to interpret a potential causal relationship between PPI intake and kidney disease.
| Proton-Pump Inhibitors and the Risk of Adverse Kidney Outcomes|| |
The recent analysis of postmarketing safety data (over ten million FDA Adverse Event Reporting System records) for PPIs pointed to an increased risk for acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD) associated with PPI monotherapy compared to the therapy with histamine (H2) receptor antagonists (H2RAs). The main results of this analysis were in general agreement with previous population-based studies that have suggested an increased risk of AKI, incident CKD, progression of preexisting CKD, and ESRD., However, for the first time, there were sufficient FDA records for analyses of the effects of individual PPIs. The authors observed a significantly increased risk for AKI, CKD, or ESRD in patients on mono- therapy with lansoprazole, esomeprazole, and omeprazole. Patients who received panto- prazole had an increased risk for AKI but no significantly increased frequencies of CKD or ESRD.
The essence of postmarking surveillance of the safety of drugs is the ability to make observations about adverse effects in a real-life environment where the drugs are being used. The major advantage of voluntary reporting is that it represents the largest possible source for observations which maximizes the likelihood of an observation being made particularly for delayed or rare events. However, unlike controlled trials, voluntary reporting is subject to various types of biases. Underreporting is a known serious deficiency, and other limitations stem from missing data on comorbi- dities or concurrent medications. It should be kept in mind that in voluntary reporting, there is also a severity-related threshold. On the other hand, population-based registers have major limitations too. Necessary information may be unavailable, data collection is not done by the researcher, and confounder information may be lacking. It is difficult to differentiate between prevalent and incident cases, and the risk of data dredging cannot be avoided.
Recent systematic reviews and meta-analyses assessed the association between PPI use and the risk of adverse kidney outcomes. Nochaiwong et al included nine studies (4 cohort and 5 case-control studies) with 2.6 million patients enrolled. Of these, 534,003 (20%) were PPI users. PPI users had a significantly higher risk of AKI [relative risk (RR): 1.44, P = 0.013] and CKD (RR: 1.36, P = 0.012) compared with non-PPI users. Moreover, PPI use increased the risk of acute interstitial nephritis (AIN) (RR: 3.61, P = 0.001) and ESRD (RR: 1.42, P = 0.001). The authors concluded that PPI usage was associated with adverse kidney outcomes. However, these findings were based on observational studies and low-quality evidence. The meta- analysis of Sun et al included five studies (662,624 individuals). They concluded that chronic use of PPI (duration of PPI exposure:
31 to 720 days) but not H2RAs was associated with CKD. This points to the duration of PPI exposure being a potential factor in progress- sion to ESRD.
| Proton-Pump Inhibitors and Acute Interstitial Nephritis|| |
Renal biopsies are an essential tool to determine the diagnosis, prognosis, and treatment options of glomerular or tubulointerstitial renal diseases. The most well-documented adverse renal outcome of PPI use is AIN. Analyses of renal biopsy registers and large case series of AIN suggest that only a small proportion of patients (2%-3%) develop AIN from PPIs. However, the incidence of biopsy- proven PPI-induced AIN has been rising over the past decades. Overall, PPIs, antibiotics, and nonsteroidal anti-inflammatory drugs are the three top drugs causing drug-induced AIN.,, The onset of PPI-induced AIN is often subtle. Patients complain most commonly of nonspecific symptoms. The classical triad of systemic allergic reactions (fever, rash, and eosinophilia) is present in <10% of the patients with PPI-induced AIN. There is a wide spectrum of renal manifestations ranging from subclinical kidney disease, unexpected isolated AKI of various severity, to delayed occurrence of incident CKD leading to progressive kidney failure or ESRD [Figure 1]. Given the lack of diagnostic utility of symptoms, signs, or laboratory tests in making the diagnosis of unexpected kidney injury or kidney disease, kidney biopsy with examination of the histology is generally required to diagnose AIN.
Currently, the precise immunologic mechanisms by which PPI may cause AIN are unknown. As with other drug-induced AINs, PPI may deposit within the tubulointerstitial tissue of the kidney and act either as a hapten or directly stimulate T-cells. Treatment strategies for PPI-induced AIN are limited to data from case reports. Early diagnosis of AIN and discontinuation of the offending PPI usually leads to recovery of renal function. Poor recovery of kidney function is correlated to a longer duration of drug exposure and a longer delay in starting corticosteroid therapy. Interstitial fibrosis in the kidney biopsy was associated with poor response to cortico- steroids, and neutrophilic predominance in kidney biopsy specimens may be associated with favorable response to steroids. Neither the initial serum creatinine concentration nor the initial requirement of renal replacement therapy was helpful in predicting the response to steroids and final recovery of renal function. Thus, conclusive evidence supporting the therapeutic efficacy of corticosteroids is lacking.,,
Patients at risk to develop PPI-induced AIN have been identified. Biopsy-proven AIN is much more common in hospitalized patients. Previous epidemiologic data suggested that AIN may account for up to 10% of patients undergoing renal biopsy for unexplained AKI and up to 25% of patients undergoing biopsy for drug-induced renal failure., Not only unwell patients but also elderly patients with a burden of comorbid diseases are at high risk for drug-induced renal failure. Finally, patients using high doses of PPI for prolonged duration may have a higher risk for this drug-induced AIN.
| Proton-Pump Inhibitors and the Risk of Acute Kidney Injury|| |
The Ontario population-based study examined nearly 600,000 residents aged 66 years and older. Their data indicate that those who started PPI therapy had an increased risk (Hazard Ratio: 2.52) for hospital admission with AKI during the study period (follow-up: 120 days) relative to patients who were not prescribed these drugs. However, serious limitations of the Ontario cohort analysis merit emphasis. The authors used administrative data and had no access to laboratory indices of renal function, renal biopsy results (performed in 8 patients only), treatment indications or medication adherence, and no record of nonprescription medications that may have influenced the risk of AKI onset, including over-the-counter NSAIDs. The definition of AKI by the authors was broad and undoubtedly included episodes of AKI unrelated to PPI use. Without kidney biopsies, it is very likely that the authors included patients with nonimmunologically mediated causes of AKI in their analyses. Importantly, more than half (59%) of the patients discharged from the hospital received a further prescription for a PPI, but only 7.5% of these rechallenged patients were readmitted to hospital with AKI in the ensuing 120 days. In addition, the sensitivity of the hospital diagnostic codes is limited, particularly for less severe clinical manifestations of the rena l syndrome. The incidence of the disease may be underestimated up to fivefold compared with definitions of AKI using serum creatinine measurements. Moreover, the authors could not identify less severe (milder) episodes of AKI not culminating in hospital admissions. Finally, as with all observational studies, it is possible that the findings of the Ontario cohort study partially reflect unmeasured confounders or intergroup differences in the baseline risk of AKI.
Lee et al examined the risk of AKI in a large, well-phenotyped inception cohort of 15,063 critically ill patients. AKI was defined by the KDIGO criteria guidelines. The risk was stratified according to prior use of PPI, H2RA, or neither. PPI users had a 28% and H2RA users had a 10% higher risk of AKI compared to those taking neither class of medication. However, in sequential models that included adjustments for demographics, cardiovascular comorbidities, indications for PPI use, and severity of illness, the effect of PPI on the risk of AKI was attenuated. In the adjusted analysis, PPI use was not associated with AKI. The presence of sterile pyuria and hypo- magnesemia did not modify the lack of an association between PPI use and AKI.
Yang et al performed a meta-analysis to investigate the association between PPI therapy and risk of AKI. The authors included seven observational studies with a total of 513,696 cases of PPI use among 2,404,35 participants. The pooled adjusted RR of AKI in patients taking PPIs was 1.61. The authors concluded that PPI use could be a risk factor for AKI. However, confounders may impact on outcomes.
Ikemura et al retrospectively investigated the effect of co-administration of PPI on the development of nephrotoxicity in 133 cancer patients who received cisplatin and fluorou- racil. The rate of nephrotoxicity in patients with PPI use was significantly lower than in patients without PPI use. Nephrotoxicity greater than Grade 2 (defined as serum creatinine 2-3 times above baseline) was not observed in patients with PPI use, whereas the rate of hematological toxicity was comparable between patients with and without PPI use. This indicates a protective effect of PPI use in this setting. Multivariate analysis revealed that co-administration of PPI with cisplatin and fluorouracil was an independent factor significantly contributing to the amelioration of nephrotoxicity by inhibition of the organic cation transporter 2.
| Proton-Pump Inhibitors and Risk of De novo Kidney Disease and Risk of End-Stage Renal Disease|| |
Recently, large independent epidemiological studies (database analyses) found that the risk of developing de novo CKD was greater (odds ratio: 1.2-1.4) among individuals on PPIs.,,,,[31
The retrospective analysis of the Stockholm CREAtinine Measurement database found that new users of PPIs, compared with users of H2RAs, had an increased risk for doubled levels of creatinine (HR: 1.26) and for a decrease in estimated glomerular filtration rate of 30% or more (HR: 1.26). PPI use was also associated with the development of ESRD (HR: 2.4). There was a graded association between cumulative exposure to PPIs and risk of CKD progression which was not the case for cumulative H2RAs use. The authors concluded that the association of PPI use and risk of CKD progression was modest in magnitude and cannot exclude residual confounding.
A case-control study, conducted in a nationwide data setting from Taiwan, suggested that the use of PPIs was associated with a significantly higher risk of ESRD (adjusted OR: 1.88) in patients with renal disease. De novo CKD thought to be associated with PPI use may be a sequela of partial recovery of AKI, but it may also be mediated by subclinical interstitial fibrosis and tubular atrophy (AIN). Xie et al used the Veterans Affairs national database to analyze whether PPI use is associated with an increased risk of CKD mediated by AKI. The proportion of the PPI effect mediated by AKI was 45.5% for incident CKD. Hence, reliance on antecedent AKI as a warning sign to guard against the risk of CKD among PPI users is notcontrol studies) with 2.6 sufficient.
| Critical Appraisal of the Current Evidence|| |
- Data from randomized controlled trials (RCTs) are currently lacking, and no RCT is being planned or is likely to be completed to provide undisputable evidence for an increased risk of kidney disease due to PPI use. Essentially, all epidemiologic studies (database analyses, cohort studies, case-control studies, case series, or case reports) are observational in nature and, therefore, unable to adjust for all confounding variables and to avoid bias. Observational studies are a tool for generating hypotheses to be tested in prospective randomized trials, and their results should be cautiously interpreted as an association, not necessarily implying causality.
- None of the administrative health-care databases or kidney biopsy registries used was specifically designed to analyze the relationship between PPI use and the development of AIN. Thus, researchers are limited to analyze the available date and covariates. There are several know biases such as misclassification bias, referral bias, selection bias, and surveillance bias.
Misclassification bias can occur if patients are inaccurately classified regarding the outcome of interest (i.e., renal disease). AIN, AKI, and CKD are heterogeneous renal syndromes. PPI use, as well as use of antimicrobials and nonsteroidal anti-inflammatory drugs are currently the most common causes of drug-induced AIN. However, AIN may be caused not only by medications but also by infections or neoplastic disorders.
Referral bias presents another challenge in pharmacoepidemiology. Patients who are more ill engage more often with the health service, leading to earlier diagnosis and admission to the hospital. They are, therefore, overrepre- sented.
Selection bias may be due to the inclusion of prevalent PPI users to define comparison groups. This may create bias since prevalent users who chose to remain on treatment have no substantial side effects. Imbalances between groups (PPI use vs. PPI nonuse, PPI use vs. H2 RA use) in baseline variables can bias statistical tests. Observed differences in outcome (AIN) between groups could be due to chance characteristics of the patients and not due to the treatment (chance bias). The individual risk for developing kidney disease is another confounder. Cases and controls participating in population-based cohort studies differed in body mass index, prevalence of hypertension, additional use of nephrotoxic antibiotics, or NSAID. Patients using PPI may differ from patients taking H2RA in “health status,” i.e., indication for the use of PPI and severity of gastric acid-induced disorder (severe upper GI comorbid disorders such as ulcers or bleeding).
Surveillance bias can also overestimate the impact of the PPI exposure. Surveillance bias can occur if a population is monitored over a period of several years. Disease ascertainment (ICD coding of AKI and CKD and awareness of potential renal side effects) may be better monitored in populations taking PPI than in the general population.
- One major limitation inherent to all observational studies is residual confounding. Even after controlling for known confoun- ders, additional unknown confounding variables exist, such as the secret use of nephrotoxic drugs (i.e., over-the-counter NSAID use).
- Few meta-analyses exploring the association between PPI use and induction of AIN incorporated retrospective studies of a relatively small sample with low scientific quality. Fundamental errors in the primary studies were carried over to the meta-analyses, where the errors may be harder to identify.
All these points demonstrate that current evidence is inadequate to establish a causal relationship between PPI use and renal disorders. Residual confounding related to study design and overextrapolation of quantitatively small estimates of effect size has probably led to much of the controversy about PPI safety.
| Conclusions|| |
The numerous pharmacoepidemiologic observational studies do not establish a causal relationship between PPI use and the renal syndromes of AKI and CKD. There is a need for randomized clinical trials to consolidate the possible effects of this drug class on renal structure and function.
Current findings do not indicate a hidden epidemic of PPI-induced renal syndromes and should not deter physicians from prescribing PPIs where medically indicated. However, it is important for health professionals to be aware of potential adverse renal reactions of PPIs, even though the evidence is weak.
Conflict of interest: None declared.
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Department of Internal Medicine IV, University Hospital Munich, Munich