Erythrocyte glutathione transferase: a potential new biomarker in chronic kidney diseases which correlates with plasma homocysteine

Abstract

The erythrocyte glutathione S-transferase (e-GST) is a member of a superfamily of inducible enzymes involved in cell detoxification that shows an increased expression in chronic kidney disease (CKD) patients. We propose a new automated analysis procedure for e-GST activity that has been validated in 72 CKD patients and 62 maintenance hemodialysis patients (MHD). Regression analysis was carried out to assess association between e-GST activity data, main clinical variables, and plasma homocysteine (Hcy), a modified sulfur amino acid known as potential risk factor for cardiovascular disease that is increased above normal levels in more than 90% of the uremic patients. An increased e-GST activity was confirmed in MHD patients (N=62; 10.2±0.4 U/gHb) compared with healthy subjects (N=80; 5.8±0.4 U/gHb), and as an original finding, a significant increase of e-GST activity was observed in pre-dialysis CKD patients with a positive correlation with disease severity weighted according to the four stages of "Kidney Disease Outcomes Quality Initiative" classification (7.4±0.5, 8±1, 9.5±0.6, 12±1 U/gHb, respectively). No correlation was found between e-GST activity and hemoglobin, transferrin, blood iron and the markers of systemic inflammation and renal function such as alpha-1 acid glycoprotein and high-sensitive C-Reactive Protein, beta-2 microglobulin and the index of malnutrition-inflammation PINI, while a significant correlation was observed for the first time between plasma Hcy and e-GST activity (r2=0.64, P<0.0001) in MHD patients. Hcy, however, was not identified as an inhibitor of e-GST enzyme. The results in this study suggest the potential for automated e-GST analysis as a valuable tool to further explore phase II-related uremic toxicity in CKD and MHD patients.

Prooxidative-Antioxidative Balance of Cells in Different Types of Renal Replacement Therapy

“…Reports about GPX activity in CKD are inconclusive. Some authors described a positive impact of PD, but others did not find differences compared with HD [21,23,24,28,29,30,31,32,33,34]. Our study showed that renal replacement therapy negatively influences GPX activity.…”

“…In our study there were no significant differences between GST activities among the whole examined groups; however, it was above the normal range. Some authors showed a higher activity of GST in HD than in PD patients [33,34,35]. The HD procedure did not influence this enzyme activity.…”

“…The negative correlation between GST and GPX activity in PD patients may indicate a competition for a common substrate. Some authors claim that GST activity depends on the stage of kidney disease and may become a marker of uraemic toxicity and kidney graft function [33,34,36,37]. …”

Inactivation of Human Salivary Glutathione Transferase P1-1 by Hypothiocyanite: A Post-Translational Control System in Search of a Role

“…Other GST isoenzymes are not represented or are below the limit of detection. This conclusion represents a clarification of the contradictory evidence reported previously in this context [7], [8], [10], [12]. Even if other GSTs may be present in trace amounts in saliva, GSTP1-1 clearly represents the most abundant isoenzyme.…”

“…Recently, a direct interaction has been described between the GSTP1-1 and the TRAF domain of TNF receptor-associated factor 2 [11]. In addition, a particular GST isoenzyme present in the erythrocytes, the GSTP1-1, is overexpressed in case of increased blood toxicity as it occurs in nephropathic patients [12] and in healthy subjects living in polluted areas [13]. Thus, erythrocyte GSTP1-1 is considered a biomarker of blood toxicity.…”