Proton Pump Inhibitors And Risk Of Chronic Kidney Disease: Evidence From Observational Studies Ⅱ

4. Sensitivity Analysis 

The findings of this study had high heterogeneity (I2 = 99.88%, p < 0.001); therefore, we conducted a sensitivity analysis to observe any change in the findings. In order to evaluate the magnitude of the overall impact of each included study on CKD risk, a sensitivity analysis was performed by excluding studies one by one. However, this study did not observe any difference in overall effect size and heterogeneity among studies (Table 3)

Publication Bias: Figure 3 shows the funnel plot of the association between PPI use and the risk of CKD. This Egger’s regression plot indicates no significant publication bias (p = 0.53).

5. Discussion 

This systematic review with meta-analysis provides a comprehensive estimation of the association between PPI use and the risk of CKD. The findings of this study are based on previously published observational studies. The present study calculated adjusted pooled effect sizes using a random effects model from 10 studies, which included a total of 6,829,905 participants. The results showed that PPI use was significantly associated with a high CKD risk of 72%. These findings are supported by previously published meta-analyses [33–36], which showed PPI use increased the risk of CKD.

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The biological mechanism underlying the positive association between PPI use and CKD risk is unclear. A previous study suggested that infection and inflammations could partially contribute to the development of CKD among PPI users [16]. Previous evidence also revealed that PPIs have a potential influence on the gut microbiota, which are responsible for intestinal microbial imbalance, thus increasing the risk of enteric infection [37–39]. Imhann et al. [40] and Jackson et al. [41] demonstrated that the rates of Enterobacteriaceae and Streptococcaceae increase in the gut among PPI users. PPIs escalate the accumulation of gut-derived uremic toxins, which ultimately induce CKD progression [42]. PPI use is associated with an increased risk of developing hypomagnesemia [43,44]. Evidence indicates that magnesium depletion leads to the induction of CKD. Previous studies also reported that PPI could cause inflammation and tubulointerstitial damage, which could ultimately lead to CKD [45–47]. 

Our subgroup analyses showed that the risk of CKD among PPI users was higher in Asian people than in Western people. Although an insignificant association was observed among Asians, it may be due to a small number of studies. Previous epidemiological studies reported that clinical, metabolic, socioeconomic, and behavioral factors could contribute to a higher risk of CKD in Asian people compared to others [48–50]. However, in Western countries, people are also at high risk of developing CKD because of the higher prevalence of diabetes and hypertension [51]. Other risk factors, such as cardiovascular disease, smoking status, and obesity, may affect ethnic groups differently, but this has not been tested due to a lack of data [3,52]. Our subgroup analyses also showed that omeprazole, rabeprazole, and esomeprazole are significantly associated with an increased risk of CKD. These PPIs disturb the balance of the pH level in the gastrointestinal tract, thereby reducing absorption mediated by TRPM6 and TRPM7 transporters [53]. Our findings also showed that male patients had a higher risk than female patients. As in other diseases, gender is a fundamental factor of CKD patients because males and females differ in renal physiology, complications, signs, and symptoms of CKD. 

6. Strengths and Limitations

To our knowledge, this is the largest collection of observational studies on the assessment of PPI use for the risk of CKD, representing more than 10 studies compared with a comprehensive meta-analysis conducted previously. Unlike most recent meta-analyses, which do not have broad subgroup and sensitivity analysis, our study has more comprehensive search methods and analyses. This study also has some limitations. First, this meta-analysis was limited by the quality of the included studies. The pooled evidence from observational studies (cohort and case-control studies) cannot provide an interpretation regarding causation. Second, the findings of this study are prone to selection bias, confounding bias, and exaggeration of associations. However, we considered only the adjusted effect size to calculate a pooled effect size. Third, the study designs, data materials, statistical approaches, duration, and quality of included studies varied. Fourth, no information on the dose and duration of PPI use was available in the included studies. Therefore, we were unable to provide the dose and duration effect on CKD risk. Finally, we are unable to classify the risk of CKD based on various stages due to a lack of data.

7. Conclusions 

This systematic review and meta-analysis showed that PPI use was associated with an increased risk of CKD. The findings of our study could contribute to a more comprehensive understanding of CKD risk among PPI users. Our study findings highlight the need for early intervention among patients at high risk of CKD and for continuous monitoring of patients with PPI.

Author Contributions: Conceptualization, C.-C.W.; Methodology, C.-C.W. and W.-M.K.; Software, W.-M.K.; Validation, W.-M.K.; Formal analysis, C.-C.W. and M.-H.L.; Resources, M.-H.L.; Data curation, M.-H.L.; Writing—original draft, C.-C.W.; Writing—review & editing, Y.-C.W. All authors have read and agreed to the published version of the manuscript. 

Funding: This research received no external funding. 

Conflicts of Interest: The authors declare no conflict of interest.

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