Proton Pump Inhibitors And Risk Of Chronic Kidney Disease: Evidence From Observational Studies
Oct 25, 2023
Abstract: 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.
Keywords: proton pump inhibitors; kidney disease; chronic kidney disease; acute kidney disease; meta-analysis
1. Introduction
The global incidence and prevalence of kidney disease are increasing steadily, imposing a significant burden and becoming the eighth-leading cause of morbidity and mortality. Kidney disease is a global public health concern; it is projected to become the 5th most common cause of mortality globally by 2040 [1,2]. Acute and chronic kidney disease (CKD) are the two main types of kidney disease, and they are associated with substantial economic burden and deficits in quality of life. The incidence and prevalence of CKD vary globally [3]; however, the risk of progressive CKD is 60% higher among people living in the lowest socioeconomic quartile than in the highest quartile [4].
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Proton pump inhibitors (PPIs) are one of the most prescribed medications for treating acid-related gastrointestinal disorders [5,6]. It is reported that the number of PPI prescriptions per year in the United States has doubled since 2000, with annual expenditures estimated at USD 13.5 billion [7,8]. A growing number of publications have raised concerns about the inappropriate use of PPIs (25–70%) [9–11]. Previous studies have reported an increased risk of hip fractures [12], community-acquired pneumonia [13], pancreatic cancer [5], and gastric cancer [14] among PPI users. Recent studies also have found a link to an increased risk of CKD among PPI users [15–17]. Although the biological mechanism of their association remains unclear, several possible mechanisms can explain the association between PPI use and CKD [18–20].
This current study aimed to provide a comprehensive and updated systematic review and meta-analysis to examine the association between PPI and CKD. Moreover, we also aimed to assess whether there is any difference in the association by region, study design, methodological quality, gender, and types of PPI.
2. Methods Study Protocol:
Our study was conducted and reported according to the meta-analysis of the Observational Studies in Epidemiology (MOOSE) checklist [21].
Search Strategy: We conducted a systematic search for observational studies in PubMed, Scopus, and Web of Science, up to 25 November 2022. The following combination keywords were used: Proton pump inhibitor/s, and chronic kidney disease. We did not restrict language in the initial search. The search strategy was developed with a discussion with experts who have 5 years of experience in conducting systematic reviews and meta-analyses. In addition, a manual search was conducted through the reference lists of previously published reviews and meta-analyses to identify missing studies.
Study Eligibility: We considered all types of observational studies that evaluated the association between PPI use and the risk of CKD. Studies were included if they were (i) published in English, (ii) provided clear information about PPI users and inclusion criteria for CKD, and (iii) provided sufficient information to calculate a pooled effect size.
Studies were excluded if they were review articles, reports, animal research, conference abstracts, editorials, case reports, or studies without a comparator group. Two authors (CCW and MHL) independently screened all titles, abstracts, and full texts of all included studies. Any discrepancy during the study screening process was resolved through discussion with a third author.
Data Extraction: The same two authors developed the data extraction form to collect relevant information from selected full-text articles. The following information was extracted from selected studies: (i) basic information: author name, publication year, and origin; (ii) population: sample size, data source, age, and gender; (iii) methods: study design, inclusion and exclusion criteria, study duration, follow-up time, and adjustments for confounding factors; (iv) outcome: effect sizes with 95% confidence intervals (CIs).
Assessment of Risk Bias: We assessed the quality of included studies using the Newcastle–Ottawa Scale recommended by the Cochrane Library [22]. It evaluates the quality of the nonrandomized studies based on the patient selection, comparability, and ascertainment of either the exposure or outcome of interest. A star system is used to judge the study quality with a maximum of 9 stars (4 stars for selection, 2 stars for comparability, and 3 stars for outcome). A study with 9 stars was classified as high quality, 7–8 stars as moderate, and <7 stars as low quality [5,12,23].
Statistical Analysis: The statistical analysis was performed using Comprehensive Meta-analysis (CMA) software. The pooled risk ratios (RR) with 95% confidence intervals were estimated using a random effects model based on the DerSimonian–Laird method. We drew forest plots to depict the visual interpretation of pooled estimates with 95% CIs. The Cochran Q test and I2 statistic were calculated to assess the degree of heterogeneity among studies. The significance level for the effect size was considered at p < 0.05.
3. Results Study Identification:
Figure 1 shows the flowchart of the study selection process in this study. The electronic databases search yielded 1131 articles; 312 of these were excluded for duplication. Moreover, 802 articles were further excluded due to irrelevant titles or abstracts. Thus, 17 full-text articles were screened, and 7 studies were further excluded due to being reviews, not a comparison of interest, and having ineligible study designs. Finally, 10 studies were included in this meta-analysis [15,24–32
Figure 1. PRISMA guidelines for searching strategy of the association between PPI and CKD risk.
Study Characteristics and Quality Assessment: Table 1 shows the characteristics of the included studies. Among the 10 articles included in this study, 7 were cohort studies, and 3 were case-control studies. The range of the publication period was 2016 to 2022. Six studies were conducted in Western countries, and four were from Asian countries. The sample size range of the included studies was between 18,504 and 5,414,695. All the included studies used standard protocols to identify PPI users and CKD. The average NOS score was 8, with an interquartile range (IQR) of 7–9.
Proton Pump Inhibitor and Chronic Kidney Disease: Ten studies examined the risk of CKD among PPI users. PPI use was significantly associated with an increased risk of CKD compared to non-PPI users. The pooled RR was 1.72 (95% CI: 1.02–2.87, p = 0.03), with significant heterogeneity among studies (Q = 8730.48, p < 0.001, I2 = 99.88%)
Subgroup Analysis: We also conducted comprehensive subgroup analyses of the included 10 studies based on study design, region, methodological quality, gender, comorbidities, comedication, and types of PPI use (Table 2).
Seven cohort and three case-control studies evaluated the risk of CKD among PPI users. The adjusted pooled analysis of the seven cohort studies showed an increased risk of CKD among PPI users compared to non-PPI users (RR: 1.69, 95% CI: 0.85–3.35, p = 0.13). The pooled RR of CKD among PPI users for case-control studies was 1.57 (95% CI: 1.20–2.05, p = 0.001). The heterogeneity among the studies were Q = 7784.31, p < 0.001, and I2 = 99.91% and Q = 83.62, p < 0.001, and I2 = 97.60, respectively.
Six studies from Western countries examined the impact of PPI therapy on the risk of CKD. The overall pooled RR was 1.28 (95% CI: 1.17–1.40, p < 0.001), with significant heterogeneity among the studies (Q = 66.03, p < 0.001, I2 = 90.91%). Moreover, the pooled RR for studies from Asia was 2.25 (95% CI: 0.74–6.81, p = 0.14), with significant heterogeneity among studies (Q = 4858.83, p = 0.001, I2 = 99.93%).
The overall pooled RRs for the risk of CKD for high- and moderate-quality methodologies were 1.35 (95% CI: 1.23–1.49, p < 0.001, number of studies, n = 4) and 1.97 (95% CI: 0.95–4.07, p = 0.06, n = 6), respectively. Three studies evaluated the risk of CKD among male PPI users, and the adjusted pooled RR was 1.14 (95% CI: 1.01–1.28, p = 0.03). Moreover, four studies assessed the risk of CKD among female PPI users, and the adjusted pooled RR was 0.95 (95% CI: 0.63–1.42, p = 0.80) (Figure 2).
The studies assessed the risk of CKD with esomeprazole; the pooled RR was 1.32 (95% CI: 1.23–1.42, p < 0.001), with non-significant heterogeneity (Q = 0.82, p = 0.66, I2 = 0). The pooled RR for studies using rabeprazole and esomeprazole were 1.50 (95% CI: 1.20–1.87, p < 0.001, n = 2), 1.53 (95% CI: 1.24–1.89, p < 0.001, n = 2).
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