Advertisement
American Journal of Kidney Diseases

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

      Carbamylation describes a nonenzymatic posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally increases. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins and have been implicated directly in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation’s relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kalim S.
        • Tamez H.
        • Wenger J.
        • et al.
        Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease.
        Clin J Am Soc Nephrol. 2013; 8: 1927-1934
        • Berg A.H.
        • Drechsler C.
        • Wenger J.
        • et al.
        Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure.
        Sci Transl Med. 2013; 5: 175ra29
        • Wöhler F.
        Ueber künstliche Bildung des Harnstoffs.
        Ann Phys. 1828; 87: 253-256
        • Walker J.
        • Hambly F.J.
        Transformation of ammonium cyanate into urea.
        J Chem Soc. 1895; 67: 746-767
        • Shutz F.
        Cyanate.
        Experientia. 1949; 5: 133-172
        • Stark G.R.
        • Stein W.H.
        • Moore S.
        Reaction of the cyanate present in aqueous urea with amino acids and proteins.
        J Biol Chem. 1960; 235: 3177-3181
        • Stark G.R.
        On the reversible reaction of cyanate with sulfhydryl groups and the determination of NH2-terminal cysteine and cystine in proteins.
        J Biol Chem. 1964; 239: 1411-1414
        • Stark G.R.
        Reactions of cyanate with functional groups of proteins. 3. Reactions with amino and carboxyl groups.
        Biochemistry. 1965; 4: 1030-1036
        • Nyc J.F.
        • Mitchell H.K.
        Synthesis of orotic acid from aspartic acid.
        J Am Chem Soc. 1947; 69: 1382-1384
        • Smyth D.G.
        Carbamylation of amino and tyrosine hydroxyl groups. Preparation of an inhibitor of oxytocin with no intrinsic activity on the isolated uterus.
        J Biol Chem. 1967; 242: 1579-1591
        • Jelkmann W.
        ‘O’, erythropoietin carbamoylation versus carbamylation.
        Nephrol Dial Transplant. 2008; 23 ([letter]) (author reply, 3034): 3033
        • Jaisson S.
        • Pietrement C.
        • Gillery P.
        Carbamylation-derived products: bioactive compounds and potential biomarkers in chronic kidney failure and atherosclerosis.
        Clin Chem. 2011; 57: 1499-1505
        • Stark G.R.
        Modification of proteins with cyanate.
        Methods Enzymol. 1972; 25: 579-584
        • Brotzel F.
        • Chu Y.C.
        • Mayr H.
        Nucleophilicities of primary and secondary amines in water.
        J Org Chem. 2007; 72: 3679-3688
        • Claxton J.S.
        • Sandoval P.C.
        • Liu G.
        • et al.
        Endogenous carbamylation of kidney medullary proteins.
        PLoS One. 2014; 8: e82655
        • Carreras J.
        • Chabas A.
        • Diederich D.
        Physiological and clinical implications of protein carbamylation.
        in: Grisolia S. Baguena R. Major F. The Urea Cycle. John Wiley & Sons Inc, New York, NY1976: 501-548
        • Dirnhuber P.
        • Schutz F.
        The isomeric transformation of urea into ammonium cyanate in aqueous solutions.
        Biochem J. 1948; 42: 628-632
        • Kraus L.M.
        • Kraus Jr., A.P.
        Carbamoylation of amino acids and proteins in uremia.
        Kidney Int Suppl. 2001; 78: S102-S107
        • Nilsson L.
        • Lundquist P.
        • Kagedal B.
        • Larsson R.
        Plasma cyanate concentrations in chronic kidney failure.
        Clin Chem. 1996; 42: 482-483
        • Kraus L.M.
        • Jones M.R.
        • Kraus Jr., A.P.
        Essential carbamoyl-amino acids formed in vivo in patients with end-stage kidney disease managed by continuous ambulatory peritoneal dialysis: isolation, identification, and quantitation.
        J Lab Clin Med. 1998; 131: 425-431
        • Bobb D.
        • Hofstee B.H.
        Gel isoelectric focusing for following the successive carbamylations of amino groups in chymotrypsinogen A.
        Anal Biochem. 1971; 40: 209-217
        • Grisolia S.
        Enzyme regulation by substrate; rapid inactivation of glutamate dehydrogenase by carbamyl phosphate.
        Biochem Biophys Res Commun. 1968; 32: 56-59
        • Rimon S.
        • Perlmann G.E.
        Carbamylation of pepsinogen and pepsin.
        J Biol Chem. 1968; 243: 3566-3572
        • Jaisson S.
        • Lorimier S.
        • Ricard-Blum S.
        • et al.
        Impact of carbamylation on type I collagen conformational structure and its ability to activate human polymorphonuclear neutrophils.
        Chem Biol. 2006; 13: 149-159
        • Jaisson S.
        • Larreta-Garde V.
        • Bellon G.
        • et al.
        Carbamylation differentially alters type I collagen sensitivity to various collagenases.
        Matrix Biol. 2007; 26: 190-196
        • Mun K.C.
        • Golper T.A.
        Impaired biological activity of erythropoietin by cyanate carbamylation.
        Blood Purif. 2000; 18: 13-17
        • Leist M.
        • Ghezzi P.
        • Grasso G.
        • et al.
        Derivatives of erythropoietin that are tissue protective but not erythropoietic.
        Science. 2004; 305: 239-342
        • Park K.D.
        • Mun K.C.
        • Chang E.J.
        • Park S.B.
        • Kim H.C.
        Inhibition of erythropoietin activity by cyanate.
        Scand J Urol Nephrol. 2004; 38: 69-72
        • Brines M.
        • Cerami A.
        Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response.
        J Intern Med. 2008; 264: 405-432
        • Legendre J.M.
        • Bergot A.
        • Turzo A.
        • Morin P.P.
        • Humphery-Smith I.
        Modifications du point isoelectrique de la chaine-alpha de l'hemoglobine sous l'action de l'uree, du cyanate de sodium, de l'anhydride succinique ou de l'anhydride diethylene triamine pentaacetique.
        Pathol Biol (Paris). 1998; 46 ([Hemoglobin alpha chain isoelectric point modification under the action of urea, sodium cyanate, succinic anhydride or diethylene triamine pentaacetic acid anhydride]): 605-612
        • Nowicki C.
        • Santome J.A.
        Modification of lysine 69 reactivity in bovine growth hormone by carbamylation of its N-terminal group.
        Int J Pept Protein Res. 1981; 18: 52-60
        • Beswick H.T.
        • Harding J.J.
        High-molecular-weight crystallin aggregate formation resulting from non-enzymic carbamylation of lens crystallins: relevance to cataract formation.
        Exp Eye Res. 1987; 45: 569-578
        • Fazili K.M.
        • Mir M.M.
        • Qasim M.A.
        Changes in protein stability upon chemical modification of lysine residues of bovine serum albumin by different reagents.
        Biochem Mol Biol Int. 1993; 31: 807-816
        • Shaw D.C.
        • Stein W.H.
        • Moore S.
        Inactivation of chymotrypsin by cyanate.
        J Biol Chem. 1964; 239: 671-673
        • De Furia F.G.
        • Miller D.R.
        • Cerami A.
        • Manning J.M.
        The effects of cyanate in vitro on red blood cell metabolism and function in sickle cell anemia.
        J Clin Invest. 1972; 51: 566-574
        • Van Lente F.
        • McHugh A.
        • Pippenger C.E.
        Carbamylation of apo-aspartate aminotransferase: a possible mechanism for enzyme inactivation in uremic patients.
        Clin Chem. 1986; 32: 2107-2108
        • Veronese F.M.
        • Piszkiewicz D.
        • Smith E.L.
        Inactivation of bovine glutamate dehydrogenase by carbamyl phosphate and cyanate.
        J Biol Chem. 1972; 247: 754-759
        • Oimomi M.
        • Hatanaka H.
        • Yoshimura Y.
        • et al.
        Carbamylation of insulin and its biological activity.
        Nephron. 1987; 46: 63-66
        • Weisgraber K.H.
        • Innerarity T.L.
        • Mahley R.W.
        Role of lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts.
        J Biol Chem. 1978; 253: 9053-9062
        • Lee T.C.
        • Gibson Q.H.
        Allosteric properties of carbamylated hemoglobins.
        J Biol Chem. 1981; 256: 4570-4577
        • Dengler T.J.
        • Robertz-Vaupel G.M.
        • Dengler H.J.
        Albumin binding in uraemia: quantitative assessment of inhibition by endogenous ligands and carbamylation of albumin.
        Eur J Clin Pharmacol. 1992; 43: 491-499
        • Erill S.
        • Calvo R.
        • Carlos R.
        Plasma protein carbamylation and decreased acidic drug protein binding in uremia.
        Clin Pharmacol Ther. 1980; 27: 612-618
        • Ha E.
        • Bang J.H.
        • Son J.N.
        • Cho H.C.
        • Mun K.C.
        Carbamylated albumin stimulates microRNA-146, which is increased in human kidney cell carcinoma.
        Mol Med Rep. 2010; 3: 275-279
        • Jaisson S.
        • Delevallee-Forte C.
        • Toure F.
        • et al.
        Carbamylated albumin is a potent inhibitor of polymorphonuclear neutrophil respiratory burst.
        FEBS Lett. 2007; 581: 1509-1513
        • Maddock A.L.
        • Westenfelder C.
        Urea induces the heat shock response in human neuroblastoma cells.
        J Am Soc Nephrol. 1996; 7: 275-282
        • Balion C.M.
        • Draisey T.F.
        • Thibert R.J.
        Carbamylated hemoglobin and carbamylated plasma protein in hemodialyzed patients.
        Kidney Int. 1998; 53: 488-495
        • Lane T.A.
        • Burka E.R.
        Decreased life span and membrane damage of carbamylated erythrocytes in vitro.
        Blood. 1976; 47: 909-917
        • Garnotel R.
        • Sabbah N.
        • Jaisson S.
        • Gillery P.
        Enhanced activation of and increased production of matrix metalloproteinase-9 by human blood monocytes upon adhering to carbamylated collagen.
        FEBS Lett. 2004; 563: 13-16
        • Gross M.L.
        • Piecha G.
        • Bierhaus A.
        • et al.
        Glycated and carbamylated albumin is more “nephrotoxic” than unmodified albumin in the amphibian kidney.
        Am J Physiol Kidney Physiol. 2011; 301: F476-F485
        • Pietrement C.
        • Gorisse L.
        • Jaisson S.
        • Gillery P.
        Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD.
        PloS One. 2013; 8: e82506
        • Raj D.S.
        • Oladipo A.
        • Lim V.S.
        Amino acid and protein kinetics in kidney failure: an integrated approach.
        Semin Nephrol. 2006; 26: 158-166
        • Carrero J.J.
        • Stenvinkel P.
        • Cuppari L.
        • et al.
        Etiology of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement from the International Society of Kidney Nutrition and Metabolism (ISRNM).
        J Ren Nutr. 2013; 23: 77-90
        • Kalantar-Zadeh K.
        • Cano N.J.
        • Budde K.
        • et al.
        Diets and enteral supplements for improving outcomes in chronic kidney disease.
        Nat Rev Nephrol. 2011; 7: 369-384
        • Schreier S.M.
        • Steinkellner H.
        • Jirovetz L.
        • et al.
        S-Carbamoylation impairs the oxidant scavenging activity of cysteine: its possible impact on increased LDL modification in uraemia.
        Biochimie. 2011; 93: 772-777
        • Iciek M.
        • Bilska A.
        • Lorenc-Koci E.
        • Wlodek L.B.
        • Sokolowska M.M.
        The effect of uremic toxin cyanate (OCN−) on anaerobic sulfur metabolism and prooxidative processes in the rat kidney: a protective role of lipoate.
        Hum Exp Toxicol. 2010; 30: 1601-1608
        • Sokolowska M.
        • Niedzielska E.
        • Iciek M.
        • et al.
        The effect of the uremic toxin cyanate (CNO(-)) on anaerobic cysteine metabolism and oxidative processes in the rat liver: a protective effect of lipoate.
        Toxicol Mech Methods. 2011; 21: 473-478
        • Go Y.M.
        • Jones D.P.
        Cysteine/cystine redox signaling in cardiovascular disease.
        Free Radic Biol Med. 2012; 50: 495-509
        • Przemyslaw W.
        • Piotr K.
        • Grazyna C.
        • et al.
        Total, free, and protein-bound thiols in plasma of peritoneal dialysis and predialysis patients.
        Int Urol Nephrol. 2011; 43: 1201-1209
        • Prakash M.
        • Upadhya S.
        • Prabhu R.
        Protein thiol oxidation and lipid peroxidation in patients with uraemia.
        Scand J Clin Lab Invest. 2004; 64: 599-604
        • Himmelfarb J.
        • McMonagle E.
        • McMenamin E.
        Plasma protein thiol oxidation and carbonyl formation in chronic kidney failure.
        Kidney Int. 2000; 58: 2571-2578
        • Mohar D.S.
        • Barseghian A.
        • Haider N.
        • Domanski M.
        • Narula J.
        Atherosclerosis in chronic kidney disease: lessons learned from glycation in diabetes.
        Med Clin North Am. 2012; 96: 57-65
        • Wang Z.
        • Nicholls S.J.
        • Rodriguez E.R.
        • et al.
        Protein carbamylation links inflammation, smoking, uremia and atherogenesis.
        Nat Med. 2007; 13: 1176-1184
        • Shapiro R.J.
        Catabolism of low-density lipoprotein is altered in experimental chronic kidney failure.
        Metabolism. 1993; 42: 162-169
        • Horkko S.
        • Savolainen M.J.
        • Kervinen K.
        • Kesaniemi Y.A.
        Carbamylation-induced alterations in low-density lipoprotein metabolism.
        Kidney Int. 1992; 41: 1175-1181
        • Horkko S.
        • Huttunen K.
        • Kervinen K.
        • Kesaniemi Y.A.
        Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein.
        Eur J Clin Invest. 1994; 24: 105-113
        • Horkko S.
        • Huttunen K.
        • Kesaniemi Y.A.
        Decreased clearance of low-density lipoprotein in uremic patients under dialysis treatment.
        Kidney Int. 1995; 47: 1732-1740
        • Apostolov E.O.
        • Ray D.
        • Savenka A.V.
        • Shah S.V.
        • Basnakian A.G.
        Chronic uremia stimulates LDL carbamylation and atherosclerosis.
        J Am Soc Nephrol. 2010; 21: 1852-1857
        • Shah S.V.
        • Apostolov E.O.
        • Ok E.
        • Basnakian A.G.
        Novel mechanisms in accelerated atherosclerosis in kidney disease.
        J Ren Nutr. 2008; 18: 65-69
        • Apostolov E.O.
        • Shah S.V.
        • Ray D.
        • Basnakian A.G.
        Scavenger receptors of endothelial cells mediate the uptake and cellular proatherogenic effects of carbamylated LDL.
        Arterioscler Thromb Vasc Biol. 2009; 29: 1622-1630
        • Apostolov E.O.
        • Shah S.V.
        • Ok E.
        • Basnakian A.G.
        Carbamylated low-density lipoprotein induces monocyte adhesion to endothelial cells through intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.
        Arterioscler Thromb Vasc Biol. 2007; 27: 826-832
        • Ok E.
        • Basnakian A.G.
        • Apostolov E.O.
        • Barri Y.M.
        • Shah S.V.
        Carbamylated low-density lipoprotein induces death of endothelial cells: a link to atherosclerosis in patients with kidney disease.
        Kidney Int. 2005; 68: 173-178
        • Apostolov E.O.
        • Basnakian A.G.
        • Yin X.
        • Ok E.
        • Shah S.V.
        Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway.
        Am J Physiol Heart Circ Physiol. 2007; 292: H1836-H1846
        • Asci G.
        • Basci A.
        • Shah S.V.
        • et al.
        Carbamylated low-density lipoprotein induces proliferation and increases adhesion molecule expression of human coronary artery smooth muscle cells.
        Nephrology (Carlton). 2008; 13: 480-486
        • Holzer M.
        • Gauster M.
        • Pfeifer T.
        • et al.
        Protein carbamylation renders high-density lipoprotein dysfunctional.
        Antioxid Redox Signal. 2011; 14: 2337-2346
        • Xiao S.
        • Wagner L.
        • Mahaney J.
        • Baylis C.
        Uremic levels of urea inhibit L-arginine transport in cultured endothelial cells.
        Am J Physiol Kidney Physiol. 2001; 280: F989-F995
        • El-Gamal D.
        • Holzer M.
        • Gauster M.
        • et al.
        Cyanate is a novel inducer of endothelial ICAM-1 expression.
        Antioxid Redox Signal. 2011; 16: 129-137
        • Koeth R.A.
        • Kalantar-Zadeh K.
        • Wang Z.
        • et al.
        Protein carbamylation predicts mortality in ESRD.
        J Am Soc Nephrol. 2013; 24: 853-861
        • Nalbandian R.M.
        • Henry R.L.
        • Barnhart M.I.
        • Camp Jr., F.R.
        Sickle cell disease: clinical advances by the Murayama molecular hypothesis.
        Mil Med. 1972; 137: 215-220
        • Dean J.
        • Schechter A.N.
        Sickle-cell anemia: molecular and cellular bases of therapeutic approaches (first of three parts).
        N Engl J Med. 1978; 299: 752-763
        • Nalbandian R.M.
        • Nichols B.M.
        • Stehouwer E.J.
        • Camp Jr., F.R.
        Urea, urease, cyanate, and the sickling of hemoglobin S.
        Clin Chem. 1972; 18: 961-964
        • Gillette P.N.
        • Peterson C.M.
        • Lu Y.S.
        • Cerami A.
        Sodium cyanate as a potential treatment for sickle-cell disease.
        N Engl J Med. 1974; 290: 654-660
        • Harkness D.R.
        • Roth S.
        Clinical evaluation of cyanate in sickle cell anemia.
        Prog Hematol. 1975; 9: 157-184
        • Nigen A.M.
        • Njikam N.
        • Lee C.K.
        • Manning J.M.
        Studies on the mechanism of action of cyanate in sickle cell disease. Oxygen affinity and gelling properties of hemoglobin S carbamylated on specific chains.
        J Biol Chem. 1974; 249: 6611-6616
        • Nicholson D.H.
        • Harkness D.R.
        • Benson W.E.
        • Peterson C.M.
        Cyanate-induced cataracts in patients with sickle-cell hemoglobinopathies.
        Arch Ophthalmol. 1976; 94: 927-930
        • Lapko V.N.
        • Smith D.L.
        • Smith J.B.
        In vivo carbamylation and acetylation of water-soluble human lens alphaB-crystallin lysine 92.
        Protein Sci. 2001; 10: 1130-1136
        • Beswick H.T.
        • Harding J.J.
        Conformational changes induced in bovine lens alpha-crystallin by carbamylation. Relevance to cataract.
        Biochem J. 1984; 223: 221-227
        • Yan H.
        • Zhang J.
        • Harding J.J.
        Identification of the preferentially targeted proteins by carbamylation during whole lens incubation by using radio-labelled potassium cyanate and mass spectrometry.
        Int J Ophthalmol. 2010; 3: 104-111
        • Zhang J.
        • Yan H.
        • Harding J.J.
        • et al.
        Identification of the primary targets of carbamylation in bovine lens proteins by mass spectrometry.
        Curr Eye Res. 2008; 33: 963-976
        • Derham B.K.
        • Harding J.J.
        Alpha-crystallin as a molecular chaperone.
        Prog Retin Eye Res. 1999; 18: 463-509
        • Liu X.
        • Li S.
        Carbamylation of human lens gamma-crystallins: relevance to cataract formation.
        Yan Ke Xue Bao. 1993; 9 (157): 136-142
        • Harding J.J.
        • Rixon K.C.
        Carbamylation of lens proteins: a possible factor in cataractogenesis in some tropical countries.
        Exp Eye Res. 1980; 31: 567-571
        • Kern H.L.
        • Bellhorn R.W.
        • Peterson C.M.
        Sodium cyanate-induced ocular lesions in the beagle.
        J Pharmacol Exp Ther. 1977; 200: 10-16
        • Steinbrecher U.P.
        • Fisher M.
        • Witztum J.L.
        • Curtiss L.K.
        Immunogenicity of homologous low density lipoprotein after methylation, ethylation, acetylation, or carbamylation: generation of antibodies specific for derivatized lysine.
        J Lipid Res. 1984; 25: 1109-1116
        • Mydel P.
        • Wang Z.
        • Brisslert M.
        • et al.
        Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis.
        J Immunol. 2010; 184: 6882-6890
        • Shi J.
        • Knevel R.
        • Suwannalai P.
        • et al.
        Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage.
        Proc Natl Acad Sci U S A. 2011; 108: 17372-17377
        • Kummu O.
        • Turunen S.P.
        • Wang C.
        • et al.
        Carbamyl adducts on low-density lipoprotein induce IgG response in LDLR−/− mice and bind plasma autoantibodies in humans under enhanced carbamylation.
        Antioxid Redox Signal. 2013; 19: 1047-1062
        • Shi J.
        • van Veelen P.A.
        • Mahler M.
        • et al.
        Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies.
        Autoimmun Rev. 2014; 13: 225-230
        • Muller P.C.
        • Anink J.
        • Shi J.
        • et al.
        Anticarbamylated protein (anti-CarP) antibodies are present in sera of juvenile idiopathic arthritis (JIA) patients.
        Ann Rheum Dis. 2013; 72: 2053-2055
        • Shaykh M.
        • Pegoraro A.A.
        • Mo W.
        • et al.
        Carbamylated proteins activate glomerular mesangial cells and stimulate collagen deposition.
        J Lab Clin Med. 1999; 133: 302-308
        • Farias G.
        • Gonzalez-Billault C.
        • Maccioni R.B.
        Immunological characterization of epitopes on tau of Alzheimer's type and chemically modified tau.
        Mol Cell Biochem. 1997; 168: 59-66
        • Roxborough H.E.
        • Millar C.A.
        • McEneny J.
        • Young I.S.
        Carbamylation inhibits the ferroxidase activity of caeruloplasmin.
        Biochem Biophys Res Commun. 1995; 214: 1073-1078
        • Kimani S.
        • Moterroso V.
        • Lasarev M.
        • et al.
        Carbamoylation correlates of cyanate neuropathy and cyanide poisoning: relevance to the biomarkers of cassava cyanogenesis and motor system toxicity.
        Springerplus. 2013; 2: 647
        • Kimani S.
        • Sinei K.
        • Bukachi F.
        • Tshala-Katumbay D.
        • Maitai C.
        Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents.
        Metab Brain Dis. 2014; 29: 105-112
        • Kassa R.M.
        • Kasensa N.L.
        • Monterroso V.H.
        • et al.
        On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure.
        Food Chem Toxicol. 2010; 49: 571-578
        • Tor-Agbidye J.
        • Palmer V.S.
        • Lasarev M.R.
        • et al.
        Bioactivation of cyanide to cyanate in sulfur amino acid deficiency: relevance to neurological disease in humans subsisting on cassava.
        Toxicol Sci. 1999; 50: 228-235
        • Fluckiger R.
        • Harmon W.
        • Meier W.
        • Loo S.
        • Gabbay K.H.
        Hemoglobin carbamylation in uremia.
        N Engl J Med. 1981; 304: 823-827
        • Kwan J.T.
        • Carr E.C.
        • Barron J.L.
        • Bending M.R.
        Carbamylated haemoglobin in normal, diabetic and uraemic patients.
        Ann Clin Biochem. 1992; 29: 206-209
        • Kwan J.T.
        • Carr E.C.
        • Barron J.L.
        • Bending M.R.
        Carbamylated haemoglobin—a retrospective index of time-averaged urea concentration.
        Nephrol Dial Transplant. 1993; 8: 565-567
        • Kwan J.T.
        • Carr E.C.
        • Neal A.D.
        • et al.
        Carbamylated haemoglobin, urea kinetic modelling and adequacy of dialysis in haemodialysis patients.
        Nephrol Dial Transplant. 1991; 6: 38-43
        • Tarif N.
        • Shaykh M.
        • Stim J.
        • Arruda J.A.
        • Dunea G.
        Carbamylated hemoglobin in hemodialysis patients.
        Am J Kidney Dis. 1997; 30: 361-365
        • Davenport A.
        • Jones S.
        • Goel S.
        • Astley J.P.
        • Feest T.G.
        Carbamylated hemoglobin: a potential marker for the adequacy of hemodialysis therapy in end-stage kidney failure.
        Kidney Int. 1996; 50: 1344-1351
        • Hasuike Y.
        • Nakanishi T.
        • Maeda K.
        • et al.
        Carbamylated hemoglobin as a therapeutic marker in hemodialysis.
        Nephron. 2002; 91: 228-234
        • Jiao Y.
        • Okumiya T.
        • Saibara T.
        • Park K.
        • Sasaki M.
        Abnormally decreased HbA1c can be assessed with erythrocyte creatine in patients with a shortened erythrocyte age.
        Diabetes Care. 1998; 21: 1732-1735
        • Nakao T.
        • Matsumoto H.
        • Okada T.
        • et al.
        Influence of erythropoietin treatment on hemoglobin A1c levels in patients with chronic kidney failure on hemodialysis.
        Intern Med. 1998; 37: 826-830
        • Wang X.
        • Peesapati S.K.
        • Renedo M.F.
        • Moktan S.
        Hemoglobin A1c levels in non-diabetic patients with end-stage kidney disease (ESRD) receiving hemodialysis.
        J Endocrinol Invest. 2004; 27: 733-735
        • Freedman B.I.
        A critical evaluation of glycated protein parameters in advanced nephropathy: a matter of life or death: time to dispense with the hemoglobin A1c in end-stage kidney disease.
        Diabetes Care. 2012; 35: 1621-1624
        • Stim J.
        • Shaykh M.
        • Anwar F.
        • et al.
        Factors determining hemoglobin carbamylation in kidney failure.
        Kidney Int. 1995; 48: 1605-1610
        • Kwan J.T.
        • Carr E.C.
        • Bending M.R.
        • Barron J.L.
        Determination of carbamylated hemoglobin by high-performance liquid chromatography.
        Clin Chem. 1990; 36: 607-610
        • Wynckel A.
        • Randoux C.
        • Millart H.
        • et al.
        Kinetics of carbamylated haemoglobin in acute kidney failure.
        Nephrol Dial Transplant. 2000; 15: 1183-1188
        • Davenport A.
        • Jones S.R.
        • Goel S.
        • Astley J.P.
        • Hartog M.
        Differentiation of acute from chronic kidney impairment by detection of carbamylated haemoglobin.
        Lancet. 1993; 341: 1614-1617
        • Han J.S.
        • Kim Y.S.
        • Chin H.J.
        • et al.
        Temporal changes and reversibility of carbamylated hemoglobin in kidney failure.
        Am J Kidney Dis. 1997; 30: 36-40
        • Tang W.H.
        • Shrestha K.
        • Wang Z.
        • et al.
        Protein carbamylation in chronic systolic heart failure: relationship with kidney impairment and adverse long-term outcomes.
        J Card Fail. 2013; 19: 219-224
        • Raj D.S.
        • Zager P.
        • Shah V.O.
        • et al.
        Protein turnover and amino acid transport kinetics in end-stage kidney disease.
        Am J Physiol Endocrinol Metab. 2004; 286: E136-E143
        • Tattersall J.
        Do we need another Kt/V?.
        Nephrol Dial Transplant. 2013; 28: 1963-1966
        • Owen Jr., W.F.
        • Meyer K.B.
        • Schmidt G.
        • Alfred H.
        Methodological limitations of the ESRD Core Indicators Project: an ESRD network's experience with implementing an ESRD quality survey. Medical Review Board of the ESRD Network of New England.
        Am J Kidney Dis. 1997; 30: 349-355
        • Holzer M.
        • Zangger K.
        • El-Gamal D.
        • et al.
        Myeloperoxidase-derived chlorinating species induce protein carbamylation through decomposition of thiocyanate and urea: novel pathways generating dysfunctional high-density lipoprotein.
        Antioxid Redox Signal. 2012; 17: 1043-1052
        • Zil A.R.
        • Rahman M.A.
        Serum thiocyanate levels in smokers, passive smokers and never smokers.
        J Pak Med Assoc. 2006; 56: 323-326
        • Carracedo J.
        • Merino A.
        • Briceno C.
        • et al.
        Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells.
        FASEB J. 2011; 25: 1314-1322