Protein glycation adducts, early glycation adducts, such as N∊-fructosyl-lysine, and advanced glycation end products (AGEs) are uremic toxins. Glycation adducts are found in plasma and tissue proteins (glycation adduct residues), in peptides (glycation adduct peptide residues), and glycated amino acids (glycation free adducts). The latter two analyte groups arise from proteolysis of glycated proteins and glycation of peptides and amino acids. Quantitation of glycation adducts in uremia is difficult because of the presence of many different AGEs at low concentrations in different forms in the presence of many potential interferences. Application of liquid chromatography with tandem mass spectrometric (LC-MS/MS) detection to plasma, urine, and dialysate samples of uremic patients has provided a comprehensive and quantitative analysis of glycation adducts in uremia. Glycation free adducts accumulate markedly in the plasma of uremic patients and are eliminated in the peritoneal dialysate. Multiple glycation adducts, and also protein oxidation and nitration adducts, may be quantified concurrently. Glycation free adducts are the major form of glycation adduct eliminated in dialysate. LC-MS/MS may now be used to quantify concentrations, extents of protein modification, clearances, and excretion rates of glycation adducts in uremia.
VanHolderR., De SmetR., GlorieuxG., ArgilesA., BaurmeisterU., BrunetP.Review on uremic toxins: Classification, concentration, and interindividual variability.Kidney Int2003; 63: 1934–43.
2.
ThornalleyP.J.Clinical significance of glycation.Clin Lab1999; 45: 263–73.
3.
AgalouS., AhmedN., Babaei-JadidiR., DawnayA., ThornalleyP.J.Profound mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol2005; 16: 1471–85.
4.
WeltenA.G.A., SchalkwijkC.G., ter WeeP.M., MeijerS., van den BornJ., BeelenR.J.H.Single exposure of mesothelial cells to glucose degradation products (GDPs) yields early advanced glycation end-products (AGEs) and a proinflammatory response.Perit Dial Int2003; 23: 213–21.
5.
ThornalleyP.J.Protecting the genome: Defence against nucleotide glycation and emerging role of glyoxalase I over expression in multidrug resistance in cancer chemotherapy.Biochem Soc Trans2003; 31: 1372–7.
WitowskiJ., KorybalskaK., WisniewskaJ., BreborowiczA., GahlG.M., FreiU.Effect of glucose degradation products on human peritoneal mesothelial cell function.J Am Soc Nephrol2000; 11: 729–39.
9.
AmoreA., CappelliG., CirinaP., ContiG., GambarutoC., SilvestroL.Glucose degradation products increase apoptosis of human mesothelial cells.Nephrol Dial Transplant2003; 18: 677–88.
10.
KangY., EdwardsL.G., ThornalleyP.J.Effect of methylglyoxal on human leukaemia 60 cell growth: Modification of DNA, G1 growth arrest and induction of apoptosis.Leuk Res1996; 20: 397–405.
11.
SpeerO., Morkunaite-HaimiS., LiobikasJ., FranckM., HensboL., LinderM.D.Rapid suppression of mitochondrial permeability transition by methylglyoxal.J Biol Chem2003; 278: 34757–63.
12.
XiangG., SchinzelR., SimmA., SebekovaK., HeidlandA.Advanced glycation end products impair protein turnover in LLC-PK1: amelioration by trypsin.Kidney Int2001; 59: 53–7.
InagiR., MiyataT., YamamotoT., SuzukiD., UrakamiK., SaitoA.Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: Role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis.FEBS Lett1999; 463: 260–4.
15.
MortierS., FaictD., SchalkwijkC.G., LameireN.H., De VrieseA.S.Long-term exposure to new peritoneal dialysis solutions: Effects on the peritoneal membrane.Kidney Int2004; 66: 1257–65.
16.
LeeH.Y., ParkH.C., SeoB.J., DoJ.Y., YunS.R., SongH.Y.Superior patient survival for continuous ambulatory peritoneal dialysis patients treated with a peritoneal dialysis fluid with neutral pH and low glucose degradation product concentration (Balance).Perit Dial Int2005; 25: 248–55.
17.
GoldbergA.L.Protein degradation and protection against misfolded or damaged proteins.Nature2003; 426: 895–9.
18.
ThornalleyP.J., BattahS., AhmedN., KarachaliasN., AgalouS., Babaei-JadidiR.Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry.Biochem J2003; 375: 581–92.
19.
MakitaZ., RadoffS., RayfieldE.J., FriedmanE.A., KaufmanA.M., KorbetS.M.Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure.Lancet1994; 343: 1519–22.
20.
KoitoW., ArakiT., HoriuchiS., NagaiR.Conventional antibody against N∊-(carboxymethyl)lysine (CML) shows cross-reaction to N∊-(carboxyethyl)lysine (CEL): Immunochemical quantification of CML with a specific antibody.J Biochem (Tokyo)2004; 136: 831–7.
21.
DruschS., FaistV., ErbersdoblerH.Determination of N∊-carboxymethyllysine in milk products by a modified reversed-phase HPLC method.Food Chemistry1999; 65: 547–53.
22.
SebekovaK., PodrackaL., BlazicekP., SyrovaD., HeidlandA., SchinzelR.Plasma levels of advanced glycation end products in children with renal disease.Pediatr Nephrol2001; 16: 1105–12.
23.
WrobelK., WrobelK., Garay-SevillaM., NavaL.E., MalacaraJ.M.Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system.Clin Chem1997; 43: 1563–9.
24.
ThomasM.C., TsalamandrisC., MacIsaacR., MedleyT., KingwellB., CooperM.E.Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes.Kidney Int2004; 66: 1167–72.
25.
BuxtonT., GuilbaultG.G.Fluorometric analysis for N'-formylkynurenine in plasma and urine.Clin Chem1974; 20: 765–8.
26.
OdettiP., FogartyJ., SellD.R., MonnierV.M.Chromatographic quantitation of plasma and erythrocyte pentosidine in diabetic and uremic subjects.Diabetes1992; 41: 153–9.
27.
WilkerS.C., ChellanP., ArnoldB.M., NagarajR.H.Chromatographic quantification of argpyrimidine, a methylglyoxal-derived product in tissue proteins.Anal Biochem2001; 290: 353–8.
28.
VerzijlN., DeGrootJ., ThorpeS.R., BankR.A., ShawJ.N., LyonsT.J.Effect of collagen turnover on the accumulation of advanced glycation endproducts.J Biol Chem2000; 275: 39027–31.
29.
AhmedN., ArgirovO.K., MinhasH.S., CordeiroC.A., ThornalleyP.J.Assay of advanced glycation endproducts (AGEs): Surveying AGEs by chromatographic assay with derivatisation by aminoquinolyl-N-hydroxysuccimidyl-carbamate and application to N∊-carboxymethyl-lysine- and N∊-(1-carboxyethyl)lysine-modified albumin.Biochem J2002; 364: 1–14.
30.
DoblerD., AhmedN., ThornalleyP.J.Peptide mapping of type IV collagen modified minimally by methylglyoxal in vitro.Ann N Y Acad Sci2004; 1043: 906.
31.
OdaniH., MatsumotoY., ShinzatoT., UsamiJ., MaedaK.Mass spectrometric study on the protein chemical modification of uremic patients in advanced Maillard reaction.J Chromatogr B Biomed Sci Appl1999; 731: 131–40.
32.
TeerlinkT., BartoR., ten BrinkH.J., SchalkwijkC.G.Measurement of N∊-(carboxymethyl)lysine and N∊-(carboxyethyl) lysine in human plasma protein by stable-isotope-dilution tandem mass spectrometry.Clin Chem2004; 50: 1222–8.
33.
AhmedN., ThornalleyP.J., LuthenR., HaussingerD., SebekovaK., SchinzelR.Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis.J Hepatol2004; 41: 913–19.
34.
IvanovV.T., KarelinA.A., BlishchenkoE.Y., PhilippovaM.M., NazimovI.V.Proteolytic degradation of hemoglobin in vivo. Role in formation of tissue specific peptide pool.Pure Appl Chem1998; 70: 67–74.
35.
GaiM., CantaluppiV., FenocchioC., MottaD., MasiniS., PacittiA.Presence of protein fragments in urine of critically ill patients with acute renal failure: A nephrologic enigma.Clin Chem2004; 50: 1822–4.
36.
FriedlanderM.A., WuY.W., ElgawishA., MonnierV.M.Early and advanced glycosylation end products. Kinetics of formation and clearance in peritoneal dialysis.J Clin Invest1996; 97: 728–35.
37.
ThornalleyP.J., ArgirovaM., AhmedN., MannV.M., ArgirovO.K., DawnayA.Mass spectrometric monitoring of albumin in uremia.Kidney Int2000; 58: 2228–34.
38.
AhmedN., DoblerD., DeanM., ThornalleyP.J.Peptide mapping identifies hotspot site of modification in human serum albumin by methylglyoxal involved in ligand binding and esterase activity.J Biol Chem2005; 280: 5724–32.
39.
AgalouS., KarachaliasN., TuckerB., ThornalleyP.J., DawnayA.Estimation of α-oxoaldehydes formed from the degradation of glycolytic intermediates and glucose fragmentation in blood plasma of human subjects with uraemia.Int Congr Ser2002; 1245: 182.
40.
MannV.M., TuckerB., ThornalleyP.J., DawnayA.Elevated plasma methylglyoxal and glyoxal in uremia: Implications for advanced glycation endproduct formation.Kidney Int1999; 55: 2582.
41.
OdaniH., ShinzatoT., MatsumotoY., UsamiJ., MaedaK.Increase in three α,β-dicarbonyl compound levels in human uremic plasma: Specific in vivo determination of intermediates in advanced Maillard reaction.Biochem Biophys Res Commun1999; 256: 89–93.
42.
WieslanderA., LindenT., MusiB., JarkelidL., SpeidelR., BeckW.Exogenous uptake of carbonyl stress compounds promoting AGE formation from peritoneal dialysis fluids.Contrib Nephrol2001; 131: 82–9.
43.
OdaniH., IijimaK., NakataM., MiyataS., KusunokiH., YasudaY.Identification of Nω-carboxymethylarginine, a new advanced glycation endproduct in serum proteins of diabetic patients: Possibly a new marker of aging and diabetes.Biochem Biophys Res Commun2001; 285: 1232–6.
44.
AhmedM.U., ThorpeS.R., BaynesJ.W.Identification of N∊-carboxymethyl-lysine as a degradation product of fructoselysine in glycated protein.J Biol Chem1986; 261: 4889–94.
45.
ThornalleyP.J., LangborgA., MinhasH.S.Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose.Biochem J1999; 344: 109–16.
46.
FuM-X, RequenaJ.R., JenkinsA.J., LyonsT.J., BaynesJ.W., ThorpeS.R.The advanced glycation end product, N∊-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions.J Biol Chem1996; 271: 9982–6.
47.
AndersonM.M., RequenaJ.R., CrowleyJ.R., ThorpeS.R., HeineckeJ.W.The myeloperoxidase system of human phagocytes generates N∊-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation.J Clin Invest1999; 104: 103–13.
AhmedN., Babaei-JadidiR., KarachaliasN., ThornalleyP.J.Degradation products of proteins damaged by glycation and oxidation increase markedly in experimental diabetes and are suppressed by high dose therapy with thiamine and Benfotiamine [Abstract].Diabetologia2005; 48(Suppl 1): A417.
50.
DrindaS., FrankeS., CanetC.C., PetrowP., BrauerR., HuttichC.Identification of the advanced glycation end products N∊-carboxymethyllysine in the synovial tissue of patients with rheumatoid arthritis.Ann Rheum Dis2002; 61: 488–92.
51.
RippeB., StelinG., HaraldssonB.Computer-simulations of peritoneal-fluid transport in CAPD.Kidney Int1991; 40: 315–25.
52.
ParkM.S., HeimburgerO., BergstromJ., WaniewskiJ., WerynskiA., LindholmB.Peritoneal transport during dialysis with amino acid-based solutions.Perit Dial Int1993; 13: 280–8.
53.
DevuystO., NielsenS., CosynsJ.P., SmithB.L., AgreP., SquiffletJ.P.Aquaporin-1 and endothelial nitric oxide synthase expression in capillary endothelia of human peritoneum.Am J Physiol Heart Circ Physiol1998; 275: H234–H242.
54.
MannG.E., YudilevichD.L., SobreviaL.Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells.Physiol Rev2003; 83: 183–252.
55.
de la MotteS., PlumJ., Passlick-DeetjenJ., GrabenseeB.One-compartment model for amino acids and other biological molecules in peritoneal dialysis.Int J Clin Pharmacol Ther2002; 40: 60–8.
56.
AhmedN., AhmedU., ThornalleyP.J., HagerK., FleischerG.A., MunchG.Protein glycation, oxidation and nitration marker residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment.J Neurochem2004; 92: 255–63.
KesslerM., NetterP., AzoulayE., MayeuxD., PereP., GaucherA.Dialysis-associated arthropathy: A multicentre survey of 171 patients receiving haemodialysis for over 10 years. The Co-operative Group on Dialysis-Associated Arthropathy.Rheumatology1992; 31: 157–62.
KaysenG.A.Biological basis of hypoalbuminemia in ESRD.J Am Soc Nephrol1998; 9: 2368–76.
61.
ThornalleyP.J.Glyoxalase I — structure, function and a critical role in the enzymatic defence against glycation.Biochem Soc Trans2003; 31: 1343–8.
62.
SuzukiK., KohY.H., MizunoH., HamaokoR., TaniguchiN.Overexpression of aldehyde reductase protects PC12 cells from the cytotoxicity of methylglyoxal or 3-deoxyglucosone.J Biochem1998; 123: 353–7.
63.
IzaguirreG., KikonyogoA., PietruszkoR.Methylglyoxal as substrate and inhibitor of human aldehyde dehydrogenase: Comparison of kinetic properties among the three isozymes.Comp Biochem Physiol Biochem Mol Biol1998; 119: 747–54.
64.
SzwergoldB.S., HowellS., BeisswengerP.J.Human fructosamine-3-kinase. Purification, sequencing, substrate specificity, and evidence of activity in vivo.Diabetes2001; 50: 2139–47.
65.
CollardF., WiameE., BergansN., FortpiedJ., VertommenD., VanstapelF.Fructosamine 3-kinase-related protein and deglycation in human erythrocytes.Biochem J2004; 382: 137–43.
66.
ThornalleyP.J.The enzymatic defence against glycation in health, disease and therapeutics: A symposium to examine the concept.Biochem Soc Trans2003; 31: 1343–8.
67.
MichalekM.T., GrantE.P., RockK.L.Chemical denaturation and modification of ovalbumin alters its dependence on ubiquitin conjugation for class I antigen presentation.J Immunol1996; 157: 617–24.
68.
ThornalleyP.J.Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs.Cell Mol Biol (Noisy-le-grand)1998; 44: 1013–23.
69.
ThornalleyP.J.Glycation, receptor-mediated cell activation and vascular complications of diabetes.Diabetes and Vascular Disease Research2004; 1: 21–2.
