Proton Pump inhibitors Adverse effects – Kidney disease, dialysis, pneumonia, heart disease, increased fracture risk, etc…

It has been known for many years that Proton Pump Inhibitors are associated with adverse events, especially kidney problems. This was brought to light ‘suddenly’ in the following abstract released in April 2016:

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. b

The abstract reads:

The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31–90, 91–180, 181–360, and 361–720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

Using the VA database, the study evaluated exposure to PPI’s and CKD (Chronic kidney disease) outcomes over 5 years showing an increased risk of lowering GFR (renal insufficiency) and chronic kidney disease and eventually, end stage renal disease (dialysis). This  type of information has been out there for a long time but now people are taking notice.

Adverse Effects Associated With Proton Pump Inhibitors

All medications are poisons. The goal is to poison the person enough so as to make them feel better I guess.

The evidence for PPI’s adverse effects is all observational in nature and it is possible that patients that use PPI’s are generally more ill than the overall population, hence the findings of many of these studies that PPI’s carry adverse health effects or that it is the other medications that they take are producing the bad side effects. However, evidence has been building to show that the adverse effects are likely causal, meaning that the PPI is causing the adverse effect.

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. b

Chronic Kidney Disease – In the Atherosclerosis Risk in Communities study (ARIC), 10439 patients followed for 13.9 years demonstrated CKD was 50% higher in PPI users relative to non users. The risk was higher in those using higher doses of the PPI and also CKD was higher in those on PPI’s versus  H2 blockers. This was also seen in a study of patients in the Geisinger Health system as well.  The mechanism f this injury to the kidneys is in part due to hypomagnesemia (low magnesium).

Acute Kidney InjuryProton pump inhibitors and the risk of acute kidney injury in older patients a population-based cohort study  290,592 study patients age 66 and above demonstrated AKI (acute kidney injury) in rates of 2.5 to 3 fold higher in PPI users compared with non-users.A 2 – fold increased risk of AKI was also seen in studies that controlled for confounding problems: Proton pump inhibitors and acute kidney injury a nested case-control study.

The FDA has issued warning regarding bad effects from PPI’s. The link is here:

Hypomagnesemia: Low magnesium is damaging to the kidney and PPI’s, when taken for periods of time, are associated with hypomagnesemia. Proton pump inhibitors linked to hypomagnesemia a systematic review and meta-analysis of observational studies . IN this metanalysis, PPI’s resulted in a 40% increase in hypomagnesemia. Also reviewed here: Hypomagnesemia and proton-pump inhibitors, along with a general overview of PPI issues here: Perils and pitfalls of long-term effects of proton pump inhibitors.  And here: The Association between the Use of Proton Pump Inhibitors and the Risk of Hypomagnesemia A Systematic Review and Meta-Analysis

Clostridium difficile Infection: Likewise, PPI increase the risk of  C. dificile infection due to lower stomach acid levels – this is a 74% increase in risk and a 2-fold increase risk based on  a metaanalysis study as follows: Risk of Clostridium difficile Infection With Acid Suppressing Drugs and Antibiotics Meta-Analysis A more generic overview can be found here: Proton pump inhibitors potential adverse effects

Pneumonia:  Pneumonia is also increased in PPI users, some 34% per one meta analysis: Use of acid-suppressive drugs and risk of pneumonia a systematic review and meta-analysis. ALso this is considered in this article as well: Are proton pump inhibitors associated with the development of community-acquired pneumonia A meta-analysis The risk applied to community pneumonia, but not hospital-acquired pneumonia. There was no increase in hospitalization for these pneumonia: Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia replicated cohort studies with meta-analysis

Cardiovascular events: Research had suggested that antiplatlet agents, in particular, clopidogrel, may interact with PPI’s such that CLopidogrel as not activated in a normal fashion due to antagonism by Protonix ( a PPI) The FDA has warned against the use of Protonix and clopidogrel due to decreased efficacy. Concomitant use of clopidogrel and proton pump inhibitors impact on platelet function and clinical outcome- a systematic review. Again the FDA site mars this interaction with a warning as well:  Yet a randomized clinical trial did not demonstrate any increased risk: Concomitant use of clopidogrel and proton pump inhibitors impact on platelet function and clinical outcome- a systematic review. In short, the evidence is not solid in regards to the safety of PPI’s in Cardiovascular disease. Another recent study in PLOS one indicates an increased risk: Proton Pump Inhibitor Usage and the Risk of MI in the general population with results in the abstract as follows: In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.

Fractures: PPI’s are associated with increased fracture risk as well. One metanalysis showed a 26% increease risk of hip and 58% increase of spine fractures even with short term use of PPI :Proton-pump inhibitors and risk of fractures an update meta-analysis . Also noted in the following study: Proton pump inhibitors and risk of fractures a meta-analysis of 11 international studies.

Gut Microbiome: Proton pump inhibitors affect the gut microbiome Those who use PPI’s tend to be heavier and have a less diverse gut microbiome. This may be why they are at risk for enteric infections and URI’s. There are changes towards a less healthy gut microbime. The odds of infection is 1.5 times as much.This was demonstrated in a study of 1815 people in the Netherlands.

B-12 deficiency: Also at risk with use of PPI’s is vitamin B12 deficiency: Proton Pump Inhibitor and Histamine 2 Receptor Antagonist use and vitamin B12 deciciency A discussion od B12 deficiency as follows: Biomarkers of vitamin B-12 status in NHANES a roundtable summary B12 deficiency is 65% more deficient in patients using PPI’s, especially when taking 1.5 pills a day or under age 30.


Long-term proton pump inhibitor therapy and risk of hip fracture.

Systematic review proton pump inhibitor-associated acute interstitial nephritis

Proton pump inhibitors and the risk of acute kidney injury in older patients a population-based cohort study.

Chronic kidney disease after acute kidney injury a systematic review and meta-analysis

Proton pump inhibitor-induced acute interstitial nephritis.

Overview of the Epidemiology Methods and Applications Strengths and Limitations of Observational Study Designs

Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials.

Active-comparator design and new-user design in observational studies

Economic evaluations of gastroesophageal reflux disease medical management.

Proton Pump Inhibitor Prescriptions and Subsequent Use in US Veterans Diagnosed with Gastroesophageal Reflux Disease

Inappropriate prescribing of proton pump inhibitors in primary care.

Bias in observational studies of prevalent users lessons for comparative effectiveness research from a meta-analysis of statins.

Multimorbidities and Overprescription of Proton Pump Inhibitors in Older Patients  << This study demonstrates that there is over prescription in 73.9% of older patients of PPI’s, with which is associated cardiac diseases (Odds ratio 4.17), metabolic diseases (OR=2.14), and corticosteroids (OR=5.39)  Magnitude and Economic Impact of Inappropriate Use of Stress Ulcer Prophylaxis in Non-ICU Hospitalized Patients < Over-utilization of PPI outside the ICU setting. The over-utilization of PPI’s in association with metabolic disease may be related to events such as Diabetes in which the medications such as Metformin use lead to GI side-effects leading to PPI prescriptions. Likewise, many physicians initiate patients on PPI’s on when corticosteroids are being used, despite no scientific evidence supporting this in the absence of other risk factors.Factors associated with inappropriate inpatient prescribing of acid-suppressive therapy


Bottom- line: The use of PPI’s is associated with a 20-50% increased risk of CKD (adjusting for clinical measurements, socioeconomic status, and concomitant medications), whereas H2 blockers are NOT. PPI’s are also associated with acute interstitial nephritis as well.  Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease 15 mllion Americans use these PPI’s at a cost of $10 billion/year, of which 70% of the prescriptions are without indication Overprescribing proton pump inhibitors ans 25% could dicontinue the medication without symptoms! Proton pump inhibitor-induced acute interstitial nephritis.


Ask your doctor about your PPI!





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