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Background: Peripheral artery disease (PAD) in hemodialysis (HD) patients has a significant social impact due to its prevalence, poor response to standard therapy and dismal prognosis. Rheopheresis is indicated by guidelines for PAD treatment., Materials and Methods: Twenty-five HD patients affected by PAD stage IV Lerichè-Fontaine and ischemic ulcer 1C or 2C according to the University of Texas Wound Classification System (UTWCS), without amelioration after traditional medical therapy and/or revascularization, were selected and underwent 12 Rheopheresis sessions in 10 weeks. Improvements in pain symptoms using Numerical Rating Scale (NRS), healing ulcers and laboratory hemorheological parameters have been evaluated., Results: A clinically and statistically significant mean value reduction and of relative percentage differences between estimated marginal means (Δ), calculated at each visits, of NRS was observed, with a maximum value (-48.5%) between the first and last visit. At the end of the treatment period 14.3% of ulcers were completely healed, 46.4% downgraded, 53.6% were stable. Overall, no ulcers upgraded. A statistically significant reduction of the Δ, between the first and last visit, for fibrinogen (-16%) was also observed., Conclusion: Rheopheresis reduced overall painful symptoms; data suggest that it could heal or improve ulcers and hemorheological laboratory parameters in HD patients with PAD and ischemic ulcers resistant to standard therapies., (© 2024 The Author(s). Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Dialysis patients display a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity. Among uremic toxins, homocysteine and cysteine are both substrates of cystathionine β-synthase and cystathionine γ-lyase in hydrogen sulfide biosynthesis, leading to the formation of two sulfur metabolites, lanthionine and homolanthionine, considered stable indirect biomarkers of its production. Hydrogen sulfide is involved in the modulation of multiple pathophysiological responses. In uremia, we have demonstrated low plasma total hydrogen sulfide levels, due to reduced cystathionine γ-lyase expression. Plasma hydrogen sulfide levels were measured in hemodialysis patients and healthy controls with three different techniques in comparison, allowing to discern the different pools of this gas. The protein-bound (the one thought to be the most active) and acid-labile forms are significantly decreased, while homolanthionine, but especially lanthionine, accumulate in the blood of uremic patients. The hemodialysis regimen plays a role in determining sulfur compounds levels, and lanthionine is partially removed by a single dialysis session. Lanthionine inhibits hydrogen sulfide production in cell cultures under conditions comparable to in vivo ones. We therefore propose that lanthionine is a novel uremic toxin. The possible role of high lanthionine as a contributor to the genesis of hyperhomocysteinemia in uremia is discussed., (Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Folate therapy reduces, but does not normalize homocysteine (Hcy) levels, frequently elevated in chronic kidney disease (CKD). The mechanisms of this folate resistance are unknown. Cellular acquisition of folate is mediated by folate receptors (FRs), whose expression is also modulated by folate status, through an Hcy-dependent regulation mechanism involving heterogeneous nuclear ribonucleoprotein-E1 (hnRNP-E1). Our objective was to evaluate whether an alteration of the FR2 (the form present in nucleated blood cells) expression is present in CKD patients on haemodialysis (HD), and its susceptibility to folate treatment., Methods: A population of chronic uraemic patients on HD was enrolled, along with a control group, and studies on FR2 receptor expression and related items were performed in plasma and mononuclear cells from peripheral blood. A subgroup of patients was treated with methyltetrahydrofolate for 1 month., Results: In HD, there was a significant reduction in FR2 protein expression compared with controls, not correlated with Hcy concentrations, while its mRNA levels were significantly increased. After folate treatment, there was a significant mRNA decrease, in the absence of significant changes in receptor protein expression. hnRNP-E1 gene and protein expression levels increased pre-treatment, while decreased post-treatment., Conclusions: In HD, FR2 expression is altered in peripheral mononuclear cells, since its levels are decreased and are not responsive to variations in Hcy concentration, while the intracellular machinery (receptor mRNA and hnRNP-E1), possibly triggering its regulation, is conserved. These findings provide insight into the mechanisms of folate resistance in uraemia.

Background: In chronic hemodialysis patients with secondary hyperparathyroidism, pathological modifications of bone and mineral metabolism increase the risk of cardiovascular morbidity and mortality. Parathyroidectomy, reducing the incidence of cardiovascular events, may improve outcomes; however, its effects on long-term survival are still subject of active research., Methods: From January 2004 to December 2006, 30 hemodialysis patients, affected by severe and unresponsive secondary hyperparathyroidism, underwent parathyroidectomy - 15 total parathyroidectomy and 15 total parathyroidectomy + subcutaneous autoimplantation. During a 5-year follow-up, patients did not receive a renal transplantation and were evaluated for biochemical modifications and major cardiovascular events - death, cardiovascular accidents, myocardial infarction and peripheral vascular disease. Results were compared with those obtained in a control group of 20 hemodialysis patients, affected by secondary hyperparathyroidism, and refusing surgical treatment, and following medical treatment only., Results: The groups were comparable in terms of age, gender, dialysis vintage, and comorbidities. Postoperative cardiovascular events were observed in 18/30 - 54% - surgical patients and in 4/20 - 20%- medical patients, with a mortality rate respectively of 23.3% in the surgical group vs. 15% in the control group. Parathyroidectomy was not associated with a reduced risk of cardiovascular morbidity and survival rate was unaffected by surgical treatment., Conclusions: In secondary hyperparathyroidism hemodialysis patients affected by severe cardiovascular disease, surgery did not modify cardiovascular morbidity and mortality rates. Therefore, in secondary hyperparathyroidism hemodialysis patients, resistant to medical treatment, only an early indication to calcimimetics, or surgery, in the initial stage of chronic kidney disease - mineral bone disorders, may offer a higher long-term survival. Further studies will be useful to clarify the role of secondary hyperparathyroidism in determining unfavorable cardiovascular outcomes and mortality in hemodialysis population.

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 <12 μmol/L, compared with 19% in the MTHF group and 16% in the control group., Conclusions: NAC therapy induces a significant additional decrease in homocysteine removal during dialysis. The advantage is limited to the time of administration., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Hydrogen sulfide, H2S, is the third endogenous gas with cardiovascular properties (the others are nitric oxide and carbon monoxide). In fact, among other important signaling functions, H2S plays a key role in regulating blood pressure. Cystathionine ß-synthase, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase are the principal enzymes devoted to H2S formation. We have recently shown that H2S levels are decreased in patients on chronic hemodialysis through the transcriptional deregulation of the CSE gene, hinting at the possibility that a link exists between this finding and hypertension and the high cardiovascular mortality typical of these patients.

Hydrogen sulfide, H(2)S, is the third endogenous gas with cardiovascular properties, after nitric oxide and carbon monoxide. H(2)S 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 H(2)S formation. Chronic kidney disease is characterized by high prevalence of hyperhomocysteinemia, hypertension, and high cardiovascular mortality, especially in hemodialysis patients. H(2)S levels are decreased in hemodialysis patients through transcriptional deregulation of genes encoding for the H(2)S-producing enzymes. Potential implications relate to the pathogenesis of the manifestations of the uremic syndrome, such as hypertension and atherosclerosis., (Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Hydrogen sulphide, H(2)S, is the third endogenous gas with putative cardiovascular properties, after nitric oxide and carbon monoxide. H(2)S is a vasorelaxant, while H(2)S deficiency is implicated in the pathogenesis of hypertension and atherosclerosis. Cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPS) catalyze H(2)S 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 H(2)S-generating pathways are altered as well in this patient population., Methods: Plasma H(2)S levels were measured with a common spectrophotometric method. This method detects various forms of H(2)S, protein-bound and non-protein-bound. Blood sulphaemoglobin, a marker of chronic exposure to H(2)S, 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, H(2)S 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 H(2)S biosynthesis, was not different. H(2)S correlated negatively with cysteine levels. CSE expression was significantly downregulated in haemodialysis patients., Conclusions: Transcriptional deregulation of genes encoding for H(2)S-producing enzymes is present in uraemia. Although the specificity of the method employed for H(2)S detection is low, the finding that H(2)S 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.

CKD is utilized as a paradigm, a chronic disease which allows decades of life conquered with great effort through a machine, a life with many losses and many dependencies. We must understand the patient's needs, which are not related to availability of drugs and machines and hospitals. We cannot provide good medical care with the limited amount of national product devoted to health care. Society is much older than ever before. We need a new cadre of economists working on health care with vision and ability, keeping in mind that there are no resources and there are no expenses which can be cut in medical care nowadays. We have to switch from curative medicine towards prevention, by implementing clinical research, bearing in mind that in the Western world, democracy was granted through the correct allocation of resources. The search for happiness and good quality of life are old concepts born in the Mediterranean area over the centuries, starting with Hesiod and Homer, and sleep and dreams were being investigated centuries before Freud was born.

Sleeping disorders are very common in patients with chronic kidney disease on dialysis (CKD5D) and are an emerging risk factor able to predict mortality. Parathyroid hormone (PTH) although considered a pivotal uremic toxin has rarely been associated with sleep disorders in uremia. In a study from our laboratory PTH concentrations failed to distinguish patients with sleep disorders from those without. In a study performed by Chou et al a 97% prevalence of insomnia was found in patients undergoing hemodialysis requiring parathyroidectomy. Surgery reduced PTH and increased sleeping hours within 3 months. The aim of this study was to study the effects of parathyroidectomy on the sleep disorders of insomniacs on maintenance hemodialysis. The study was performed in 16 insomniac patients on maintenance hemodialysis who successfully underwent surgery with autotransplantation of autologous parathyroid tissue (40 mg) under the skin of the forearm. Patients (5 F and 11 M) were studied from 1 month before surgery to 1 year after. Sleep disorders were assessed by means of a 27-item questionnaire--Sleep Disorder questionnaire (SDQ)--that identified sleeping disorders according to Diagnostic and Statistical Manual of Mental Disorders - IV Edition (DSM-IV) criteria. The Charlson Comorbidity Index (CCI) was also measured along with systolic and diastolic blood pressure, Hb, PTH, Ca, P. A 95.5% prevalence of sleep disorders was found pre operatively. Patients slept 4.90+/-1.2 hours, Ca averaged 10.09+/-0.54 mg/dL, Phosphate 5.5+/-1.93, CCI 9.8+/-1.1, PTH 1498+/-498 ng/mL. After 1 year follow-up 2 out 16 patients had normal sleep, 6 out 16 patients had subclinical sleep disorders and 8 remained insomniacs (p=0.008, Mc Nemar Test for paired data, insomniacs vs. no disturbance + subclinical disorders). Sleeping hours increased up to 6.0+/-1.24 (p<0.05), PTH was normalized, the Charlson Comorbidity Index was reduced (p<0.05) as were plasma calcium and phosphate (p<0.01). The study indicates that insomnia in patients with severe hyperparathyroidism on maintenance hemodialysis is ameliorated by parathyroidectomy.

Background: L-Carnitine, the acyl carrier into mitochondria, is derived from trimethyllysine. The formation of the latter compound is catalyzed by an S-adenosylmethionine methyltransferase, yielding S-adenosylhomocysteine (AdoHcy), the homocysteine direct precursor, as a product. Aim of this work was to determine if exogenously administered L-propionyl carnitine affects plasma levels of homocysteine, a cardiovascular risk factor, and its active metabolite AdoHcy, in chronic renal failure patients on hemodialysis., Methods: Plasma homocysteine and AdoHcy were determined by means of HPLC separation and detection in 14 hemodialysis patients before and after two months of i.v. L-propionyl carnitine treatment., Results: No significant differences were observed in plasma concentrations of homocysteine or AdoHcy after therapy., Conclusions: Treatment with a carnitine derivative does not significantly influence the plasma concentrations of homocysteine or of its active metabolite, AdoHcy, which are involved as risk factors for cardiovascular disease in chronic hemodialysis patients.

Plasma proteins in hemodialysis patients display a significant increase in deamidated/isomerized Asx (asparagine and aspartic acid) content, a marker of protein fatigue damage. This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage. The hypothesis that lack of reduction in protein damage could be due to protein increased intrinsic instability, as result of interference with the uremic milieu rather than to hyperhomocysteinemia, was put forward. The deamidated/isomerized Asx content of normal plasma incubated with several uremic toxins for 24 h, 72 h, and 7 d was measured, identifying a group of toxins that were able to elicit this kind of damage. Uremic toxins were also incubated with purified human albumin, and dose-response experiments with the two most toxic agents in terms of protein damage (guanidine and guanidinopropionic acid) were carried out. The effect of the hemodialysis procedure on protein damage was evaluated. For investigating also the consequences of these alterations, human albumin was treated in vitro to produce an increase in deamidated/isomerized Asx residues, and the effects of albumin deamidation on protein binding were evaluated. Among the uremic toxins that are able to elicit protein damage, guanidine produced a dose-dependent increase in protein damage. No difference was found after a hemodialysis session. Deamidated albumin shows normal binding capacity to warfarin, salicylic acid, or diazepam but reduced binding to homocysteine. In conclusion, uremic toxins, especially guanidine, display an ability to induce significant protein damage, which can in turn have functional consequences.

Background: Plasma homocysteine, a new cardiovascular risk factor in both children and adults, is higher in chronic renal failure or kidney transplant patients. This alteration has been linked, in chronic renal failure, to plasma protein damage, represented by increased L-isoaspartyl residues. We measured plasma homocysteine levels and plasma protein damage in pediatric patients from four different Italian regions with conservatively treated renal failure; hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), or transplants, to establish the presence of protein damage and the relative role of hyperhomocysteinemia., Methods: High performance liquid chromatography (HPLC) separation measured total plasma homocysteine levels, using precolumn derivatization with ammonium 7-fluorobenzo-2-oxa-1, 3-diazole-4-sulphonate (SBD-F). Plasma protein L-isoaspartyl residues were quantitated using human recombinant protein carboxyl methyl transferase (PCMT)., Results: In all patient groups, homocysteine levels were significantly higher with respect to the control (Control: 6.87 +/- 0.73 microM) conservatively treated, 14.19 +/- 1.73 microM; hemodialysis, 27.03 +/- 4.32 microM; CAPD, 22.38 +/- 3.73 microM; transplanted, 20.22 +/- 2.27 microM, p < 0.001 vs. control]. Plasma protein damage was significantly higher in conservatively treated, hemodialysis (HD) and CAPD patients, while in transplant patients it was no different from the control., Conclusions: We concluded that in pediatric patients of different Italian geographical origin, plasma homocysteine levels were significantly higher in all groups with respect to healthy children; therefore contributing to the elevated cardiovascular risk present in these patients. Plasma protein L-isoaspartyl content was higher in renal failure patients, but kidney transplant patients had normal levels, indicating that this kind of protein damage relates more to the toxic action of uremic retention solutes, than to plasma homocysteine levels.

The field of uremic toxicity comprises the study of a large number of different substances, classified in relation to various characteristics, for example, protein-binding, dimensions, and so forth. The endogenous compounds of a gaseous nature have received much attention lately from the scientific community because of their increasingly recognized importance in health and disease. Among these substances, some are uremic toxins per se, others are related to uremic toxins, or can become toxic under some circumstances. We divided them into two broad categories: organic and inorganic compounds. Among the organic compounds are phenols, indols, 2-methoxyresorcinol, p-hydroxy hippuric acid and phenyl acetic acid, trimethylamine, and dimethylamine; among the inorganic solutes are ammonia, nitric oxide, carbon monoxide, and hydrogen sulfide. In this article, these substances are described in relation to the elements that they affect or by which they are affected in uremia, which are the blood, breath, stools, and the gastrointestinal tract. In addition, the effect of the dialysis procedure on exhaled gases are described.