Markers of Oxidative Stress and Endothelial Dysfunction Predict Haemodialysis Patients Survival

Abstract

Introduction: Overall survival of patients with end-stage renal disease (ESRD) remains poor. Oxidative stress is one of the major risk factors associated with mortality in this patient group. As glutathione S-transferases (GST) are well-established antioxidants, we hypothesized that a model including GST gene polymorphisms, oxidative damage byproducts and cell adhesion markers has a prognostic role in ESRD patient survival. Methods: A prospective study of 199 patients with ESRD on haemodialysis was conducted. GST genotype, oxidative stress byproducts and cell adhesion molecules were measured in plasma. Multivariate Cox regression and Kaplan-Meier survival analyses were performed to test the predictive ability of these parameters in the 8-year follow-up period. Results: GSTM1-null genotype was associated with significantly shorter overall (HR 1.6, p = 0.018) and cardiovascular-specific (HR 2.1, p = 0.010) survival. Oxidative stress byproducts (advanced oxidation protein products [AOPP], prooxidant-antioxidant balance [PAB], malondialdehyde [MDA]) and cell adhesion molecules (soluble vascular cell adhesion molecule-1 [sVCAM-1] and soluble intercellular adhesion molecule-1 [sICAM-1]) demonstrated a significant predictive role in terms of overall and cardiovascular survival. When 6 biomarkers (GSTM1 genotype, high AOPP/PAB/MDA/­sVCAM-1/sICAM-1) were combined into a scoring model, a significantly shorter overall and cardiovascular survival was observed for patients with the highest score (p < 0.001). Conclusion: We identified a novel panel of biomarkers that can be utilized in predicting survival in ESRD patients. This biomarker signature could enable better monitoring of patients and stratification into appropriate treatment groups.

Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients

“…An interesting approach to elucidate the mechanisms, by which genetic variations influence ESRD development and its prognosis, was applied in a study investigating the role of glutathione S-transferase (GST) family members, which are known as Nrf2 targets. GST gene variations, particularly the deletion polymorphism of the GSTM1 gene, have been shown to influence not only the risk of ESRD development, but also oxidative and clinical phenotypes in ESRD patients [13,14]. In light of the presented evidence, we hypothesized that polymorphisms in regulatory and catalytic proteins of antioxidant defense, such as Nrf2, SOD2, and GPX1, individually and in combination, have a direct effect on the level of oxidative stress and, consequently, impact negatively on the prognosis of ESRD patients undergoing hemodialysis.…”

Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients with Homozygous Glutathione Transferase M1 Gene Deletion

“…Yet, in spite of a wealth of data accruing, there is still no conclusive evidence to prove that there is a clear advantage of these membranes over standard polysulfone membranes [ 17 ]. Although patients with GSTM1 deletion are at particular risk for poor outcome due to increased oxidative stress [ 12 ], no strategy to prevent this risk has been found to date. Therefore, the availability of VEM has provided a promising opportunity to individualize the treatment and to provide this membrane primarily to the most vulnerable population.…”

“…HD patients lacking GSTM1 activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with an active GSTM1 enzyme [ 6 ]. A recent study showed that GSTM1-null genotype is a risk factor for general and CV mortality in the HD population [ 12 ].…”

“…Furthermore, previous studies have shown that the use of VEM either decreased, in some capacity, markers of inflammation or oxidative stress [ 10 , 11 , 12 , 13 ]. Since dialysis patients with homozygous deletion of GSTM1 have been shown to be more prone to oxidative stress and exhibit poorer cardiovascular survival [ 6 , 12 ], we hypothesized that they would benefit from a VEM dialysis regimen in terms of lower oxidative damage and inflammation. Therefore, we performed the first randomized controlled study in order to determine the effect of VEM on by-products of oxidative stress and inflammation in dialysis patients with homozygous deletion of the GSTM1 gene.…”

Immune Dysfunction in Uremia 2020

“…Oxidative stress increases in parallel with the development of CKD [61]. Markers of oxidative stress predict the survival of HD patients [62]. Moreover, antioxidant systems are compromised in CKD patients and deteriorate gradually with the degree of renal failure [63].…”