Kidney Disease

This page has been provided largely in response to claims made that PPIs cause kidney disease and looks at the evidence.

 The links below are to research findings gleaned from the Research Archive 2012-2022 in chronological order. Key statements from conclusions have been highlighted.

Note: With a few exceptions all are association studies though most are moderated by other evidence or statements:

   A states the association may be overstated and M agrees adverse reports may be exaggerated.

   C, G and K say further research is needed.

   J says the evidence is inconclusive while L and U say evidence is weak.

   P agrees there's no indication that stopping PPIs would reduce kidney disease.

   Q says there are probably confounding issues while V states correlation does not equal causation.

   These are all a case of "Do umbrellas make it rain?"

   E says the associations do not fit their experience, while F says PPI users already have other comorbidities.

   H says if there any risks, they are outweighed by the benefits.

   T says other causes of Kidney Disease are more likely.

   R suggests PPIs may actually protect against kidney disease.

  AA provides the best evidence because of the type of study and the large patient base and length of observations. It is also more recent than other papers shown here.

A better summary will be provided at a later date.

Research papers

A) 16 April 2015 Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study "We found that older patients who started PPI therapy had an increased risk of acute kidney injury and interstitial nephritis. However, the association between PPIs and acute kidney injury may be overstated given the low risk of recurrence following rechallenge" (Canadian Medical Association Journal)

B) 27 October 2015 Acid reflux medications may increase kidney disease risk "those who took PPIs were less likely to have vascular disease, cancer, diabetes, hypertension, and chronic obstructive pulmonary disease, but PPI use was linked with a 10% increased risk of CKD [Chronic Kidney Disease]" (American Society of Nephrology)

C) 11 January 2016 Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease "Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD." (JAMA Internal Medicine)

D) 18 November 2016 Reflux and ulcer medications linked to kidney stones and chronic kidney disease "use of PPIs was associated with a 12% higher risk of developing a kidney stone, and use of H2 blockers with a 13% higher risk"

E) 27 January 2017 Clinical Implications of Emerging Data on the Safety of Proton Pump Inhibitors. "concerns regarding PPIs and cardiovascular events have resurfaced as have issues related to kidney disease and dementia. The methodology of these studies allows us to find an association with these events but does not provide us with sufficient evidence to determine causality. In general, the findings of the available studies do not fit with our clinical experience nor is the magnitude of the association sufficient to result in a major change in our practice." (Current Treatment Options in Gastroenterology)

F) 22 February 2017 Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury "Overall, new users of PPIs and H2 blockers had comparable demographic characteristics, but PPI users were more likely to have diabetes, chronic lung disease, hyperlipidemia, and cardiovascular disease" (Kidney International)

G) 14 October 2017 Chronic use of proton pump inhibitors, adverse events and potential biological mechanisms: A translational analysis. "Even if PPI are usually considered as safe, there is a growing concern for a range of adverse effects of chronic PPI therapy often in the absence of appropriate indications. We propose, after a summary of renal, cardiovascular and neurological complications (dementia, chronic kidney disease, myocardial infarction and stroke), an integrative overview of the potential biological mechanisms involved." (Therapie)

H) February 2018 Proton Pump Inhibitors: Review of Emerging Concerns. (full text) "Use of PPIs has been reported to be associated with increased risk for development of a multitude of adverse effects. The majority of the data are based on results from retrospective observational studies, which have inherent biases, risk for confounding variables, and the inability to demonstrate a definite causal relationship. Most of these studies reported mild to moderate overall associations (with RRs of 1 to 2) between PPI use and the risks of bone fracture, CDI, pneumonia, vitamin and mineral deficiencies, kidney disease, and dementia. Thus, because many of these adverse effects are uncommon, the absolute risk to patients remains quite small.

Based on current recommendations, the American Gastroenterological Association does not recommend routine laboratory monitoring or use of supplemental calcium, vitamin B12, and magnesium in patients taking PPIs daily. ... In summary, the best strategy is to prescribe PPIs at the lowest dose on a short-term basis when appropriately indicated so that the potential benefits outweigh any adverse effects associated with the use of PPIs." (Mayo Clinic Proceedings)

I) 9 February 2018 The association of proton pump inhibitors and chronic kidney disease: cause or confounding? "The constellation of evidence from all available studies suggests that PPI use is associated with increased risk of adverse kidney outcomes. Exercising vigilance in the use of PPI is warranted." (Current Opinion in Nephrology & Hypertension)

J) March 2018 Association of proton pump inhibitor use with renal outcomes in patients with coronary artery disease. (full text) "Our results suggest that PPI use increases the risk of AKI development, and that PPI use is more significantly associated with acute and chronic renal injuries in younger patients." (Kidney Research & Clnical Practice)

"Recent studies suggested that PPI use was a significant risk factor for CKD development [8–10,18]; however, the association between PPI use and CKD development was not conclusive in our study."

K) 12 April 2018 Acid-suppressive drugs and risk of kidney disease: A systematic review and meta-analysis. "PPI therapy significantly increased the risks of AIN, AKI, CKD and ESRD. Similar risks were not identified for H2 RA therapy. More clinical trials are needed to confirm our findings." (Journal of Gastroenterology & Hepatology)

L) 17 April 2018 The Association Between Proton Pump Inhibitor Use With Acute Kidney Injury and Chronic Kidney Disease. "This paper reviews the currently available literature about these associations and considers their possible underlying pathophysiological mechanisms. The level of evidence-linking PPI use with acute kidney injury and chronic kidney disease is weak and does not establish causality." (Journal of Clinical Gastroenterology)

M) 25 May 2018 Prevalence and outcomes of proton pump inhibitor associated hypomagnesemia in chronic kidney disease. (full text) "We explored the prevalence of PPI associated hypomagnesaemia (PPIH) in different Chronic Kidney Disease (CKD) stages, in different PPI agents, and the impact of PPIH on survival in CKD." "There is a potentially exaggerated importance of adverse outcome associated with PPIH specifically in chronic kidney disease (CKD) patients." (PLoS one)

N) 2 August 2018 Proton Pump Inhibitors: Risks and Rewards and Emerging Consequences to the Gut Microbiome. "current data suggest that PPI use is not associated with an increased risk of bone fractures, community-acquired pneumonia, cardiovascular events, hypocalcemia, and gastric malignancies. A mild increased risk of vitamin B12 deficiency and chronic kidney disease, and a moderate increase in the risk of rebound hypersecretion, small intestinal bacterial overgrowth, and enteric infections, including Clostridium difficile, has been noted with PPI therapy" (Nutrition in Clinical Practice)

O) 13 September 2018 Chronic kidney disease (CKD) patients are exposed to more proton pump inhibitor (PPI)s compared to non-CKD patients. "Chronic kidney disease patients are taking proton pump inhibitors for a much longer duration compared to non-chronic kidney disease patients. Physicians should pay careful attention when prescribing proton pump inhibitors to high risk groups." (PLoS one)

P) 17 October 2018 Duration and dosing of Proton Pump Inhibitors associated with high incidence of chronic kidney disease in population-based cohort. (full text) "In this study, we found that use of Proton Pump Inhibitors is associated with an increased risk in the development of CKD, especially after a total exposure time of more than three months and if high doses are used.

"Although cause and effect cannot be determined with an observational study, providers should consider whether PPI therapy is indicated for the individuals. Careful monitoring of kidney function while on PPI use and cessation of PPIs when there is no clear indication for use might reduce the population burden of CKD." (PLoS One)

Q) 21 October 2018 Cardiovascular and non-cardiovascular concerns with proton pump inhibitors: Are they safe? "Clinical epidemiology evidence coming from well-designed analyses of observational data consistently reported that long-term use of PPIs may increase the risk of cardiovascular events among patients treated with thienopyridines, tubular-interstitial nephritis and chronic kidney disease, hypomagnesemia, and fractures. Conversely, currently available evidence about the impact of PPIs on cardiovascular risk among patients not treated with thienopyridines, infections, nutritional disorders, cognitive impairment and dementia is limited by confounding." (Trends in Cardiovascular Medicine)

R) 16 November 2018 Omeprazole protects against cisplatin-induced nephrotoxicity by alleviating oxidative stress, inflammation, and transporter-mediated cisplatin accumulation in rats and HK-2 cells. (full text) "OME showed renoprotective effect against CP-induced toxicity in HK-2 cells and rat kidneys, by suppressing oxidative stress and mediating NF-κB-dependent inflammation, apoptosis, and transporter function." (Chemico-biological interactions)

S) 18 February 2018 Proton pump inhibitors and risk of acute and chronic kidney disease: a retrospective cohort study. "Proton pump inhibitors use is associated with an increased risk of incident AKI and CKD." (Pharmacotherapy)

T) 28 March 2019 Lipid Accumulation and Chronic Kidney Disease (full text) "Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys." (Nutritients)

U) 29 March 2019 Investigating the association of proton pump inhibitors with chronic kidney disease and its impact on clinical practice and future research: a review (full text) "the observational study design of this study together with other studies included in the review suggests that the strength of evidence associating PPI use with CKD is weak and does not establish true causality." (Journal of pharmaceutical policy & practice)

V) March 2019 The Dark Side of the Long-Term Use of Proton Pump Inhibitors in Chronic Liver Disease (full text) "In recent years, several observational studies have raised concern regarding the potential long-term side effects of PPIs, including acute and chronic kidney disease, hypomagnesemia, cardiovascular events, bone fractures, dementia, and infections such as Clostridium difficile colitis, bacterial pneumonia, and spontaneous bacterial peritonitis (SBP). ... However, as pointed out by most studies, correlation does not imply causation. Furthermore, even if the risk of overall infections may be higher, there does not appear to be a signal for increased mortality associated with PPI use." (Portuguese Journal of Gastroenterology)

W) 1 May 2019 Effects of Chronic Proton-Pump Inhibitor Use on Kidney Function in Older Adults "Chronic PPI use was associated with a significant reduction in eGFR in ambulatory older adults at two years, beyond that expected based on increased age alone." (Senior care pharmacist)

X) 30 May 2019 Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study (full text) "Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer." (BMJ)

Investigating the causes of death attributable to use of proton pump inhibitors (BMJ Opinion)

Y) 6 June 2019 Risk of acute kidney injury in patients with HIV receiving proton pump inhibitors "A nationwide cohort study supported the relationship of an increased risk of AKI in patients receiving PPIs." (Journal of Comparative Effectiveness Research)

Z) 12 February 2020 Molecular pathways driving omeprazole nephrotoxicity (full text) "Omeprazole, a proton pump inhibitor used to treat peptic ulcer and gastroesophageal reflux disease, has been associated to chronic kidney disease and acute interstitial nephritis. However, whether omeprazole is toxic to renal cells is unknown. Omeprazole has a lethal effect over some cancer cells, and cell death is a key process in kidney disease." "omeprazole nephrotoxicity may be related to induction of oxidative stress and renal tubular cell death." (Redox Biology)

AA) 10 July 2019 Large Randomized Trial Supports Safety of PPIs,

"Previous analyses tended to be association studies with the disclaimer that prospective, randomized data are needed to confirm their findings. The new trial, with more than 17,000 randomized patients, provides that evidence.

"With more than 53,000 years of patient follow-up, use of PPIs was not associated with any of the events so far described with the possible exception of enteric infection."

Page updated 14 February 2023