Impact of Proton Pump Inhibitors on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review

Proton pump inhibitors (PPIs) are widely prescribed medications for the management of various gastrointestinal disorders, primarily gastroesophageal reflux disease (GERD) and peptic ulcers. However, recent concerns have emerged regarding their potential adverse effects on kidney function and their role in the progression of chronic kidney disease (CKD). This systematic review aims to comprehensively analyze the existing literature to assess the impact of PPI use on kidney function and CKD progression. We took information from PubMed, PubMed Central (PMC), and Google Scholar articles from the last 10 years, from 2013 to 2023, and looked for links between PPI use and a number of kidney-related outcomes. These included acute kidney injury, a drop in the estimated glomerular filtration rate (eGFR), and new cases of CKD. The findings of this systematic review highlight the need for a thorough evaluation of the benefits and risks associated with PPI use, particularly in patients with pre-existing kidney conditions, in order to inform clinical decision-making and improve were taken out and looked at to see if there were any links between PPI use and different kidney-related events, such as acute kidney injury, a drop in the estimated eGFR, and the development of CKD. The review also explores potential mechanisms underlying PPI-induced nephrotoxicity. The findings of this systematic review highlight the need for a thorough evaluation of the benefits and risks associated with PPI use, particularly in patients with pre-existing kidney conditions, in order to inform clinical decision-making and improve patient care. Further research is warranted to better understand the complex interplay between PPIs, kidney function, and CKD progression.


Introduction And Background
This article was previously posted to the Research Square preprint server on September 21, 2023 [1].
Worldwide, proton pump inhibitors (PPIs) are extensively utilized in acid suppression therapy.In addition to antibiotics, they are frequently prescribed for a number of acid-related conditions, such as gastroesophageal reflux disease (GERD), peptic ulcer disease, esophagitis, gastritis, Barrett esophagus, and the removal of Helicobacter pylori.They are also frequently administered in conjunction with nonsteroidal antiinflammatory medications (NSAIDs) and for preventive purposes.
An estimated 15 million people in the US are reported to be using prescription PPIs (estimated prevalence of 7.8% in the adult population) [2].Because PPIs can also be purchased over-the-counter without a prescription, the actual prevalence of PPI use is probably substantially greater.Market research reports indicate that 385 million units of over-the-counter "heartburn" medications, of which PPIs account for 85% of the market, were sold in 2017, with an estimated $2.6 billion in sales [3].Some studies show that people with chronic kidney disease (CKD) are given PPIs more often and for longer periods of time than people without CKD.This means that the number of people who use PPIs is probably higher in the CKD community than in the non-CKD community [4].
PPIs are frequently used for durations of usage and indications that the US Food and Drug Administration (FDA) has never evaluated or approved.They are commonly prescribed excessively, infrequently taken down, and frequently started incorrectly when a patient is in the hospital.Furthermore, their use is prolonged even when there is no medical need for it [5][6][7][8][9][10].It is believed that between 53% and 69% of PPI prescriptions are written for unsuitable purposes [5,11], wherein in many situations the advantages of using PPIs (or not using them) may not outweigh the dangers [11][12][13].

Inclusion and Exclusion Criteria
In our analysis, we looked at all full-text papers, studies with people as subjects, and papers that were published in English.In the 10 years from 2013 to 2023, many studies were written about how PPIs affect kidney function and the progression of chronic kidney disease.These studies included clinical trials,

Discussion
PPIs are associated with the development of CKD (Figure 2).PPIs have been generated to prevent the stomach from secreting stomach acids and raise the pH of the stomach fluid.They distinguish themselves from other medications employed for the treatment of gastrointestinal illnesses by additionally blocking the final phase in the formation of hydrochloric acid, which prevents the enzyme called H+/K+-ATPase from carrying out its function and preventing the substitution of K+ for hydrogen ions.PPIs are currently the medicine of preference since this mechanism increases their effectiveness of resistance [40,41].PPIs obstruct the activity of the enzyme by interacting with its binding partner and linking it covalently to irrevocable inhibitory residues of cysteine.The proton pump cannot regenerate after the process has begun, and acid generation only happens after the creation of freshly generated enzymes.Irreversible suppression guarantees that the drug remains effective for a period of between 24 and 48 hours [42][43][44].

FIGURE 2: Pathophysiology of PPI and CKD proggression
Relationship between PPI use and the development of CKD PPIs -proton pump inhibitors, CKD -chronic kidney disease Among the drugs that are most frequently prescribed in the United States is PPI, and anywhere from 25% to 70% of scripts are thought to be written without the proper justification [5].The amount of time used regularly exceeds advised limits [45].Additionally, there is a tendency for PPI usage in young children and babies [46].In 2013, more than fifteen million individuals took prescription PPIs, spending over $10 billion on them in America [47].According to 29 investigations, 70% of those medications are unneeded, and 25% of chronic PPI consumers may stop taking their medication without incurring any side effects [48].
PPIs are classified as weak acidic compounds that vary primarily in their particles and have a similar fundamental molecular framework as other weak acids.Whenever delivered, they have no effect; however, if the environment is acidic, they produce sulfamide metabolites or sulfenic acid.PPIs have a gastro-resistant layer to stop the medicine from activating and degrading earlier than it reaches the intended location.After management, the medications are promptly assimilated and active due to their approximately one-to twohour plasma half-lives.PPIs undergo metabolism by hepatic enzymes called cytochrome P450, which therefore might impact how other drugs are biotransformed.Additionally, alterations in the pH of the stomach may modify how different medicines are absorbed [49,50].
But as time passed, PPIs started to be indiscriminately administered to individuals for purposes that weren't intended, for a more significant duration than was advised, and by people who were taking their medication [51].Aside from the side effects listed above, more and more evidence is showing that PPIs can cause bone fractures, respiratory infections, magnesium deficiency, dementia, and kidney diseases like acute kidney injury (AKI), acute interstitial nephritis (AIN), and CKD [52,53].
AIN is one of the infrequent side effects that PPIs are most frequently linked to.The interstitium and the tubules of the kidneys are both involved in this immune-driven response.Infection, blood abnormalities, autoimmune diseases, and medications all have the potential to cause it.Tubule tissue cells are initially damaged, and then a mononuclear inflammatory infiltration with a predominance of T cells is seen.The renal cortex may start to scar as a result of the infiltration spreading, which will also cause a decline in kidney function.Individuals with drug-induced AIN can acquire CKD with fibrosis of the interstitial space and atrophy of the tubular walls if no improvement in symptoms is apparent after stopping the alleged medication and starting steroids [54,55].
According to estimates, AIN accounts for 8% of cases of acute kidney damage, between 70% and 90% of which are drug related.Antibiotics, PPIs, and NSAIDs constitute the primary pharmacological categories associated with AIN [56,57].Numerous studies published after the initial case study from 1992 [39,58] confirmed the link between AIN and PPI consumption.PPI users had a three-fold increased incidence of AIN, according to Antoniou et al. (95% CI 1.47-6.14;n = 290,592).It is not known what causes the inflammation of the kidneys in these people, but the buildup of PPIs and/or their related metabolites in the interstitial tubes and the autoimmune reaction that follows have been suggested as a possible explanation [23,59].
Acute kidney injury could be accelerated by the rapid decline in kidney functioning caused by tubulointerstitial pathologies.The investigation into the underlying causes of this condition led to the discovery of AIN, which a kidney biopsy frequently confirms.Gallium-67 scintigraphy is a technique that can be used to distinguish between AIN and acute necrosis of the tubes in cases where biopsy is not advised.About 30% of those who improve from AKI continue to have an elevated risk of developing CKD [60][61][62][63].A further adverse consequence of PPI usage is hypomagnesemia.PPIs were linked to a twice-rise in the probability of having low magnesium levels, according to research of 9,818 participants (95% CI: 1.36 to 2.93).The physiological process underlying the reduction in magnesium, or Mg, levels caused by PPIs is not fully understood.Reduced urine concentrations imply that the intestinal tract is where magnesium depletion occurs.Studies suggest that CKD and low blood levels of magnesium (0.7 mmol/L) are related.Prolonged interstitial nephritis can eventually result in failure of the kidneys and, in extreme situations, CKD [56,64].
Lazarus et al. were the initial researchers to propose a link between PPIs and CKD in 2016.The authors investigated the possibility that histamine H2-receptor antagonists (H2) and PPIs individually pose a possibility for CKD.The researchers employed 10,482 participants from the Atherosclerosis Risk in Communities (AIRC) research group.10,482 individuals in ARIC had an average follow-up of 13.9 years.248,751 people in the confirmation population were monitored for an average duration of 6.2 years.The investigation was then conducted again with 248,751 Geisinger Health System patients.The results were comparable across each of the groups of individuals, and PPI usage was linked to an increased likelihood and a 1.17 to 1.5-fold greater chance of developing CKD.The relationship had to be verified using PPIs.In ARIC, there were a total of 56 occurrences of CKD events in the group of 322 baseline PPI users (14.2 per 1,000 person-years) and 1,382 events among the 10,160 baseline those who were not users (10.7 per 1,000 personyears), compared to non-users who had a greater beginning BMI and were taking antihypertensive, pain reliever, or statin drug medications.Among 322 initial PPI users, the anticipated 10-year overall likelihood of developing CKD was 11.8%; however, their predicted risk would have been 8.5% had patients avoided using PPIs (absolute risk difference, 3.3%) [65].
A work by Xie et al. linked PPIs with CKD and the development of failure of the kidneys.The participants selected were tracked for a period of five years (n = 173,321 for PPIs and n = 20,270 for H2RA).According to the investigation, people taking PPIs had a 1.28 times increased chance of getting CKD, along with a 1.96 times higher risk of going on to develop chronic renal failure.As in other investigations, no connection between H2RA and renal illness was discovered [10].A three-week treatment with PPIs, such as omeprazole, lansoprazole, and pantoprazole at a dose of thirty milligrams per kilogram in rodents merely resulted in an increase in serum levels of IS, according to the study.The increased amounts of liver CYP2E1 protein, which promotes IS production, are likely responsible for this impact.This process may help to explain the link between the use of PPIs and a higher risk of developing CKD [17].We should follow specific guidelines while prescribing PPIs [66].

Conclusions
Our systematic review of the impact of PPIs on kidney function and CKD progression has provided valuable insights into this important medical topic.Through a comprehensive analysis of existing research, it has become evident that the use of PPIs is associated with certain risks to kidney health.While PPIs have been effective in managing various gastrointestinal conditions, their potential adverse effects on kidney function cannot be ignored.The findings of this review suggest that healthcare professionals should exercise caution when prescribing PPIs, especially for patients with pre-existing kidney conditions or those at risk of developing CKD.Close monitoring of kidney function and thoughtful consideration of alternative treatment options should be integral parts of clinical decision-making.In summary, while PPIs have revolutionized the management of acid-related disorders, their impact on kidney function underscores the importance of a balanced approach to their use, taking into account individual patient factors and a commitment to minimizing potential harm to kidney health.

FIGURE 1 :
FIGURE 1: PRISMA flow chart PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis; MeSH: Medical Subject Headings; SANRA: scale for quality assessment of narrative review articles; PMC: PubMed Central.
2.46 and 2.01, respectively.The predicted IRR and aIRR for the period including PPIs and macrolide antibiotics in comparison to those involving PPIs alone were 1.26 and 0.82, respectively.
(IS), as a potential cause of chronic kidney disease (CKD).which is an important enzyme in the creation of IS.This is because PPIs prevent this enzyme from being broken down, which raises the exposure to IS.It is noteworthy that kidney impairment with mild glomerular structural alterations and fibrosis symptoms only happened after three weeks of high-dose PPI treatment (30 mg/kg).was5.88[4.17;8.28]compared to those who received fewer than 5. Dialysis, all-cause death, and the progression of CKD were all markedly more likely to occur in the PPI group (aHR, 1.83; 95% CI, 1.53 to 2.19; aHR, 1.84; 95% CI, 1.26 to 2.67; and Acute interstitial nephritis (0.32 vs. 0.11 per 1000 person-years; HR 3.00, 95% CI 1.47 to 6.14) and acute kidney damage (13.49 vs. 5.46 per 1000 person-years; HR 2.52, 95% CI 2.27 to 2.79) were more common in people who were given PPI than in people who were not.There was a statistically significant correlation between PPIs and CKD (adjusted hazard ratio [HR] = 3.753, 95% CI = 2.385-5.905).PPI use and the risk of post-hospitalization AKI were not statistically significantly associated after adjusting for baseline comorbidities, drug use histories, and demographic characteristics (rate ratio [RR], 0.91; 95% CI, 0.38 to 1.45).According to baseline AKI status, there were no significant associations between the use of PPIs and the incidence or risk of recurrent AKI (RR, 1.inhibitors (hazard ratio 2.30, 95% confidence interval 1.26-4.20).A significantly higher risk of the secondary outcome of any major renal incident was also linked to the use of proton pump inhibitors (hazard ratio 2.61, 95% confidence interval 1.80-3.80).2023Parmaret al.Cureus 15(12): e49883.DOI 10.7759/cureus.49883renalinjury.21,643patients in all-6,000 PPI and 15,643 non-PPI-met all research requirements.When compared to controls, the PPI cohort had a twice as high incidence of AKI (2.12, hazard ratio: 1.46-3.1).CKD and eGFR<60 ml/min per 1.73 m2 were more likely to happen in the PPI group compared to the H2 blockers group (HR, 1.22; 95% CI, 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively).Patients taking PPI also had a higher chance of having their serum creatinine level double (HR, 1.53; 95% CI, 1.42 to 1.65), their eGFR drop by more than 30% (HR, 1.32; 95% CI, 1.28 to 1.37), and they developing end-stage renal disease (HR, 1.96; 95% CI, 1.21 to 3.18).were rate: 6.1/10 000 person-years).Compared to prior PPI usage, the use of PPIs is currently linked to a greater risk of AKI (unadjusted OR, 4.09; 95% CI, 3.09 to 5.44).In comparison to the present use of PPIs alone, the unadjusted ORs of AKI for the combination of PPIs and