Relationship between gastroesophageal reflux and chronic kidney disease: A meta-analysis of 4 million patients

Relationship between gastroesophageal reflux and chronic kidney disease: A meta-analysis of 4 million patients Item Type info:eu-repo/semantics/article Authors Chaponan-Lavalle, Andres; Godoy, Ambar; Estrada-Grossmann, Jose M.; Acosta, Eduardo S.; Chaponan-Lavalle, Yolanda; Azañedo-Garcia, Luis G.; Ordaya-Gonzales, Karina; GonzalesPalomo, Manuel; Príncipe-Meneses, Fortunato S.; Mohan, Arjunmohan; Beas, Renato; Arriola-Montenegro, Jose DOI 10.4103/sjg.sjg_133_25 Publisher Wolters Kluwer Medknow Publications Journal Saudi Journal of Gastroenterology Rights info:eu-repo/semantics/openAccess; Attribution 4.0 International Download date 04/11/2025 01:32:58 Item License http://creativecommons.org/licenses/by/4.0/ Link to Item http://hdl.handle.net/10757/686811 206 © 2025 Saudi Journal of Gastroenterology | Published by Wolters Kluwer ‑ Medknow Relationship between gastroesophageal reflux and chronic kidney disease: A meta‑analysis of 4 million patients Andres Chaponan‑Lavalle1, Ambar Godoy2, Jose M. Estrada‑Grossmann1, Eduardo S. Acosta1, Yolanda Chaponan‑Lavalle1, Luis G. Azañedo‑Garcia1, Karina Ordaya‑Gonzales3, Manuel Gonzales‑Palomo1, Fortunato S. Príncipe‑Meneses1, Arjunmohan Mohan4, Renato Beas5, Jose Arriola‑Montenegro4 1Departamento de Medicina, Universidad Peruana de Ciencias Aplicadas, Lima, Perú, 2Department of Medicine, Indiana University School of Medicine, Indianapolis, USA, 3Departamento de Medicina, Universidad Científica del Sur, Lima, Perú, 4Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, 5Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA INTRODUCTION Gastroesophagealrefluxdisease(GERD)isacommon condition that affects around 20% of the adult population in Western countries.[1]Itischaracterizedbytherefluxof stomach contents into the esophagus, leading to symptoms such as heartburn and acid regurgitation.[2] Well stablished risk factors for GERD include obesity, alcohol consumption, smoking, and the use of certain medications such as calcium channel blockers, opioids, anticholinergics, and nitrates.[3‑5] However, some underlying causes remain unknown and are currently under Background: Chronic kidney disease (CKD) has been associated with higher risk of gastrointestinal disorders, particularly Gastroesophageal reflux disease (GERD). However, the magnitude of this association and the underlying mechanisms remains unclear. Methods: A systematic search was conducted across major databases from inception to November 2024. We included cross-sectional and case-control studies evaluating the relationship between CKD and GERD. Data were extracted and analyzed using a random-effects model to calculate pooled odds ratios (ORs) and prevalence rates. Study quality was assessed using the Newcastle-Ottawa Scale, and heterogeneity was evaluated using the Cochran’s Q test and I² statistic. Results: Nine studies involving 4,650,709 participants were included. The pooled prevalence of GERD among CKD patients was 18% (95% CI: 0.10–0.26, I² =93.64%). The pooled crude OR for the association between CKD and GERD was 2.53 (95% CI: 1.30–4.92) and adjusted OR was 1.48 (95% CI: 1.05–2.08). Conclusion: This meta-analysis reveals a marginally significant association between CKD and GERD, highlighting higher prevalence of GERD among individuals with CKD. Furthers studies are needed to elucidate the underlying pathophysiological mechanisms and potential clinical implications. Keywords: Chronic kidney disease, esophageal reflux, gastroesophageal reflux disease, uremia Address for correspondence: Dr. Andres Chaponan-Lavalle, Avenida Mexico 975 – 15033, Mexico. E-mail: chaponanla[email protected] Submitted: 15-Apr-2025 Revised: 12-May-2025 Accepted: 13-May-2025 Published: 09-Jun-2025 Access this article online Quick Response Code: Website: https://journals.lww.com/sjga DOI: 10.4103/sjg.sjg_133_25 How to cite this article: Chaponan-Lavalle A, Godoy A, Estrada-Grossmann JM, Acosta ES, Chaponan-Lavalle Y, Azañedo-Garcia LG, et al. Relationship between gastroesophageal reflux and chronic kidney disease: A meta-analysis of 4 million patients. Saudi J Gastroenterol 2025;31:206-11. This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] Systematic Review/Meta‑Analysis Abstract Chaponan‑Lavalle, et al.: Gastroesophageal reflux and chronic kidney disease Saudi Journal of Gastroenterology | Volume 31 | Issue 4 | July-August 2025 207 investigation.GERDnotonlysignificantlyimpairsquality of life but it is also associated with complications such as erosive esophagitis, esophageal strictures, and Barrett’s esophagus, which may increase the risk of esophageal cancer.[6] Chronic kidney disease (CKD) is a progressive condition defined by structural or functional abnormalities of the kidney lasting at least three months.[7] CKD represent a major global public health burden, affecting approximately 10% of global population,[8] with a prevalence of 14.9% among U.S. adults.[9] Recent studies suggest a higher incidence of acid‑related gastrointestinal dysfunction in patients with CKD compared to the general population (23.5% vs 14.8%).[2] The mechanisms underlying GERD in CKD patients arelikelymultifactorial.Chronicsystemicinflammation, impaired gastrointestinal motility, metabolic disturbances, uremic toxins, electrolyte imbalances, elevated gastrin levels and comorbidities may all contribute to esophageal dysfunctionandreflux.[10‑13] However, the true magnitude of this association and the underlying pathophysiological pathways remain unclear. This study aims to evaluate the prevalence of GERD in patients with CKD and to determine the strength of the association between these two conditions through a systematic review and meta‑analysis. MATERIALS AND METHODS Study design, registration, and reporting guidelines This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidelines. Data sources and search strategy A comprehensive literature search was carried out to examine the association between CKD and the risk of developing GERD. The search included multiple databases: PubMed, Scopus, Ovid Medline, and Web of Science. Searches were performed on November 22, 2024, and included studies published from inception to that date. Both DeCS/MeSH terms and free‑text keywords were used to enhance sensitivity. Studies published in English and Spanish were considered for inclusion. Study selection and data extraction The studies retrieved from the databases were imported into Covidence, a data management software, where duplicate entries were removed. Two independent reviewers (AC‑L, JME‑G) evaluated each study by reviewing the titles and abstractsaccordingtopredefinedinclusioncriteria.We included cross‑sectional and case‑control studies that assessed the association between CKD and the risk of developing GERD, and studies conducted in adults. Case reports, narrative reviews, scoping reviews, conference abstracts, systematic reviews, and letters to the editor were excluded. Following this initial assessment, the full text of each article was reviewed. Articles that did not meet the criteria were excluded. Any disagreements regarding study inclusion or exclusion were resolved through consensus. Relevant data from the selected articles was then extracted and organized into an Excel spreadsheet. The extracted data included aspects such as study title, authors, country, publication year, study design, demographic information (age, sex), number of patients with CKD, CKD stage, number of patients on hemodialysis, number of patients with GERD, and comorbidities (e.g., esophageal cancer, Barrett’s esophagus, gastroparesis). Assessment of study quality and publication bias Study quality was assessed using the Newcastle‑Ottawa Scale (NOS) for case‑control studies and its adapted version forcross-sectionalstudies(NOS-CS).Studiesscoring≥7 were considered low risk of bias, while those with <7 stars, were considered high risk. Two reviewers (JME‑G, AC‑L) assessed quality independently, resolving discrepancies by team consensus. Data analysis for the association between CKD and GERD STATA 16.0 was used for the statistical analysis. A pooled analysis of the odds ratio (ORs) was performed to estimate the association between CKD and GERD. Given the anticipated heterogeneity, a random effects model (Restricted Maximum Likelihood) was applied. Heterogeneity was evaluated using the Cochran’s Q test and I2 statistic, with I2 > 60% and P value <0.05 indicatingsignificantheterogeneity.Asensitivityanalysis including only studies reporting adjusted ORs was also included. Data analysis for the prevalence of GERD in patients with CKD Data from selected studies were also analyzed to estimate the pooled prevalence of GERD in CKD patients using STATA 16.0. A random effects model (Der Simonian and Laird)wasapplied,and95%confidenceintervals(CIs) were calculated using the Clopper Pearson method. Heterogeneity was again assessed using the Cochran’s Q test and the I² statistic, following the same thresholds. An additional sensitivity analysis was performed by excluding studies with high risk of bias. Chaponan‑Lavalle, et al.: Gastroesophageal reflux and chronic kidney disease 208 Saudi Journal of Gastroenterology | Volume 31 | Issue 4 | July-August 2025 RESULTS Systematic search Asystematicsearchidentified1,821studies.Afterremoving duplicates (n=296),1,525articlesremainedfortitleand abstract screening. Of these, 1,504 were excluded for not meeting the inclusion criteria. Consequently, 21 full text articles were assessed for eligibility, and nine studies were ultimately included in the qualitative and quantitative synthesis. The study selection process is illustrated in Figure 1. Study characteristics Amongtheninestudiesincluded,fivewerecross-sectional studies and four were case‑control in design. The total number of participants across these studies was 4,650,709, with 55.61% female and 44.39% male. The diagnosis ofGERDwasconfirmedusingendoscopy,validated questionnaires,orofficialhealthdatabases.Geographically, the studies were conducted in the United States (n=2), India (n=2),andoneeachfromTaiwan,China,Iran,and the Philippines. Detailed characteristics of the included studies are presented in Table 1. Assessment of study quality and publication bias Study quality was assessed using the Newcastle–Ottawa Scale, applied to both cross‑sectional and cohort studies. The quality scores ranged from 6 to 9 stars. Seven studies wereconsideredhighquality(≥6stars);whiletwowere rated as lower quality (<6 stars). Pooled estimates of the included studies The prevalence of GERD among CKD patients varied across studies and regions. The pooled prevalence was 18% (95% CI: 0.10–0.26) with substantial heterogeneity (I2=93.64%). The pooled crude odds ratio (OR) for the association between CKD and GERD was 2.53 (95% CI: 1.30–4.92; I²=99.89%),whilethepooledadjustedORwas1.48(95% CI:1.05–2.08;I²=78.40%).Onlystudiesreporting ORs—primarily case‑control studies—were included in the meta‑analysis. Forest plots and statistical details are presented in Figures 2, 3, and 4. DISCUSSION Our study findings notably confirmed a consistent association between GERD in CKD patients with a pooled crude OR of 2.53. This reinforces previous research suggesting a potential link between GERD in patients with CKD. The prevalence of GERD in patients with CKD varies across studies and geographical contexts. In Korea, Song et al.[14] reported a prevalence of 36.8%, which was slightly higher in patients undergoing hemodialysis (39.5%) compared to those on peritoneal dialysis (33.3%). In contrast, a large‑scale study in the USA by Wang et al.,[2] including 7,159,694 hospitalized patients, found a lower prevalence of 20.6% in CKD patients diagnosed with GERD. On the other hand, Reddy et al.,[15] in India, reported a prevalence of only 16% in CKD patients with GERD. Figure 1: Flowchart of the systematic review search process Figure 2: Forest plot depicting the pooled OR of GERD in patients with CKD Chaponan‑Lavalle, et al.: Gastroesophageal reflux and chronic kidney disease Saudi Journal of Gastroenterology | Volume 31 | Issue 4 | July-August 2025 209 Among the factors associated with GERD in patients with CKD, delayed gastric emptying contributes as a significantfactor(ClinicalEvaluationandManagement of Chronic Kidney Disease ‑ ClinicalKey). Strid et al.[16] found that 36% of patients with CKD exhibited delayed gastric emptying. Similarly, Wang et al.[17] reported that 13.5% and 29.7% of CKD patients exhibited grade 2 gastric content 6 hours after a meal on dialysis and non‑dialysis days, respectively, suggesting a tendency toward slower gastric emptying in this population. Gastric dysmotility is another contributing factor (Clinical Evaluation and Management of Chronic Kidney Disease ‑ ClinicalKey). In the study by Grant et al.[18] which included 35 non‑diabetic subjects (12 patients with CKD stages 4/5 and 23 healthy controls), showed thatthemeangastricemptyingtimewassignificantly prolonged in the CKD group (96 ± 32 min) compared to healthy participants (74 ± 27 min, P =0.04). The pathophysiology of how CKD patients develop GERD is still unclear, however, several mechanisms of the patient’s renal condition are proposed to explain the association of both pathologies. Factors such as uremia related to altered renal function, altered gastrointestinal motility, elevated gastrin levels, electrolyte abnormality, and endocrine disorders are attributed as the main contributors[2,19] Uremia related to altered renal function in CKD can increase the risk of GERD development. Uremia causes delayed gastric emptying, which leads to prolonged exposure of the esophagus to gastric acid.[20] Additionally, uremia increases gastric mucosal permeability and makes it more susceptible to acid injury, leading to greater mucosal damagewhengastriccontentsrefluxintotheesophagus.[21] Besides uremic neuropathy, which is a known cause of gastric dysmotility, other factors in CKD such as electrolyte imbalance (calcium and phosphate) and elevated levels of peptides like gastrin also play a role.[22] Gastrointestinal amyloidosis, common in dialysis dependent CKD patients, further affects the structural integrity and motility of the gastrointestinal tract, aggravating GERD.[23] In patients with CKD, elevated gastrin levels are often observed due to the impaired kidney function, leading to increased acid secretion, which contributes to GERD. In addition, one study reported that gastrin reduces lower esophageal sphincter (LES) pressure and increases transient LESrelaxation,bothofwhichareassociatedwithreflux.[13] Table 1: Characteristics of included studies Author Study year Study designs Country Total population Mean Age Female (%) CKD patients (n) GERD patients (n) GERD diagnosis Study population Mortazavi et al.2022 Case-Control Iran 1,337 52.2 years 39.6% 597 316 Questionnaire Adult volunteers on dialysis Lee et al.2015 Case-Control Taiwan 17,910 55 years 51.9% 8,955 395 Endoscopy Adult volunteers on dialysis Wang et al.2023 Case-Control US 7,159,694 49.6 years 56.3% 1 005 568 1 144998 Endoscopy Adults with CKD Alkhayyat et al.2020 Case-Control US 36,469,260 45.5 years 55.46% 1 367 870 4 725 290 Endoscopy Adults with CKD Hao et al.2014 Cross Sectional China 432 53.8 years 39.4% 432 141 Questionnaire Adult volunteers on dialysis Biradar et al.2024 Cross Sectional India 52 60.8 years 32.7% 52 3 Endoscopy Adults with CKD Pakfetrat et al.2020 Cross Sectional Iran 1,256 37.6 years 35.9% 1 256 211 Endoscopy Patients with CKD Meena et al.2024 Cross Sectional India 50 47.7 years 44% 50 12 Endoscopy Adults with CKD Takahashi et al.2022 Cross Sectional Philippines 264 55.5 years 44% 264 36 Questionnaire Adult volunteers on dialysis CKD=chronic kidney disease, GERD=Gastroesophageal reflux disease, US=United states, NHI=National Health Insurance, NIS=National Inpatient Sample Figure 3: Forest plot depicting the pooled adjusted OR of GERD in patients with CKD Figure 4: Forest plot depicting the pooled prevalence of GERD in patients with CKD across different countries Chaponan‑Lavalle, et al.: Gastroesophageal reflux and chronic kidney disease 210 Saudi Journal of Gastroenterology | Volume 31 | Issue 4 | July-August 2025 Endocrine disorders, such as hyperparathyroidism, a common complication of CKD caused by hypocalcemia and phosphate accumulation, can also play a role. Studies have reported that after parathyroidectomy, LES pressure increases, improving motility and relieving GERD symptoms.[2] Furthermore, the pathophysiology of GERD is associated with the continuous activation of the renin‑angiotensin‑aldosterone system (RASS), a process also observed in CKD patients. GERD has also been associated with cytokine‑mediated pathways, which are prominent in CKD along with oxidative stress.[2,4] The evidence regarding the relationship between GERD and CKD can be controversial, as some studies suggest that CKDhassignificanteffectsonthegastrointestinalsystem, while others show that this relationship does not always hold true.AccordingtoKarahanandŞahin,[24] although GERD symptoms were more frequent in patients with PD compared toHDandpredialysis,nostatisticallysignificantdifferences were found between the groups (38% in predialysis, 34% in HD, and 45% in PD). Similarly, Bacci and Chehter[25] reported a higher prevalence of GERD in the control group (without CKD) than in the CKD and HD groups, althoughthisdidnotreachstatisticalsignificance(P=0.075). In Cekin et al.’s[23] study, although the overall prevalence of GERD and other related manifestations was similar between patients with ESRD and controls (81% vs. 84.8%, P =0.423),thefindingsdidnotshowsignificantdifferences in parameters such as microscopic esophagitis, esophageal pH, or endoscopic esophagitis. This systematic review and meta‑analysis confirm a marginally significant association between CKD and GERD, with CKD patients showing a higher prevalence of GERD compared to the general population. The pooled crude odds ratio of 2.53 indicates a notable increase in the risk of developing GERD among CKD patients. Several factors, including delayed gastric emptying, uremia, and altered gastrointestinal motility, may contribute to this relationship, though the precise pathophysiological mechanisms remain unclear. Giventhesefindings,healthcarepractitionersareadvised to consider screening for GERD symptoms in individuals diagnosed with CKD. This facilitates the early detection of GERD and emphasizes the necessity for ongoing research to inform targeted interventions and improve quality of life of individuals with CKD. Limitations This study has some limitations that should be considered when interpreting the results. First, there is high heterogeneity among the included studies, suggesting significantdifferencesinthedesignsordiagnosticmethods used for CKD or GERD, which may affect the external validity. Additionally, there is an inherent risk of bias when including observational studies, as certain confounders cannot be controlled. In this study, we included case‑control and cross‑sectional studies. For these reasons, it is recommended to interpret the results with caution and conductadditionalprospectivestudiestoconfirmthis association. Financial support and sponsorship Nil. Conflicts of interest Therearenoconflictsofinterest. REFERENCES 1. Shaqran TM, Ismaeel MM, Alnuaman AA, Al Ahmad FA, Albalawi GA, Almubarak JN, et al. Epidemiology, causes, and management of gastro‑esophageal reflux disease: A systematic review. Cureus 2023;15:e47420. 2. Wang X, Wright Z, Patton‑Tackett ED, Song G. The relationship betweengastroesophagealrefluxdiseaseandchronickidneydisease. JPM 2023;13:827. 3. Hampel H, Abraham NS, El‑Serag HB. 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