Abstract
Arginine (Arg) and lysine (Lys) moieties of proteins undergo various post-translational modifications (PTM) including enzymatic NG- and Nε-methylation and non-enzymatic NG- and Nε-glycation. In a large cohort of stable kidney transplant recipients (KTR, n = 686), high plasma and low urinary concentrations of asymmetric dimethylarginine (ADMA), an abundant PTM metabolite of Arg, were associated with cardiovascular and all-cause mortality. Thus, the prediction of the same biomarker regarding mortality may depend on the biological sample. In another large cohort of stable KTR (n = 555), higher plasma concentrations of Nε-carboxymethyl-lysine (CML) and Nε-carboxyethyl-lysine (CEL), two advanced glycation end-products (AGEs) of Lys, were associated with higher cardiovascular mortality. Yet, the associations of urinary AGEs with mortality are unknown. In the present study, we measured 24 h urinary excretion of Lys, CML, and furosine in 630 KTR and 41 healthy kidney donors before and after donation. Our result indicate that lower urinary CML and lower furosine excretion rates are associated with higher mortality in KTR, thus resembling the associations of ADMA. Lower furosine excretion rates were also associated with higher cardiovascular mortality. The 24 h urinary excretion rate of amino acids and their metabolites decreased post-donation (varying as little as − 24% for CEL, and as much as − 62% for ADMA). For most amino acids, the excretion rate was lower in KTR than in donors pre-donation [except for S-(1-carboxyethyl)-l-cysteine (CEC) and NG-carboxyethylarginine (CEA)]. Simultaneous GC–MS measurement of free amino acids, their PTM metabolites and AGEs in urine is a non-invasive approach in kidney transplantation.
Highlights
Amino acid residues in proteins undergo numerous enzymatic and non-enzymatic post-translational modifications (PTMs)
In a study of one of our groups involving 555 stable kidney transplant recipients (KTR), we found that plasma concentrations of CML and CEL were independently associated with long-term risk of cardiovascular mortality (Sotomayor et al 2019)
In the same KTR cohort, we found that higher plasma concentrations of asymmetric dimethylarginine (ADMA), a major PTM metabolite of Arg, were associated with a higher risk for cardiovascular and all-cause mortality (Frenay et al 2015a), whereas higher urinary excretions of ADMA and its isomer symmetric dimethylarginine (SDMA) were associated with a lower risk for mortality (Said et al 2019b)
Summary
Amino acid residues in proteins undergo numerous enzymatic (e.g., citrullination and methylation) and non-enzymatic (e.g., glycation) post-translational modifications (PTMs). The so-called early-stage products or Amadori products, such as hemoglobin A1c (HbA1c), which is an established clinical marker for diabetes, can react further to form the socalled advanced glycation end-products (AGEs) (Nagai et al 2014; see Rabbani and Thornalley 2020; and Sibbersen and Johannsen 2020). AGEs are often measured in blood and sporadically in urine, and in clinical trials they serve as markers for carbohydrate metabolism and protein denaturation (Nagai et al 2014). The chemical structures of commonly measured AGEs are shown in Scheme 1. They include N6-carboxymethyl-l-lysine (CML), N6-carboxyethyl-l-lysine (CEL), S-carboxymethyl-l-cysteine (CMC), S-(1-carboxyethyl)-l-cysteine (CEC), furosine, i.e., the AGE of fructose and Lys, and pentosidine, i.e., the AGE of Lys and Arg
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