Evaluation of the Gut-Kidney Axis in Kidney Stone Disease
| dc.contributor | National Institutes of Health |
| dc.contributor.author | Tasian, Gregory |
| dc.contributor.author | Denburg, Michelle |
| dc.contributor.other | Children's Hospital of Philadelphia |
| dc.date.accessioned | 2025-04-02T18:29:46Z |
| dc.description | The long-term goal of this project is to identify metabolic pathways in the gut-kidney axis that could be targets for novel therapeutics to prevent kidney stones. The study group investigates how diet and antibiotics alter the gut-kidney axis in humans using nutritional profiling, mediation analyses of high-dimensional microbiome and metabolomic data, and large data analytics. We demonstrated that insufficient zinc intake, which decreases gut microbiome diversity, is associated with an increased risk of calcium stones in adolescents. <br> Pilot data showed that butyrate-producing and oxalate-degrading taxa are less abundant in individuals with calcium stones (N = 44) versus controls. Butyrate is a short-chain fatty acid (SCFA) that maintains the gut mucosal barrier and regulates expression of SLC26 oxalate transporters in the intestine. Loss of bacteria that produce butyrate and degrade oxalate may act synergistically to increase intestinal absorption and urinary excretion of oxalate. Also demonstrated at a population level that exposure to certain oral antibiotics (fluoroquinolones, sulfas, cephalosporins, nitrofurantoin, and broad-spectrum penicillins) is a risk factor for kidney stones. The risk was greatest for those exposed at younger ages, which is consistent with reports that antibiotic exposures at younger ages produce more profound alterations of host macronutrient metabolism than those later in life. Collectively, these findings have informed our central hypothesis that diet and antibiotics contribute to nephrolithiasis by perturbing the gut-kidney axis through alterations of the gut microbiome. <br> #### Study aims 1. Identify perturbations of the microbiome and metabolome in kidney stone disease. Sequence the gut microbiome using shotgun metagenomics. Measure downstream metabolites using untargeted metabolomics of stool and urine, targeted SCFA metabolomics of stool, and 24-hour urine chemistries. The results of this Aim will reveal intermediary metabolites that may contribute to kidney stones. 2. Define the link between oral antibiotic exposure and urine chemistries in kidney stone disease. Leverage the HealthCore database of >48 million individuals with medical and pharmacy coverage and link pharmaceutical claims and clinical data with 24-hour urine chemistry results. Conduct a nested case-control study to determine the relationship between the dose and duration of antibiotic exposure and kidney stones and to identify sub-groups at greatest risk. Conduct a cohort study to identify how oral antibiotics alter urine chemistries among 228,665 individuals 4-65 years of age. The results of this Aim will identify urine chemistries through which antibiotics may contribute to kidney stones. <br> #### Hypotheses - Lower abundance of metabolites in stool that affect intestinal absorption of oxalate (e.g. butyrate) mediate diet-related changes of the gut microbiome in patients with kidney stones. - Greater exposure to fluoroquinolones, sulfas, cephalosporins, nitrofurantoin, and broad-spectrum penicillins increase stone risk by increasing urine oxalate. |
| dc.description.abstract | Study to identify metabolites that contribute to kidney stones following perturbation of the gut microbiome and provide key insights for future studies of primary and secondary stone prevention. |
| dc.identifier.uri | https://pedsnet.org/metadata/handle/20.500.14642/996 |
| dc.publisher | PEDSnet |
| dc.relation.isreferencedby | MANUSCRIPT PENDING |
| dc.rights | a CC-BY 4.0 Attribution license. |
| dc.rights.uri | https://creativecommons.org/licenses/by-sa/4.0/ |
| dc.subject | NIH P50 |
| dc.subject | PEDSnet Data Source |
| dc.subject | Non-Network Data Source |
| dc.subject | CHOP Data Source |
| dc.subject | Case-Control Study |
| dc.subject | Study::Cohort Study |
| dc.subject.mesh | Kidney Calculi |
| dc.subject.mesh | Nephrolithiasis |
| dc.subject.mesh | Kidney Diseases |
| dc.subject.mesh | Urogenital Diseases |
| dc.subject.mesh | Nutrition Therapy |
| dc.title | Evaluation of the Gut-Kidney Axis in Kidney Stone Disease |
| dspace.entity.type | Study |
| local.admin.note | Aliyah is PM for this project. https://chop365.sharepoint.com/:f:/r/teams/RSCH-ACRC/Shared%20Documents/PEDSnet/PEDSnet%20Studies/Active%20Studies/Denburg_Furth%20PEDSnet%20Projects/Furth_P50%20Original%20Award/Denburg_Tasian%20Linkage%20R01?csf=1&web=1&e=yLr0r3 |
| local.subject.flat | NIH P50 |
| local.subject.flat | PEDSnet Data Source |
| local.subject.flat | Non-Network Data Source |
| local.subject.flat | CHOP Data Source |
| local.subject.flat | Case-Control Study |
| local.subject.flat | Cohort Study |
| local.subject.flat | Federally Funded Research |
| project.startDate | 2019-07 |