NARRATIVE REVIEW Accumulation of Advanced Glycation End Products and Chronic Complications in ESRD Treated by Dialysis Robbert Meerwaldt, MD, PhD, 1 Clark J. Zeebregts, MD, PhD, 2 Gerjan Navis, MD, PhD, 3 Jan-Luuk Hillebrands, PhD, 4 Joop D. Lefrandt, MD, PhD, 5 and Andries J. Smit, MD, PhD 5 Cardiovascular and connective tissue disorders are very common in patients with end-stage renal disease (ESRD), and the accumulation of advanced glycation end products (AGEs) is significantly increased in these patients. Accumulation of AGEs is believed to have a role in tissue protein aging and the pathogenesis of such age-related diseases as diabetes and ESRD. AGEs accumulate in patients with ESRD as a result of nonenzymatic glycation, oxidative stress, and diminished clearance of AGE precursors. Some AGEs show characteristic brown pigmentation and fluorescence, form protein-protein cross-links, and may ligate with AGE-specific receptors, inducing oxidative stress and cytokine production. This review focuses on the clinical relevance of AGE accumulation in patients with ESRD treated by dialysis for the development of long-term complications. The formation and accumulation of AGEs in patients with ESRD are discussed, as well as the relationship between AGE accumulation and such major complications of ESRD as cardiovascular and connective tissue disorders. Am J Kidney Dis 53:138-150. © 2008 by the National Kidney Foundation, Inc. INDEX WORDS: Advanced glycation end products; uremia; end-stage renal disease; cardiovascular disease; connective tissue; transplantation. M ortality is markedly increased in patients with decreased kidney function, particu- larly in patients with end-stage renal disease (ESRD). 1 The leading cause of death in patients with ESRD is cardiovascular disease, and one- third of all deaths are caused by cardiac arrest, acute myocardial infarction, and cardiac arrhyth- mias. 2 Some of the traditional cardiovascular risk factors in the general population also appear to be applicable to the hemodialysis population, whereas other factors do not correlate with ath- erosclerotic cardiovascular diseases in patients with ESRD. 3 Nontraditional risk factors, such as advanced glycation end products (AGEs), are associated with the development of long-term complications of ESRD. 4 This review focuses on the relationship between AGE accumulation and long-term complications in patients with ESRD treated by dialysis, interventions against AGEs, and the clinical relevance of assessing AGE accumulation in patients with ESRD. Serum levels of low-molecular-weight AGEs, that is, AGE free adducts, which result from proteolysis of glycated proteins, increase with decreasing kidney function, and both serum and tissue AGE levels are markedly increased in patients with ESRD. 5,6 Levels of tissue and plasma AGEs are determined by numerous fac- tors, described in more detail later. AGE free adducts are removed by the kidney through glo- merular filtration with subsequent tubular reab- sorption and degradation. 7 In patients with diabe- tes, AGE levels are related to decreased kidney function and the presence of diabetic nephropa- thy. 8 Also, as described in Ceballos-Picot et al, 9 patients without diabetes with mild chronic kid- ney failure estimated creatinine clearance, 41 to 80 mL/min) show AGE levels and other markers of oxidative stress dependency on kidney impair- ment. Interestingly, AGE levels, strongly and independently of other risk factors, predict the progression of kidney impairment in patients with diabetes. 10,11 Currently available methods of kidney replace- ment therapy are ineffective in clearing AGEs From the 1 Department of Surgery, Isala Clinics, Zwolle; and 2 Department of Surgery, Division of Vascular Surgery, 3 Department of Internal Medicine, Division of Nephrology, 4 Department of Cell Biology, and 5 Department of Internal Medicine, Division of Vascular Medicine, University Medi- cal Center Groningen, Groningen, The Netherlands. Received May 20, 2008. Accepted in revised form August 29, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.08.031 on November 26, 2008. Address correspondence to Robbert Meerwaldt, MD, PhD, Department of Surgery, Isala Clinics, Dr Heesweg 2, 8025 AB, Zwolle, The Netherlands. E-mail: r.meerwaldt@isala.nl © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5301-0020$36.00/0 doi:10.1053/j.ajkd.2008.08.031 American Journal of Kidney Diseases, Vol 53, No 1 (January), 2009: pp 138-150 138