Volume 62, Issue 5, Pages 1524-1538 (November 2002) The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia  Jonathan Himmelfarb, Peter Stenvinkel, T. Alp Ikizler, Raymond M. Hakim  Kidney International  Volume 62, Issue 5, Pages 1524-1538 (November 2002) DOI: 10.1046/j.1523-1755.2002.00600.x Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 1 The blind men and the elephant. Poem by John Godfrey Saxe (Cartoon originally copyrighted by the authors; G. Renee Guzlas, artist). Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 2 Potential mechanisms for the role of oxidatively-modified low-density lipoprotein (LDL) in atherogenesis. Endothelial cells, vascular smooth muscle cells, or macrophages may catalyze the oxidative modification of circulating LDL leading to: (I) recruitment of circulating monocytes; (II) macrophage “trapping” in the vessel intima; (III) enhanced uptake of oxidized LDL by resident macrophages leading to foam cell formation; and (IV) endothelial cell destruction as a result of oxidized LDL toxicity (reprinted with permission from Quinn MT et al, Proc Natl Acad Sci USA, 82:5949–5953, 1985). Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 3 Pathways of oxidant generation by activated leukocytes. Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 4 Biochemistry of oxidant stress biomarkers. (A) Oxidation of tyrosine residues. (B) F2-isoprostane generation from arachidonic acid via free radicals. (C) Generation of reactive aldehydes (carbonyls). (D) Amino acid thiol group oxidation. (E) DNA oxidation. Abbreviations are: HOCL, hypochlorous acid; MPO, myeloperoxidase; CML, carboxymethyllysine; HNE, hydroxynonenal. Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 5 Elevated plasma protein 3-chlorotyrosine, a specific biomarker of myeloperoxidase-catalyzed oxidation, in hemodialysis patients. (Adapted with permission from Himmelfarb et al, Free Radical Biology & Medicine 31:1163–1169, 2001.) Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 6 Plasma protein thiol group oxidation (A) and carbonyl formation (B) in patients with chronic kidney disease and hemodialysis patients, demonstrating that plasma protein oxidation develops in renal disease well before ESRD. (Adapted with permission from Himmelfarb et al, Kidney Int 58:2571–2578, 2000.) Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 7 The malnutrition inflammation syndrome tips the redox balance toward oxidative stress and cardiovascular disease. Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions

Figure 8 Major end points of the SPACE Study. Symbols are: () placebo; (▪) vitamin E. (Adapted with permission from Boaz et al, Lancet 356:1213–1218, 2000.) Kidney International 2002 62, 1524-1538DOI: (10.1046/j.1523-1755.2002.00600.x) Copyright © 2002 International Society of Nephrology Terms and Conditions