Background: Proton pump inhibitors (PPIs) are commonly prescribed medications for dyspepsia and gastroesophageal reflux. There are concerns about their use in the development of chronic kidney disease (CKD). Summary: The available published literature fails to support an association with PPI and the development of CKD. Placebo-controlled trials demonstrate no difference in the incidence of CKD between placebo and PPI. If one examines the data according to the Bradford Hill perspective incorporating temporal relationship, the strength of association, dose-response relationship, replacement of findings, cessation of exposure, specificity of the association, and consistency with other knowledge, one can only conclude that there is no consistent relationship between PPI use and the development of CKD, or its progression. Key Messages: There is insufficient evidence to link PPI exposure with the development or progression of CKD.

Prescription and over-the-counter (OTC) use of proton pump inhibitors (PPIs) have risen dramatically in the past decade. They are among the most commonly prescribed medications for dyspepsia and gastroesophageal reflux symptoms. While the PPIs are considered generally safe, there have been reports of adverse outcomes associated with PPI use, especially as it pertains to the development of acute kidney injury (AKI) and acute interstitial nephritis. There are also reports that PPI may be associated with an increase in the incidence of chronic kidney disease (CKD) and even lead to end-stage kidney disease (ESKD). Thus, a careful review of the literature is important to examine the quality of the epidemiological data.

The kidneys represent a unique anatomy with a network of blood vessels and renal tubular epithelial cells to cleanse the blood, eliminate volume excess, and metabolize hormones that are involved in the regulatory processes of many endocrine pathways in the body. At birth, people have anywhere from 600,000 to 1.2 million glomeruli. The glomeruli are responsible for serving as a barrier to maintain the constituents of the blood including proteins, red cells, white cells on one side of the glomerular membrane, and the filtrate on the other. The subsequent filtrate is directed into the renal tubules which then provide a complex exchange system to maintain an appropriate level of sodium, potassium, chloride, bicarbonate, and other electrolytes within the blood, cleanse the blood, and at the same time delicately adjust the amount of sodium and water in the body in order to maintain appropriate volume levels and blood pressure. Injury to the filters and or tubules may be simultaneous or occur separately. Often, an inflammatory condition that damages the glomerular filters ultimately leads to damage and death of the tubules, whereas damage that occurs to the tubules may ultimately lead to a tubular glomeruli and subsequent glomerular obsolescence. The net result is that insults to either the filters or the tubules if sustained, and continuous, may lead to progressive loss of kidney function. The interstitium of the kidney cortex and medulla surround the tubules and glomeruli and appear as a scar after the loss of glomeruli and tubules. Kidney function depends not only on the net ability to filter blood but also the effect of the tubules to cleanse the filtrate.

The monitoring of kidney function with laboratory tests such as serum creatinine and can may not always be sufficiently sensitive to detect kidney injury, especially early on in the kidney-damaging process. Clinical symptomatology associated with kidney disease is not sensitive to changes in kidney function until a substantial proportion of kidney function is lost (more than 80%). It is only then that symptoms such as fatigue, malaise, decreased appetite, and weight loss become clinically apparent.

AKI, often defined as an acute 30% increase in serum creatinine, may occur in response to an inciting event, such as low blood pressure, exposure to a nephrotoxin, or obstruction of the urinary tract [1]. It is often reversible, as the tubules of the kidneys are often able to regenerate. Injury to the glomerular filters is more serious and often may not be reversible. Repeated episodes of AKI lead to scarring of kidney tissue and can lead to loss of kidney function over time.

CKD occurs when there is an ongoing process or processes that lead to kidney injury. The most common causes are diabetes, hypertension, and immunological glomerular kidney disease. With specific treatments like better control of blood pressure and diabetes treatment, treatment of infection, or removal of a nephrotoxin, the rate of progression of kidney disease can be attenuated. Close monitoring of kidney function over time is essential in tracking the progress of the interventions to slow the progression of CKD, and it may be helpful in determining recovery, or not, from AKI.

There are many potential causes of interstitial nephritis in the kidneys. Drug-induced causes are about 70–75%. However, systemic diseases such as sarcoidosis, systemic lupus erythematosus, Sjogren’s syndrome, and others may explain 10–20% of cases, whereas infections may comprise 4–10%, and tubulointerstitial nephritis and uveitis may explain less than 5%. Idiopathic causes may never be identified [2‒5].

Drug-induced interstitial nephritis is an inflammatory condition within the renal tubular interstitial matrix of the kidney [2‒5]. It depends on the exposure to a medication that leads to an immune system response. This condition may be acute, which then immediately resolves. On the other hand, if there is a continuous injury process due to the continued presence of a medication or another autoimmune disease, the pro-inflammatory process may lead to scarring and progressive loss of renal function.

However, it is impossible to connect the two together from a causal standpoint without sequential kidney biopsies to link a cause and effect. The hallmark pathologic observations with acute interstitial nephritis are tubular and interstitial inflammation with a predominance of T-lymphocytes, which are white blood cells which facilitate not only direct cellular damage to the tissues but may also attract other forms of white blood cells and eosinophils which may contribute to the injurious process [5]. B lymphocytes, if activated, may produce antibodies, and attract proteins called complement, leading to damage of renal tubular epithelial and renal interstitial dendritic cells. In addition, the cellular damage may release intracellular constituents which may also serve as a foreign antigen and attract more immunologic cells which may further propagate injury. The inflammatory process progresses with continued antigenic stimulation leading to fibroblast activation and subsequent interstitial fibrosis and tubular atrophy [6].

It is not possible to determine if an acute interstitial injury leads to chronic interstitial injury. Chronic interstitial injury (nephritis) is a nonspecific pathological finding which cannot necessarily be linked to a prior acute injury or exposure. It may be nothing more than the final common pathway of a lifetime of exposures, such as vascular diseases, diabetes, etc., which lead to a reduction in kidney function.

Medical literature describes many different exposures that have been associated with acute and chronic interstitial nephritis. The list of possible medications is long and includes many different classes of medications.

PPIs were developed to effectively block gastric acid secretion by irreversibly binding to, and inhibiting the hydrogen-potassium ATPase pump which resides on the luminal surface of the parietal cells in the gastric mucosa of the stomach [7]. PPIs are the first-line antisecretory therapy in the treatment of peptic ulcer disease, gastroesophageal disease, and may also be utilized in patients who develop gastric ulcers while receiving nonsteroidal anti-inflammatory drugs, and in the eradication of Helicobacter pylori infection [8‒10].

PPIs are powerful in inhibiting the final steps of gastric acid secretion. PPIs are prodrugs that are activated by low pH within the parietal cells of the stomach where they undergo an acid-catalyzed conversion to the reactive species, the thiophilic sulfonamides. These species interfere with the hydrogen-potassium ATPase at the surface of the cell, which limits gastric acid secretion [7]. The result of this is to raise gastric pH and reduce the likelihood of gastric surface injury due to the low pH. Many of the PPI vary with regard to their bioavailability, peak plasma levels, and route of excretion. However, the magnitude of these differences is small, and the clinical relevance has not been established [11]. Overall, they are similar in structure and mechanisms of action. PPIs are most effective when the gastric parietal cells are stimulated to secrete acid after eating; a relationship that has important clinical implications with the timing of administration. Once daily PPI dosing for 5 days inhibits maximum gastric output by approximately two-thirds [11, 12]. Restoration of acid secretion after discontinuing a PPI depends upon enzyme turnover and the biological reversibility of its binding processes. Secretory activity may be restored in 1–2 days if the PPI is not taken on a daily basis, as more inactive enzymes may be recruited into the parietal cell, and acid secretion will ensue. This is why taking PPI prn does not completely suppress acid secretion [7, 11].

Clinically important drug interactions with PPI are rare, and reports are conflicting. However, some do exist including such medications as clopidogrel, methotrexate, and HIV protease inhibitors [13]. PPIs have also been associated with some degree of magnesium wasting. However, the clinical implications of this have not yet been determined. Major adverse effects related to long-term use of PPI are primarily related to enteric infections, specifically with clostridium difficile [14, 15]. There is also an increased risk for the development of atrophic gastritis and intestinal colonization with multidrug-resistant organisms [16].

As will be discussed later, there are concerns that PPI may cause acute interstitial nephritis with associated AKI [17, 18]. Similar to other causes of drug-induced acute interstitial nephritis, the use of PPI does not appear to be dose-dependent, and recurrence of exacerbation can occur with additional exposure. It has been hypothesized that recurrent exacerbations of interstitial nephritis may lead to CKD progression [6]. PPIs have also been associated with an increased risk for CKD, CKD progression, and ESKD [19‒23]. However, there is insufficient evidence to show or conclude that PPIs cause CKD, CKD progression, or ESKD. No plausible biological process has been demonstrated that would explain the development of CKD following PPI use. There is no evidence of direct renal toxicity with PPI.

Many different efforts have been made from an epidemiological standpoint to examine the relationship between PPI use and the development of CKD. Unfortunately, retrospective observational cohort studies, as well as case-control studies, are afflicted with substantial bias including information bias, exposure bias, selection bias, along with substantial residual confounding [24]. Several approaches have been utilized to reduce bias in observational epidemiology [25]. However, none completely eradicate the problem. Larger studies are not necessarily better. Greater numbers may provide precision but not improve validity [26]. Therefore, very large studies like meta-analyses may give the wrong answers, excellent reproducibility, but poor validity due to problems related to section bias and residual confounding. With a large sample size, trivial differences may yield minuscule p values and high statistical significance along with narrow confidence intervals. These p values reflect precision but not validity.

Because case-control studies are especially vulnerable to bias, these studies require more stringent safeguards against false findings. Odds ratios of three or more may merit consideration for being valid on the adverse side. Unfortunately, odds ratios less than three are unlikely to be valid and more likely to be inaccurate. Likewise, the reciprocal of 3, results of 0.33 or less, would merit consideration for being accurate on the protective side. Because cohort studies are less prone to bias, the recommended relative risk threshold is two on the adverse side and a correspondingly reciprocal of 0.5 or less on the protective side [24, 25]. Thus, even in the absence of full reassurance about correction for bias, it may be prudent policy to assess such associations as not being casual [26‒28]. Strong associations especially if observed in multiple studies are more likely to be real, with true causality especially if the studies used architecturally different methodologies and study groups. But, with most epidemiologic data, this is not the case. Although individual studies with hazard ratios indicating validity may indicate valid associations, they may not necessarily indicate causality. On the other hand, often the problem with nonexperimental studies is that they are crude and imprecise. The small amount of bias that it takes to distort relative risk estimates and their expression can occur over and over again if the studies use similar designs. Even if studies with better odds ratios (e.g., greater than 2.0), despite suggesting validity, still do not necessarily equate with causality. Thus, observational epidemiology studies need to be scrutinized and interpreted accordingly, both in terms of validity and causality [24‒28].

Over time, a number of studies suggested that an increased risk of CKD occurred in people who used PPI [29‒33]. However, many of these studies had substantial statistical and epidemiologic weaknesses, including adjustments for baseline kidney function, concomitant medication use, medical comorbidities, and issues surrounding residual confounding.

Since 2016, there have been several non-randomized observational studies and reviews of administration databases linking the use of PPI with CKD. Two studies [20, 22] had better methodology with acceptable observational methods and statistical controls but had substantial problems with bias. Lazarus et al. [20] completed 2 cohort studies using the Atherosclerosis Risk in Communities (ARIC) database (n = 10,482), and the Geisinger Health System database (n = 248,751) to examine the relationship of PPI with incident CKD. They identified a hazard ratio of 1.5 in the ARIC, and 1.17 in the Geisinger database. Both were statistically significant. Xie et al. [22] examined the relationship between PPI use and subsequent occurrence of CKD or ESRD in a Veterans Affairs (VA) database. They analyzed the outcomes of PPI users (n = 173,321) and H2 receptor antagonist (H2RA) users (n = 20,270) over a period of at least 5 years. They observed statistically significant hazard ratios of 1.28 for CKD and 1.96 for ESRD with PPI users. However, the validity for both of these sets of observations is of concern due to confounding, misclassification [20], selection bias, missing data, outcome misclassification, and selective reporting [22]. Moreover, neither study met the statistical endpoint of 2.0 for a hazard ratio that would be considered adequate for validity.

There have been multiple non-randomized observational studies [17, 19, 21, 29‒34] prospective studies [35, 36], and case-control studies [37‒41] published. All these studies have the same limitations as the Lazarus et al. and Xie et al. studies [20, 22]: residual baseline confounding, and CKD outcome misclassification due to differential laboratory surveillance during follow-up. Other issues with these studies included problems with selection bias, estimation of relative risk with uncertain relationship, use the special patient populations, selective reporting methods, and describing results in an unacceptable manner. Most of the hazard ratios reported were in the 1.2–1.4 range, and the one was 0.99, showing no risk. All these non-randomized studies fall below the HR risk of 2.0 needed to assume some degree of validity.

Evidence of dose, duration, or cessation of therapy has not consistently been observed in clinical studies. Klepser et al. [30] conducted a nested case-control study in a privately insured Midwestern US Population and noted that the OR linking PPI to renal disease was 1.72. Lee et al. [42] examined an inception cohort of 15,063 critically ill patients to evaluate the risk of AKI in PPI users. They noted that PPIs were not associated with AKI (OR: 1.02) after careful adjustment. Note that none of these studies meet the criteria for validity in epidemiologic studies that were discussed previously. Cholin et al. [43] utilized the CKD registry at the Cleveland Clinic to evaluate the relationship between PPI and H2RA use and outcomes among patients with eGFR <60 mL/min. More than 25,000 patients were studied. At 4 years of follow-up, the cumulative incidence of ESRD or death as a competing risk was 2.0% in the PPI group (n = 8,646) (95% CI: 1.7–24), 1.5% in the H2RA group (n = 848) (95% CI: 0.8–2.8), and 1.6% in the no antacid group (n = 15,961)(95% CI: 1.4–1.9). The overall p value was 0.22. The authors concluded that the use of PPI in a CKD population was not associated with progression to ESRD or death compared to H2RA therapy, or no antacid therapy.

A meta-analyses of several studies examining the associations between PPI and the development of AKI found a relative risk of 1.16 (1.07–1.25) but identified a large amount of heterogeneity between studies [44]. In addition, this risk was identified as occurring only in patients less than 60 years of age, and who were not using PPI at baseline. Nochaiwong conducted a systemic review and meta-analysis of more than 2,000 studies involving approximately 2 million patients [45]. They observed a relative risk for CKD use of 1.36 (p = 0.012). However, they noted multiple limitations of the data including observational data validity, lack of key baseline characteristics, lack of documentation of concomitant medications, information bias from the EMR, lack of data on medication adherence, OTC medication use, misclassification bias, a moderate degree of inconsistency of the results, and publication bias. One meta-analyses examined the association between PPI use and CKD in over 500,000 subjects [46]. The relative risk of 1.22 (1.14–1.30) exists only for the association between PPI use and incident CKD and 1.88 (1.71–2.06) for developing ESKD. Interestingly, this same meta-analysis examined the association between H2RA use and CKD, and found no significant association, despite the fact that others have described a relationship between H2RA use and CKD [2‒4]. Also worth noting is that the risk of incident CKD and ESRD positively correlates with the duration of PPI exposure over the first 2 years of use but declines somewhat thereafter. Another meta-analysis described an increased risk of CKD and ESKD with PPI use, but stated the data were based on observational studies and low-quality evidence [47]. Note that none of the relative risk measures approach 2.0, which would merit consideration for validity.

A more recent prospective, multicenter matched-cohort study (n = 340) evaluated the relationship between PPI use, and risk of post-hospitalization AKI [48]. The results indicated that PPI use was not a significant risk factor for post-hospitalization AKI and progression of kidney disease, regardless of the AKI status of the participants at baseline [48].

An important issue to consider when reviewing the data from the observational studies is the associated medical problems that are seen in patients with CKD. Patients with CKD often have more problems with gastrointestinal bleeding, or the use of aspirin and anticoagulants for cardiac comorbidities, which increases the utilization of PPI. In addition, there is great potential for unrecorded medication use in observational epidemiologic studies. Many patients do not report the use of OTC NSAIDs and aspirin. These OTC medications are frequently used together with PPI in patients with CKD, who often have osteoarthritis, ectopic tissue calcification, and increased risk for cardiovascular disease. Given that the majority of these observations and studies do not reach the adverse relative risk of 2.0, although the studies may be precise in their observations, the likelihood that the observations are valid with regard to the association of PPI with CKD is limited. Moreover, PPI discontinuation after prolonged continuous use in people with CKD has not been associated with a significant change in kidney function after 1 year of observation [49].

In addition, several case-control studies have been done to examine the relationship between PPI use and CKD. Large numbers of patients have been included in several different countries around the world. Rarely has the OR exceeded 1.5. As previously discussed, the amount of inherent bias in these studies requires a relative risk ratio of 3 or greater to provide validity of the observations. Nor has a change in kidney function been seen in kidney transplant recipients maintained on a PPI [50]. The lack of consistency of the observations from observational cohort studies and case-control studies indicates no validity of the data.

Ma et al. [49] conducted a cross-sectional analysis of data from the National Medical Care Survey from 2006 to 2015. The primary outcome of interest was a clinical encounter for a diagnosis reportedly associated with PPI use including CKD. After adjusting for age, sex, race, and medical comorbidities through multivariable logistic regression, there was no association between PPI use and a variety of medical comorbidities. However, an association with CKD was noted to be 1.26. However, several significant associations with CKD were also associated in their study, including several commonly used medication classes such as statins, calcium channel blockers, and beta blockers. These authors noted that after adjusting for a variety of different demographic factors and comorbidities, many associations between PPI and previously associated conditions such as CKD become less, or not significant. Although their adjusted results show a significant association between PPI and CKD, this association also exists for many other commonly used medications. They concluded that it was extremely unlikely that all the medications are associated with increased risk for CKD and that these observations are likely related to residual confounding. Moreover, the relative risk ratio of PPI use with CKD was 1.26, which is well below the 2.0 threshold for assuring validity. Other factors that need to be considered with this analysis and others like it are the lack of data on duration, dose and cumulative exposure of PPI, and the implications of intermittent PPI use. Similar concerns were observed in a study by Jena et al. [51]. They conducted a retrospective claims-based cohort study of 6 private health plans who filled at least one prescription for PPI (n = 26,436) versus those who never did (n = 28,054) over 11 years. Those patients using PPI, compared to nonusers, not only had a higher adjusted rate of pneumonia but also had higher rates of other medical conditions implausibly linked to PPI use, such as chest pain and urinary tract infections. Thus, the risk of confounding is substantial, and the lack of data clearly may lead to false assumptions. Moreover, as mentioned previously, despite the epidemiologic studies having odds ratios indicating the validity of associations, they do not necessarily reflect causality.

Only one large prospective clinical trial has been conducted comparing a PPI to a placebo. Moayyedi et al. [52] organized a large multi-year trial of patients receiving the anticoagulant rivaroxaban versus aspirin who were randomized to receive either the PPI, pantoprazole, or placebo. Patients were followed up for a median of 3.01 years with 53,152 patient-years of follow-up. The investigators noted no statistically significant difference between the use of pantoprazole (PPI) and the placebo groups with regard to patient safety events or long-term harm with the exception of enteric infections. There were no associated events of incident CKD. The authors concluded that PPI therapy is safe for up to a median of 3 years.

Two long prospective multicenter open-label parallel group studies were conducted in Europe comparing the efficacy and safety of the PPI (omeprazole or esomeprazole) versus anti-reflux surgery in patients with chronic GERD. In the SOPRAN study (n = 298), patients were followed for 5 years. In the LOTUS Study (n = 514), patients were followed for 12 years. No major safety concerns were identified in either study [53].

In summary, the available published material fails to demonstrate an association between the development of incident CKD and the use of PPI. There is a lack of evidence for a plausible mechanism by which PPI could cause incident CKD or progression of CKD. In terms of the hierarchy of evidence, the only placebo-controlled randomized clinical trial showed no difference in the incidence of CKD between PPI and placebo [51]. The lack of consistency of the observations from not only observational cohort studies and case-control studies indicates no validity to the observations linking PPI use to CKD. The relative risk ratios of these observational studies are uniformly below the criteria for validity. The main concern of these observational and case-controlled studies is related to bias and how best to adjust for it. One can attempt to adjust for the different forms of bias. Patients who develop CKD often have other medical comorbidities including osteoarthritis, different forms of bone disease, and tissue calcification which lead to increased pain. Treatment often requires greater utilization of NSAID drugs and other pain remedies. Often this leads to gastrointestinal intolerance, and initiation of treatment with PPI as a means of alleviating the symptomatology. Patients with CKD also may require anticoagulation. This requirement, plus the need for anti-arthritis medications, could pose a greater risk for gastrointestinal bleeding, which again may require utilization of PPI. Plus, there is abundant observational data that associate NSAID use with interstitial nephritis [54]. Patients with CKD may have more problems with GERD [55], and lifestyle factors which lead to PPI use [56]. Thus, the combination of arthritic conditions and cardiovascular comorbidities being so much more commonplace in people with CKD creates substantial bias due to confounding by indication. Moreover, there are no data suggesting a PPI-related drug: drug interaction is associated with incident CKD or CKD progression.

The wider implications as one reviews all of the available published data on the relationship of PPI and CKD is that we cannot be confident about inferring causality for any low-magnitude association that has been identified through observational data. Unless there is a high magnitude of relative risk that can be identified in a population of patients at baseline risk, we cannot assume the validity of the data. Thus, we have to rely on the data from prospective randomized controlled clinical trials (such as Moayyedi et al. [52]) for providing perspective on the associated risk of PPI and CKD. Moreover, the strength of the association in the epidemiologic studies is at best, weak, and inconsistent, and the risk estimates are often less than 1.8. Additionally, the consistency of observations is lacking such as the study of Lee et al. [42] showing no association, and the large prospective study of Moayyedi et al. [52] also demonstrating no safety concerns for CKD progression after 3 years of treatment with PPI.

With reasonable medical certainty, if one examines the data according to the Bradford Hill perspectives [57], incorporating temporal relationship, strength of the association, dose-response relationship, replication of findings, biological plausibility, consideration of alternative explanations, cessation of exposure, specificity of the association, and consistency with other knowledge, one can only conclude that there is no consistent relationship between PPI use and either the development of CKD, or its progression.

Given the lack of evidence of direct nephrotoxicity or a mechanistic cause of renal injury and the dearth of adequate epidemiologic data linking PPI to incident CKD or CKD progression, there is no need to limit the use of PPI in patients with CKD. There are no data suggesting that the PPI dose needs to be adjusted in patients with reduced kidney function. They should be considered as important, safe, and effective therapeutic considerations in patients with CKD who have gastric acid-associated clinical symptoms and disease. The dose and duration need to be carefully considered on an individual basis considering their known risks and benefits.

Dr. Weir has served as a scientific advisor and has received Honoria from Astra Zeneca Bayer, CSL Vifor, Novo Nordisk, Takeda, Johnson and Johnson, and Mineralys.

This study did not receive any funding.

Dr. Weir wrote and edited the manuscript.

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