Nonvitamin K-dependent oral anticoagulants (NOACs) in chronic kidney disease patients with atrial fibrillation.

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, in CKD patients AF is associated with an increased risk of thromboembolism and stroke. However, CKD patients, especially those on renal replacement therapy (RRT), also exhibit an increased risk of bleeding, especially from the gastrointestinal tract. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF presenting increased risk of stroke. Limited evidence on efficacy, the increased risk of bleeding as well as some concern regarding the use of warfarin in CKD, has often resulted in the underuse of anticoagulation CKD patients. A large body of evidence suggests that non-vitamin K-dependent oral anticoagulant agents (NOACs) significantly reduce the risk of stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with vitamin K antagonist such as warfarin in normal renal function subjects. Hence, they are currently recommended for patients with atrial fibrillation at risk for stroke. However, NOACs metabolism is largely dependent on the kidneys for elimination and little is known in patients with creatinine clearance <25ml/min who were excluded from all pivotal phase 3 NOACs trials. This review focuses on the current pharmacokinetic, observational, and prospective data on NOACs in patients with moderate to advanced chronic kidney disease (creatinine clearance 15-49ml/min) and those on dialysis.

Sudden cardiac death and chronic kidney disease: From pathophysiology to treatment strategies.

Chronic kidney disease (CKD) patients demonstrate higher rates of cardiovascular mortality and morbidity; and increased incidence of sudden cardiac death (SCD) with declining kidney failure. Coronary artery disease (CAD) associated risk factors are the major determinants of SCD in the general population. However, current evidence suggests that in CKD patients, traditional cardiovascular risk factors may play a lesser role. Complex relationships between CKD-specific risk factors, structural heart disease, and ventricular arrhythmias (VA) contribute to the high risk of SCD. In dialysis patients, the occurrence of VA and SCD could be exacerbated by electrolyte shifts, divalent ion abnormalities, sympathetic overactivity, inflammation and iron toxicity. As outcomes in CKD patients after cardiac arrest are poor, primary and secondary prevention of SCD and cardiac arrest could reduce cardiovascular mortality in patients with CKD.

[Cardiac magnetic resonance and uremic cardiomyopathy]. / Storia naturale della cardiomiopatia uremica analizzata con gli "occhi" della risonanza magnetica nucleare.

Cardiovascular disease (CV) represents the main risk factor for morbidity and mortality in chronic kidney disease (CKD) patients. Large epidemiological studies have shown direct association between severity of CKD and CV event rates. Although patients with end-stage renal disease (ESRD), including dialysis ones, are at greater CV risk, cardiovascular involvement is already evident at the early stages of CKD. End-stage CKD is characterized conventional atherosclerotic risk factor but they cannot account for CV risk as reflected in high rates of sudden cardiac death, heart failure and myocardial infarction. Non-atherosclerotic processes, including left ventricular hypertrophy and fibrosis, mostly account for the excess risk of CV. Employment of cardiac magnetic resonance (CMR) in CKD has brought an improved understanding of the adverse CV changes, known as uremic cardiomyopathy. It is due to ability of cardiac magnetic resonance to provide a comprehensive non - invasive examination of cardiac structure and function, arterial function, myocardial tissue characterization (T1 mapping and inversion recovery imaging), and myocardial metabolic function (spectroscopy).

[Two centers with a native fistula prevalence higher than 90%: organization and activity]. / Due centri accomunati da una prevalenza di fistole con vasi nativi maggiore del 90%: attività e modelli organizzativi a confronto.

Vascular access (AV) dysfunction is a major cause of morbidity and hospitalisation in hemodialysis population. Despite of guidelines statements which consider native arteriovenous fistula (nAVF) the gold standard, epidemiological studies still show a decline in their prevalence with an increase of central venous catheters (CVC). In this study we compared the activity of two Dialysis Units both characterized by a high prevalence (> 90%) of nAVF, in order to highlight the possible reasons. No collaboration existed between the two centres until the decision to design this work. The "policy" on creation and management of vascular access and organizational models of the two centres were assessed, in particular focusing on surgeons, presence of dedicated nephrologists, preoperatory ultrasound evaluation, follow-up and diagnosis of complications, resort to interventional radiology, complications management, in particular the timing of intervention after AVF thrombosis. Of the two dialysis populations were analysed: age, time on dialysis, coexistence of diabetes and the prevalence of various types of vascular access to 31 December 2007. It was evaluated the AV incidence in the last 4 years. The statistical analysis was performed by T student and Chi square tests. There were no substantial differences in the organizational models of the two centres, which had both a routine ECD use in preoperatory mapping and in monitoring of complications; in case of thrombosis both centres performed surgery within 12-24 hours; in case of stenosis both centres performed the correction, surgical or by angioplasty, within 15 days from the diagnosis. Another common element was the presence of a multidisciplinary team with a interventionist nephrologist, a vascular surgeon and a vascular interventional radiologist, where nephrologist has the coordination role. The data analysis showed a prevalence of nAVF in the two centres of 92.5% and 96.1%, Pescara and Lecce respectively, with a prevalence of forearm nAVF of more than 80% and 90% respectively. The analysis of incident interventions showed high percentage of forearm AVF in case of revisions for complications (stenosis, thrombosis), and a little recourse to proximal AVF and graft.

[Clearances in automated intermittent peritoneal techniques: a new formula to use morning blood sampling]. / Clearances in tecniche peritoneali automatizzate intermittenti: una nuova formula per utilizzare il prelievo ematico del mattino.

According to the main guidelines, dialysis adequacy monitoring is fundamental in the management of patients on peritoneal dialysis. In order to avoid mistakes in the calculation of the peritoneal urea and creatinine clearance in patients on dialysis with intermittent techniques, the collection of blood samples about 6 hours after the end of the dialysis session is advised. In fact, because the creatinine and urea values at the end of dialysis (the morning values in NIPD) are the lowest, the resulting clearances could be overestimated. The mean values between the start and the end of the dialysis session are considered the gold standard. However, collecting a blood sample at 2.00 p.m. may be difficult and uncomfortable both for the nurse and the patient. In this paper we present two formulas (the first for urea and the second for creatinine) which, starting from the values at the end of dialysis, predict the values at the beginning of the session and consequently the mean values. The aim of this study was to validate the formulas by evaluating their capability to predict the mean urea and creatinine values when only end-of-dialysis blood sampling was performed. Statistical analysis was carried out using the Bland-Altman test. The two formulas proved able to predict the mean urea and creatinine values; the differences between the measured and calculated values were not statistically significant.

Early experiences of intraoperative ultrasound guided angioplasty of the arterial stenosis during upper limb arteriovenous fistula creation.

In recent years the high prevalence of diabetes and atherosclerosis in elderly uremic patients starting hemodialysis (HD) has led to the increase in the risk of vascular access (VA) failure caused by pre-existing arterial diseases, including both VA slow maturation and early failure, and upper limb ischemic symptoms. Recently, in performing radial (R), brachial (B) and ulnar (U) artery (A) percutaneous transluminal angioplasty (PTA) in HD patients affected by access thrombosis, with insufficient blood flow and severe upper limb ischemia, good outcomes have been reported. Nevertheless, these procedures were performed after arteriovenous fistula (AVF) creation. About 2 years ago, we approached an intra-operative ultrasound-guided transluminal angioplasty (IUTA) performed during AVF creation, using the arterial incision, necessary because of the anastomosis, to introduce the necessary devices for the IUTA. The arterial stenosis having undergone IUTA was diagnosed by a preliminary ultrasound examination. Ultrasound guidance during the procedure is necessary for correct balloon location in the stenosis site. We treated seven patients (four diabetics), mean age 76 + 5 yrs. In all cases, the radial arteries because of hyposphygmia, were unfit for AVF creation. Four distal radio-cephalic AVFs at the wrist were created in patients 1, 3, 4 and 5; in the other three patients (2, 6 and 7), with failure or thrombosis of previous distal AVFs, an immediately upstream anastomosis was performed. In all cases, first, the area selected to perform the AV anastomosis was exposed, then the AR was incised, and the introductory metallic guide wire and the angioplasty catheter (with dimensions decided after PUS), were introduced. The balloon was inflated to 8-13 atm for 30-35 sec. In two patients a stent was also positioned. Later, a side-to-side AVF was created, closing the distal venous vessel. Patient follow-up ranged from 6-22 months. The ultrasound evaluation after IUTA showed the correction of all the stenosis treated. AVF maturation was good, except for the stented ones, which were inadequate. In conclusion, our early experience shows IUTA could be an adequate and effective procedure allowing the use of the stenotic arteries (otherwise unsuitable) for AVF creation. In our experience, stenting after IUTA does not add any other advantages.

Quantitative profiling of the pathological prion protein allotypes in bank voles by liquid chromatography-mass spectrometry.

The conversion of the cellular prion protein (PrP(C)) into a misfolded isoform (PrP(TSE)) that accumulates in the brain of affected individuals is the key feature of transmissible spongiform encephalopaties (TSEs). Susceptibility to TSEs is influenced by polymorphisms of the prion gene suggesting that the presence of certain amino acid residues may facilitate the pathological conversion. In this work, we describe a quantitative, fast and reliable HPLC-MS method that allowed to demonstrate that in the brain of 109(Met/Ile) heterozygous bank voles infected with the mouse adapted scrapie strain 139A, there are comparable amounts of PrP(TSE) with methionine or isoleucine in position 109, suggesting that in this TSE model the two allotypes have similar rates of accumulation. This method can be easily adapted for the quantitative determination of PrP allotypes in the brain of other natural or experimental TSE models.

Ultrasound guided brachial arterial angioplasty during the creation of a radio-cephalic arteriovenous fistula: a case report.

UNLABELLED: To prevent arteriovenous fistula (AVF) early failure, due to radial or brachial artery stenosis, ultrasound guided angioplasty performed while surgically creating the AVF could be an effective procedure. CASE REPORT: A 76-year-old diabetic male patient, on hemodialysis (HD) for 15 months, presented extensive thrombosis of the radio-cephalic AVF at the right arm, which had lasted for about 10 days. Ultrasound examination showed a 40% brachial artery stenosis with eccentric calcified plaque. The stenosis was localized about 1.5 cm before the artery bifurcation. The brachial artery diameter was 0.45 cm before and 0.26 cm at the level of the stenosis, the latter being 0.45 cm long. At the left wrist, under local anesthesia, the radial artery and the cephalic vein were exposed; the radial artery was then longitudinally incised for 7-8 mm in the area selected to create the AVF. A 6 Fr introducer, a metallic guide wire and a catheter for angioplasty were inserted one after the other in the radial artery. When the correct position of the angioplasty catheter in the stenotic area was established by ultrasound examination, the balloon was blown up to 13 atm for 35 sec, reducing the stenosis from 40-20%. Finally, a side-to-side radio-cephalic fistula was created, legating the distal vein. The AVF was used for HD after 3 weeks. The follow-up at 6 months demonstrated fair access performance and it was used without problems. Our satisfactory experience suggests that ultrasound guided angioplasty of brachial artery stenosis, performed simultaneously with surgical AVF creation, is possibly a successful procedure. This technique reduces the risk of early AVF failure and also allows, when required, stent implantation.

[Pre-dialysis arteriovenous fistula results in better patency rate]. / Fistola artero venosa pre-dialisi = migliori risultati.

BACKGROUND: The timing of creation of the first permanent vascular access is crucial to the clinical history of haemodialysis patients. Our strategy is to create vascular access early enough to allow its maturation before the start of the treatment. METHODS: Aim of the study is to evaluate patency of primary A-V fistulas in patients treated between 1985 and 2000 in our dialysis unit. One hundred and thirty A-V fistulas created before haemodialysis treatment (range 10-540 days) and used at its beginning (pre-HD group) are compared with 74 A-V fistulas created and/or used after the start of the haemodialysis treatment (post-HD group). RESULTS: Pre-HD group fistulas resulted in higher patency rate than the post-HD group, immediately at the start of the treatment (94.6% vs. 86.5%, p<0.05), at 6 months (89.2% vs. 75.6%, p<0.025), at 12 months (84.5% vs. 64.6%, p< 0.005), at 24 months (77.2% vs. 54.8%, p< 0.005). CONCLUSIONS: A-V fistula is to be preferred in the choice of primary vascular access for chronic haemodialysis patients. It should be created early enough before the beginning of the treatment (when serum creatinine reaches 6 to 7 mg/dL). This planning avoids central venous catheter placement, preserves vessels and the choice of the best surgical option thus resulting in a better fistula survival.

Intra- and post-dialytic platelet activation and PDGF-AB release: cellulose diacetate vs polysulfone membranes.

BACKGROUND: During haemodialysis the blood-membrane contact causes a release of platelet granule content, which contains platelet-derived growth factor AB (PDGF-AB). In view of the potential role of this in altering biocompatibility during haemodialysis, we evaluated the intra- and post-dialytic changes in PDGF-AB serum levels during haemodialysis sessions performed with cellulose diacetate (CDA) and polysulfone (PS) membranes respectively. METHODS: PDGF-AB, platelet factor 4 (PF4), beta thromboglobulin (betaTG), and mean platelet volume (MPV) levels were determined in 30 patients, each of whom underwent six dialysis sessions: three with a CDA and three with a PS membrane. Blood samples were taken at times 0, 15, 30, 120, 180, and 240 min during dialysis and at 1, 4, and 20 h after the end of the session. Statistical analysis was performed using a one-way ANOVA and Student's t test. RESULTS: PDGF-AB at 15 min was increased to +41+/-9% with CDA vs +20+/-5% with PS (P<0.001) from the T0 values, and at 120 min it was +19+/-8% with CDA vs -25+/-9% with PS (P<0.001) from T0 levels. At 240 min it was +95+/-14% with CDA vs +49+/-15% with PS (P<0.001) from the T0 values, returning to basal only 20 h after the end of the session. betaTG at 15 min was +60+/-8% for CDA vs +24+/-7.5% for PS (P<0.001) from the T0 values. PF4 showed a similar trend to betaTG. MPV at 30 min from the start of dialysis was 7.4+/-0.3 fl with CDA and 8+/-0.3 fl with PS (P<0.001), and at 240 min MPV was 7.9+/-0.3 fl with CDA and 8.4+/-0.3 fl with PS (P<0.001). CONCLUSIONS: Platelet activation and platelet release reactions are lower with PS than with CDA membranes. PDGF-AB, released during and after dialysis, represents a clear biocompatibility marker. Its slow return to basal values and its action on vascular cells make it a potential risk factor for atherosclerosis in uraemic patients.

A novel venombin B from agkistrodon contortrix contortrix: evidence for recognition properties in the surface around the primary specificity pocket different from thrombin.

A novel thrombin-like enzyme (named contortrixobin) has been purified to homogeneity from the venom of Agkistrodon contortrix contortrix by affinity chromatography on arginine-Sepharose, anionic exchange chromatography, and HPLC. The complete amino acid sequence has been determined by Edman degradation and by mass spectral analysis of peptides generated by enzymatic cleavage. A microheterogeneity at the level of residue 234 has been detected, as demonstrated by peptides differing for the occurrence of Pro234 ( approximately 85%) or Asp234 ( approximately 15%). Contortrixobin (i) has six disulfide bonds whose sequence positions have been determined by mass spectrometry and (ii) does not contain carbohydrates in its structure. As expected, the 234 residue sequence of contortrixobin exhibits strong homology with snake venom serine proteases acting on either fibrinogen or other blood coagulation components. The interaction of contortrixobin with chromogenic substrates indicates a higher specificity for arginine over lysine in the primary subsite and a faster attack to ester than amides. The hydrolytic activity of contortrixobin is strongly inhibited by diisopropyl fluorophosphate and to a less extent by phenylmethylsulfonyl fluoride, benzamidine, and 4', 6-diamidino-2-phenylindole; hirudin (a specific alpha-thrombin inhibitor) as well as basic pancreatic trypsin inhibitor has a small effect on contortrixobin's catalytic properties. Contortrixobin (i) preferentially releases fibrinopeptide B from human fibrinogen, (ii) activates blood coagulation Factors V and XIII with a rate 250-500-fold lower than human alpha-thrombin, and (iii) does not induce thrombocyte aggregation, intracytoplasmatic calcium ion increase in platelets, and activation of Factor VIII. Evidence for biorecognition properties different from thrombin is also reported.

Prediction of solute kinetics, acid-base status, and blood volume changes during profiled hemodialysis.

A mathematical model of solute kinetics oriented to the simulation of hemodialysis is presented. It includes a three-compartment model of body fluids (plasma, interstitial and intracellular), a two-compartment description of the main solutes (K+, Na+, Cl-, urea, HCO3-, H+), and acid-base equilibrium through two buffer systems (bicarbonate and noncarbonic buffers). Tentative values for the main model parameters can be given a priori, on the basis of body weight and plasma concentration values measured before beginning the session. The model allows computation of the amount of sodium removed during hemodialysis, and may enable the prediction of plasma volume and osmolarity changes induced by a given sodium concentration profile in the dialysate and by a given ultrafiltration profile. Model predictions are compared with clinical data obtained during 11 different profiled hemodialysis sessions, both with all parameters assigned a priori, and after individual estimation of dialysances and mass-transfer coefficients. In most cases, the agreement between the time pattern of model solute concentrations in plasma and clinical data was satisfactory. In two sessions, blood volume changes were directly measured in the patient, and in both cases the agreement with model predictions was acceptable. The present model can be used to improve the dialysis session taking some characteristics of individual patients into account, in order to minimize intradialytic unbalances (such as hypotension or disequilibrium syndrome).

Evaluation of intradialytic solute and fluid kinetics. Setting Up a predictive mathematical model.

A mathematical model of solute kinetics for the improvement of hemodialysis treatment is presented. It includes a two-compartment description of the main solutes and a three-compartment model of body fluids (plasma, interstitial and intracellular). The main model parameters can be individually assigned a priori, on the basis of body weight and plasma concentration values measured before beginning the session. Model predictions are compared with clinical data obtained in vivo during 11 different hemodialysis sessions performed on 6 patients with a profiled sodium concentration in the dialysate and a profiled ultrafiltration rate. In all cases, the agreement between the time pattern of model solute concentrations in plasma and the in vivo data proves fairly good as to urea, sodium, chloride, potassium and bicarbonate kinetics. Only in two sessions was blood volume directly measured in the patient, and in both cases the agreement with model predictions was good. In conclusion, the model allows a priori computation of the amount of sodium removed during hemodialysis, and makes it possible to predict the plasma volume changes and plasma osmolarity changes induced by a given sodium concentration profile in the dialysate and by a given ultrafiltration profile. Hence, it can be used to improve clinical tolerance to the dialysis session taking the characteristics of individual patients into account, in order to minimize intradialytic hypotension.

PDGF-AB release during and after haemodialysis procedure.

BACKGROUND: During haemodialysis blood membrane contact causes the release of the content of platelet alpha-granules, which contain platelet-derived growth factor (PDGF). In view of its possible role in accelerated atherosclerotic processes, we evaluated the intra- and post-dialytic changes in PDGF-AB serum levels during haemodialysis sessions performed using a cellulosic membrane. METHODS: Using the ELISA method, PDGF-AB, platelet factor-4 (PF4) and beta-thromboglobulin (beta-TG) levels were determined in peripheral blood, as well as in arterial and venous haemodialyser lines, in 10 patients each of whom underwent five consecutive dialysis sessions with a CU membrane. Blood samples were taken at 0, 15, 30, 60, 120, 180 and 240 min during dialysis and at 1, 4 and 20 h after the end of the session. In the same group of patients the levels of the same molecules were also determined after a heparin bolus injection of 4500 IU, blood samples were taken at 0, 15 and 30 min after injection of the bolus. RESULTS: PDGF-AB serum levels increased, remained consistently high during the haemodialysis session (in particular +134+/-20% after 30 min, P<0.001, and +140+/-5% after 240 min, P<0.001) and returned to basal values only after 20 h following the end of the session. PF4 and beta-TG showed a similar trend to PDGF. The heparin bolus injection caused only a small increase (+15+/-5% at 30 min) in PDGF-AB serum levels. CONCLUSIONS: PDGF-AB is released during dialysis mainly as consequence of the blood-membrane contact and it returns only slowly to basal values.

Severe gastrointestinal bleeding in a uremic patient treated with estrogen-progesterone therapy.

Gastrointestinal bleeding is a frequent complication in hemodialysis patients; angiodysplasia is a potential cause, with a higher incidence in uremic patients. We describe a case of severe anemia (Hemoglobin up to 3.5 g/dl) secondary to diffuse angiodysplastic lesions in a hemodialysis patient with mixed connective tissue disease. The case is characterised both by the severity of the clinical picture (extension and entity of angiodysplastic lesions, frequency of bleeding episodes) and by the patient's religious faith which made her reject blood transfusions. We underline the efficacy of estrogen-progesterone therapy in view of the modest results obtained with other therapeutic strategies on bleeding.

Effects of dialysis membrane nature on intradialytic phagocytizing activity.

Blood-membrane contact in the extracorporeal circuit affects the activation of many biological systems. Among these, phagocytizing activity has been reported to be influenced by the nature of the hemodialysis membrane used, whether cellulosic or synthetic. This work reports on an ex-vivo, comparative test between cellulosics and synthetics concerning the effects of blood-membrane contact on the polymorphonucleate and monocyte phagocytizing function, both during and after the hemodialysis session. By means of flow cytometry, we evaluated the capacity for phagosoma formation and oxidative burst both in polymorphonucleates and monocytes. Ten hemodialysis patients were included in the study. Six separate dialysis procedures for each patient were considered, one per dialyzer (3 cellulosic and 3 synthetic membranes). Tests were performed at 15', 60', 210' and 4 hours after the session end. Comparative evaluation was made according to Student's t test. Polymorphonucleate phagocytosis and oxidative burst activation were globally more marked for synthetic than cellulosic membranes, tending to level out in the post-dialysis. This result could be affected by their functional exhaustion following pulmonary sequestration. Monocyte intradialytic phagocytosis and oxidative burst proved more activated by cellulosic membrane. All differences tended to vanish in the post-dialysis.

Mathematical modeling of solute kinetics and body fluid changes during profiled hemodialysis.

A mathematical model of solute kinetics oriented to improve hemodialysis treatment is presented. It includes a two-compartment description of the main solutes (K+, Na+, Cl-, urea, HCO3-, H+, CO2), acid-base equilibrium through two buffer systems (bicarbonate and non-carbonic buffers) and a three-compartment model of body fluids (plasma, interstitial and intracellular). The main model parameters can be individually assigned a priori, on the basis of body weight and plasma concentration values measured before beginning the session. Model predictions are compared with clinical data obtained during 11 different hemodialysis sessions performed on six patients with profiled sodium concentration in the dialysate and profiled ultrafiltration rate. In all cases, the agreement between the time pattern of model solute concentrations in plasma and clinical data turns out fairly good as to urea, sodium, chloride and potassium kinetics. Finally, the time patterns of plasma bicarbonate concentration and pH can be reproduced fairly well with the model, provided CO2 concentration remains constant. Only in two sessions, blood volume was directly measured in the patient, and in both cases the agreement with model predictions was good. In conclusion, the model allows a priori computation of the amount of sodium removed during hemodialysis, and may enable the prediction of plasma volume changes and plasma osmolarity changes induced by a given sodium concentration profile in the dialysate and by a given ultrafiltration profile. Hence, it can be used to improve the dialysis session taking the characteristics of individual patients into account, in order to minimize intradialytic imbalances (such as hypotension or disequilibrium syndrome).