The Effect of Gastric Bypass Surgery on Renal Function and Metabolism

Summary

Principal Investigator: Benjamin K Canales
Abstract: DESCRIPTION (provided by applicant): Obese patients are at increased risk for kidney disease due to circulation of pro-inflammatory mediators and underlying renal metabolic and hemodynamic disturbances, including glomerular hyperfiltration. These patients also have unfavorable lithogenic urinary metabolic profiles, such as low urinary pH, hypocitrituria, hyperuricosuria, that predispose them to kidney stone disease. Gastric operations, in particular Roux-en-Y-gastric bypass (RYGB), are increasing as an interventional strategy to facilitate weight loss in this population. Despite the theoretical renal advantages gained during weight loss for glycemic and hypertension control, up to 75% of RYGB patients will develop sustained hyperoxaluria post-operatively, and a subset will develop kidney stones, nephrocalcinosis, impaired renal function, or even renal failure due to oxalate nephropathy. Currently, the mechanisms behind these adverse renal events are unknown. Preliminary data from an obese rat model of RYGB surgery indicates that gastric bypass causes more glomerular injury, interstitial macrophage migration, increased osteopontin production than sham surgery or pair-fed obese controls. Therefore, we hypothesize that obesity is a low-grade inflammatory process that amplifies renal host responses to RYGB-associated hyperoxaluria. In this setting, glomerular, interstitial, and papillary cells are chronically exposed to high amounts of oxalate and/or calcium oxalate crystals, leading to the production of reactive oxygen species, oxidative stress, renal injury, and inflammation. The objective of this application is to provide a training environment for the principal investigator to examine the role of RYGB-associated hyperoxaluria in the development of renal injury and nephrolithiasis, with special focus on renal histology, transport physiology, tissue proteomics, and genomics. Our specific aims are: 1) To further characterize renal effects of RYGB surgery in a diet-induced obese rodent model versus controls by comparing metabolic profiles, pro-inflammatory mediators, histology, protein expression, and pathway-focused gene expression profiles;2) To further our understanding of RYGB induced hyperoxaluria by investigating segmental differences in intestinal oxalate handling and the effect of Oxalobacter colonization on urinary oxalate levels;3) To compare protein and gene expression profiles from renal papillary tips of human RYGB stone formers with and without Randall's plaque deposition. Understanding the mechanisms of hyperoxaluria following RYGB will provide insights into the pathogenesis of oxalate nephrolithiasis associated with obesity. My K08 program is structured to allow me to further explore relevant rodent models of obesity, to validate preliminary hypothesis generated by a recent minority supplement award, to enhance my understanding of oxalate transport within the gut and kidney, and then, most importantly, translate these efforts into mechanisms of disease within human renal tissue. PUBLIC HEALTH RELEVANCE: Morbidly obese patients who undergo Roux en Y gastric bypass (RYGB) may develop sustained post-operative hyperoxaluria that leads to kidney stones, impaired renal function with calcium oxalate deposition within kidney collecting ducts associated with inflammation and fibrosis, or even renal failure due to oxalate nephropathy. The objective of this application is the establishment of a training environment for the candidate to develop an animal model that explores gut and renal mechanisms of RYGB-associated hyperoxaluria in the development of renal injury and nephrolithiasis, with special focus on renal histology, transport physiology, tissue proteomics, and genomics. As a boarded urologic surgeon with a strong track record of publications in urologic stone disease, the candidate is professionally trained to develop a surgical model of stone disease and renal metabolism, and his K08 program is structured to allow him to further explore relevant rat models of obesity, to validate preliminary hypothesis generated by a recent minority supplement award, to enhance his understanding of oxalate transport within the gut and kidney, and to translate these efforts into mechanisms of disease within human renal tissue.
Funding Period: 2010-09-23 - 2015-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Perillyl alcohol inhibits the expression and function of the androgen receptor in human prostate cancer cells
    Byung Ha Chung
    Department of Urology and the Urological Science Institute, College of Medicine, Yonsei University, Yongdong P O Box 1217, Seoul, Korea
    Cancer Lett 236:222-8. 2006
  2. pmc Renal glomerular and tubular injury after gastric bypass in obese rats
    Benjamin K Canales
    Department of Urology, Center for the Study of Lithiasis and Pathological Calcification, University of Florida, Gainesville, Florida, USA
    Nutrition 28:76-80. 2012
  3. pmc Steatorrhea and hyperoxaluria occur after gastric bypass surgery in obese rats regardless of dietary fat or oxalate
    Benjamin K Canales
    Department of Urology, University of Florida, Gainesville, Florida 32610, USA
    J Urol 190:1102-9. 2013
  4. pmc Kidney stone risk following modern bariatric surgery
    Ricardo D Gonzalez
    Department of Urology, University of South Florida, Tampa, FL, USA
    Curr Urol Rep 15:401. 2014

Research Grants

Detail Information

Publications5

  1. ncbi Perillyl alcohol inhibits the expression and function of the androgen receptor in human prostate cancer cells
    Byung Ha Chung
    Department of Urology and the Urological Science Institute, College of Medicine, Yonsei University, Yongdong P O Box 1217, Seoul, Korea
    Cancer Lett 236:222-8. 2006
    ..These novel properties of POH strongly suggest that POH could be highly useful for intervention of pCa...
  2. pmc Renal glomerular and tubular injury after gastric bypass in obese rats
    Benjamin K Canales
    Department of Urology, Center for the Study of Lithiasis and Pathological Calcification, University of Florida, Gainesville, Florida, USA
    Nutrition 28:76-80. 2012
    ..To test this, the renal histology of diet-induced obese rats that underwent RYGB surgery was compared with that of pair-fed and sham obese controls...
  3. pmc Steatorrhea and hyperoxaluria occur after gastric bypass surgery in obese rats regardless of dietary fat or oxalate
    Benjamin K Canales
    Department of Urology, University of Florida, Gainesville, Florida 32610, USA
    J Urol 190:1102-9. 2013
    ..We determined the effect of dietary fat and oxalate on fecal fat excretion and urine parameters in a rat model of Roux-en-Y gastric bypass surgery...
  4. pmc Kidney stone risk following modern bariatric surgery
    Ricardo D Gonzalez
    Department of Urology, University of South Florida, Tampa, FL, USA
    Curr Urol Rep 15:401. 2014
    ....

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Regulation of Liver by Nuclear Ca2+ Signaling
    Michael H Nathanson; Fiscal Year: 2013
    ..abstract_text> ..
  3. Oklahoma Shared Clinical and Translational Resources
    Judith A James; Fiscal Year: 2013
    ..The Management Core will provide Navigator Services to allow investigators from diverse locations to access CTR infrastructure. ..
  4. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  5. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
    ....
  6. Innate/Adaptive Immune Interactions in Gut Inflammation
    Sergio A Lira; Fiscal Year: 2013
    ..Overall the focus and interactive nature of the program (20 joint publications in 4 years, 3 additional NIH grants on related areas) provide a solid basis for a productive outcome. ..
  7. Hereditary Causes of Nephrolithaisis and Kidney Failure
    DAWN SCHMAUTZ MILLINER; Fiscal Year: 2013
    ..This work will address barriers of rare diseases research through vigorous multidisciplinary cooperation. ..
  8. ROLE OF TAMM-HORSFALL PROTEIN IN URINARY TRACT DEFENSE
    Xue ru Wu; Fiscal Year: 2013
    ....
  9. IBD: Genetic and Immunopathologic Mechanisms
    Stephan R Targan; Fiscal Year: 2013
    ..The work described in the program project proposal will further understanding of the causes of these diseases and aid in the development of patient-specific therapies. TABLE OF CONTENTS Overall Description 2 ..
  10. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    ....
  11. Drosophila model of oxalate nephrolithiasis
    Michael F Romero; Fiscal Year: 2013
    ....
  12. Porphyria Rare Disease Clinical Research Consortium (RDCRC)
    Robert J Desnick; Fiscal Year: 2013
    ..Kushner, MD, Professor of Medicine at UoU. Additional affiliate centers will be included over time as funding permits, including support from other grants and philanthropic sources. ..
  13. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  14. Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery
    David R Flum; Fiscal Year: 2013
    ..Plasma levels of GLP-1, GIP. PYY, and ghrelin will be made during standardized meals throughout these experiments in both species, to clarify roles for these gut peptides in changes we observe. ..
  15. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  16. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  17. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  18. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  19. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  20. BIOLOGY OF NEUROENDOCRINE PEPTIDES
    Marc R Montminy; Fiscal Year: 2013
    ..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
  21. Genetics of Renal End Organ Damage in Hypertension
    Michael R Garrett; Fiscal Year: 2013
    ..abstract_text> ..
  22. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  23. Long-term effects of acute renal failure
    David P Basile; Fiscal Year: 2013
    ....
  24. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  25. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..