Proton pump inhibitor-induced risk of chronic kidney disease is associated with increase of indoxyl sulfate synthesis via inhibition of CYP2E1 protein degradation

Lu, Shuanghui; Zhao, Jieping; Chen, Xiu; Xu, Shanshan; Yang, Xi; Zhang, Yingqiong; Ma, Zhiyuan; Jiang, Huidi; Zhou, Hui

doi:10.1016/j.cbi.2022.110219

Cited by 8 publications

(8 citation statements)

References 32 publications

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“…A previous study showed that PPIs affect gut-derived uremic toxin metabolism, suggesting that PPIs disturb the gut microbiome balance, which leads to the accumulation of gut-derived uremic toxin precursors, and that gut-derived uremic toxins aggravate CKD progression. 18 Our results showed that, in patients that received treatment with esomeprazole, rabeprazole, or vonoprazan, the time to occurrence of a 30% eGFR reduction and the incidence of the 30% eGFR reduction at 180 days were not significantly different between the CYP2C19 PM group and the non-PM group (Figure 2b-d). These observations may be partly explained by the relatively small contribution of CYP2C19 to the metabolism of esomeprazole, rabeprazole, and vonoprazan compared with lansoprazole.…”

Section: Discussionmentioning

confidence: 65%

“…Our results suggest that the exposure levels of lansoprazole are related to their nephrotoxicity. A previous study showed that PPIs affect gut‐derived uremic toxin metabolism, suggesting that PPIs disturb the gut microbiome balance, which leads to the accumulation of gut‐derived uremic toxin precursors, and that gut‐derived uremic toxins aggravate CKD progression 18 . Our results showed that, in patients that received treatment with esomeprazole, rabeprazole, or vonoprazan, the time to occurrence of a 30% eGFR reduction and the incidence of the 30% eGFR reduction at 180 days were not significantly different between the CYP2C19 PM group and the non‐PM group ( Figure ).…”

Section: Discussionmentioning

confidence: 99%

“…17 It has recently been shown that a high exposure dose of lansoprazole leads to increased plasma concentrations of gut-derived uremic toxins and progression of renal injury in mice. 18 Thus, we hypothesized that there is a relationship between high plasma concentrations of PPIs and the occurrence of renal injury.…”

mentioning

confidence: 99%

“…There is increasing evidence that the reduction in gastric acidity by PPI leads to changes in the gut microbiome and that PPI‐induced dysbiosis is associated with the progression of PPI‐related adverse effects 17 . It has recently been shown that a high exposure dose of lansoprazole leads to increased plasma concentrations of gut‐derived uremic toxins and progression of renal injury in mice 18 . Thus, we hypothesized that there is a relationship between high plasma concentrations of PPIs and the occurrence of renal injury.…”

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confidence: 99%

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Relationships of Proton Pump Inhibitor‐Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study

Fukui,

Noda,

Ikeda

et al. 2024

Clin Pharma and Therapeutics

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Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI‐induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non‐PM group (hazard ratio for PM vs. non‐PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non‐PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Relationships of Proton Pump Inhibitor‐Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study

Fukui,

Noda,

Ikeda

et al. 2024

Clin Pharma and Therapeutics

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“…Recent studies also have found a link to an increased risk of CKD among PPI users [ 15 , 16 , 17 ]. Although the biological mechanism of their association remains unclear, several possible mechanisms can explain the association between PPI use and CKD [ 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Proton Pump Inhibitors and Risk of Chronic Kidney Disease: Evidence from Observational Studies

Liao

Kung

et al. 2023

JCM

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Previous epidemiological studies have raised the concern that the use of proton pump inhibitors (PPIs) is associated with an increased risk of kidney diseases. To date, no comprehensive meta-analysis has been conducted to assess the association between PPIs and the risk of chronic kidney disease (CKD). Therefore, we conducted a systematic review and meta-analysis to address the association between PPIs and CKD. The primary search was conducted in the most popular databases, such as PubMed, Scopus, and Web of Science. All observational studies evaluated the risk of CKD among PPI users, and non-users were considered for inclusion. Two reviewers conducted data extraction and assessed the risk of bias. Random-effect models were used to calculate pooled effect sizes. A total of 6,829,905 participants from 10 observational studies were included. Compared with non-PPI use, PPI use was significantly associated with an increased risk of CKD (RR 1.72, 95% CI: 1.02–2.87, p = 0.03). This updated meta-analysis showed that PPI was significantly associated with an increased risk of CKD. Association was observed in the same among moderate-quality studies. Until further randomized control trials (RCTs) and biological studies confirm these results, PPI therapy should not stop patients with gastroesophageal reflux disease (GERD). However, caution should be used when prescribing to patients with high-risk kidney disease.

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CYP2E1 mediated advanced oxidation protein products exacerbate acetaminophen induced drug-derived liver injury in vitro and in vivo

Xun,

Zhang,

Wei

et al. 2024

European Journal of Pharmaceutical Sciences

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Proton pump inhibitor-induced risk of chronic kidney disease is associated with increase of indoxyl sulfate synthesis via inhibition of CYP2E1 protein degradation

Cited by 8 publications

References 32 publications

Relationships of Proton Pump Inhibitor‐Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study

Relationships of Proton Pump Inhibitor‐Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study

Proton Pump Inhibitors and Risk of Chronic Kidney Disease: Evidence from Observational Studies

CYP2E1 mediated advanced oxidation protein products exacerbate acetaminophen induced drug-derived liver injury in vitro and in vivo

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