Irreversible advanced glycosylation end products (AGE) are shown to induce tissue damage by a variety of chemical and cellular mechanisms. When administered to normal animals, AGE-modified albumin reacts covalently with tissue proteins to produce complex vascular alterations closely resembling diabetic vasculopathy. In humans, the clearance of serum with renal insufficiency and is severely impaired in diabetic patients with end-stage renal disease (ESRD). The renal clearance of AGE-peptides was estimated at 0.72 +/- 0.23 ml/min for normal subjects, and 0.61 +/- 0.2 ml/min for diabetics with normal glomerular filtration rate (GFR) (p value NS). After comparing different modes of treatment of patients with ESRD, we noted that, although conventional hemodialysis is ineffective, high-flux dialysis (HF) markedly reduces AGE levels only to return to near-pretreatment levels within 3 h. In chronic ambulatory peritoneal dialysis (CAPD)-treated patients, serum AGE are similar to those achieved by hemodialysis. In contrast, AGE levels in diabetics with renal transplantation decreased 8 h after surgery and remained within the normal range over the long term. Human serum AGE peptides (M.W. between 2,000 and 6,000) are shown to retain strong cross-linking activity with collagen in vitro. AGE peptides in human circulation may represent a thus far unrecognized class of reactive and potentially toxic substances which can exacerbate extrarenal vascular pathology, through their covalent attachment onto matrix proteins.