Search

Hydrogen sulfide, H2S, is the third endogenous gas with cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a potent vasorelaxant, and its deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase, cystathionine gamma- lyase, and 3-mercaptopyruvate sulfurtransferase catalyze H2S formation. Chronic kidney disease is characterized by high prevalence of hyperhomocysteinemia, hypertension, and high cardiovascular mortality, especially in hemodialysis patients. H2S levels are decreased in hemodialysis patients through transcriptional deregulation of genes encoding for the H2S-producing enzymes. Potential implications relate to the pathogenesis of the manifestations of the uremic syndrome, such as hypertension and atherosclerosis. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved.

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function. © 2009 Wiley Periodicals, Inc.

Objective: Although there has been contrasting evidence for a causative role of parathyroid hormone (PTH) in sleep disorders in patients on maintenance hemodialysis, a recent study disclosed the possibility that this role might exist at least in patients requiring parathyroidectomy because of failure of medical therapy. The present study was devised to assess a possible difference in sleep disorders of patients on hemodialysis needing parathyroidectomy and those in whom medical therapy controlled hyperparathyroidism. Design and Patients: To this end, a group of 22 patients requiring parathyroidectomy were studied by means of a sleep questionnaire, along with a group of 44 patients matched for age, gender, body weight, and duration of dialytic treatment. Results: Patients requiring parathyroidectomy slept fewer hours (P < .001), had a higher prevalence of sleep disorders (P < .001), and were more often insomniac (P < .001). Conclusions: This study indicates that patients on hemodialysis requiring parathyroidectomy for intractable hyperparathyroidism comprise a good model for investigating the causative role of PTH on disordered sleep, and that these patients have very poor sleep. These data support recent findings on the prevalence of sleep disorders in dialyzed patients with insuppressible hyperparathyroidism. © 2008 National Kidney Foundation, Inc.

BACKGROUND: Chronic kidney disease (CKD) accelerates vascular stiffening related to age. Arterial stiffness may be evaluated measuring the carotid-femoral pulse wave velocity (PWV) or more simply, as recommended by KDOQI, monitoring pulse pressure (PP). Both correlate to survival and incidence of cardiovascular disease. PWV can also be estimated on the brachial artery using a Mobil-O-Graph; a non-operator dependent automatic device. The aim was to analyse whether, in a dialysis population, PWV obtained by Mobil-O-Graph (MogPWV) is more sensitive for vascular aging than PP. METHODS: A cohort of 143 patients from 4 dialysis units has been followed measuring MogPWV and PP every 3 to 6 months and compared to a control group with the same risk factors but an eGFR > 30 ml/min. RESULTS: MogPWV contrarily to PP did discriminate the dialysis population from the control group. The mean difference translated in age between the two populations was 8.4 years. The increase in MogPWV, as a function of age, was more rapid in the dialysis group. 13.3% of the dialysis patients but only 3.0% of the control group were outliers for MogPWV. The mortality rate (16 out of 143) was similar in outliers and inliers (7.4 and 8.0%/year). Stratifying patients according to MogPWV, a significant difference in survival was seen. A high parathormone (PTH) and to be dialysed for a hypertensive nephropathy were associated to a higher baseline MogPWV. CONCLUSIONS: Assessing PWV on the brachial artery using a Mobil-O-Graph is a valid and simple alternative, which, in the dialysis population, is more sensitive for vascular aging than PP. As demonstrated in previous studies PWV correlates to mortality. Among specific CKD risk factors only PTH is associated with a higher baseline PWV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02327962.

Objective: Uremia represents a state where hyperhomocysteinemia is resistant to folate therapy, thus undermining intervention trials' efficacy. N-acetylcysteine (NAC), an antioxidant, in addition to folates (5-methyltetrahydrofolate, MTHF), was tested in a population of hemodialysis patients. Design: The study is an open, parallel, intervention study. Setting: Ambulatory chronic hemodialysis patients. Subjects: Clinically stable chronic hemodialysis patients, on hemodialysis since more than 3 months, undergoing a folate washout. Control group on standard therapy (n = 50). Intervention: One group was treated with intravenous MTHF (MTHF group, n = 48). A second group was represented by patients treated with MTHF, and, during the course of 10 hemodialysis sessions, NAC was administered intravenous (MTHF + NAC group, n = 47). Main Outcome Measure: Plasma homocysteine measured before and after dialysis at the first and the last treatment. Results: At the end of the study, there was a significant decrease in predialysis plasma homocysteine levels in the MTHF group and MTHF + NAC group, compared with the control group, but no significant difference between the MTHF group and MTHF + NAC group. A significant decrease in postdialysis plasma homocysteine levels in MTHF + NAC group (10.27 ± 0.94 μmol/L, 95% confidence interval: 8.37-12.17) compared with the MTHF group (16.23 ± 0.83, 95% confidence interval: 14.55-17.90) was present. In the MTHF + NAC group, 64% of patients reached a postdialysis homocysteine level

Background. Hydrogen sulphide, H2S, is the third endogenous gas with putative cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a vasorelaxant, while H2S deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPS) catalyze H2S formation, with different relative efficiencies. Chronic kidney disease (CKD) is characterized by elevation of both plasma homocysteine and cysteine, which are substrates of these enzymes, and by a high prevalence of hypertension and cardiovascular mortality, particularly in the haemodialysis stage. It is possible that the H2S-generating pathways are altered as well in this patient population. Methods. Plasma H2S levels were measured with a common spectrophotometric method. This method detects various forms of H2S, protein-bound and non-protein-bound. Blood sulphaemoglobin, a marker of chronic exposure to H2S, was also measured, as well as related sulphur amino acids, vitamins and transcriptional levels of relevant genes, in haemodialysis patients and compared to healthy controls. Results. Applying the above-mentioned methodology, H2S levels were found to be decreased in patients. Sulphaemoglobin levels were significantly lower as well. Plasma homocysteine and cysteine were significantly higher; vitamin B6, a cofactor in H2S biosynthesis, was not different. H2S correlated negatively with cysteine levels. CSE expression was significantly downregulated in haemodialysis patients. Conclusions. Transcriptional deregulation of genes encoding for H2S-producing enzymes is present in uraemia. Although the specificity of the method employed for H2S detection is low, the finding that H2S is decreased is complemented by the lower sulphhaemoglobin levels. Potential implications of this study relate to the pathogenesis of the uraemic syndromemanifestations, such as hypertension and atherosclerosis. Background. Hydrogen sulphide, H2S, is the third endogenous gas with putative cardiovascular properties, after nitric oxide and carbon monoxide. H2S is a vasorelaxant, while H2S deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPS) catalyze H2S formation, with different relative efficiencies. Chronic kidney disease (CKD) is characterized by elevation of both plasma homocysteine and cysteine, which are substrates of these enzymes, and by a high prevalence of hypertension and cardiovascular mortality, particularly in the haemodialysis stage. It is possible that the H2S-generating pathways are altered as well in this patient population.Methods. Plasma H2S levels were measured with a common spectrophotometric method. This method detects various forms of H2S, protein-bound and non-protein-bound. Blood sulphaemoglobin, a marker of chronic exposure to H2S, was also measured, as well as related sulphur amino acids, vitamins and transcriptional levels of relevant genes, in haemodialysis patients and compared to healthy controls.Results. Applying the above-mentioned methodology, H2S levels were found to be decreased in patients. Sulphaemoglobin levels were significantly lower as well. Plasma homocysteine and cysteine were significantly higher; vitamin B-6, a cofactor in H2S biosynthesis, was not different. H2S correlated negatively with cysteine levels. CSE expression was significantly downregulated in haemodialysis patients.Conclusions. Transcriptional deregulation of genes encoding for H2S-producing enzymes is present in uraemia. Although the specificity of the method employed for H2S detection is low, the finding that H2S is decreased is complemented by the lower sulphhaemoglobin levels. Potential implications of this study relate to the pathogenesis of the uraemic syndrome manifestations, such as hypertension and atherosclerosis.

Hyperhomocysteinemia, highly prevalent in well-nourished patients with chronic renal failure and in uremia, causes toxic effects that can be envisioned in terms of cardiovascular risk increase. However, its effects on cellular metabolism and on gene expression, not to mention receptor regulation, only recently are being evaluated. For example, it has been shown that hypomethylation induced by hyperhomocysteinemia can alter erythrocyte membrane protein repair and gene expression. In addition, increased plasma protein L-isoaspartyl content, related to hyperhomocysteinemia and uremic toxicity, determines specific effects on protein function, with a reduced binding of homocysteine to albumin. We propose that uremia is a state in which proteins present a widespread derangement of structure-function relationships. Hyperhomocysteinemia, highly prevalent in well-nourished patients with chronic renal failure and in uremia, causes toxic effects that can be envisioned in terms of cardiovascular risk increase. However, its effects on cellular metabolism and on gene expression, not to mention receptor regulation, only recently are being evaluated. For example, it has been shown that hypomethylation induced by hyperhomocysteinemia can alter erythrocyte membrane protein repair and gene expression. In addition, increased plasma protein L-isoaspartyl content, related to hyperhomocysteinemia and uremic toxicity, determines specific effects on protein function, with a reduced binding of homocysteine to albumin. We propose that uremia is a state in which proteins present a widespread derangement of structure-function relationships. © 2006 Elsevier Inc. All rights reserved.

Possible mechanisms of homocysteine toxicity. Hyperhomocysteinemia is a risk factor for cardiovascular disease in the general population. In chronic renal failure (CRF), plasma homocysteine levels rise when the glomerular filtration rate (GFR) is reduced 50%, and in uremia the majority of patients are hyperhomocysteinemic. The purpose of this study was to review possible mechanisms of homocysteine toxicity. Homocysteine, a sulfur amino acid found in blood in micromolar concentrations, can have toxic effects through a handful of general possible mechanisms. These mechanisms include oxidative stress (through the production of reactive oxygen species), binding to nitric oxide, production of homocysteinylated/acylated proteins, and accumulation of its precursor, S-adenosyl-homocysteine, a potent inhibitor of transmethylation reactions. Methyltransferase inhibition actually occurs in CRF and in uremia, and can have several functional consequences.