Glucose degradation products in peritoneal dialysis fluids

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 (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.