Research Progress on the Potential Mechanisms of Acute Kidney Injury and Chronic Kidney Disease Induced by Proton Pump Inhibitors

Abstract

Proton pump inhibitors (PPIs) are acid-suppressing medications widely used in peptic ulcers; however, their widespread use has led to many adverse renal events. Among these events, the most common form of acute kidney injury (AKI) is acute interstitial nephritis (AIN), which is the clinical manifestation. Several clinical trials and cohort studies have shown a significant relationship between PPIs and AKI induction; however, the pathogenesis of PPIs leading to AKI is unclear. In this paper, we reviewed the potential mechanisms by which PPIs cause AKI and proposed new conjectures. We considered that PPIs led to the development of AKI through a combination of mechanisms. By searching and reviewing PubMed and Embase, a total of 29 studies were finally included and reviewed, and the findings suggested that the mechanisms by which PPIs induce AKI are mainly related to oxidative stress, immune response, inflammatory response, mitochondrial damage, calcium overload, and the induction of cellular necrosis. In addition, tubular cell necrosis can cause tubulointerstitial fibrosis and progressive renal unit loss. Long-term follow-up observations also suggested that PPIs can contribute to AKI progression to chronic kidney disease (CKD). Therefore, we will also explore the potential link between PPIs and CKD.

INTRODUCTION

Acute kidney injury (AKI) is characterized by a rapid loss of renal excretory function and is diagnosed according to the 2012 KDIGO Clinical Practice Guidelines for AKI.^[1] It is measured clinically as an increase in serum creatinine (Scr) ≥ 0.3 mg/dL (26.5 μmol/L) within 48 h or 1.5 times higher than the baseline value within 7 days or oliguria within ≥ 6 h. A meta-analysis of AKI incidence in high-income countries in North America, Northern Europe, and East Asia showed a combined incidence of 21.6% (95% confidence interval (CI): 19.3–24.1) for adults and 33.7% (95% CI: 26.9–41.3) for children with AKI. Combined AKI-related mortality was 23.9% (95% CI: 22.1–25.7) in adults and 13.8% (95% CI: 8.8–21.0) in children.^[2] The global epidemiology and outcomes of AKI suggest that infections, sepsis, and the use of nephrotoxic drugs are common risk factors for AKI in almost all countries.^[3] Drug nephrotoxicity is one of the major causative factors of AKI because the body relies on the kidneys to excrete waste products and metabolites from the blood, and the kidneys are susceptible to nephrotoxicity from direct exposure to drugs and metabolites. The adverse effects of drug nephrotoxicity on the kidneys are difficult to diagnose in the early phase; they are not detected until they cause a rapid rise in Scr and a rapid decrease in glomerular filtration rate. Drug-induced acute kidney injury (DI-AKI) damages the vascular system, glomeruli, tubules, and interstitium, and its common pathogenesis includes direct drug nephrotoxicity, inflammatory immune response, obstructive lesions, metabolic disturbances, and hemodynamic effects.^[4] DI-AKI can be classified into four phenotypes: acute vascular disease, acute glomerular disease, acute tubular injury/necrosis, and acute interstitial nephritis, but usually, drug-induced AKI is divided into two types: acute tubular necrosis (ATN) and AIN.^[5] DI-AKI accounts for approximately 19%–26% of all AKI cases in hospitalized patients.^[6]

Proton pump inhibitors (PPIs) are widely used as acid suppressants for the treatment of peptic ulcers, upper gastrointestinal bleeding, and Helicobacter pylori infection. However, their nephrotoxicity has only received attention in recent years, with adverse renal outcomes including AKI, ATN, chronic kidney disease (CKD), and renal disease progression. In a multicenter cross-sectional survey on hospital-acquired AKI from China,^[7] 1960 cases were diagnosed with hospital-acquired AKI, of which 735 were DI-AKI (37.50%, 735/1960), with in-hospital mortality rates of 13.88% and 54.34%, respectively. A total of 1642 drugs were associated with AKI in these cases, and PPIs were the third most relevant drugs among the 10 drugs associated with DI-AKI (10.48%, 172/1642). The first reported PPI-induced AKI developed from AIN, where several infiltrating inflammatory cells were discovered in the renal interstitium, and PPI-induced AIN (PPI-AIN) may be a specific immune response or drug hypersensitivity reaction.^[8] A Dutch cohort study showed that PPI users were at higher risk of hypomagnesemia, which is associated with endothelial dysfunction, oxidative stress, and renal interstitial inflammation, compared to patients without PPIs, suggesting that hypomagnesemia may be associated with PPI-AIN.^[9–11] There are many cohort studies, animal experiments, and case reports on PPI-AKI. Corsonello summarized the full range of possible adverse effects of PPIs ^[12] and the section on the kidney only mentioned tubulointerstitial inflammation as a potential mechanism of renal injury caused by PPIs; however, the comprehensive mechanism is unclear.

In this study, we reviewed and summarized the incidence of PPI-AKI and multiple potential mechanisms.

METHODS

We conducted a systematic search of electronic databases such as PubMed and Embase to determine the studies on PPIs as the cause of AKI. A combination of the following two terms was used as search terms: “PPIs” OR “proton pump inhibitors” AND “acute kidney injury” OR “kidney injury “ OR “nephrotoxicity”. Inclusion criteria were full-text English literature related to the topic. The specified exclusion criteria were as follows: (a) case reports, clinical studies, case series, editorials, and reviews; (b) concurrent use of PPIs and other medications; (c) metabolites of PPIs; (d) articles not written in English; and (e) the years searched range from 2016–2022. We added some important, relevant literature before 2016. A summary of the literature search process is presented in Figure 1.

Figure 1.: Summary of the literature search process, Proton pump inhibitors (PPIs).

RESULTS

Studies characteristics and mechanism

A total of 29 potentially relevant studies were finally included; 12 cohort studies, 3 data mining studies, 4 clinical and experimental studies, and 10 other relevant studies. Eleven studies were included to analyze AKI incidence, and they met the inclusion and exclusion criteria (Figure 1). In Table 1, all 11 studies were cohort studies. For the database mining studies, the incidence of AKI resulting from PPI use could not be calculated because PPI users without renal adverse events were not included in the US Food and Drug Administration Adverse Event Reporting System. These studies reported the incidence of AKI due to PPI use in different countries, the relative risk magnitude of AKI due to different types of PPI use, and the comparative risk of AKI and CKD due to PPI use. According to the results of these studies, there is a high correlation between PPI use and AKI occurrence. PPIs can also cause AKI progression to CKD. According to clinical and experimental studies, the pathway of PPIs-induced AKI mainly causes interstitial inflammation and tubular cell necrosis in the kidney.

Table 1 - Cohort studies on the use of PPIs leading to AKI in different populations

Author	Study period	Population	Nation	RR (95% CI)	Incidence
Leonard et al. [13]	2012	27,982	UK	1.05(0.97–1.14)	4.61%(765/16,593)
Li et al. [14]	2013–2015	11,496	China	1.36(1.20–1.55)	17.07%(1962/11,496)
Liu et al. [7]	2014	1642	China	/	10.48%(172/1642)
Antoniou et al. [15]	2015	290,592	Canada	1.47(1.06–2.04)	0.61%(1787/290,592)
Lazarus et al. [16]	2016	248,751	US	1.31(1.22–1.42)	6.79%(16,900/248,751)
Lee et al. [17]	2016	3725	US	1.02(0.92–1.11)	20.05%(747/3725)
Ikuta et al. [18]	2005–2017	219,082	Japan	2.79(2.06–3.79)	0.14%(317/219,082)
Avinash [19]	2017	175	India	/	10.86%(19/175)
Cho et al. [20]	2018	934	Korea	1.46(1.05–2.02)	16.50%(154/934)
Hart et al. [21]	2019	16,593	US	4.35(3.14–6.04)	0.89%(148/16,593)
Sutton et al. [22]	2019	21,643	US	2.12(1.64–3.1)	27.72%(6000/21,643)

Regarding the mechanisms, PPIs induce AKI through the actions or effects of oxidative stress, immune response, inflammatory response, mitochondrial damage, calcium overload, and induction of cellular necrosis. In addition, we speculated other possible mechanisms (Figure 2), which we will discuss later in this section. These mechanisms are described in detail below.

Figure 2.: This Figure identified eight potentially existing mechanisms of PPI-AKI: Oxidative stress, Hapten/IC, Direct nephrotoxic, Calcium overload, Renal injury markers, Hypomagnesemia, induced cell necrosis, pyroptosis. Many crosstalks existed in these mechanisms, and their mutual effects caused the injury of tubular and renal interstitial cells, which induced AKI occurrence. ↑ Upregulation; ↓ Downregulation.

Oxidative stress and mitochondrial damage

PPI-induced renal cell death is closely associated with increased production of reactive oxygen species (ROS), and PPIs induce intense oxidative stress ^[23,24] with massive intracellular ROS production, mainly from mitochondria and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase. Simultaneously, the production of large amounts of ROS leads to lipid peroxidation, which can alter cellular fluidity and permeability, thereby causing cellular damage.^[25] ROS can also cause mitochondrial damage, making mitochondria unable to maintain cellular redox and energy homeostases, such as mitochondrial dysfunction and mitochondrial membrane loss, leading to mitochondrial permeability transition (MPT) and the release of pro-apoptotic proteins to induce cell death.^[26–28] Renal tubular cells are rich in mitochondria, and AKI mainly affects the tubules; alterations in tubular mitochondrial homeostasis are important markers of AKI.^[29,30] ROS directly affect protein and DNA synthesis and cellular repair mechanisms, whereas increased tumor necrosis factor (TNF-α) and transforming growth factor-β (TGF-β) are also cytotoxic, leading to toxic tubular injury.^[31] ROS promotes the process of renal tissue fibrosis by enhancing inflammation; inflammation and fibrosis will increase ROS production, forming a vicious cycle that leads to severe renal injury.^[28]

PPIs can cause lysosomal alkalinization by inhibiting lysosomal membrane H⁺/K⁺, ATPase, and lysosomal hydrolase activity while decreasing intracellular ATP levels, and a significant decrease in ATP can lead to mitochondrial damage.^[32,33] Both mitochondrial dysfunction and reduced lysosomal hydrolase activity produce the damaging oxidative stress substance—ROS, which leads to renal tubular cell death through direct nephrotoxicity.^[30] Therefore, it can be inferred that the combined effect of the decrease in intracellular ATP levels caused by PPIs and the oxidative stress product—ROS is a synergistic factor leading to renal tubular cell death.

Inflammation and immunity

Renal biopsies performed in 25 PPI-AIN cases showed that all patients had features of acute tubular inflammation and interstitial inflammation accompanied by a large infiltration of inflammatory cells with no glomerular involvement.^[34] The inflammatory cells and cytokines were mainly CD4⁺ lymphocytes, monocytes, and interleukin (IL)-17, suggesting that the inflammation may be helper t-cell (Th) 17-mediated, whereas the direct contact of Th17-produced IL-17 with renal cells may have led to tubular and interstitial cell injury.

PPIs and their metabolites may be deposited on the tubular basement membrane and act as haptens that bind to certain macromolecular proteins to produce immunogenicity,^[35] inducing an immune response. This process results in the activation of macrophages and fibroblasts and the infiltration of large numbers of neutrophils into the renal interstitium.^[36] In addition, the production of several inflammatory cytokines and their direct contact with the renal tissue leads to severe renal injury.

PPIs and their metabolites may stay in circulation for too long due to slow metabolism in the host body and continuously stimulate the body to produce antibodies and bind to them, forming medium-sized circulating immune complexes, causing type III hypersensitivity reactions, activating complement, producing allergenic toxins and recruiting neutrophils, etc., causing inflammatory reactions and kidney injury.

PPIs can cause hypomagnesemia, and it has been shown that renal endothelial cells in a hypomagnesemic environment activate the nuclear factor-κB (NF-κB) signaling pathway, whereas increased production of the inflammatory cytokines IL-8 and TNF-α can lead to tubular endothelial cell necrosis.^[37] Thus, hypomagnesemia leads to tubular endothelial cell dysfunction or renal interstitial inflammation through the induction of pro-inflammatory effects, which leads to the development of AKI.

Calcium overload

It has been shown that intracellular Ca²⁺ concentration and renal cell activity were inhibited in human embryonic kidney cells and rat renal tubular duct epithelial cells under the effect of different PPIs positively correlated with the concentration of PPIs. The mechanism may be that PPIs increase the intracellular Ca²⁺ concentration by inhibiting intracellular Na⁺ and K⁺-ATPase activity, leading to intracellular Ca²⁺ overload, which activates the p38MAPK pathway, leading to an inflammatory response.^[38–40] It also increases the expression of the cysteinyl aspartate specific proteinase (caspase) 3 protein, which is associated with apoptosis, and the expression of endothelin-1 (ET-1), which causes vasoconstriction and ischemia, causing renal tubular injury, and is increased in AKI.^[41] Therefore, Ca²⁺ overload may be one of the mechanisms by which PPIs cause AKI.

Induced cellular necrosis

Ye et al. induced AKI in mice by cisplatin with daily continuous administration of lansoprazole (LPZ), a common PPI. The results showed that LPZ significantly aggravated renal injury after cisplatin-induced AKI with a further elevation of Scr and blood urea nitrogen.^[42] Compared with the control group treated with cisplatin alone, LPZ increased the number of renal tubular necrotic cells, not cisplatin-induced apoptosis. From the Bax/Bcl-2 ratio, PPI upregulated the expression of the anti-apoptotic protein Bcl-2 and downregulated the expression of the pro-apoptotic protein Bax. The morphology of necrotic cells was swollen and ruptured under electron microscopy, which was not consistent with the crumpled cell morphology caused by normal apoptosis. Meanwhile, the detection of mRNA expression of pro-inflammatory factors and inflammatory cells manifested increased mRNA expressions of nucleotide-oligomerization domain-like receptor 3 (NLRP3), IL-1β, TNF-α, and infiltration of neutrophils, which revealed one of the mechanisms of action of PPI-induced AKI, leading to necrosis rather than apoptosis of renal tubular cells through the pro-inflammatory effect. This is consistent with the findings when renal biopsies of PPI-AIN patients showed no glomerular involvement and inflammatory infiltration in the tubules and interstitium.

Miguel's experiment showed that omeprazole induced necrosis in human and murine proximal renal tubular cells, and necrotic features such as vacuolization and irregular chromatin coalescence were observed.^[24] Although weak activation of the apoptosis-related protein caspase3 was observed, inhibitors of necroptosis (Necrostatin-1) or iron death (Ferrostatin-1) did not prevent omeprazole-induced death, suggesting that cell death induced by PPIs is necrotic rather than apoptotic, which is consistent with the experimental results of Ye et al. In renal tubular cells, omeprazole also increased the expression of renal injury and oxidative stress (expression of neutrophil gelatinase-associated lipocalin (NGAL) and heme oxygenase-1 (HO-1)) markers. Thus, the mechanism of AKI induction by PPIs may be related to the induction of tubular cell necrosis through pro-inflammatory effects and oxidative stress.

Relationship between PPIs, CKD, and renal fibrosis

The regular use of PPI is associated with a higher risk of CKD.^[43] A meta-analysis including 10 observational studies showed that the risk ratio (RR) of CKD associated with PPI use was 1.35 (95% CI: 1.15–1.56) compared to patients without PPIs, p < 0.001.^[44] After analysis of several observational and cohort studies, we identified a strong association between PPI use and the occurrence and progression of CKD events. High doses or prolonged use of any type of PPI increased the risk of CKD events, especially after 3 months of administration.^[45] A case-control study in Taiwan, China showed an odds ratio (OR) of 1.41 (95% CI: 1.34–1.48) for CKD in patients using PPIs compared to those who never used PPIs, and all major types of PPIs were associated with CKD events.^[46] In a retrospective cohort study in Brazil with 199 patients diagnosed with CKD, 42.7% were PPI users. The percentage of CKD progression was higher in PPI users than non-users, with an hazard ratio (HR) of 7.34 (95% CI: 3.94–13.71) after review and analysis.^[47] A prospective cohort study had a similar result, and follow-up of CKD patients using PPIs revealed that multiple patients developed AKI or CKD progression. For CKD progression, the adjusted HR associated with PPI prescription was 1.74 (95% CI: 1.26–2.40); the adjusted HR for AKI associated with PPI prescription was 2.89 (95% CI: 1.91–4.38).^[48]

A retrospective database study from the United States showed that the overall weighted prevalence of PPI use was 8.7%.^[49] The rate of PPI use varied by race, so the prevalence would differ by race, which may be one reason for the different prevalence rates in studies from the same country or different countries. Differences in the metabolism of PPIs in different ethnic groups may be another reason.

PPI-AKI is the basis of PPIs leading to CKD events and CKD progression and is not a direct result of PPIs. We speculated that PPIs leading to CKD events and CKD progression might occur through two pathways: renal interstitial fibrosis and renal tubular endothelial dysfunction (Figure 3). PPIs leading to AKI produce a cytokine, TGF-β, which is involved in the regulation of tissue response to injury.^[50] TGF-β is a major driver of fibrosis and scar formation that ultimately leads to renal failure. It also plays a significant role in multiple mechanisms leading to renal fibrosis.^[51,52]

Figure 3.: Drug-induced hypomagnesia and the elevation of TGF-β are two major aspects that contribute to the progression of CKD. TGF-β is an important regulator of renal fibrosis, which promotes the progression of renal fibrosis through four pathways. A series of changes accompanied by hypomagnesemia will lead to renal tubular endothelial dysfunction. Renal fibrosis and tubular endothelial dysfunction ultimately lead to the onset of CKD. ROS: reactive oxygen species; CKD: chronic kidney disease.

Cellular injury caused by PPI-AIN or PPI-ATN leads to fibrotic matrix deposition and fibroblasts' proliferation. Initially, this deposition may contribute to tissue repair, with mild injury allowing the fibrotic matrix to be absorbed during tissue repair.^[53] Severe injury, however, leads to an excessive deposition that destroys and replaces normal renal structures, leading to renal failure. PPIs exacerbate the development of recurrent AIN. Continuous inflammation and repeated cycles of renal injury and repair can also accelerate the progression of interstitial fibrosis and CKD.^[54]

Renal interstitial fibrosis is the main pathological mechanism of CKD, characterized by the proliferation of renal interstitial fibroblasts and excessive deposition of extracellular matrix (ECM), which destroys and replaces normal renal structures, leading to renal failure.^[53] Renal interstitial fibrosis may be regulated through four signaling pathways: Notch/Jagged, TGF-β/Smad, TGF-β/STAT3, and TGF-β/p53. Some experimental studies have shown that TGF-β induces Jagged1 expression in human renal tubular epithelial cells (HK-2) and that Jagged1 expression is enhanced with the development of renal interstitial fibrosis.^[55,56] TGF-β induced renal epithelial-mesenchymal transdifferentiation (EMT) when first mediated by Smad and then indirectly activated the Notch/Jagged signaling pathway, and EMT is critical in the development of renal tubular interstitial fibrosis.^[57] Recent evidence also suggests that the TGF-β/Smad signaling pathway regulates renal fibrosis via an epigenetic-correlated mechanism^[58] which involves crosstalk with the Notch/Jagged signaling pathway. An in vitro study showed that TGF-β promoted fibrotic changes in HK-2 cells through the STAT3 signaling pathway, and the main fibrotic indicators were collagen and fibronectin.^[59] P53 promotes apoptosis and proliferation inhibition in renal tubular cells, and the epithelial cell growth arrest that occurs after AKI and the development of renal fibrosis involve the TGF-β/p53 signaling pathway.^[60] The intense oxidative stress caused by PPIs generates large amounts of ROS, whereas TGF-β-triggered p53 phosphorylation and upregulation of the expression of several pro-fibrotic genes are dependent on the rapid production of ROS.^[51]

Renal tubular endothelial dysfunction affects renal reabsorption, secretion, and excretion, leading to CKD development. PPI use may lead to endothelial dysfunction through multiple mechanisms, including endothelial lysosomal dysfunction and impairment of enzymatic activity, decreased nitric oxide (NO) synthesis, and increased superoxide anion production.^[61] In addition, hypomagnesemia caused by PPIs led to renal tubular endothelial cell dysfunction by inducing pro-inflammatory effects, secretion of pro-atherogenic factors, and increased platelet aggregation to form thrombi.^[62] A study from Italy showed that 36% of patients on long-term PPIs had hypomagnesemia on admission and that the prevalence of CKD was higher in patients with hypomagnesemia than in healthy patients (18.6% vs. 8.0%, p < 0.05).^[63]

Comparison of the risk of AKI and CKD due to PPI use

A retrospective analysis from the Nordic Health System showed that initiation of PPI therapy and cumulative PPI exposure was associated with an increased risk of CKD progression.^[64]

A study by Lazarus showed that PPI use was more strongly associated with AKI than CKD,^[16] and participants using PPIs had a 1.72-fold greater risk of AKI than those not using PPIs (HR: 1.64; 95% CI: 1.22–2.21; p < 0.001); PPI use was associated with incident CKD (HR: 1.45; 95% CI: 1.11–1.90, p < 0.001).

A study by Nam-Jun Cho showed that PPI use was associated with AKI (HR: 1.46; 95% CI: 1.05–2.02), whereas the association between the duration of PPI use and CKD development was not statistically significant (HR: 1.50; 95% CI: 0.61–3.67).^[20]

Thus, PPIs are associated with adverse renal outcomes—AKI and CKD, and the risk of causing AKI is higher.

DISCUSSION

The mechanism of PPI-AKI may result from the combined action of multiple pathways. In addition to direct nephrotoxicity, the formation of immune complexes or hapten causing immune and inflammatory responses, intense oxidative stress, calcium overload, elevated expression of renal injury and oxidative stress markers, and the pro-inflammatory effects of hypomagnesemia, we speculate that several potential mechanisms contribute to AKI occurrence.

ROS produced by intense oxidative stress due to PPIs and the cytokine TNF-α in the immune response produces NLRP3 inflammatory vesicles and activates the NF-κB signaling pathway, leading to the activation of caspase-1 and elevated proIL-18/proIL-1β expression. They cause lysosomal and mitochondrial damage and induce IL-18 and IL-1β secretion, contributing to pyroptosis and inflammatory necrosis of kidney cells or tissues.^[65,66] The mRNA expression of NLRP3, IL-1β, and TNF-α was observed in Ye's experiment. Pyroptosis is likely one of the potential mechanisms of AKI caused by PPIs; however, experimental validation is still needed to detect the presence of NLRP3 inflammatory-body formation and increased expression of caspase-1, IL-18, and IL-1β.

PPIs induce NLRP3 inflammatory bodies that stimulate the modification of necrotic vesicles. This involves phosphorylation of receptor-interacting protein kinase 1 (RIPK1) and RIPK3, leading to phosphorylation of mixed lineage kinase domain-like protein (MLKL), which induces membrane permeation and cell disruption, triggering RIPK3-induced necroptosis.^[67] The NLRP3 inflammatory body activated Caspase-1, secreted IL-18 and IL-1β through Gasdermin pores, and released damage-associated molecular patterns (DAMPs). Furthermore, in the absence of infection, a RIPK-independent inflammatory response can be induced by DAMP activation of necroptosis.^[68,69] During the drive of necroptosis, Caspase-8 activity must be impeded because it can inhibit necroptosis by shearing RIPK1 and RIPK3. The morphology of necrotic cells was observed to be swollen and ruptured by electron microscopy; however, not all cell crumpling was due to apoptosis. Therefore, necrotic apoptosis may also be one of the potential mechanisms of PPI-AKI.

PPIs lead to increased expression of TNF-α in the immune inflammatory response, which may involve the TNFR-induced cell necrosis pathway,^[70] and activation of RIPK1 is required for the TNFR-mediated cell necrosis pathway.^[71] Therefore, the presence of activated RIPK1 needs to be tested.

Simultaneously, the intense oxidative stress produced by omeprazole leads to lipid peroxidation, which may involve iron death, a cell death caused by iron-dependent lipid peroxidation.^[72,73] However, in the experimental study by Miguel on the toxicity of omeprazole in renal tubular cells, inhibitors of iron death (Ferrostatin-1) or necroptosis (Necrostatin-1) did not prevent omeprazole-induced renal tubular cell death. This is probably because the iron death and necroptosis pathways are secondary to the mechanisms of PPI-AKI or are affected by other mechanisms. Therefore, it also needs to be verified experimentally whether PPIs lead to smaller mitochondria, reduced mitochondrial cristae, increased mitochondrial membrane density, and increased mitochondrial membrane rupture in renal tubular or renal interstitial cells. In addition, the existence of phosphorylated RIPK1, RIPK3, and MLKL should be detected. Most importantly, Caspase-8 activity must be inhibited.

Available evidence suggests that PPIs are effective and relatively safe in the short term; however, long-term or inappropriate PPI use should be avoided in older adults or patients with mildly impaired renal function. In addition, the combined use of NSAIDs, cephalosporins, and fluoroquinolones should be avoided in patients using PPIs, as the synergistic use of these drugs can significantly increase the risk of AKI.^[18] Also, patients with kidney disease must be aware of the risk of AKI and CKD associated with long-term PPI use.

Whether PPI-induced renal injury is age-related is not yet reported in the literature and relevant clinical studies. From clinical experience, the probability of AKI induced by long-term PPI use in older non-renal patients is greater than in other age groups, as is the case in patients with underlying renal disease.

CONCLUSION

PPI-AKI occurs mainly through two pathways: the induction of AIN (PPI-AIN) and ATN (PPI-ATN). The mechanisms of PPI-AKI may include oxidative stress and mitochondrial damage, immunity and inflammation, calcium overload, and induction of cellular necrosis.

In the PPI-AIN pathway, PPIs and their metabolites can act as haptens to bind macromolecular proteins to achieve immunogenicity and trigger immune inflammatory reactions. Binding with autoantibodies to form immune complexes leads to type III hypersensitivity reactions and triggers immune inflammatory reactions. Direct exposure of the kidney to high concentrations of PPIs leads to renal cell damage by direct nephrotoxicity. A series of immune-inflammatory reactions and direct nephrotoxicity severely affect the kidney, mainly manifesting as interstitial inflammation.

In the PPI-ATN pathway, PPIs induce renal tubular cell necrosis through the oxidative stress process of ROS production, leading to mitochondrial damage and lipid peroxidation. PPIs activate the NF-κB signaling pathway by causing hypomagnesemia, resulting in pro-inflammatory effects leading to tubular cell necrosis and inducing AKI. PPIs inhibit intracellular Na⁺ and K⁺-ATPase activity, leading to intracellular Ca²⁺ overload, activating the p38MAPK pathway, contributing to an inflammatory response, increasing ET-1 expression, and causing tubular injury. The massive necrosis of tubular cells subsequently leads to AKI.

This study shows that oxidative stress is the main mechanism of PPI-AKI. Previous studies have demonstrated that PPIs cause severe oxidative stress and mitochondrial damage, resulting in massive tubular cell damage. This is consistent with the decreased abundance of mitochondria in renal tubular cells; however, whether other mechanisms are the main mechanism of PPI-AKI is unclear, and more animal or cellular experiments are needed to clarify this.

We suggest that the mechanism of PPI-AKI is dominated by oxidative stress and mitochondrial injury, and other mechanisms are jointly involved in inducing and exacerbating AKI. The limitation of this study is that there are few relevant experimental studies, and we will explore the mechanism in depth through experiments at a later stage.

There is less direct evidence on the mechanism of PPIs inducing CKD or CKD progression. We speculate that PPIs leading to CKD events and CKD progression may occur via two pathways: Renal interstitial fibrosis and renal-tubular endothelial dysfunction. TGF-β is the primary mediator of renal interstitial fibrosis, and a total of four signaling pathways may be involved; renal tubular endothelial dysfunction may result from lysosomal dysfunction caused by hypomagnesemia, increased nitric oxide production, and thrombus formation, among other pathways.