Proton Pump Inhibitors (PPIs) & Kidney Disease: A Legitimate Risk?

Proton-pump inhibitors (PPIs) are among the effective medications for the treatment of gastroesophageal reflux disease (GERD).

It is estimated that nearly ~15 million people in the United States use PPIs each year – with omeprazole being the 9^th most-prescribed drug in 2019.

One concern among PPI users – particularly long-term PPI users – is the potential onset of kidney disease (i.e. renal impairment/dysfunction).

PPIs & Kidney Disease (Research)

Included below are studies that investigated a link between PPI use and kidney disease/dysfunction.

For reference:

• AKI = acute kidney injury
• AIN = acute interstitial nephritis
• CKD = chronic kidney disease
• ERSD = end-stage renal disease

Proton Pump Inhibitors (PPI): StatPearls [Internet] (2022) (R)

StatPearls provides the peer-reviewed, up-to-date information/data on a variety of medications and medical conditions.

Clarke: “Isolated retrospective analyses suggested a potential link between PPI use and kidney disease. However, these associations have not occurred to date in prospective studies, and there have been significant concerns raised with the retrospective analyses given potential confounding.”

For reference, retrospective studies = individuals are sampled and information is collected about the past vs. prospective studies = individuals followed over time and data about them is collected as circumstances change.

Association between low-dose PPIs & kidney function decline (2021) (R)

Wakabayashi et al.: “A low dose of PPIs may be safe in clinical settings, but further prospective studies are needed to clarify our findings.”

• Aim: Evaluate whether low-dose PPIs are associated with CKD in elderly patients – in a retrospective observational study.
• 152 patients (~74.5 years old) were evaluated between 2017-2019.
• Measures: Renal parameters (eGFR, Scr) before treatment/baseline; PPI use (cumulative exposure over 3-year term)

What were the results?

35.5% of the 152 patients used PPIs in this study (low dose = 17.1% vs. high dose = 18.4%).

A significant decrease in eGFR (estimated glomerular filtration rate) and increase in Scr (serum creatinine) were observed between 3 years before treatment and at the baseline in the high-dose PPI group.

No significant changes in eGFR or Scr were observed in the low-dose PPI users.

Proton pump inhibitors associated AKI & CKD (2021) (R)

Wu et al.: “Findings suggest PPI-associated AKI and CKD should be taken into account, and the importance of PPI rational use should be reemphasized.”

• Aim: Examine the relationship between PPI use and AKI & CKD.
• Methods: Analyze adverse reports of acute kidney injury (AKI) and chronic kidney disease (CKD) based on U.S. FDA Adverse Event Reporting System (FAERS) database from 2004-2019 – among 6 specific PPIs. Reporting odds ratios (RORs) were utilized to detect signals.
• 6 PPIs compared: Omeprazole; pantoprazole; lansoprazole; rabeprazole; esomeprazole; dexlansoprazole.
• Data: 3,187 PPI-associated AKI cases & 3,457 PPI-associated CKD cases.

What were the results?

• Most cases reported of PPI-associated AKI & CKD occurred with lansoprazole.
• Signal strength was stronger for CKD (ROR = 8.8) than AKI (ROR = 3.95) with PPI use.
• Dexlansoprazole exhibited a stronger association for CKD (ROR = 34.94) and AKI (ROR = 8.18) than the other 5 PPIs.
• Median time from PPI use to event occurrence was 23 days for AKI and 177 days for CKD.
• The biggest yearly reports proportion of PPI-associated AKI & CKD events occurred in the first year (AKI = 81.67% & CKD = 57.34%).
• PPI-associated AKI led to larger proportion of: death, life-threatening, hospitalization, and disability events than PPI-associated CKD.
• PPIs (lowest to highest AKI risk): rabeprazole; esomeprazole; omeprazole; pantoprazole; lansoprazole; dexlansoprazole. (Based on RORs).
• PPIs (lowest to highest CKD risk): omeprazole; rabeprazole; esomeprazole; pantoprazole; lansoprazole; dexlansoprazole. (Based on RORs).
• Dosage analysis revealed that the median daily dose of dexlansoprazole was highest (60 mg) – and 2-fold the WHO recommended daily dosing guidelines, followed by esomeprazole at 1.33-fold the WHO recommended daily dosing guidelines (though all were within daily dosing guidelines issued by drug manufacturers) – which might’ve explained the stronger association for CKD with dexlansoprazole.

Long-term continuous use of PPIs is associated with renal function decline in patients without AKI (2021) (R)

Hatakeyama et al.: “PPI use was significantly associated with an increased risk of chronic kidney disease development compared to that with H2RA use.”

• Aim: Estimate progress rate of renal dysfunction in patients taking PPIs in clinical settings and compare results to patients taking H2RAs.
• Methods: Retrospectively review patient data collected from a medical information system between 2001-2019. Patients were classified as: (1) PPI users vs. (2) H2RA users.
• Measures: Survival time = period between drug initiation and ~30% decrease in eGFR.

What were the results?

• PPI users were associated with higher event incidence rates compared to H2RA users.
• PPI users had significantly higher rates of underlying disease relative to the H2RA users – with no significant differences in age or sex between groups.
• PPI users had significantly higher administration rates of aspirin, clopidogrel, statins, and ACE-2 blockers – relative to H2RA users. H2RA users had higher administration rates of NSAIDs than PPI users.
• PPI users had a significantly higher survival rate and eGFR decrease (>30%) than H2RA users at 730 days – but not earlier.
• PPI use, older age, and eGFR > 90 mL/min/1.73m2 exhibited high hazard ratios.

Proton Pump Inhibitors & the Kidney (2020) (R)

Al-Aly et al.: Reviewed preexisting literature of examining the relationship between PPIs and kidney damage/impairment.

PPIs & kidney damage (AKI, AIN, CKD)

• “Taken together, the constellation of evidence strongly suggests PPI use should be considered as a putative culprit in the evaluation of AKI and AIN, especially in a hospital setting.”
• “Substantial evidence has accumulated from multiple large cohort studies suggesting that PPI use is associated with increased risk for CKD outcomes.”
• “Studies have consistently described a graded increase in risk with higher doses and more prolonged duration of PPI therapy.”
• “A significant proportion (nearly 50%) of the association between PPI use and risk for CKD outcomes is not mediated by the occurrence of intervening AKI or AIN, suggesting a direct pathway of indolent chronic kidney injury.”
• “Several meta-analyses have supported the association between PPI use and increased risks for incident CKD, CKD progression, and kidney failure.”
• “The sum of evidence woven together suggests that prevention strategies and effort aimed at reducing the risk for CKD progression should address PPI use as a likely contributor to risk for the development and progression of CKD.”

Analysis of postmarketing safety data for PPIs (2019) (R)

Makunts et al.: “Our analysis of renal adverse effects as in general agreement with previous studies that have documented an increased risk of AKI, CKD, CKD progression, and ERSD.”

Researchers evaluated over 10M FDA Adverse Event Reporting System (FAERS) records and evaluated rates of AKI, CKD, ERSD, nephrolithiasis, renal impairment, and

AKI: Patients who received PPIs as “monotherapy” had significant increases in AKI reports.

• Omeprazole (OR = 5.8)
• Esomeprazole (OR = 3.3)
• Pantoprazole (OR = 1.8)
• Lansoprazole (OR = 10.8)
• Rabeprazole: The only medication associated with a statistically insignificant increase in AKI.

CKD: Patients who received PPIs as “monotherapy” had significant increases in CKD reports.

• Omeprazole (OR = 18.1)
• Esomeprazole (OR = 29.9)
• Lansoprazole (OR = 154.9)
• Rabeprazole & Pantoprazole: Associated with an increase in CKD frequency but the significance criteria were not met.

ERSD: Patients who received various PPIs as “monotherapy” had significant increases in ERSD reports.

• Omeprazole (OR = 30.1)
• Esomeprazole (OR = 34.7)
• Lansoprazole (OR = 97.6)
• Pantoprazole: Frequency of ERSD did not reach statistical significance.
• Rabeprazole: Zero reports of ERSD.

Nephrolithiasis: Patients who received various PPIs as “monotherapy” had significant increases in nephrolithiasis reports.

• Omeprazole (OR = 3.4)
• Esomeprazole (OR = 2.4)
• Pantoprazole (OR = 3.3)
• Lansoprazole (OR = 3.9)
• Rabeprazole: FAERS reports revealed an increased risk of nephrolithiasis among rabeprazole users but it didn’t meet significance criteria.

Renal impairment: Many renal impairment reports didn’t provide details about the injury such that it was reported renal impairment NOS (not otherwise specified).

• Omeprazole (OR = 11.5)
• Esomeprazole (OR = 7.9)
• Pantoprazole (OR = 2.9)
• Lansoprazole (OR = 5.0)
• Rabeprazole (OR = 12.4)

Electrolyte imbalances: All PPIs were associated with a significant increase in hypomagnesemia (low magnesium) and hypocalcemia (low calcium). Some were also associated with hypokalemia (low potassium) and hyponatremia (low sodium).

• Hypomagnesemia: All PPIs associated.
• Hypocalcemia: All PPIs associated.
• Hypokalemia: Omeprazole, esomeprazole, pantoprazole, lansoprazole.
• Hyponatremia: Omeprazole, lansoprazole, rabeprazole.

Researchers: “It may be beneficial to monitor renal function and electrolytes including potassium, calcium, magnesium, and sodium” (in PPI users).

Lansoprazole ORs: Lansoprazole may be the most problematic of all PPIs with regard to AKI, CKD, and ERSD – as evidenced by the highest ORs of any PPI in these categories.

Investigating the association of PPIs with CKD (Review) (2019) (R)

Cheema: “The current evidence related to the potential association of CKD with PPI use remains inconclusive in establishing true causality. Further prospective studies including RCTs and cohort studies would be required to confirm the findings reported in this review and to draw any conclusions.”

• Aim: Investigate the relationship between PPI use and CKD – by evaluating studies with various designs.
• Methods: Literature search for terms “proton pump inhibitors,” “chronic kidney disease,” and “association” – including both observational studies and RCTs.
• Data: 10 observational studies with 1,005,899 patients. Of the 10 studies: 6 were retrospective; 2 were prospective; 2 were case-controlled.

What were the results?

• One large prospective cohort study (144,032 patients) included in this review reported that PPI use was associated with increased risk of CKD (HR = 1.28).
• However, the totality of evidence (across all studies in this review) indicated that the strength of evidence associating PPI use with CKD is “weak” and does NOT prove causality.

Proton pump inhibitors & risk of acute/chronic kidney disease (2019) (R)

Hart et al.: “Proton pump inhibitor use is associated with increased risk of incident AKI and CKD. This relationship could have a considerable public health impact.”

• Aim: Examine association between PPI use and risk of AKI & CKD in large population-based health-maintenance organization (HMO) cohort.
• Sample: Patients aged 18+ without evidence of preexisting renal disease, started on PPI therapy, and continuously enrolled for at least 12 months from 1993-2008 were identified within an HMO database.
• Rates of AKI & CKD were defined with ICD-9-CM codes or a glomerular filtration rate less than 60 mL/min/1.73m2 after initiation of PPI therapy.
• Patients with AKI were followed for ~90 days (cohort 1) and patients with CKD were followed for 1+ years (cohort 2).
• Multivariate logistic regression analyses used to adjust for differences in demographics (sans race), comorbidities, and medication use between groups.

What were the results?

• AKI cohort: 16,593/93,335 patients were exposed to PPIs.
• Incidence rate of AKI was higher in the PPI group than non-PPI users (36.4 vs. 3.54 per 1000 person-years, respectively).
• In adjusted models: PPI exposure was associated with increased risk of AKI.
• CKD cohort: 14,514/84,600 patients were exposed to PPIs.
• Incidence rate of CKD was higher in PPI users than non-PPI users (34.3 vs. 8.75 per 1000 person-years, respectively).
• In adjusted models: PPIs were associated with higher risk of CKD compared to controls.

Association between PPI use & risk of adverse kidney outcomes (Systematic Review & Meta-Analysis) (2018) (R)

Nochaiwong et al.: “PPI usage was associated with adverse kidney outcomes, however, these findings were based on observational studies and low quality evidence.”

• Researchers conducted a systematic review and meta-analysis.
• A literature search was carried out for all studies in which associations between PPI use and adverse kidney/renal events were evaluated.
• Risk ratios (RRs) and confidence intervals (Cis) were pooled with a random-effects model.

What were the results?

• ~2.6M patients across 4 cohort and 5 case-control studies were included in the review.
• 534,003 (20.2%) of the total patients were PPI users.
• PPI users exhibited significantly higher risk of AKI (RR = 1.44) and CKD (RR = 1.36) relative to non-PPI users – but the strength of evidence was “low.”
• PPI users also exhibited higher risk of AIN (RR = 3.61) and ERSD (RR = 1.42) relative to non-PPI users – but the strength of evidence was deemed “insufficient.”

Duration & dosing of PPIs associated with high incidence of CKD (2018) (R)

Rodriguez-Poncelas et al.: “PPI use is associated with a higher risk of incident CKD. The association is greater for high doses and becomes apparent after 3 months’ exposure.”

• Aim: Quantify association between PPI use and CKD incidence in population-based cohort.
• 51,360 participants ages 15 or older were analyzed for this study between 2005-2012.
• PPI use was measured by recording prescriptions.
• Incident CKD was defined as eGFR < 60 mL/min/1.73m2 and/or urinary albumin level to creatinine level > 30 mg/g in 2+ determinations over a period of at least 3 months of follow-up.

What were the results?

• PPI use was associated with incidence CKD in analysis adjusted for various clinical variables in: (1) PPI users at baseline AND (2) those who started PPI during follow-up.
• High doses of PPI increased risk of CKD incidence for any type of exposure and for those who used high doses throughout the follow-up.
• Risk of incident CKD increased after 3 months exposure to PPIs: (1) between the third and sixth months and (2) after the sixth month.

PPI use & Risk of AKI (Meta-analysis) (2017) (R)

Yang et al.: “PPI use could be a risk factor for AKI and should be administered carefully.”

• Researchers performed a meta-analysis to evaluate the association between PPI use & risk of AKI.
• Data: Studies that evaluated the relationship between PPI use and risk of AKI up to 2016 were included if they reported RRs, ORs, or HRs.
• Calculation: Pooled RRs with 95% CI using a random-effects model.

What were the results?

• 7 observational studies (5 cohort & 2 case-control) were identified and included.
• 513,696 PPI users vs. ~2.4M total participants.
• Pooled adjusted RR of AKI in PPI users was ~1.61.
• PPI use was associated with ~61% higher risk of AKI than non-use.
• Younger patients may be more likely to develop AKI than elderly patients (as there was no significant association in patients over 60 years of age).

Conclusion: Healthcare providers should closely monitor patients taking PPIs via urinalysis and renal function tests to recognize any renal injury in time.

Proton Pump Inhibitor Use & Risk of Chronic Kidney Disease (2017) (R)

Lazarus et al.: “PPI use is associated with 20% to 50% higher risk of incident CKD.”

• Aim: Quantify association between PPI use and incident CKD in a population-based cohort.
• 10,482 participants in the Atherosclerosis Risk in Communities (ARIC) study with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73m2 were followed from baseline visit (1996-1999) to December 31, 2011.
• 248,751 patients with eGFR > 60 mL/min/1.73m2 in an administration cohort were used to replicate findings.
• Measures: Self-reported PPI use in ARIC or an outpatient PPI prescription in the replication cohort.

What were the results?

• PPI users were more often: white, obese, using antihypertensive agents.
• ARIC: PPI use associated with incident CKD in: (1) unadjusted analysis; (2) adjusted analysis (demographics, socioeconomic status, clinical parameters); (3) analysis with PPI-ever use modeled as a time-varying variable.
• The association persisted when baseline PPI users were compared directly to users of H2RAs and propensity-score matched non-users.
• PPI use was associated with CKD in all analyses – including a time-varying new user design.
• Twice daily (b.i.d.) PPI use was associated with higher risk of CKD than once-daily dosing.

PPIs & Kidney Disease (2017) (R)

Toth-Manikowski & Grams: “The majority of studies showed higher risk of kidney outcomes among persons prescribed PPI medications, with effect sizes that were slightly higher for AKI (~2-3-fold) vs. CKD & ERSD (~1.2-1.8-fold).”

• “There is strong observational evidence of an association between PPI use and acute and chronic kidney disease.”
• One cannot definitively conclude that PPI therapy causes reversible or irreversible kidney damage.
• Associations between PPI therapy and kidney disease persist in many studies with controlling for confounds.
• There are various biologically plausible mechanisms by which PPIs could induce chronic renal damage and recurrent episodes of AIN, AKI, chronic hypomagnesemia, and interference with the renoprotective alkaline tide phenomenon.

Association between PPI use & risk of progression to CKD (2017) (R)

Klatte et al.: “Initiation of PPI therapy and cumulative PPI exposure is associated with increased risk of CKD progression in a large, North European healthcare system.”

• Aim: Evaluate if PPIs increase risk of CKD in a retrospective analysis using the Stockholm creatinine measurements database (which includes diagnoses, dispensation claims, lab test results for all citizens in the Stockholm region from 2007-2010).
• 105,305 new PPI users and 9,578 new H2RA users were identified & renal outcomes were collected for 2.7 years (median).
• Measures: Progression CKD (doubling of creatinine or decrease in eGFR ~30% or more); end-stage renal disease (ESRD); acute kidney injury (AKI).
• Researchers modeled time-dependent risk associated with cumulative PPI exposure.

What were the results?

• 2,112 individuals doubled serum creatinine during observation & 11,760 individuals exhibited relative decline in eGFR of >30%.
• Incidence rates and the proportion of individuals developing these events were higher among PPI users than H2RA users.
• Kaplan-Meier curves indicate a higher occurrence over time of these events among PPI users.
• Fully adjusted Cox regressions revealed hazard ratios for PPI users (relative to H2RA users) of 1.26 higher for both outcomes of: (1) doubling serum creatinine & (2) >30% decline in eGFR.
• There was a non-statistically significant but high magnitude increase in risk of ERSD and AKI associated with PPI use.
• Increasing cumulative PPI use was associated with a graded higher risk for doubling of serum creatinine and eGFR decline (>30%) – suggesting that PPI use is associated with higher risk of CKD.

Proton pump inhibitors & risk of AKI in older patients (2015) (R)

Antoniou et al.: “Those who started PPI therapy had an increased risk of acute kidney injury (AKI) and acute interstitial nephritis (AIN).”

• Aim: Examine risk of AKI & AIN in a large population of older patients taking PPIs.
• 290,592 individuals who started PPI therapy vs. equal number of matched controls – from 2002-2011.
• Measures: Hospital admission with AKI & AIN within ~120 days of PPI therapy.

What were the results?

• AKI rates: 13.49 (PPI) vs. 5.46 (non-PPI) per 1000 person-years, respectively.
• AIN rates: 0.32 (PPI) vs. 0.11 (non-PPI) per 1000 person-years, respectively.

PPIs & AKI: Nested Case-Control Study (2013) (R)

Klepser et al.: “Patients with renal disease diagnosis were twice as likely to have used a previous prescription for a PPI.”

• Aim: Determine if PPIs are associated with kidney failure and estimate effect size for relationship between PPI use and renal disease.
• 184,480 patients (18+ years old) were evaluated between 2002-2005 – each for at least 24 months.
• 854 cases were identified as having at least 2 claims for acute renal disease diagnosis – and these cases were matched with four controls (N = 3,289) based on age, gender, county, date of cohort entry.

What were the results?

• PPI use was positively associated with renal disease (OR = 1.72) even after controlling for confounds.
• Removal of patients with potential confounding disease states from the study population yielded 195/854 cases and 607/3,289 controls – but the relationship between PPI use and renal disease “remained consistent.”

Other potentially-relevant studies…

There are other studies in which researchers sought to analyze the effects of PPIs in persons with preexisting kidney disease – as well as in kidney transplant recipients.

Adverse outcomes of PPIs in patients with CKD (2021) (R)

Liabeuf et al.: “Long-term PPI prescription was common in CKD patients. Our results call attention to its potential risks of both acute and chronic kidney failure.”

• Aim: Evaluate the prevalence of PPI prescriptions and relationship to kidney outcomes in persons with CKD.
• 3,023 nephrology outpatients with CDK (stages 2-5 at inclusion): 981 prevalent users (32%) at baseline; 366 new users (12%) prescribed PPI over 3.9 years after baseline.
• Measures: Hazard ratios (HRs) for AKI; ESRD; mortality associated with new PPI prescriptions (as a time-dependent variable); eGFR.

What were the results?

• PPI was associated with both AKI and progression to ESRD – relative to zero PPI use.
• Degree of association between AKI and PPI exposure was stronger in new users vs. prevalent (preexisting) users – and was large enough to be clinically relevant.
• The results were consistent for both prevalent (preexisting) and new PPI users in sensitivity analyses.
• Strength of associations were not significantly altered after adjustment for notable confounds.
• A dose-response effect was observed as well – such that higher daily doses of PPIs were associated with greater risk of AKI & ERSD.
• Risk of ESRD was highest in younger patients and those with eGFR > 30 mL/min/1.73m2.

Conclusion: “It may be time to reconsider whether the use of PPIs in self-medication should be restricted in CKD patients and PPI deprescription in patients who may need it.”

Effect of PPI use on kidney function in patients with CKD stages G3a to G4 (2021) (R)

Giusti et al.: “The data suggest that chronic PPI use accelerates progression of kidney disease and is associated with increased mortality in CKD patients.”

• Researchers evaluated the relationship between chronic PPI use in veterans with CKD G3a to G4.
• Comparison: 1,406 PPI users vs. 1,425 non-PPI users (control group).
• Measure: Rate of decline in renal function (eGFR).
• Propensity score matching based on age, sex, race, and Charlson Comorbidity Index were utilized – and Kaplan-Meier curve & Cox regression were performed to assess relations of PPI use with dialysis, all-cause mortality, metabolic acidosis, and CKD progression.

What were the results?

• PPI users had a significantly increased risk of CKD progression, dialysis, all-cause mortality – relative to non-PPI users.
• PPI users exhibited a trend for development of metabolic acidosis but the difference wasn’t statistically significant.

Omeprazole use & risk of CKD evolution (2020) (R)

Note: This study examined the risk of CKD progression among those with preexisting CKD (rather than those who developed CKD without prior kidney issues).

Guedes et al.: “An association between omeprazole use and progression of CKD stage was identified, showing a higher risk of disease evolution among omeprazole users.”

• Aim: Analyze the association between ongoing use of omeprazole and progression of CKD in adult and elderly individuals – in a retrospective cohort study.
• Sample: 199 CKD patients at a nephrology clinic in Brazil (2016-2017).
• Participants were divided into 2 groups: (1) omeprazole users vs. (2) non-users of omeprazole.
• Measures: Progression of CKD.
• Information about clinical and sociodemographic data; health behaviors; and medication use were collected from all patients diagnosed with CKD via consultation of medical charts.

What were the results?

• 7% of the 199 CKD patients were omeprazole users.
• There was a higher percentage of CKD progression in omeprazole users (70.6%) compared to non-users (10.5%).
• The hazard ratio was 7.34 – indicating a higher risk of progression to worse stages of CKD in omeprazole users than non-users.
• There were no significant differences between groups in other variables (e.g. clinical and sociodemographic data, health behaviors, and medication use).

Note: It’s unclear as to whether researchers ruled out the use of other PPIs (besides omeprazole) in the “non-omeprazole” group. (I assume they did, but it wasn’t mentioned – and thus could be a major limitation.)

Proton pump inhibitors & adverse effects in kidney transplant recipients: Meta-analysis (2019) (R)

Boonpheng et al.: “PPI use was NOT associated with significant risks of higher acute rejection, graft loss, or 1-year mortality.”

• Aim: Determine whether the adverse effect of PPIs have clinical significance in kidney transplant recipients.
• Methods: Review studies published in various medical databases from inception through 2018 – that evaluated adverse effects of PPIs in kidney transplant recipients (including biopsy-proven acute rejection, graft loss, hypomagnesemia, renal function, and overall mortality).
• 14 observational studies with 6,786 kidney transplant recipients were evaluated.

What were the results?

• No significant association was discovered between PPI exposure and risk of biopsy-proven acute rejection at > 1 year; graft loss at 1 year; or 1-year morality.
• PPI exposure was significantly associated with hypomagnesemia.

Limitations: Based only on observational studies; baseline characteristics unattainable across all studies; specific immunosuppressive regimens, drug level, dosage, and adherence were unknown; definitions of outcomes varied across studies; short-term follow-up data (~1 year).

Long-term kidney outcomes among users of PPI without intervening acute kidney injury (2016) (R)

Note: This study evaluated whether AKI was a reliable indicator warning sign of eventual CKD.

Xie et al.: “PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI.”

• 144,032 incident users of acid suppression therapy (PPI = 125,596 vs. H2 blockers = 18,436) were evaluated.
• Evaluation: Whether PPI use was associated with increased risk of chronic renal outcomes in absence of intervening AKI.

What were the results?

• Incident users of PPI had increased risk of an eGFR under 60 mL/min/1.73m2 (HR = 1.19); incident CKD (HR = 1.26); eGFR decline over 30% (HR = 1.22); and ERSD or eGFR decline over 50% (HR = 1.30).
• Results were consistent in models that excluded participants with AKI before chronic renal outcomes, during the time in the cohort, or before entry.
• Proportion of PPI effect mediated by AKI was: 44.7% (eGFR under 60 ml/min/1.73m2); 45.47% (incident CKD); 46% (eGFR decline over 30%); and 46.72% (ERSD or eGFR decline over 50%).

Conclusion: Reliance on AKI as a warning sign to guard against risk of CKD among PPI users is NOT sufficient as a sole mitigation strategy.

In sum, what does the research of PPIs & kidney disease suggest?

PPI therapy is associated with significantly increased risk of: CKD (chronic kidney disease); AKI (acute kidney injury); acute interstitial nephritis (AIN); end-stage renal disease (ESRD).

Evidence is consistent across all study types and designs.

I encountered zero studies that suggested: (A) no relationship between PPI use and kidney disease/injury OR (B) decreased risk of kidney disease/injury with PPI use.

• Wu et al. (2021): PPI use as strongly associated with CKD and to a lesser extent AKI.
• Hatakeyama et al. (2021): PPI use is associated with increased risk of CKD relative to H2RA use.
• Al-Aly et al. (2020): Evidence indicates PPIs should be considered culprits in AKI & AIN.
• Makunts et al. (2019): PPI monotherapy increases risk of AKI, CKD, ERSD, nephrolithiasis, renal impairment, and electrolyte imbalance.
• Hart et al. (2019): PPI users had increased risk of CKD vs. controls.
• Nochaiwong et al. (2018): PPI users had higher risk of AKI & CKD vs. non-users.
• Rodriguez-Poncelas et al. (2018): PPIs associated with increased CKD risk – particularly at high-doses and/or with long-term use.
• Lazarus et al. (2017): PPI associated with increased CKD risk – especially with twice daily dosing.
• Toth-Manikowski & Grams (2017): Strong observational evidence between PPIs & CKD. Associations persist after controlling for confounds. Biologically plausible mechanisms.
• Klatte et al. (2017): PPI therapy is associated with risk of CKD.
• Antoniou et al. (2015): Higher rates of AKI & AIN within 120 days of PPI therapy vs. non-PPI therapy.
• Klepser et al. (2013): Patients with renal disease 2-fold more likely to have used a PPI.
• Liabeuf et al. (2021): PPI associated with AKI & progression to ERSD vs. no use. Dose-response effect observed. Risk higher in younger patients.
• Giusti et al. (2021): Increased risk of CKD progression in PPI users vs. non-users.
• Guedes et al. (2020): Omeprazole associated with higher percentage of CKD progression (70.6%) vs. non-users.

All of the above studies/reports were consistent in suggesting PPIs are associated with increased risk of renal disease/injury.

Cheema et al. (2019) reported that the strength of evidence associating PPI use with CKD is “weak” – and that causality cannot be proven due to lack of randomized controlled trials (RCTs).

Obviously there are significant limitations associated with preexisting research of proton-pump inhibitor (PPI) use and adverse kidney-related events including: (1) zero randomized controlled trials (RCTs); (2) potential confounds (e.g. general health; BMI; comorbidities; age; sex; medication use; substance use; etc.); (3) adherence to PPI therapy; (4) predisposition to renal disease (e.g. genetically-mediated); (5) no renal biopsy results; (6) no lab indices of renal function in some studies; etc.

Everything considered, we cannot definitively conclude that PPI administration causes: kidney disease (CKD); kidney injury (e.g. AKI & AIN); renal impairment; end-stage renal disease (ESRD); etc.

However, we can conclude that there appears to be a significant relationship between PPI administration and kidney disease/injury – and that PPI is a clear risk factor for kidney disease/injury.

How PPIs cause kidney disease/injury (Hypothetical mechanisms)

Understand that PPIs haven’t yet been proven to cause kidney disease or kidney injury.  However, researchers have proposed biologically plausible mechanisms by which PPIs could damage the kidneys.

Morschel et al. (2018) hypothesize the pathogenesis of kidney disease/injury resulting from PPI therapy. (R)

1. Hypomagnesemia

Chronically low magnesium concentrations (hypomagnesemia) which can occur as a result of PPI therapy via modulation of the GI tract – may be a direct mechanism by which PPIs cause chronic kidney disease (CKD). Low blood levels of magnesium (< 0.7 mmol/L) are associated with CKD. (R)

2. Tubulo-interstitium deposits

Various researchers have noted that certain PPIs are not stable and undergo spontaneous degradation wherein they generate a series of breakdown products (i.e. metabolites) such as 2-mercaptobenzimidazoles. Accumulation of these metabolites could lead to tubular atrophy and mineralization of the kidneys. (R)

It is thought that PPIs or PPI metabolites may end up deposited into the tubulo-interstitium (intertubular, extraglomerular, extravascular space) – which in turn triggers a cascade of the following physiological changes:

Immune response: The immune system might react to PPI deposits within the tubulo-interstitium such that it ends up attacking the kidneys – causing impairment, injury, and possibly disease. Some have described the immune response as “idiosyncratic” and “cell-mediated.”

Interstitial inflammatory infiltrate & edema: Tubule epithelial cells may become injured by an initial immune response. Subsequently, a lymphocytic inflammatory infiltrate containing mostly T cells may be observed.

Kidney biopsy demonstrated a diffused interstitial cellular infiltrate of eosinophils and lymphocytes – both with and without tubulitis but normal glomeruli and vasculature.

Acute interstitial nephritis (AIN): Eventually a renal lesion may appear that causes a decline in kidney function (as a result of the immune response to interstitial inflammatory infiltrate).

• Acute kidney injury (AKI): AIN causes AKI which can lead to CKD.
• Interstitial fibrosis & tubular atrophy: Can occur secondary to AIN and lead to CKD.

CKD -> end-stage renal disease (ESRD): CKD as a result of (A) hypomagnesemia; (B) AKI; and/or (C) interstitial fibrosis & tubular atrophy – may lead to end-stage renal disease (ESRD).

Risk factors for kidney disease with PPIs

Included below are some risk factors that might increase risk of kidney disease/injury with PPI therapy.

Understand that while some of these risk factors have been documented in research – others are mere speculation/conjecture on my part.

Higher daily PPI dosage: Higher daily doses of PPIs are associated with significantly increased risk of kidney disease/injury relative to lower daily doses of PPIs.

Twice daily PPI dosing: Some studies have reported higher risk of kidney disease/injury with twice-daily PPI dosing vs. once-daily PPI dosing. However, it’s unknown as to whether this effect is truly mediated by twice-daily dosing or merely attributable to a higher average daily dose.

1-24 months PPI use (?): Risk of kidney disease/injury appears highest among those who’ve used PPIs for less than 1 year.

• One study found significantly increased risk of kidney disease/injury after 3 months – and again after the 6^th
• A different study found the mean time from PPI use to event occurrence was ~23 days for AKI & 177 days for CKD.
• This study found the largest annual proportion of PPI-associated AKI & CKD events occurred in the first year (AKI = 81.67% & CKD = 57.34%).
• A third study found that eGFR decreases (>30%) became significant at around 730 days but not earlier – suggesting that kidney decline may take 1-2 years.

Specific PPIs: Multiple studies have suggested increased risk of adverse kidney-related events with specific PPIs lansoprazole and dexlansoprazole relative to other PPIs. However, this could’ve been due to a combination of factors such as: refractory/severe cases (that’ve already tried omeprazole) and relative dosing (due to unresponsiveness with prior PPI therapy).

• Lansoprazole: One study reported lansoprazole as carrying the second-highest risk of AKI & CKD of all PPIs. A different study found lansoprazole as being the most likely PPI to cause AKI, CKD, and nephrolithiasis.
• Dexlansoprazole: One study found dexlansoprazole was associated with the highest risk of both AKI & CKD of all PPIs. However, this could’ve been due to its sheer potency or the group of patients taking this PPI (e.g. refractory cases).

Preexisting conditions: Studies indicate that risk of kidney disease/injury may be higher among individuals with preexisting medical conditions.

• Rates of kidney disease/injury with PPIs were lower among healthier patients.
• This makes logical sense given that preexisting conditions may: (A) increase susceptibility to drug-induced kidney damage and/or (B) medications used to treat preexisting conditions may interact with PPIs to cause kidney damage.

Age (old vs. young): Data are mixed. Somewhat of a conundrum. My instinct would’ve been that older adults/elderly tend to have higher rates of PPI-related kidney disease – but this wasn’t always the case.

• Some studies found a relationship between old age and increased risk of PPI-related kidney dysfunction and this would make logical sense given that kidney function declines with age & older adults have poorer overall health.
• Other studies have found the exact opposite: younger patients (e.g. under 60) are more likely to experience PPI-related kidney dysfunction – and this might make some sense given that immunoreactivity to PPIs may be stronger in this population and/or there may be less overall desensitization to PPIs.

Co-administered substances (medications, drugs, supplements): Anyone using other substances with PPIs (particularly substances that have potential to alter kidney function) might increase risk of kidney disease/injury with PPIs.

Dehydration: Severe dehydration alone can result in kidney damage. Dehydration or suboptimal hydration while using PPIs could theoretically impair kidney function and make the kidneys more susceptible to PPI-induced damage (e.g. via greater accumulation of tubulo-interstitium deposits).

Zero prior PPI therapy: Some research suggests that prior PPI therapy (before current regimen) may reduce risk of kidney disease/injury from PPIs via a desensitization effect. Whether this is true remains unclear – but some evidence suggests it could be the case. In my opinion though, this doesn’t make logical sense because all PPI users have a “first time” of therapy – such that I suspect it’s more likely a survivorship type bias at play.

Preexisting kidney impairment: Obviously individuals with preexisting kidney dysfunction (e.g. CKD, AKI, AIN, etc.) could be at higher risk of kidney damage from PPIs relative to those with normal kidney function. Why? Those with preexisting kidney impairment may not be able to filter/excrete as much PPI medication/metabolites as those with normal kidney function – and this may increase risk of or accelerate onset of damage.

Poor health status: Individuals with poor general health status such as due to medical conditions, suboptimal diet/lifestyle choices, high BMI (e.g. obesity), illicit substance use, circadian rhythm disorders, etc. – may be at increased risk of kidney damage from PPI use for logical reasons (e.g. higher inflammation, immune dysregulation, poorer kidney function, co-administered medications, suboptimal nutrition, oxidative stress, etc.).

How to minimize risk of kidney disease with PPIs… (Hypotheses)

Included below are strategies that I hypothesize might decrease risk of kidney disease/injury with PPIs.

Obviously there are zero guarantees that these strategies will be effective – but they may be better than doing nothing.

1. Minimal effective PPI dose: Use the lowest necessary dose of PPIs to alleviate symptoms. Consider alternative acid-reducing agents like H2RAs, alginates, antacids, etc. if these provide adequate relief from the condition for which you use a PPI and/or enable the reduction of PPI dosage.
2. Minimum term of PPI use: Do NOT use a PPI for longer than recommended by a medical doctor. Some studies have found that long-term PPI use significantly increases risk of kidney damage/injury. Using PPIs for less than 3 months is ideal if possible (as one study found risk of kidney damage/injury significantly increases between 3-6 months after PPI therapy initiation).
3. Maintain adequate hydration: Hydration is essential for maintaining optimal kidney function. Dehydration can impair kidney function and increase susceptibility to kidney damage/injury. (Obviously don’t go overboard here as drinking too much water can cause hyponatremia – but adequate hydration may help reduce risk of kidney disease). (R)
4. Regularly evaluate kidney function (nephrologist or MD): Nehra et al. (2018) recommend annually monitoring eGFR (estimated glomerular filtration rate) as recommended for patients on potentially nephrotoxic drugs. (R) Other researchers recommend monitoring electrolyte concentrations to detect imbalances – as low magnesium in particular may increase risk of kidney disease.
5. Avoid other substances that can cause/exacerbate kidney impairment: If possible, avoid all meds/substances that have potential to impair kidney function while using PPIs. Talk to a medical doctor and/or pharmacist about this.
6. Avoid rhabdomyolysis: Excessive muscle strain (such as from exercising) in hot conditions and/or while dehydrated can cause accumulation of myoglobin in the kidneys which inflicts damage. Rhabdomyolysis itself is a serious medical condition that can cause major kidney damage/injury – and this may be exacerbated by PPIs. I’d personally avoid intense aerobic workouts just to be safe while on PPIs.
7. Magnesium carbonate: Magnesium carbonate is a supplement that can be used by those with acid reflux conditions (e.g. GERD) because it’s higher pH. Essentially it functions as an antacid and simultaneously replenishes low magnesium levels. Talk to a medical doctor to ensure this supplement is safe/effective for you. (FYI: I included an affiliate link here and earn a small commission if you make a purchase. It’s the product that I use.)
8. Supplements to protect/preserve kidney function: Ask a doctor and/or pharmacist about medications and/or supplements that may help preserve kidney health/function while on PPIs. Specifically, investigate whether administration of nephroprotective agents might be a smart move while on PPIs. (A common supplement example is calcium-d-glucarate). (This is an affiliate link FYI – I earn a small % if you buy via my link.)
9. Switch PPIs (?): Some research indicates that both lansoprazole and dexlansoprazole are associated with increased risk of kidney disease/injury. Whether this is due to the actual drugs or due to the fact that users of these agents tend to have refractory acid reflux conditions and thus require high doses remains unclear. Nonetheless, the association is concerning and unless these are the only PPIs that manage symptoms – I’d consider switching to a different PPI.

Did the PPI really cause kidney disease? (Consider other factors…)

Because there are zero large-scale, double-blind, randomized, controlled trials that’ve investigated the effect of PPI administration on: (A) kidney function; (B) kidney injury; and (C) kidney disease – it remains unknown as to whether PPIs actually cause kidney disease.

The most common causes chronic kidney disease (CKD) include: (R)

• Type 2 diabetes (30-50%)
• Hypertension (27.2%)
• Primary glomerulonephritis (8.2%)
• Type 1 diabetes (3.9%)
• Chronic tubulointerstitial nephritis (3.6%)
• Secondary glomerulonephritis or vasculitis (2.1%)
• Plasma cell dyscrasias or neoplasm (2.1%)

Many PPI users have a variety of comorbid medical conditions such as: obesity/overweight; type 2 diabetes; hypertension; dyslipidemia; dysbiosis; anxiety/depression; etc. – such that it’s difficult to know for certain whether PPIs are legitimately causing kidney disease.

However, if a person’s kidney function declines while using PPIs – it’s important to evaluate all potential risk factors.

Common risk factors for progression of chronic kidney disease include:

• Older age
• Male gender
• Non-Caucasian ethnicity
• SNPs (TCF7L2 & MTHFS)
• Systemic hypertension
• Proteinuria
• Metabolic factors

If a healthy person utilized PPI “monotherapy” (i.e. no other substances with PPIs) and developed kidney disease/injury – then it’s likely that the PPI was the primary cause.

However, if PPIs were administered with a host of other substances (that have potential to cause kidney disease/injury) and in a person with suboptimal general health (e.g. comorbid medical conditions) – then it’s more difficult to know whether the PPI was truly the sole or primary cause.

What are the symptoms of PPI-induced kidney disease/injury?

A challenge associated with detecting kidney disease/injury is that it can often be completely asymptomatic – particularly in early stages.

Moledina & Perazella (2016) report that PPI-induced acute interstitial nephritis (AIN) is generally subtle and subclinical – and is typically unsuspected prior to biopsy. (R)

Xie et al. (2016) note that acute kidney injury (AKI) isn’t a sufficient warning sign to predict CKD onset in PPI users, such that if MDs think AKI is a mandatory occurrence before CKD – they’re mistaken. (R)

For this reason, it is important to receive regular screening/blood work while on a PPI in order to detect early signs of kidney damage.

Symptoms of CKD commonly emerge in Stage 4 & Stage 5 of the disease, and include:

• Nausea
• Vomiting
• Loss of appetite
• Fatigue/weakness
• Cognitive impairment
• Muscle twitches/cramps
• Swollen feet/ankles
• Itchiness
• Chest pain
• Shortness of breath
• Hypertension
• Infrequent urination

How long does it take to develop kidney disease after PPI therapy?

Unclear – probably contingent upon the specific user.  However, on average, the data indicate that most individuals who experience kidney disease/injury from PPIs will do so within the first year of PPI therapy.

Wu et al. (2021): Most acute kidney injury (AKI) and chronic kidney disease (CKD) occurred within the first year of use. (AKI = 81.67% & CKD = 57.34%).

• Median time from PPI use to event occurrence was: 23 days (AKI) & 177 days (CKD). (R)

Hatakeyama et al. (2021): PPI users had significantly higher eGFR decrease (>30%) relative to H2RA users at 730 days (~2 years) but not earlier. (R)

Rodriguez-Poncelas et al. (2018): Risk of incident CKD from PPI therapy increased: (1) between the third and sixth months and (2) again after the sixth month. (R)

Moledina & Perazella (2016): Median time from drug initiation to acute interstitial nephritis (AIN) often exceeds 6 months. (R)

Could there be a delayed onset such that kidney disease develops after PPI is stopped?

A question I have is whether it’s possible that some individuals might experience delayed-onset kidney injury/disease that emerges following cessation of PPI therapy.

For example: Administer a PPI for several months then discontinue the PPI – and then experience kidney disease/injury. My initial impression is that this would be unlikely and rare.

It’s possible that some individuals experience subclinical kidney impairment/damage while on a PPI – such that it remains undetected by most clinical evaluations during PPI therapy, but eventually progresses and becomes detectable post-PPI therapy.

Moledina & Perazella (2016) reported that PPI-induced AIN is often subclinical – leading to gradually progressive kidney failure.

Therefore, it’s possible that a subclinical state of AIN is set in motion while using PPIs – and that it eventually progresses post-PPI therapy wherein it’s detected long after PPI discontinuation.

Is kidney disease from PPIs reversible?

Depends on the case. If detected early, it may be possible to completely reverse the onset of kidney disease.

In other cases, it may be possible to partially reverse kidney disease/damage inflicted by the PPI – such that kidneys are nearly 100% but still suboptimal relative to pre-PPI functioning.

If kidney injury/damage remains undetected for a long duration such that it becomes severe/advanced – complete reversibility will likely be impossible.

Brewster & Perazella (2007): “While most patients recover kidney function, many are left with some level of chronic kidney disease.” (R)

Have you experienced kidney disease or injury with PPIs?

If you’ve developed kidney disease (e.g. CKD) or kidney injury (AIN and/or AKI) while using PPIs – feel free to leave a comment describing your situation.

Provide some details such as:

• Age, BMI, sex
• PPI specifics: Daily dosage; duration of therapy; specific drug
• Other substances used (medications, supplements, drugs – including caffeine, nicotine, alcohol, cannabis, etc.)
• Medical conditions
• Type & severity/stage of kidney disease/injury
• Reason for PPI therapy

How long after starting the PPI did kidney disease/injury occur?

What were the first signs/symptoms of kidney disease/injury?

How strongly do you believe the PPI contributed to kidney disease/injury? (Low vs. moderate vs. high conviction) (Explain why…)