New-generation androgen receptor signaling inhibitors (ARSIs) in metastatic hormone-sensitive prostate cancer (mHSPC): pharmacokinetics, drug-drug interactions (DDIs), and clinical impact.

INTRODUCTION: The therapeutic scenario of metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically changed in recent years, with the approval of new-generation Androgen Receptor Signaling Inhibitors (ARSIs), in combination with the androgen deprivation therapy (ADT), which was the previous standard of care. Despite showing a similar clinical efficacy, ARSIs, all of which are administered orally, are different in terms of pharmacokinetic and drug-drug interactions (DDIs). AREAS COVERED: This review covers the main pharmacokinetic characteristics of ARSIs that have been approved for the first-line therapy of mHSPC patients, underlying the differences among these molecules and focusing on the known or possible interactions with other drugs. Full-text articles and abstracts were searched in PubMed. EXPERT OPINION: Since prostate cancer occurs mainly in older age, comorbidities and the consequent polypharmacy increase the DDI risk in mHSPC patients who are candidates for ARSI. Waiting for new therapeutic options, in the absence of direct comparisons, pharmacokinetic knowledge is essential to guide clinicians in prescribing ARSI in this setting.

Pharmacy Workload in Clinical Trial Management: A Preliminary Complexity Assessment Tool for Sponsored Oncology and Haematology Trials.

Investigational drug services need to be organised in a structured approach, especially for sites with a large number of ongoing clinical trials. The aim of this study was to develop a tool to assess the complexity of pharmacy involvement in a sponsored oncology clinical trial. Categorisation into ordinal complexity categories was used to assess the complexity of the clinical trials for consistent pharmacy grant applications. The 15 items of the tool were divided into three sections, and individual item scores were agreed upon among four pharmacists with experience in the conduct of clinical trials at two different centres. A final version of the tool, named Pharm-CAT, was approved. The pharmacists were instructed to use Pharm-CAT to assign a score to each new sponsored trial. To determine the cut-offs for the complexity categories, the scores were sorted in ascending order and the cut-offs corresponding to the first and third tertiles of the score distribution were selected. To verify the reproducibility of the results, Pharm-CAT was applied by two pharmacists independently for each trial. Pharm-CAT proved to be user-friendly. Sixty clinical trials were evaluated and a total of 120 scores were recorded. Low-complexity scores ranged from 0 to 19, medium-complexity scores ranged from 20 to 25, and high-complexity scores were 26 or higher. The average score recorded was 22.88 points. Prospective multicentre validation of Pharm-CAT is needed to confirm its applicability.

Efficacy of Immune Checkpoint Inhibitors vs. Tyrosine Kinase Inhibitors/Everolimus in Adjuvant Renal Cell Carcinoma: Indirect Comparison of Disease-Free Survival.

BACKGROUND: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. The aim of our study was to compare the efficacy of these treatments using an innovative method of reconstructing individual patient data. METHODS: Nine phase III trials describing adjuvant RCC treatments were selected. The IPDfromKM method was used to reconstruct individual patient data from Kaplan-Meier (KM) curves. The combination treatments were compared with the control arm (placebo) for disease-free survival (DFS). Multi-treatment KM curves were used to summarize the results. Standard statistical tests were performed. These included hazard ratio and likelihood ratio tests for heterogeneity. RESULTS: In the overall population, the study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas both TKIs and mTORIs were inferior. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown. CONCLUSIONS: This novel approach to investigating survival has allowed us to conduct all indirect head-to-head comparisons between these agents in a context where no "real" comparative trials have been conducted.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Background: Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. Methods: A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. Results: One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Conclusion: Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Impact of Single Hemodialysis Treatment on immune Cell Subpopulations.

Hemodialysis (HD) is known to trigger a chronic inflammatory status, affecting the innate and acquired immune response. This study was aimed at a comparative analysis of immune cell subsets, proliferation, and apoptosis in subjects receiving chronic HD treatment with respect to a healthy control. Regardless of the dialysis filter used, we observed a reshaping of the acquired immune component both with respect to healthy patients and between the various sessions of dialysis treatment, with an impairment of CD3 cells, along with an increase in CD4 and CD8 cell populations producing pro-inflammatory factors such as IL-17 and IFN-gamma. The population of B cells, monocytes and NK cells were not impaired by the dialysis procedure. These results confirmed the high impact of the HD treatment on the patient's immune system, underlying the imbalance of T cell counterparts.

Anti-Inflammatory Approach in Chronic Dialysis Patients with SARS-CoV-2: ATA or PMMA Dialyzers?

INTRODUCTION: High-flux hemodialysis membranes may modulate the cytokine storm of SARS-CoV-2, but their impact on chronic hemodialysis (CHD) patients is unknown. The aim of the study was the evaluation of asymmetric cellulose triacetate (ATA) and polymethylmethacrylate (PMMA) dialyzers on inflammatory markers and clinical outcomes in CHD patients with SARS-CoV-2. METHODS: A prospective, observational study on CHD patients with SARS-CoV-2 was carried out. Patients were enrolled from March 2020 to May 2021. Pre- and postdialysis C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) were determined at each session. Patients who underwent on-line hemodiafiltration (OLHDF) with a PMMA dialyzer were compared with those treated with OLHDF with a ATA dialyzer. The primary endpoint was the differences in the reduction ratio per session (RR) of CRP, PCT, IL-6, and IL-6 RR >25%. RESULTS: We consecutively enrolled 74 CHD patients with COVID-19, 48 were treated with ATA membrane, and 26 with PMMA. Median IL-6 RR was higher in the ATA group compared to PMMA (17.08%, IQR -9.0 to 40.0 vs. 2.95%, IQR -34.63 to 27.32). Median CRP RR was 7.77% (IQR 2.47-13.77) in the ATA group versus 4.8% (IQR -2.65 to 11.38) in the PMMA group (p = 0.0017). Median PCT-RR% was 77.38% (IQR 70.92-82.97) in ATA group versus 54.59% (IQR 42.62-63.16) in the PMMA group (p < 0.0001). A multiple logistic regression analysis with IL-6 RR >25% as the outcome including the membrane employed, pre-dialysis IL-6, CRP, PCT, and ferritin showed that ATA led to a higher probability to reach the outcome (OR 1.891, 95% CI 1.273-2.840, p = 0.0018) while higher CRP favors the risk of lower IL-6 RR values (OR 0.910, 95% CI 0.868-0.949, p ≤ 0.0001). CONCLUSIONS: In SARS-CoV-2 CHD patients treated with OLHDF, ATA showed a better anti-inflammatory profile, regarding IL-6 RR, compared to PMMA.

The role of clinical trials in the sustainability of the Italian national health service cancer drug expenditure.

OBJECTIVE: Clinical trials offer new and potentially more effective therapeutic options for cancer patients and a potential cost-saving opportunity, especially considering that trial drugs are provided free-of-charge. The aim of this study was to analyse drug-related cost savings in clinical trials in a cancer institute over a 3 year period. The cost savings relate to the pharmaceutical expenditure of our centre, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori". METHODS: We conducted a retrospective analysis of patients taking part in interventional clinical cancer trials approved by a local independent Ethics Committee between 1 January 2018 and 31 December 2020. The standard of care (SOC) was identified as the standard treatment that would have been offered to a patient if he/she had not been enrolled in the study. The sum of SOC costs of all patients represents the potential cost avoidance during the study period. Results were stratified by year, trial promoter, trial phase and tumour type. The same approach was used to perform a secondary analysis of compassionate use programmes. RESULT: In the 3 year analysis, 1,257 patients were treated with experimental therapies in 244 clinical trials, of which 157 were profit and 87 academic. Results showed an overall cost savings of €13,266,518, more than 50% of which (€7,035,009) was related to phase III studies. Profit clinical trials generated €9,069,764 (68.4%) of the drug cost savings compared with €4,196,754 (31.6%) of academic studies. The stratification for tumour type was €3,552,592 (26.8%) genitourinary cancer, €3,268,074 (24.6%) melanoma, €2,574,127 (19.4%) haematological malignancies, €2,330,791 (17.6%) lung cancer, €728,149 (5.5%) gastrointestinal cancer, €557,608 (4.2%) rare tumours and €255,178 (1.9%) breast cancer. The secondary analysis on compassionate use included 122 patients involved in 28 different access programmes and revealed cost savings of €1,649,550. CONCLUSION: The results of our analysis point to the benefits of participating in and planning clinical trials for the public healthcare sector.

Sotrovimab in SARS-COV-2 chronic hemodialysis patients in the Omicron era. Is intradialytic administration feasible? Report of 4 cases.

Chronic hemodialysis patients are at high risk of morbidity and mortality in case of SARS-CoV-2 infection and they may need to be treated with monoclonal antibodies, either because they have not been vaccinated, or because they have a low anti spike antibody titer. Administration of Sotrovimab has recently been proposed for hemodialysis patients, but data are on the results lacking. We report on four cases of chronic dialysis patients who received Sotrovimab during intermittent dialysis sessions. In our series, no adverse reactions were recorded; intradialytic administration resulted safe and allowed an adequate observation time without prolonging hospital stay in chronic hemodialysis outpatients.

Interleukin-6 and Outcome of Chronic Hemodialysis Patients with SARS-CoV-2 Pneumonia.

Background and Objectives: Chronic hemodialysis (CHD) patients are at increased risk of SARS-CoV-2 infection and the related complications and mortality of COVID-19 due to the high rate of comorbidities combined with advanced age. This observational study investigated the clinical manifestations of SARS-CoV-2 infection in CHD and the risk factors for patients' death. Materials and Methods: The study included 26 CHD patients with SARS-CoV-2 pneumonia detected by positive RT-PCR on nasopharyngeal swabs and high-resolution computed tomography at hospital admission, aged 71 + 5.9 years, 14 of which (53.8%) were male, 20 (77%) under hemodiafiltration, and 6 (23%) on standard hemodialysis, with a median follow-up of 30 days. Results: Simple logistic regression analysis revealed that the factors associated with a higher risk of death were older age (OR: 1.133; 95%CI: 1.028−1.326, p = 0.0057), IL-6 levels at admission (OR: 1.014; 95%CI: 1.004−1.028, p = 0.0053), and C-reactive protein (OR: 1.424; 95%CI: 1.158−2.044, p < 0.0001). In the multiple logistic regression model, circulating IL-6 values at admission remained the only significant prognosticator of death. The ROC curve indicated the discriminatory cut-off value of 38.20 pg/mL of blood IL-6 for predicting death in chronic hemodialysis patients with SARS-CoV-2 pneumonia (sensitivity: 100%; specificity: 78%; AUC: 0.8750; p = 0.0027). Conclusions: This study identified a threshold of IL-6 levels at hospital admission for death risk in CHD patients with SARS-CoV-2 pneumonia. This might represent a valuable outcome predictor, feasibly better than other clinical, radiological, or laboratory parameters and preceding the IL-6 peak, which is unpredictable.

Efficacy of Supra-HFR in Removing FGF23 and Cytokines: A Single Session Analysis.

BACKGROUND/AIM: Supra hemodiafiltration with reinfusion of the endogenous ultrafiltrate (Supra-HFR) is a dialysis technique used to improve uremic toxin removal in the range of the middle molecular weight molecules. Supra-HFR does not require the preparation and online infusion of high-purity dialysis water because it allows the production of an endogenous ultrafiltrate that undergoes detoxification through an adsorbing resin. PATIENTS AND METHODS: We investigated the ability of Supra-HFR to remove fibroblast growth factor 23 (FGF23), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interleukin 8 (IL-8), and transforming growth factor alpha (TGF-alpha) after a single session dialysis in nine patients affected by end stage renal disease (ESRD). The same patients underwent a single session of online hemodiafiltration (OL-HDF) to evaluate possible differences in FGF23 and IL-6 levels. RESULTS: A significant reduction in FGF23 was observed with both Supra-HFR (p=0.001) and OL-HDF. As for TNF-alpha and TGF-alpha, which were measured using Supra-HFR only, their percentage values were significantly lower at the end of dialysis than at the start (p=0.0028 and p=0.03, respectively). This did not change with post-dialysis rebound. Supra-HFR was found to have no effect on IL-6 and IL-8. Interestingly, the removal rate for FGF23 and IL-6 was similar to that observed with OL-HDF. CONCLUSION: Supra-HFR was not superior to OL-HDF, with suboptimal convective volume in the removal of the molecules tested, especially FGF23, which is considered a large middle molecular weight uremic toxin.

Early Light Chains Removal and Albumin Levels with a Double Filter-Based Extracorporeal Treatment for Acute Myeloma Kidney.

Renal impairment in Multiple Myeloma (MM) represents one of the most important factors that influences patient survival. In fact, before the introduction of modern chemotherapy, less than 25% of patients with acute kidney injury (AKI) and MM who required dialysis recovered sufficient renal function to become independent from dialysis, with a median overall survival of less than 1 year. There are many other factors involved in determining patient survival. In this study we aimed to investigate the role of double filter-based extracorporeal treatment for removal of serum free light chains (sFLC) in acute myeloma kidney (AKI for MM) and to evaluate patient overall survival. All patients received Bortezomib-based chemotherapy and extracorporeal treatment for sFLC removal. For each session 2 dialyzers of the same kind were used. The dialytic dose was not related to the degree of renal function but to the removal of sFLC. The factors that have been found to be significantly associated with lower mortality were reduction of sFLC at day 12 and day 30, >50% reduction of sFLC at day 30, number of sessions and independence from dialysis. Among baseline characteristics, albumin level was statistically associated with the patients' outcome. Our analysis highlights the importance of the early treatment for removal of sFLC in AKI for MM. These results indicate that the early removal of sFLC can improve patient's outcome.

Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease.

Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD-mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk-benefit profiles. The future holds great promise for novel drug therapies modulating ALP.

Safety of Intradialytic Bamlanivimab/Etesevimab Administration in Two COVID-19 Dialysis Outpatients.

Chronic hemodialysis patients are at high risk of severe COVID-19 disease and death related to the infection. Anti-spike monoclonal antibodies administration reduces risk of disease progression and hospitalization in high-risk subjects but no clear data on end-stage renal disease are available. We report 2 cases of Bamlanivimab/Etesevimab administration to two not hospitalized chronic hemodialysis patients with SARS-CoV2 infection. Since they are large molecules (human immunoglobulin G1) with molecular weight of 146,000 Da, administration was conducted during the second hour of the dialysis session with no adverse reaction. Conclusions: Intradialytic administration of Bamlanivimab/Etesevimab could be considered safe and may allow adequate clinical observation time without hospital-stay prolongation.

The Role of Vitamin K in CKD-MBD.

PURPOSE OF REVIEW: We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). RECENT FINDINGS: Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.

Oral Calcitriol Use, Vertebral Fractures, and Vitamin K in Hemodialysis Patients: A Cross-Sectional Study.

Fractures and vascular calcifications (VCs) are common in patients with chronic kidney disease (CKD). They are related to abnormalities in vitamin D metabolism, calcium, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23)/Klotho that occur with CKD. Impaired vitamin D metabolism and abnormal levels of calcium, phosphate, parathyroid hormone (PTH), and FGF23/Klotho drive bone and vascular changes in CKD. It is unclear if oral calcitriol safely mitigates fracture risk without increasing the burden of calcifications. Therefore, we investigated whether treatment with calcitriol affected the prevalence of fractures and VC progression in hemodialysis (HD) patients. This report is a secondary analysis of the Vitamin K Italian (VIKI) study, a cross-sectional study involving 387 HD patients. We assessed vitamin 25(OH)D, alkaline phosphatase, PTH, calcium, phosphate, osteocalcin or bone Gla protein, matrix Gla protein, and vitamin K levels. Vertebral fractures (VFs) and VCs were determined by spine radiograph. A reduction of >20% of vertebral body height was considered a VF. VCs were quantified by the length of calcific lesions along the arteries. The patients treated with oral calcitriol were 177 of 387 patients (45.7%). The prevalence of VF was lower in patients receiving oral calcitriol than in those untreated (48.6% versus 61.0%, p = 0.015), whereas the presence of aortic and iliac calcifications was similar (aortic: 81.9% versus 79.5%, respectively, p = 0.552; iliac: 52.0% and 59.5%, respectively, p = 0.167). In multivariable logistic regression analysis, oral calcitriol was associated with a 40.2% reduced odds of fracture (OR 0.598; 95% confidence interval [CI], 0.363-0.985; p = 0.043). In conclusion, we found a significant association between oral calcitriol and lower VF in HD patients without an increase in the burden of VC. Further prospective and interventional studies are needed to confirm these findings. © 2021 American Society for Bone and Mineral Research (ASBMR).

The Vessels-Bone Axis: Iliac Artery Calcifications, Vertebral Fractures and Vitamin K from VIKI Study.

Vascular calcification and fragility fractures are associated with high morbidity and mortality, especially in end-stage renal disease. We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aortic calcifications (AACs) with the risk for vertebral fractures (VFs) in hemodialysis patients. The VIKI study was a multicenter cross-sectional study involving 387 hemodialysis patients. The biochemical data included bone health markers, such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, and phosphate. VF, IACs and AACs was determined through standardized spine radiograms. VF was defined as >20% reduction of vertebral body height, and VC were quantified by measuring the length of calcium deposits along the arteries. The prevalence of IACs and AACs were 56.1% and 80.6%, respectively. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p = 0.028), whereas we found no association (p = 0.294) for AACs. IACs were associated with VF irrespective of calcification severity. Patients with IACs had lower levels of vitamin K2 and menaquinone 7 (0.99 vs. 1.15 ng/mL; p = 0.003), and this deficiency became greater with adjustment for triglycerides (0.57 vs. 0.87 ng/mL; p < 0.001). IACs, regardless of their extent, are a clinically relevant risk factor for VFs. The association is enhanced by adjusting for vitamin K, a main player in bone and vascular health. To our knowledge these results are the first in the literature. Prospective studies are needed to confirm these findings both in chronic kidney disease and in the general population.

Vitamin D Effects on Bone Homeostasis and Cardiovascular System in Patients with Chronic Kidney Disease and Renal Transplant Recipients.

Poor vitamin D status is common in patients with impaired renal function and represents one main component of the complex scenario of chronic kidney disease-mineral and bone disorder (CKD-MBD). Therapeutic and dietary efforts to limit the consequences of uremia-associated vitamin D deficiency are a current hot topic for researchers and clinicians in the nephrology area. Evidence indicates that the low levels of vitamin D in patients with CKD stage above 4 (GFR < 15 mL/min) have a multifactorial origin, mainly related to uremic malnutrition, namely impaired gastrointestinal absorption, dietary restrictions (low-protein and low-phosphate diets), and proteinuria. This condition is further worsened by the compromised response of CKD patients to high-dose cholecalciferol supplementation due to the defective activation of renal hydroxylation of vitamin D. Currently, the literature lacks large and interventional studies on the so-called non-calcemic activities of vitamin D and, above all, the modulation of renal and cardiovascular functions and immune response. Here, we review the current state of the art of the benefits of supplementation with native vitamin D in various clinical settings of nephrological interest: CKD, dialysis, and renal transplant, with a special focus on the effects on bone homeostasis and cardiovascular outcomes.

Toxin Removal and Inflammatory State Modulation during Online Hemodiafiltration Using Two Different Dialyzers (TRIAD2 Study).

Uremic toxins play a pathological role in atherosclerosis and represent an important risk factor in dialysis patients. Online hemodiafiltration (HDF) has been introduced to improve the clearance of middle- and large-molecular-weight solutes (>500 Da) and has been associated with reduced cardiovascular mortality compared to standard hemodialysis. This non-randomized, open-label observational study will explore the efficacy of two dialyzers currently used for online HDF, a polysulfone-based high-flux membrane, and a cellulose triacetate membrane, in hemodialysis patients with signs of middle-molecule intoxication or intradialytic hypotension. In particular, the two filters will be evaluated for their ability in uremic toxin removal and modulation of inflammatory status. Sixteen subjects in standard chronic bicarbonate hemodialysis requiring a switch to online HDF in view of their clinical status will be enrolled and divided into two treatment arms, according to the previous history of hypersensitivity to polysulfone/polyethersulfone dialysis filters and hypersensitivity to drugs or other allergens. Group A will consist of 16 patients without a previous history of hypersensitivity and will be treated with a polysulfone filter (Helixone FX100), and group B, also consisting of 16 patients, with a previous history of hypersensitivity and will be treated with asymmetric triacetate (ATA; SOLACEA 21-H) dialyzer. Each patient will be followed for a period of 24 months, with monthly assessments of circulating middle-weight toxins and protein-bound toxins, markers of inflammation and oxidative stress, lymphocyte subsets, activated lymphocytes, and monocytes, cell apoptosis, the accumulation of advanced glycation end-products (AGEs), variations in arterial stiffens measured by pulse wave velocity (PWV), and mortality rate. The in vitro effect on endothelial cells of uremic serum collected from patients treated with the two different dialyzers will also be investigated to examine the changes in angiogenesis, cell migration, differentiation, apoptosis and proliferative potential, and gene and protein expression profile. The expected results will be a better awareness of the different effects of polysulfone gold-standard membrane for online HDF and the new ATA membrane on the removal of uremic toxins removal and inflammation due to blood-membrane interaction.

Time evolution of restless legs syndrome in haemodialysis patients.

BACKGROUND: Restless legs syndrome (RLS) is characterized by an urge to move the extremities, accompanied by paraesthesiae, in the evening and at night. Uraemic RLS, a type of secondary RLS, occurs commonly in chronic kidney disease and end-stage renal disease. Progression of uraemic RLS over time is unclear. Therefore we investigated the prevalence, progression over time, risk factors and impact on survival of uraemic RLS in a cohort of dialysis patients. METHODS: We reviewed at the 7-year follow-up a cohort of haemodialysis (HD) patients we had previously investigated for RLS, through interviews, validated questionnaires and analysis of demographic and clinical data. RESULTS: At the 7-year follow-up, RLS was present in 16% of patients, with a persistence rate of 33%. A correlation was obtained between RLS and older age, diabetes, low albumin and low body mass index. RLS was associated with reduced overall survival (median survival of 3.3 versus 3.7 years), particularly with the continuous form of RLS (1.61 years). There was a higher incidence of myocardial infarction and peripheral vascular disease, although not reaching statistical significance. RLS patients had absolute higher scores in all quality of life domains. A large majority of study patients (96%) reported being symptom-free within a few days or weeks following kidney transplantation. CONCLUSIONS: The development of RLS, especially the continuous form, in patients undergoing HD has important consequences associated with decreased survival. Our results indicated an association between uraemic RLS and ageing, diabetes and malnutrition. Considerable efforts should be focused on the treatment of RLS, since it significantly and persistently impacts the quality of life of HD patients. Kidney transplantation could represent an effective treatment option for that RLS impacts on dialysis patients' quality of life, thus confirming the secondary nature of RLS in most HD patients.