Blood thiol status and erythrocyte glutathione-S-transferase in chronic kidney disease patients on treatment with frequent (daily) hemodialysis

Abstract

Background. Chronic kidney disease (CKD) is a condition of impaired homeostasis of blood thiols characterized by a severe hyperhomocysteinemia (HH) and abnormal expression of the red blood cell glutathione (GSH)-consuming enzyme GSH S-transferase (eGST) (Galli et al., Clin Chem 1999). The correlation between plasma Hcy and eGST recently identified by our group (Dessì et al., Amino Acids 2012) suggests a role of this detoxifying enzyme in the impaired thiol status of CKD treated with hemodialysis therapy (HD). This retrospective study is aimed at investigating whether frequent HD can alleviate these biochemical symptoms of CKD. Methods. Laboratory data of a population of 98 HD patients investigated for plasma Hcy and blood thiol status between 1999 and 2004 were examined. A frequent HD method carried out with a 2-h daily schedule (daily HD) (DHD) was compared with standard 4-h × 3/week protocol of HD (SHD) in either cross-sectional (n = 70 SHD vs. n = 28 DHD) and prospective A-B design (n = 18 SHD patients shifted to DHD). Results. The results demonstrate that DHD produces a better correction than SHD of the uremic retention solute Hcy as well as of Cys and Cys-Gly measured in plasma. Such a correction effect of DHD on HH correlates with that on the detoxification enzyme eGST and on pGSH. Conclusions. These findings point to a role of frequent dialysis in the depuration of uremic retention solutes that may interfere with thiol metabolism and redox in HD patients. These solutes may include substrates of eGST that await further investigation for molecular identification and better removal by more efficient dialysis therapies.

Keywords::

• daily hemodialysis
• blood thiols
• homocysteine
• glutathione
• glutathione S-transferase
• uremic toxins

Acknowledgments

We dedicate this work to Prof. Ardesio Floridi (Giorgio) [1/12/1939–26/04/2005]. Since few weeks before he prematurely and suddenly departed on 2005, he was active together with BU in co-supervising clinical trials on CKD and dialysis patients. His role in these trials as main laboratory investigator, has originated the database used in the retrospective analysis shown in this study. Beginning of 2000, he founded the research unit in applied and clinical biochemistry at the Department of Internal Medicine, University of Perugia, which has originated in 2006 the Laboratory of Clinical Biochemistry and Nutrition and all its scientific achievements reached so far.

All we are indebted with Prof. Floridi for his moral example and heartfelt friendship. He was a good guide for students and researchers, and a model of devotion to lab work.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

Notice of Correction

The Early Online version of this article published online ahead of print on the 26th November 2013 contained an error on pages 6 and 7.

The last paragraph of page 6 ending on page 7 should be amended as follows:

The sentence “To provide rough estimation of this adverse contribution of eGST overexpression by the whole uremic RBC mass, with the approximation of an average enzymatic activity (as estimated by the conjugation reaction of GSH with the alkylating substrate CDNB) in SHD patients of 7.5 U/g Hb vs. 3.0 U/g Hb in healthy controls (average data calculated from results in this study and in [20,31,32]) and average Hb levels of 12 and 15 g %, respectively, within a total blood volume of 5 L, a value of 4.5 mol of GSH equivalents would be consumed per min. in SHD patients against 2.2 mol in healthy controls (approx. 6.5 vs. 3.2 × 10³ mol of GSH spent in 24 h, respectively)” should have read

“To provide rough estimation of this adverse contribution of eGST overexpression by the whole uremic RBC mass, it can be calculated that with the approximation of an average enzymatic activity in SHD patients of 7.5 U/g Hb vs. 3.0 U/g Hb in healthy controls (average data calculated from results in this study and in [20,31,32]) and Hb levels that on average are 12 and 15 g %, respectively, in a total blood volume of 5 L, a value of 4.5 mmol of GSH equivalents would be consumed per min. in SHD patients against 2.2 mol in healthy controls (approx. 6.5 vs. 3.2 mol of GSH spent in 24 h, respectively). These figures are obviously overestimating the actual in vivo consumption rate of eGSH in the RBC of patients and healthy controls. In fact, these rates were calculated starting from the conditions of the Habig assay in which saturating concentrations of the substrate CDNB were used and these are expected to be higher than the actual in vivo concentrations of endogenous alkylating substrates of eGST. However, these figures clearly demonstrated the likelihood for the uremic milieu of creating blood levels of these substrates and eGST catalyst expression that together provide conditions of at least a two-fold higher than normal consumption rate of eGSH in CKD.”

The corrected version is shown in this issue.