{"doi":"10.34067/kid.0005852021","title":"Do Proton-Pump Inhibitors Cause CKD and Progression of CKD?: CON","abstract":"Introduction Proton-pump inhibitors (PPIs) are a class of drugs that reduce gastric acid secretion by irreversibly binding to the H+/K+-ATPase enzyme in the stomach. Their effectiveness as an acid suppressing therapy has led to their widespread use; PPIs are now one of the most commonly prescribed medications in the United States. With the gain in popularity, however, has also come a growing list of possible adverse events. Specific to the kidney, several studies have linked PPI use with increased risk of developing hypomagnesemia, AKI, and acute interstitial nephritis (AIN) (1). More recently, reports have also suggested an association between PPI use and incident CKD and CKD progression. Limitations to the Data Suggesting Harm In 2016, several epidemiologic studies came out in quick succession, proposing the use of PPIs as a risk factor for the development of CKD. However, these studies were subject to several important limitations. First, multiple trials had higher rates of comorbidities in the PPI group versus the placebo group (see Table 1). In addition, important CKD information (i.e., baseline eGFR, proteinuria, and concomitant medication use) was not widely available when comparing between different medication groups. Furthermore, in the studies comparing PPI versus histamine-2 receptor blocker (H2RB) use, it is unlikely that participants were well matched for the severity of their respective gastrointestinal disorders since PPIs are first-line therapy for more serious disorders, including Helicobacter pylori infection, gastroduodenal ulcers, and bleeding. The positive signal toward CKD progression in PPI users may therefore more accurately reflect a sicker group at baseline. Table 1. - Studies on proton-pump inhibitor use and risk of adverse kidney outcomes Study Design Outcome Limitations Lazarus et al. (2016) (2) Cohort Population: 10,482 participants in ARIC cohort and 248,751 participants in Geisinger cohort Measure: PPI use versus H2RB use and incidence of CKD HR=1.39 (95% CI, 1.01 to 1.91) in ARIC cohort and HR=1.29 (95% CI, 1.19 to 1.40) in Geisinger cohort • PPI group, in both cohorts, had higher rate of comorbidities • ARIC cohort defined CKD using diagnostic codes at hospital discharge (limited sensitivity) • ARIC cohort subgroup analysis found no increased risk in those who were young, Black, women, diabetic, on an ACE-I/ARB, or on diuretics • Geisinger cohort subgroup analysis found no increased risk in young patients Peng et al. (2016) (3) Case-control Population: 3808 ESKD patients versus 3808 CKD patients Measure: risk of ESKD in patients with kidney disease and PPI use Adjusted OR=1.92 (95% CI, 1.74 to 2.13) with <100 DDD, and adjusted OR=1.74 (95% CI, 1.52 to 2.00) with >100 DDD • Baseline characteristics were compared by ESKD versus CKD group and not by medication use • More PPI users were in the ESKD group • No baseline eGFR available (unclear if PPI users had more advanced CKD to begin with) Arora et al. (2016) (4) Case-control Population: 99,269 participants seen in primary care clinic at VA Upstate NY Measure: PPI versus no PPI use and incidence of CKD OR=1.10 (95% CI, 1.05 to 1.16) • One-time reading of eGFR <60 ml/min per 1.73 m2 was considered diagnostic of CKD • Subgroup analysis found no increased risk in those who were older (>65 years), women, Black, or diagnosed with diabetes, gastrointestinal disorder, vascular disease, or cancer • Baseline eGFR and concurrent medication use not available • Selective population Xie et al. (2016) (5) Cohort Population: national VA cohort, including 173,321 new PPI users versus 20,270 new H2RB users Measure: PPI use versus H2RB use and incidence of CKD HR=1.26 (95% CI, 1.23 to 1.34) • Association between duration of exposure and risk of renal outcomes among new PPI users diminished after 720 days • Selective population Klatte et al. (2017) (6) Cohort Population: Stockholm creatinine measurements cohort with 105,305 new PPI users and 9578 new H2RB users Mea","journal":"Kidney360","year":2022,"id":285976,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":911277,"name":"Georges Nakhoul","orcid":"0000-0002-8997-1940","position":1,"is_corresponding":false},{"id":964900,"name":"Liza Cholin","orcid":"0000-0001-5975-3822","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T00:29:48.841035Z","pmid":"35919541","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}