The Official Journal of the National Kidney Foundation VOL 35, NO 3, MARCH 2000 A J KD American Journal of Kidney Diseases IN-DEPTH REVIEW Advanced Glycation End Products: A Nephrologist’s Perspective Dominic S.C. Raj, MD, Devasmita Choudhury, MD, Tomas C. Welbourne, PhD, and Moshe Levi, MD ● Advanced glycation end products (AGEs) are a heterogeneous group of molecules that accumulate in plasma and tissues with advancing age, diabetes, and renal failure. There is emerging evidence that AGEs are potential uremic toxins and may have a role in the pathogenesis of vascular and renal complications associated with diabetes and aging. AGEs are formed when a carbonyl of a reducing sugar condenses with a reactive amino group in target protein. These toxic molecules interact with specific receptors and elicit pleiotropic responses. AGEs accelerate atherosclerosis through cross-linking of proteins, modification of matrix components, platelet aggregation, defec- tive vascular relaxation, and abnormal lipoprotein metabolism. In vivo and in vitro studies indicate that AGEs have a vital role in the pathogenesis of diabetic nephropathy and the progression of renal failure. The complications of normal aging, such as loss of renal function, Alzheimer’s disease, skin changes, and cataracts, may also be mediated by progressive glycation of long-lived proteins. AGEs accumulate in renal failure as a result of decreased excretion and increased generation resulting from oxidative and carbonyl stress of uremia. AGE-modified  2 - microglobulin is the principal pathogenic component of dialysis-related amyloidosis in patients undergoing dialysis. Available dialytic modalities are not capable of normalizing AGE levels in patients with end-stage renal disease. A number of reports indicated that restoration of euglycemia with islet-cell transplantation normalized and prevented further glycosylation of proteins. Aminoguanidine (AGN), a nucleophilic compound, not only decreases the formation of AGEs but also inhibits their action. A number of studies have shown that treatment with AGN improves neuropathy and delays the onset of retinopathy and nephropathy. N-Phenacylthiazolium bromide is a prototype AGE cross-link breaker that reacts with and can cleave covalent AGE-derived protein cross-links. Thus, there is an exciting possibility that the complications of diabetes, uremia, and aging may be prevented with these novel agents.  2000 by the National Kidney Foundation, Inc. INDEX WORDS: Advanced glycation end products (AGEs); diabetes; renal failure; dialysis; aging; aminoguanidine (AGN); oxidant stress. N O OTHER MOLECULE has the versatile structure and protean toxic potential of advanced glycation end products (AGEs). They are of special interest to the nephrologist because they are a potential uremic toxin and may have an etiologic role in vascular and renal complica- tions associated with diabetes and aging. In 1912, a French chemist, L.C. Maillard, 1 reported the formation of a yellow-brown product on heating mixtures of amino acids and sugars and laid the foundation for the science of AGEs. Glycation is a posttranslational modification of proteins result- ing from condensation of reducing sugars with -amino groups of lysine residue of proteins. The resulting Schiff base undergoes rearrangement to form relatively stable ketoamines, the Amadori products. These glycated proteins undergo pro- From the Department of Medicine, Lousiana State Univer- sity Medical Center, Shreveport, LA; and the Veterans Af- fairs Medical Center and the University of Texas Southwest- ern Medical Center, Dallas, TX. Received May 28, 1999; accepted in revised form Septem- ber 24, 1999. Address reprint requests to Moshe Levi, MD, Chief, Divi- sion of Nephrology, 4500 South Lancaster Rd, Mail Code 151, Dallas, TX 75216. E-mail: mmjjl@aol.com  2000 by the National Kidney Foundation, Inc. 0272-6386/00/3503-0002$3.00/0 American Journal of Kidney Diseases, Vol 35, No 3 (March), 2000: pp 365-380 365