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DOROTA SŁOWIK-ŻYŁKA

REDUCTION OF CARBONYL STRESS WITH RENAL REPLACEMENT
THERAPY IN CHRONIC RENAL FAILURE


Summary
Advanced glycation end products (AGEs) play a significant role in the pathogenesis of chronic renal failure and diabetic complications. Their accumulation in these disorders leads to the formation of intermolecular crosslinks and lowers susceptibility to protein denaturation and proteolysis. By binding with specific receptors, AGEs initiate processes that result in the generation and release of cytokines, growth factors, and reactive oxygen species (ROS). This work concentrated on pentosidine as a representative AGE. High tissue and plasma concentrations of pentosidine observed in chronic renal failure result from accumulation of pentosidine precursors containing highly reactive carbonyl groups and responsible for carbonyl stress in uremia. The aim of this work was to evaluate clinical and biochemical parameters that affect pentosidine concentration in plasma of chronic renal failure patients and renal graft recipients. A pentosidine standard was synthesized and purified and its chromatographic separation method was optimized. RP-HPLC was applied using an octadecylsilane (ODS) column and HFBA or TFA as solvents. 53 chronically haemodialyzed patients and 14 renal graft recipients were studied. The chromatographic method proved to be sensitive and specific enough for precise measurements of plasma concentrations of both total and free pentosidine. The results served to evaluate the efficiency of renal replacement therapy for the reduction of carbonyl stress in patients with chronic renal failure. Numerous factors influencing the concentration of pentosidine in plasma were identified. Some are not amenable (gender, age), while others, like type of dialysis membrane, efficiency of dialysotherapy, surface of dialyser, or body mass index (BMI) can be controlled. Patients undergoing more dialysis sessions with polysulphone membranes three months prior to the study demonstrated lower plasma concentrations of total pentosidine. Lower concentrations of total and free pentosidine were observed in patients with higher BMI values. On the other hand, there was a positive correlation between pentosidine concentration, efficiency of dialysotherapy and ultrafiltration. Modification of these parameters may decrease carbonyl stress. The study demonstrated that renal transplantation is the only effective therapy for decreasing pentosidine concentrations and the intensity of carbonyl stress. A transplanted kidney efficiently and quickly eliminates carbonyl derivatives, immediately reduces the rate of pentosidine synthesis, and in consequence leads to a slow decrease in its concentration resulting from whitch elimination half-time of plasma proteins. The study showed that the concentration of total pentosidine prior to transplantation has a significant influence on diuresis after transplantation. It is possible that haemodialysotherapy whitch effectively decreases carbonyl stress in patients awaiting renal grafting and contributes to improved function of the transplanted organ.

K e y w o r d s : chronic renal failure – carbonyl stress – pentosidine – high performance liquid chromatography.

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