Unveiling the Link: Proton Pump Inhibitors and Burden of Kidney Disease

Proton pump inhibitors (PPIs) such as pantoprazole, omeprazole, rabeprazole, lansoprazole, and esomeprazole are medications commonly employed to reduce stomach acid secretion by blocking the action of an enzyme called H+/K+-ATPase, which is responsible for acid production. Unlike other drugs used to treat gastric conditions, PPIs possess unique biological activity—they inhibit the final step in the production of hydrochloric acid, making PPIs the preferred choice in clinical practice. (1)

PPIs are widely used to treat various gastric conditions, including gastric and duodenal ulcers, gastroesophageal reflux disease, and erosive esophagitis. There is emerging evidence linking PPIs to severe adverse events. These comprise an increased risk of bone fractures, pneumonia, dementia, hypomagnesemia (low magnesium levels), and renal diseases, ranging from acute interstitial nephritis (AIN), acute kidney injury (AKI), and chronic kidney disease (CKD). (1)

Understanding the Burden and Etiology of Kidney Diseases in India

Chronic kidney disease (CKD) caused a significant public health challenge due to its high prevalence, morbidity, and mortality. More than 50% of advanced CKD cases are identified only when the estimated glomerular filtration rate (eGFR) drops below 15 ml/min per 1.73 m², indicating severe kidney dysfunction. (2)

This alarming statistic emphasizes the critical need for robust screening programs targeting individuals at risk of developing CKD. Notably, data from the International Society of Nephrology's Kidney Disease Data Center Study reported an incidence of 17% of chronic kidney disease in India. (2)

The etiology of CKD in India exhibits considerable variability. Poverty, pollutants, contamination of water, heavy metal toxins, and the increase in the number of patients with diabetes and hypertension lead to an increasing burden of glomerular and interstitial forms of kidney diseases. (2) Proton pump inhibitors are generally prescribed for gastrointestinal diseases but with the rampant injudicious use of the drug, it has been found that PPIs trigger acute interstitial nephritis, which is commonly associated with acute kidney injury. It has also been established that prolonged use of PPIs increases the risk of chronic kidney disease. (1)

Connecting the Dots: Uncovering the Association Between PPIs and Kidney Diseases

Proton-pump inhibitors (PPIs) are widely recognized for their effectiveness and safety; however, kidney-related side effects, primarily acute tubulointerstitial nephritis (ATIN), can sometimes complicate their use. PPIs have the potential to induce hyponatremia, drug interactions, and hypomagnesemia from gastrointestinal losses. Furthermore, emerging evidence suggests that the use of PPIs may contribute to the development of chronic kidney disease (CKD). (3)

It is hypothesized that prolonged ATIN, a form of kidney inflammation, may progress to chronic tubulointerstitial nephritis, ultimately resulting in CKD and potentially end-stage kidney disease (ESKD). PPIs have been identified as one of the leading causes of drug-induced ATIN worldwide, particularly in patients who experience acute kidney injury (AKI) during hospitalization and have biopsy-confirmed ATIN. (3)

Decoding the Mechanisms: How PPIs May Cause Kidney Injury

There is a hypothesis that within the tubulointerstitium, proton-pump inhibitors (PPIs) and/or their metabolites may undergo reactions that lead to their function as haptens. Alternatively, they may directly stimulate T cells, resulting in the mediation of acute tubulointerstitial nephritis (ATIN). (3) The deposition of proton pump inhibitors and their metabolites in the tubulointerstitium causes an immune response which leads to interstitial inflammation, edema, and acute interstitial nephritis (AIN) which causes acute kidney injury (AKI) or interstitial fibrosis and tubular atrophy; eventually developing into chronic kidney disease and end-stage renal disease. (1)

Exploring the Types and Clinical Manifestations for PPI-Related Kidney Disease

The use of proton-pump inhibitors (PPIs) has been increasingly associated with a spectrum of renal diseases, including acute interstitial nephritis (AIN), acute kidney injury (AKI), and chronic kidney disease (CKD). While the symptoms of AIN are nonspecific and may resemble other conditions such as malaise, fatigue, weakness, arthralgia, myalgia, fever, and skin rash, eosinophilia is frequently observed as a characteristic finding. AIN is estimated to contribute to approximately 8% of cases of acute kidney injury, with medication being the primary cause in 70-90% of these cases. Among the drug classes implicated in AIN, antibiotics, PPIs, and non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly linked. (1)

Examining the Evidence: Studies Correlating Use of PPIs and Kidney Disease

• A population-based study was conducted by Antoniou et al. in which a total of 290,592 individuals were included with age 66 years and older who were on PPI therapy. The primary outcome was hospital admission with acute kidney injury in 120 days and secondary analysis showed acute interstitial nephritis. Patients prescribed proton-pump inhibitors (PPIs) had higher rates of acute kidney injury compared to controls resulting in a hazard ratio (HR) of 2.52 (95% CI 2.27 to 2.79). The incidence of acute interstitial nephritis was also higher in the PPI group compared to the control group with an HR of 3.00 (95% CI 1.47 to 6.14). This concludes that PPI therapy is associated with an increased risk of acute kidney injury and acute interstitial nephritis. (4)
• A case-control study was conducted by Peng et al. to find out the association between PPI use and the occurrence of end-stage renal disease (ESRD) in which data from 3808 patients suffering from renal diseases was extracted aged >20 years who were recently diagnosed with ESRD compared to 3808 patients with renal disease without ESRD. It was found that among patients with renal disease, the utilization of proton pump inhibitors (PPIs) was found to be significantly associated with an increased risk of end-stage renal disease (ESRD) (adjusted odds ratio [OR] = 1.88, 95% CI = 1.71–2.06). This concludes that the use of PPIs is associated with ESRD in renal disease patients. (5)

Current Recommendations on Deprescribing PPIs (6)

In order to address the use of proton pump inhibitors (PPIs) in patients who experience adverse kidney outcomes associated with PPIs, several strategies can be implemented.

Clinical practice guidelines are being developed as per a Canadian report to guide on deprescribing of proton pump inhibitors (PPIs) in various patient categories. These categories include:

1. Patients without a clear indication for PPI use:

Recommendation: Deprescription of the medication.

2. Patients with an unknown indication for PPI use:

Recommendation: A cautious approach should be opted involving dose reduction, discontinuation and monitoring the need for continued use may be appropriate for deprescription.

3. Patients with mild or moderate esophagitis or gastroesophageal reflux disease (GERD):

Recommendation: If symptoms have resolved after 4 to 8 week course of PPI use, either deprescription should be done by reducing the dose or discontinuation of the medication should be done and using it on as-needed basis. Regular follow-ups should be done.

4. Patients who were initially treated with PPIs for a specific indication (such as peptic ulcer disease caused by NSAID use or H. pylori infection, intensive care unit prophylaxis, or upper gastrointestinal symptoms) but have continued PPI treatment beyond the recommended duration despite symptom resolution:

Recommendation: PPIs should be deprescibed by stopping their use.

5. Patients with conditions requiring long-term PPI use, such as Barrett's esophagus, bleeding ulcers, severe esophagitis, and long-term NSAID users at risk of bleeding:

Recommendation: Long-term PPI treatment is recommended in these cases.

Acknowledging the link between kidney inflammation and PPI usage, the DCGI (Drug Controller General of India) mandate all Indian manufacturers of PPI to mention AKI as an alert in their packages and advertising materials in November 2019. (7)

Key Pointers

• Proton pump inhibitors are commonly used medications for reducing stomach acid secretions in the treatment of various gastrointestinal diseases.
• PPIs have been associated with renal diseases such as acute interstitial nephritis, acute kidney injury, and chronic kidney disease.
• Studies have shown an increased risk of acute kidney injury, acute interstitial nephritis, and CKD associated with PPI therapy.
• Clinical guidelines recommend lifestyle changes and monitoring of relevant parameters to manage and prevent kidney disease.
• Clinicians may consider opportunities for deprescribing PPIs, as needed. Keeping in mind the adverse effect of PPIs, other treatment options such as H2 blockers could be considered.

References:

1. Morschel, C. F., Mafra, D., Eduardo, J. C. C. (2018). The relationship between proton pump inhibitors and renal disease. Jornal Brasileiro de Nefrologia: órgão Oficial de Sociedades Brasileira e Latino-Americana de Nefrologia, 40(3), 301–306.

2. Varughese, S., & Abraham, G. (2018). Chronic kidney disease in India: A clarion call for change. Clinical Journal of the American Society of Nephrology: CJASN, 13(5), 802–804.

3. Paueksakon, P., & Fogo, A. B. (2022). Do proton-pump inhibitors cause CKD and progression of CKD?: COMMENTARY. Kidney360, 3(7), 1141–1143.

4. Antoniou, T., Macdonald, E. M., Hollands, S., Gomes, T., Mamdani, M. M., Garg, A. X., Paterson, J. M., & Juurlink, D. N. (2015). Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open, 3(2), E166-71.

5. Peng, Y.-C., Lin, C.-L., Yeh, H.-Z., Chang, C.-S., Wu, Y.-L., & Kao, C.-H. (2016). Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: A population-based, case-control study: A population-based, case-control study. Medicine, 95(15), e3363.

6. Al-Aly, Z., Maddukuri, G., & Xie, Y. (2020). Proton pump inhibitors and the kidney: Implications of current evidence for clinical practice and when and how to deprescribe. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation, 75(4), 497–507.

7. Central Drugs Standard Control Organisation. 2018. Proton Pump Inhibitor - Kidney Disease (Report No. 24).