Erythrocyte glutathione transferase: a new biomarker for hemodialysis adequacy, overcoming the Kt/Vurea dogma?

Abstract

Kt/Vurea ratio is commonly used to assess the delivered dose of dialysis in maintenance hemodialysis (MHD) patients. This parameter only reflects the efficacy of dialytic treatments in removing small toxins, but not middle and protein-bound toxins. Erythrocyte glutathione transferase (e-GST), an enzyme devoted to cell depuration against a lot of large and small toxins, is overexpressed in uremic patients. Aim of the present study is to verify whether e-GST may represent a novel biomarker to assess the adequacy of different dialytic techniques complementary to Kt/Vurea parameter. Furthermore, it will be investigated whether e-GST could reflect the ‘average' adequacy of multiple dialytic sessions and not of a single one treatment as it occurs for Kt/Vurea. One hundred and three MHD patients and 82 healthy subjects were tested. Fourty four patients were treated with standard bicarbonate hemodialysis (HD) and 59 patients were on online hemodiafiltration (HDF). In all MHD patients e-GST activity was 60% higher than in healthy controls. In HDF, e-GST activity was lower than in HD subgroup (8.2±0.4 versus 10.0±0.4 U/gHb, respectively). Single-pool Kt/Vurea and total weekly Kt/Vurea were higher in HDF than in HD, but no correlation was found between e-GST activity and Kt/Vurea data. e-GST, whose level is stable during the erythrocyte life-span, provides information on the long-term depurative efficacy of dialysis treatments.

Erythrocyte glutathione transferase: a non-antibody biomarker for systemic sclerosis, which correlates with severity and activity of the disease

“…As found in our previous studies, renal failure causes an hyper-expression of e-GST due to the increase of circulating toxins. 7, 8 Similarly, hypoxia due to lung damage by SSc may cause accumulation of toxic metabolites, e.g., lactate 12 that are normally removed by circulation. Surprisingly, the degree of damage of these specific organs does not correlate with the hyper-expression of e-GST.…”

“…Alternatively, e-GST hyper-expression could be due to an unknown factor that triggers impairments of specific organs but it is not caused by them. For example, the presence or progressive accumulation of single or selected toxins could trigger this autoimmune disease and also stimulate the hyper-expression of e-GST, simulating what occurs in non-sclerodermic nephropathic patients 7, 8 or in subjects living in polluted environments. 6 The target organ that will be damaged by the autoimmune disease (kidney and/or lung and/or heart, etc) could be determined on the basis of genetic predisposition or only by random factors.…”

“…All these findings suggest that e-GST behaves like an endogenous biosensor, which reveals the levels of circulating toxic compounds and the efficiency of dialytic procedures. 8 The rationale of the present study was that SSc often causes kidney damage and therefore a possible correlation might exist between the severity of this disease and e-GST expression. Renal disease remains one of the most important cause of morbidity and mortality in SSc, 9 even if lung failure (both pulmonary hypertension and pulmonary fibrosis) seems to be the primary cause of scleroderma-related death today.…”

Glutathione S-transferase Activity in Diagnostic Pathology

“…Human GSTs are divided into three main families, namely, the cytosolic, mitochondrial and membrane-bound microsomal GSTs [5,8]. For instance, the cytosolic human GSTP1-1 isoform (hGSTP1-1), which is a major intra-erythrocyte transferase-representing 95% of its entire GST pool [20,40], is a homodimeric intracellular protein of about 46 kDa expressed in different organs and cell types [26]. Specifically, the molecular mass of the cytosolic GSTs monomers are in the range of 22-29 KDa and exhibit activity over a wide variety of substrates with considerable overlap [1,2,4].…”

“…Each monomer contains an active site with two sub-sites: a less conserved H site for binding to varieties of hydrophobic substrates and a highly conserved G site for GSH binding [14]. The general mammalian cytosolic GSTs encompass dissimilar dimeric isoenzymes within molecular mass of 45-55 KDa, which have been assigned to at least four generic classes, namely, α-, µ-, π-, and Ө-GSTs [2,3,26,41,42] in addition to the K-Ω-, δ-GSTs [5,43], whereas the membrane bound microsomal GSTs are component of another classified proteins, the so called membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) [44][45][46]. The MAPEG entities are involved in endogenous metabolism of leukotrienes-and prostaglandins-derived mediators of pain, fever, and inflammation as well as in biotransformation and detoxification of electrophilic substances [14,46].…”