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Glucose degradation products in peritoneal dialysis fluids

Erixon, Martin LU (2007)
Abstract (Swedish)
Popular Abstract in Swedish

Patienter som lider av kronisk njursvikt måste avlägsna extracellulärt vatten och slaggprodukter från kroppen för att överleva. Ett alternativ är behandling med peritoneal dialys (PD). Vid en PD behandling fylls och töms bukhålan kontinuerligt med en till tre liter PD vätska fyra gånger om dagen som oftast innehåller glukos som osmotiskt agens. Glukosen skapar ett osmotiskt tryck över peritonealmembranet vilket är orsaken till att patienten kan avlägsna vatten och slaggprodukter effektivt från blodbanan till dialysatet.



Under produktionen av PD vätskor är värme steriliseringen ett måste för att få en steril produkt. Under processen bildas bl.a. reaktiva karbonylföreningar som... (More)
Popular Abstract in Swedish

Patienter som lider av kronisk njursvikt måste avlägsna extracellulärt vatten och slaggprodukter från kroppen för att överleva. Ett alternativ är behandling med peritoneal dialys (PD). Vid en PD behandling fylls och töms bukhålan kontinuerligt med en till tre liter PD vätska fyra gånger om dagen som oftast innehåller glukos som osmotiskt agens. Glukosen skapar ett osmotiskt tryck över peritonealmembranet vilket är orsaken till att patienten kan avlägsna vatten och slaggprodukter effektivt från blodbanan till dialysatet.



Under produktionen av PD vätskor är värme steriliseringen ett måste för att få en steril produkt. Under processen bildas bl.a. reaktiva karbonylföreningar som kallas glukosnedbrytningsprodukter (GDPs). Dessa substanser förstör bukhinnan och är en bidragande orsak till ultrafiltrationsproblem hos patienter. GDPs har även visat en toxikologisk effekt på många in vivo system som exempelvis ökad bildning av AGEs, ökade halter av tillväxtfaktorer som VEGF samt hämmar de bildandet av CA 125 och uppvisar cytotoxicitet i olika in vitro system. Ett steg i rätt riktning är förekomsten av nya biokompatibla multikompartment påsar som har introducerats på marknaden. Dessa vätskor har ett lågt pH (mellan 2.2-3.2) i glukosdelen samtidigt som glukoskoncentrationen är hög vilket resulterar i att låga halter av GDPs bildas. Trotts detta varierar GDP halterna kraftigt mellan olika fabrikanter, både mellan de biokompatibla och de konventionella vätskorna. Detta beror främst på att produktionsföretagen har olika tillverkningssätt och olika steriliseringsprocesser.



3,4-dideoxyglukoson-3-en (3,4-DGE) har visat sig vara den mest toxiska GDP som bildas i PD vätskor. Dess toxicitet har konfirmerats i flera in vitro studier, bl.a. inhibering av fibroblastcell tillväxt, sårläkningshämning med mesotelceller, inducering av apoptos i leukocyter och i njurceller samt hämmande effekt på immunceller. 3,4-DGE står i en temperaturberoende jämvikt med en pool av 3-deoxyglukoson (3-DG) och 3-deoxyaldos-2-en (3-DA). Vid lagringstemperaturer över rumstemperatur ändras jämvikten i poolen och koncentrationen av 3,4-DGE ökar medan 3-DG minskar (3-DA har ej identifierats). Vid lagring och transport av konventionella PD vätskor kan korta temperaturökningar snabbt generera höga halter av 3,4-DGE från dess pool, vilket kan göra vätskan högt cytotoxisk. När temperaturen sänks minskar minskar även 3,4-DGE koncentrationen men med en mycket långsammare takt. Det är därför viktigt att optimera olika parametrar som pH, glukoskoncentration, påsdesign och lagringstemperatur för att minimera bildandet av GDPs. Det är också viktigt att ha kontroll över vilka temperaturer PD vätskorna blivit utsatta för innan patienten använder dem. (Less)
Abstract
Patients suffering from renal failure must remove extracellular water and waste products from their body in order to survive. One way of doing this is by treatment with peritoneal dialysis (PD). During PD treatment the abdominal cavity is filled and drained continuously with one to three liters of dialysis solution, often containing glucose, which act as an osmotic agent. Glucose creates a pressure gradient over the membrane which forces water and solutes to migrate from the blood into the dialysis fluid.



During the production of these fluids, heat sterilization is a must in order to obtain a sterile product. During the heat sterilization glucose degrades to different carbonyl compounds named glucose degradation products... (More)
Patients suffering from renal failure must remove extracellular water and waste products from their body in order to survive. One way of doing this is by treatment with peritoneal dialysis (PD). During PD treatment the abdominal cavity is filled and drained continuously with one to three liters of dialysis solution, often containing glucose, which act as an osmotic agent. Glucose creates a pressure gradient over the membrane which forces water and solutes to migrate from the blood into the dialysis fluid.



During the production of these fluids, heat sterilization is a must in order to obtain a sterile product. During the heat sterilization glucose degrades to different carbonyl compounds named glucose degradation products (GDPs). GDPs are known to damage the peritoneum, might be responsible for ultrafiltration failure in patients and have a toxic impact on several in vivo systems such as generation of higher plasma advanced glycation end products, stimulation of growth factors (VEGF) and lower dialysate CA 125 levels. GDPs also display higher cytotoxicity in various in vitro systems. As a result, new biocompatible multicompartment PD fluids, low in GDPs, have been produced. The reason for the low concentrations of GDPs in these fluids is mainly a low pH (pH ? 3.1) in the glucose compartment in combination with a high glucose concentration during sterilization. The difference in the concentration of GDPs within and between the new biocompatible and the conventionally manufactured PD fluids is great. This is mainly due to different manufacturing conditions and different sterilization processes.



3,4-dideoxyglucosone-3-ene (3,4-DGE) is the most toxic GDP formed in PD fluids. Its toxicity has been confirmed in several in vitro studies, for example in inhibition of growth in cultured cell fibroblasts, retardation of wound healing, downregulation of zonula occludens protein 1 expression in mesothelial cells, inducing apoptosis in leukocytes and in renal tubular epithelial cells and suppressing effects on immune cells. 3,4-DGE exists in a temperature dependent equilibrium with a pool of 3-deoxyglucosone (3-DG) and 3-deoxyaldose-2-ene (3-DA). If stored above room temperature, the equilibrium in the pool changes and the concentration of 3,4-DGE increases, whereas 3-DG decreases (3-DA has not been identified in PD fluids). During storage and transport of conventional PD fluids short temperature impulses may rapidly form high amounts of 3,4-DGE from its pool making the fluid highly cytotoxic. As the temperature drops the concentration only slowly decreases. Therefore it is important to optimize different parameters during the manufacture of such fluids so as to minimize GDP formation, and a further important question concerns the temperatures at which the fluids are stored and transported before patient use. (Less)
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author
supervisor
opponent
  • Prof, PhD, MD Breborowicz, Andrzej, Department of Pathophysiology
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicine (human and vertebrates), 4-dideoxyglucosone-3-ene, 3, cytotoxicity, storage, temperature, Glucose degradation products biocompatibility, sterlization, Medicin (människa och djur), Analytical chemistry, Analytisk kemi
publisher
Elanders Malmö Sallerupsvägen 138, Box 16500 200 25 Malmö
defense location
Center for Chemistry and Chemical Engineering, Sölvegatan 39, Lund in Lecture Hall B
defense date
2007-11-23 13:15
ISBN
978-91-7422-180-0
language
English
LU publication?
yes
id
533c19f5-19d7-4752-9fe4-e33b7b4a952b (old id 599158)
date added to LUP
2007-11-13 07:35:48
date last changed
2016-09-19 08:45:02
@phdthesis{533c19f5-19d7-4752-9fe4-e33b7b4a952b,
  abstract     = {Patients suffering from renal failure must remove extracellular water and waste products from their body in order to survive. One way of doing this is by treatment with peritoneal dialysis (PD). During PD treatment the abdominal cavity is filled and drained continuously with one to three liters of dialysis solution, often containing glucose, which act as an osmotic agent. Glucose creates a pressure gradient over the membrane which forces water and solutes to migrate from the blood into the dialysis fluid.<br/><br>
<br/><br>
During the production of these fluids, heat sterilization is a must in order to obtain a sterile product. During the heat sterilization glucose degrades to different carbonyl compounds named glucose degradation products (GDPs). GDPs are known to damage the peritoneum, might be responsible for ultrafiltration failure in patients and have a toxic impact on several in vivo systems such as generation of higher plasma advanced glycation end products, stimulation of growth factors (VEGF) and lower dialysate CA 125 levels. GDPs also display higher cytotoxicity in various in vitro systems. As a result, new biocompatible multicompartment PD fluids, low in GDPs, have been produced. The reason for the low concentrations of GDPs in these fluids is mainly a low pH (pH ? 3.1) in the glucose compartment in combination with a high glucose concentration during sterilization. The difference in the concentration of GDPs within and between the new biocompatible and the conventionally manufactured PD fluids is great. This is mainly due to different manufacturing conditions and different sterilization processes.<br/><br>
<br/><br>
3,4-dideoxyglucosone-3-ene (3,4-DGE) is the most toxic GDP formed in PD fluids. Its toxicity has been confirmed in several in vitro studies, for example in inhibition of growth in cultured cell fibroblasts, retardation of wound healing, downregulation of zonula occludens protein 1 expression in mesothelial cells, inducing apoptosis in leukocytes and in renal tubular epithelial cells and suppressing effects on immune cells. 3,4-DGE exists in a temperature dependent equilibrium with a pool of 3-deoxyglucosone (3-DG) and 3-deoxyaldose-2-ene (3-DA). If stored above room temperature, the equilibrium in the pool changes and the concentration of 3,4-DGE increases, whereas 3-DG decreases (3-DA has not been identified in PD fluids). During storage and transport of conventional PD fluids short temperature impulses may rapidly form high amounts of 3,4-DGE from its pool making the fluid highly cytotoxic. As the temperature drops the concentration only slowly decreases. Therefore it is important to optimize different parameters during the manufacture of such fluids so as to minimize GDP formation, and a further important question concerns the temperatures at which the fluids are stored and transported before patient use.},
  author       = {Erixon, Martin},
  isbn         = {978-91-7422-180-0},
  keyword      = {Medicine (human and vertebrates),4-dideoxyglucosone-3-ene,3,cytotoxicity,storage,temperature,Glucose degradation products biocompatibility,sterlization,Medicin (människa och djur),Analytical chemistry,Analytisk kemi},
  language     = {eng},
  publisher    = {Elanders Malmö Sallerupsvägen 138, Box 16500 200 25 Malmö},
  school       = {Lund University},
  title        = {Glucose degradation products in peritoneal dialysis fluids},
  year         = {2007},
}