Structure- and Concentration-Specific Assessment of the Physiological Reactivity of α-Dicarbonyl Glucose Degradation Products in Peritoneal Dialysis Fluids

Abstract

In peritoneal dialysis (PD), glucose degradation products (GDPs), which are formed during heat sterilization of dialysis fluids, lead to structural and functional changes in the peritoneal membrane, which eventually result in the loss of its ultrafiltration capacity. To determine the molecular mechanisms behind these processes, the present study tested the influence of the six major α-dicarbonyl GDPs in PD fluids, namely, glyoxal, methylglyoxal, 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), and glucosone with respect to their potential to impair the enzymatic activity of RNase A as well as their effects on cell viability. For comprehensive risk assessment, the α-dicarbonyl GDPs were applied separately and in concentrations as present in conventional PD fluids. Thus, it was shown that after 5 days, glucosone impaired RNase A activity most distinctly (58% remaining activity, p < 0.001 compared to that of the control), followed by 3,4-DGE (62%, p < 0.001), 3-DGal (66%, p < 0.001), and 3-DG (76%, p < 0.01). Methylglyoxal and glyoxal caused weaker inactivation with significant effects only after 10 days of incubation (79%, 81%, p < 0.001). Profiling of the advanced glycation end products formed during the incubation of RNase A with methylglyoxal revealed predominant formation of the arginine modifications imidazolinone, CEA/dihydroxyimidazoline, and tetrahydropyrimidine at Arg10, Arg33, Arg39, and Arg85. Particularly, modification at Arg39 may severely affect the active site of the enzyme. Additionally, structure- and concentration-specific assessment of the cytotoxicity of the α-dicarbonyl GDPs was performed. Although present at very low concentration, the cytotoxic effect of PD fluids after 2 days of incubation was exclusively caused by 3,4-DGE (14% cell viability, p < 0.001). After 4 days of incubation, 3-DGal (13% cell viability, p < 0.001), 3-DG (24%, p < 0.001), and, to a lower extent, glyoxal and methylglyoxal (both 57%, p < 0.01) also reduced cell viability significantly. In conclusion, 3,4-DGE, 3-DGal, and glucosone appear to be the most relevant parameters for the biocompatibility of PD fluids.

5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

“…It has been previously demonstrated that under these experimental conditions there is a slow accumulation of reactive dicarbonyl compounds GO and MGO. 6–8 When incubated with glucose without any additives (Figure S3A) bzArg was modified to the extent of 5.0 ± 0.05 % by GO (peaks in chromatogram preceding bzArg peak 19 ) and 3.6 ± 0.40 % by MGO (later product appearing as a shoulder immediately following bzArg peak 20 ). PM as well as pentyl-PM or hexyl-PM effectively scavenged the dicarbonyl products of glucose autoxidation, thus leaving bzArg unscathed (Figure S3B).…”

Peritoneal Dialysis in Children

“…GDPs exert local and systemic toxicity and contribute to formation of advanced glycation end products (AGE). 3,4-DGE is present in relatively low concentrations in PD fluids but exerts particular high toxicity [79]. Markedly reduced GDP formation could be achieved by separation of glucose and electrolytes from the buffer compound in a double-chamber bag system (Table 2).…”

High complexity of toxic reactions: parallels between products of oxidative stress and advanced glycation end products

“…In food toxicology, AGEs are long known to the result from the Maillard reaction (Maillard 1912) during heat processing of foods. With recent progress in biochemistry and analytical chemistry (Distler et al 2014), this scientific field is currently receiving pronounced interest (Delgado-Andrade and Fogliano 2018). AGEs are non-enzymatic protein and amino acid adducts which are formed from carbohydratederived dicarbonyls.…”