The authors of this article have demonstrated that erythrocytes from patients affected by either chronic renal failure or ESRD, conditions associated with erythrocyte membrane disorders, show reduced levels of methyl esterified membrane proteins because of elevated S-adenosylhomocysteine concentration. The enzyme protein L-isospartyl (D-aspartyl) O-methyltransferase, responsible for the bulk of this methyl esterification, is implicated in the repair of proteins containing isomerized and racemized aspartyl residues, which arise from L-asparaginyl and L-aspartyl residues. The presence of these altered residues, spontaneously generated during protein aging, can adversely affect protein function. The amount of D- and L-aspartyl residues (and their isomerized derivatives) in erythrocyte membranes from hemodialysis patients was determined. The total level of D-aspartyl derivatives (D-Asx) actually was found to be lower than in controls. In contrast, neither the abundance of several other amino acids, nor of total non-Asx D-amino acids, differs between patients and controls. Mathematical simulation of relevant reactions supports the hypothesis that these effects reflect the lessening of the normal D-isoaspartyl residue accumulation that occurs as a side reaction in the methyltransferase-induced repair process. This evidence is the first that D-Asx content is influenced in vivo by L-isoaspartyl (D-aspartyl) O-methyltransferase activity and can be significantly altered in a disease where this activity is inhibited, thus representing a red flag in a disrupted circuit.