Association of plasmaortho-tyrosine/para-tyrosine ratio with responsiveness of erythropoiesis-stimulating agent in dialyzed patients

Abstract

Objectives Patients with end-stage renal failure (ESRF) treated with erythropoiesis-stimulating agents (ESAs) are often ESA-hyporesponsive associated with free radical production. Hydroxyl free radical converts phenylalanine into ortho-tyrosine, while physiological isomer para-tyrosine is formed enzymatically, mainly in the kidney. Production of 'para-tyrosine' is decreased in ESRF and it can be replaced by ortho-tyrosine in proteins. Our aim was to study the role of tyrosines in ESA-responsiveness. Methods Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n = 16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n = 8), hemodialyzed patients with ESA-treatment (ESA-HD; n = 40), and patients on continuous peritoneal dialysis (CAPD; n = 21). Plasma ortho-, para-tyrosine, and phenylalanine levels were detected using a high performance liquid chromatography (HPLC)-method. ESA-demand was expressed by ESA-dose, ESA-dose/body weight, and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Results We found significantly lower para-tyrosine levels in all groups of dialyzed patients when compared with control subjects, while in contrast ortho-tyrosine levels and ortho-tyrosine/para-tyrosine ratio were comparatively significantly higher in dialyzed patients. Among groups of dialyzed patients the ortho-tyrosine level and ortho-tyrosine/para-tyrosine ratio were significantly higher in ESA-HD than in the non-ESA-HD and CAPD groups. There was a correlation between weekly ESA-dose/body weight, ERI1, and ortho-tyrosine/para-tyrosine ratio (r = 0.441, P = 0.001; r = 0.434, P = 0.001, respectively). Our most important finding was that the ortho-tyrosine/para-tyrosine ratio proved to be an independent predictor of ERI1 (β = 0.330, P = 0.016). In these multivariate regression models most of the known predictors of ESA-hyporesponsiveness were included. Discussion Our findings may suggest that elevation of the ratio of ortho-tyrosine/para-tyrosine could be responsible for decreased ESA-responsiveness in dialyzed patients.

Examination of serum phenylalanine and tyrosine isomers in acute coronary syndrome patients

“…The current data are in line with data obtained from our previous studies that we recalculated (The data presented in Figure S2 are based partly on literature data) [4,7,8,10]. These results further support the idea that diminished conversion of Phe to Tyr by PAH may be due to increased production of reactive oxygen species, which can cause a decrease in the cofactor BH4 that takes part in the enzymatic reaction [4,[7][8][9].…”

“…The current study found that serum p-Tyr and the p-Tyr/Phe ratio were both lower in ACS patients compared to controls. Similar results have been described in patients with diseases associated with inflammation and immune activation, such as sepsis, diabetes, renal failure, and in burn patients [7][8][9][10].…”

Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review

“…There was also direct relationship of plasma o-Tyr/p-Tyr ratio and indices of EPO-resistance, as verified using correlation (with R values of approx. 0.4 and p values < 0.005) and regression analyzes [ 77 ].…”

Disturbances in Metabolic Pathways and the Identification of a Potential Biomarker Panel for Early Cartilage Degeneration in a Rabbit Anterior Cruciate Ligament Transection Model

“…Of note, 2-hydroxyphenylalanine can be generated by oxidative stress through the destruction by the hydroxyl radical of the benzyl ring of l-phenylalanine. 31 2-Hydroxyphenylalanine is therefore considered to be a biochemical marker of oxidative stress. 31,32 Taken together, the results indicating the presence of l-phenylalanine metabolic alterations in ACL injury models may show that l-phenylalanine could serve as a sensitive biomarker for cartilage degeneration by revealing matrix breakdown and oxidative stress.…”