title: Addition of Alanyl-Glutamine to Dialysis Fluid Restores Peritoneal Cellular Stress Responses - A First-In-Man Trial.
abstract: BACKGROUND
  Peritonitis and ultrafiltration failure remain serious complications of chronic peritoneal dialysis (PD). Dysfunctional cellular stress responses aggravate peritoneal injury associated with PD fluid exposure, potentially due to peritoneal glutamine depletion. In this randomized cross-over phase I/II trial we investigated cytoprotective effects of alanyl-glutamine (AlaGln) addition to glucose-based PDF.
  
  
  METHODS
  In a prospective randomized cross-over design, 20 stable PD outpatients underwent paired peritoneal equilibration tests 4 weeks apart, using conventional acidic, single chamber 3.86% glucose PD fluid, with and without 8 mM supplemental AlaGln. Heat-shock protein 72 expression was assessed in peritoneal effluent cells as surrogate parameter of cellular stress responses, complemented by metabolomics and functional immunocompetence assays.
  
  
  RESULTS
  AlaGln restored peritoneal glutamine levels and increased the primary outcome heat-shock protein expression (effect 1.51-fold, CI 1.07-2.14; p = 0.022), without changes in peritoneal ultrafiltration, small solute transport, or biomarkers reflecting cell mass and inflammation. Further effects were glutamine-like metabolomic changes and increased ex-vivo LPS-stimulated cytokine release from healthy donor peripheral blood monocytes. In patients with a history of peritonitis (5 of 20), AlaGln supplementation decreased dialysate interleukin-8 levels. Supplemented PD fluid also attenuated inflammation and enhanced stimulated cytokine release in a mouse model of PD-associated peritonitis.
  
  
  CONCLUSIONS
  We conclude that AlaGln-supplemented, glucose-based PD fluid can restore peritoneal cellular stress responses with attenuation of sterile inflammation, and may improve peritoneal host-defense in the setting of PD.
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Zytoprotec GmbH, Vienna, Austria.
authors: Klaus
authors: http://orcid.org/0000-0003-0803-614X
authors: K
authors: Kratochwill
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors: Michael
authors: M
authors: Boehm
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Zytoprotec GmbH, Vienna, Austria.
authors: Rebecca
authors: R
authors: Herzog
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors: Katharina
authors: K
authors: Gruber
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Zytoprotec GmbH, Vienna, Austria.
authors: Anton Michael
authors: AM
authors: Lichtenauer
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.|Zytoprotec GmbH, Vienna, Austria.
authors: Lilian
authors: L
authors: Kuster
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors: Dagmar
authors: D
authors: Csaicsich
authors: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors: Andreas
authors: A
authors: Gleiss
authors: Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Seth L
authors: SL
authors: Alper
authors: Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors: Christoph
authors: C
authors: Aufricht
authors: Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Andreas
authors: A
authors: Vychytil
mesh_terms: D000368:Aged; D018592:Cross-Over Studies; D015314:Dialysis Solutions; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013312:Stress, Physiological
chemical_list: D015314:Dialysis Solutions; D004151:Dipeptides; D006360:Heat-Shock Proteins; C054122:alanylglutamine