Mechanisms for the formation of glycoxidation products in end-stage renal disease

Background. Advanced glycation end products (AGEs) accumulate on tissue and plasma proteins in patients with renal failure far in excess of normal agi ng or diabetes. The aim of these studies was to elucidate the nature of the precursors and the pathways that lead to an accelerated formation of two s tructurally identified AGEs [pentosidine and N-epsilon(carboxymethyl)lysine (CML)] in the uremic milieu. Methods. Serum levels of the glycoxidation products, pentosidine and CML, w ere quantitated by high-performance liquid chromatography in uremic patient s treated by dialysis. The formation of early glycation products (as furosi ne) and late glycoxidation products was modeled in uremic serum and in spen t peritoneal dialysate. Results. Clinical factors that affect circulating levels of AGEs included d ialysis clearance and dialyzer membrane pore size, but not the presence or absence of diabetes. Both pentosidine and CML form at an accelerated rate i n serum from uremic patients. Chelating agents most effectively slow the fo rmation in vitro. In uremic fluids, the primary mechanism of formation of p entosidine is through the Amadori pathway. The primary mechanism of formati on of CML is through metal-chelated autoxidation of reducing sugars generat ing reactive carbonyl precursors. In uremic serum, the presence of an unide ntified reactive low molecular weight precursor accelerates the formation o f pentosidine. Conclusions The formation of the two glycoxidation products, pentosidine an d CML, proceeds by different pathways and is enhanced by different precurso rs in the uremic milieu. The formation of both AGEs is markedly enhanced by metal-catalyzed reactions, evidence for the presence of increased metal-io n mediated oxidant stress in uremia.