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Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novokidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC0–24of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC0–24and Cminfor both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novokidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC0-24of tacrolimus on day 1 was approximately 30 lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.hmL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC0-24and Cminfor both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Purpose ß2-microglobulin amyloidosis (Aß2M) is one of the main long-term complications of dialysis treatment. The incidence and the onset of Aß2M has been related to membrane composition and/or dialysis technique, with non-homogeneous results. This study was carried out to detect: i) the incidence of bone cysts and CTS from Aß2M; ii) the difference in Aß2M onset between cellulosic and synthetic membranes; iii) other risk factors besides the membrane.Methods 480 HD patients were selected between 1986 to 2005 and grouped according to the 4 types of membranes used (cellulose, synthetically modified cellulose, synthetic low-flux, synthetic high-flux). The patients were analyzed before and after 1995, when the reverse osmosis treatment for dialysis water was started at our center, and the incidence of Aß2M was compared between the two periods. Routine plain radiography, computer tomography (CT) and nuclear magnetic resonance imaging (MRI) as well as electromyography were used to investigate the clinical symptoms.Results Bone cysts occurred in 29.2% of patients before 1995 vs. 12.2% after 1995 (p<0.0001). CTS occurred in 24% of patients before 1995 vs. 7.1% after 1995 (p<0.0001). Bone cysts and CTS occurred in older patients, who began dialysis at a late age, with high CRP, low albumin, low residual GFR, and low Hb. Cox regression analysis showed that the risk factor for bone cysts was high CRP (RR 1.3, p<0.01), while albumin (RR 0.14, p<0.0001) and residual GFR (RR 0.81, p<0.0001) were revealed to be protective factors. Cox analysis for CTS confirmed CRP as a risk factor (RR 1.2, p<0.01), and albumin (RR 0.59, p<0.0001) and residual GFR (RR 0.75, p<0.0001) as protective factors. The comparison obtained between membranes did not suggest any protective effect on Aß2M.Conclusions The findings that the inflammatory status as well as low albumin and the residual GFR of the uremic patient are predictive of Aß2M lesions suggests that Aß2M has a multifactorial origin rather than being solely a membrane- or technique-related side effect.

The demographic characteristics of hemodialysis (HD) patients increase the need for the tunneled cuffed permanent catheter (TCC) as a definitive vascular access (VA) for HD. The internal jugular vein is increasingly being used as a route for TCC or temporary catheter placement and can be associated with serious complications. Among them other authors have described arteriovenous fistula (AVF) creation between the common carotid artery and the right jugular vein. We describe a case of an AVF between the right internal jugular vein and the right internal mammary artery. The fistula was detected during the TCC placement in a patient who underwent several jugular and subclavian catheterisms for HD in her clinical history.

Hemodiafiltration with on-line regeneration of ultrafiltrate (HFR) is a technique indicated for the treatment of dialysis patients affected by inflammatory syndrome and malnutrition. In the present work, a mathematical model, which describes intradialytic fluid and solute kinetics during standard diffusive dialysis, has been adapted to analyze solutes and fluid dynamics during HFR. The model is an improved version of our previous ones, and represents a good compromise between simplicity and reliability. It considers the intradialytic kinetics of sodium, potassium and urea, and two body fluid compartments: intracellular and extracellular. Moreover, the model includes simple equations to predict the intradialytic time pattern of osmolarity.The model has been experimentally validated by using 9 HFR sessions on 9 patients (one per each patient), comparing the time course of plasma solutes and osmolarity measured every 30 minutes during HFR, with those predicted by the model. Predictions are performed a priori, i.e., without any parameter adjustment, but just starting from knowledge of a few quantities (plasma sodium, potassium, urea, osmolarity and body weight) at the beginning of the session.The average deviations between model and real data (sodium: 1.9 mEq/L; potassium: 0.32 mEq/L; urea: 1.04 mmol/L; osmolarity: 5.02 mosm/L) are of the same order as measurement errors and similar to those obtained using our previous models in standard and profiled hemodialysis. Moreover, the prediction on sodium concentration only scarcely worsens (from 1.9 to 2.02 mEq/L) if default values are used for the initial value of other solutes in blood (i.e., if the algorithm uses only initial body weight and initial sodium concentration in plasma).The results confirm the good predictive capacity of the model in HFR, and suggest its possible innovative use to optimize sodium balance in HFR, from knowledge of only the sodium concentration in the ultrafiltrate. (Int J Artif Organs 2006; 29: 1031–41)

Background Chronic oral anticoagulation is currently used to avoid thrombosis and the malfunction of tunneled cuffed catheters (TCCs) for hemodialysis (HD). The aim of the study was to assess the efficacy of early warfarin administration, after TCC placement, in comparison to its administration after the first thrombosis or malfunction event of the TCC.Patients and methods One hundred and forty-four chronic dialysis patients, who underwent TCC placement between June 2001 and June 2005, were randomized into two groups: 81 patients, group A, started oral anticoagulation 12 hr after the TCC placement (target international normalized ratio (INR) 1.8–2.5), in association with ticlopidine 250 mg/die; 63 patients, group B, started warfarin after the first thrombosis/malfunction episode (target INR 1.8–2.5) in association with ticlopidine 250 mg/die. The efficacy of oral anticoagulation therapy in preventing TCC thrombotic complications was evaluated in a 12-month follow-up period, after TCC placement, in terms of: a) the number of patients with thrombotic-malfunction events; b) the number of thrombotic-malfunction events with urokinase infusion (events/patient/year); c) intradialytic blood flow rate (BFR, ml/min); d) negative blood pressure (BP) from the arterial line of the TCC (AP, mmHg); e) positive BP, in the extracorporeal circuit from the venous line (VP, mmHg); and f) bleeding complications.Results Ten patients (12%) in group A showed TCC thrombosis/malfunction vs. 33 patients (52%) in group B (p<0.01). In group A, 0.16 events of thrombosis/malfunction per patient/year vs. 1.65 in group B (p<0.001) were observed. BFR was respectively 305 ± 34 vs. 246 ± 42 ml/min (p<0.001). AP was –124 ± 13 in group A vs. –174 ± 21 mmHg in group B (p<0.05). VP was 112 ± 28 in group A vs. 168 ± 41 mmHg in group B (p<0.05). No patient showed any bleeding events.Conclusions Early warfarin therapy allows a significant reduction in TCC thrombotic complications and an improvement in both arterial and venous fluxes in comparison with the same therapy administered after the first TCC thrombotic/malfunction event. This therapy did not induce any bleeding complications in the patients included in the study.

Purpose Acute liver failure (ALF) and acute on chronic liver failure (ACLF) still show a poor prognosis. MARS was used in 22 patients with ALF or ACLF to prolong patient survival for liver function recovery or as a bridge to transplantation.Design Evaluation of depurative efficiency, biocompatibility, hemodynamics, encephalopathy (HE) and clinical outcome.Procedures During 71 five-hour sessions we evaluated (0', 60', 120', 180', 240', 300'): bilirubin, ammonia, cholic acid (CCA), chenodeoxycholic acid (CCDCA), leukocytes, platelets, hemoglobin and mean arterial pressure (MAP). Serum creatinine, electrolytes, cardiac output, cardiac index (bioimpedence) and HE (West Haven Criteria score) were evaluated at 0' and 300'. Statistical methods and outcome measures: Student's t-test for pre- vs. end-session values was used. For bilirubin and ammonia the correlation test was made between pre- and end-session values and between pre-session values and removal rates (RRS).Main Findings Survival was 90.9% at 7 days, 40.9% at 30 days. Pre- vs. end-session: bilirubin from 37.2±12.5 mg/dL to 24.9±8.9 mg/dL (p<0.01), ammonia from 88.0±60.4 µmol/L to 43.6±32.9 µmol/L (p<0.01), CCA from 42.8±21.0 µmol/L 18.2±9.8 µmol/L (p<0.01), CCDCA from 26.3±6.3 µmol/L to 15.7±7.6 µmol/L (p<0.01). The correlation test between pre-session values of bilirubin and ammonia vs. RRSwas respectively 0.32 (p=0.01) and 0.30 (p=0.04). Leukocytes, platelets and hemoglobin remained stable. MAP increased from 82.0±12.0 mmHg to 87.0±13.0 mmHg (p<0.05), West Haven Criteria score decreased from 2.7±0.7 to 0.7±0.7 (p<0.001).Conclusion MARS treatment led in all patients to an improvement of clinical, hemodynamic and neurological conditions, with significant reduction in the hepatic toxins blood level. Treatment biocompatibility and tolerance were satisfactory

AbstractBackground: To compare standard heparin (SH) and low molecular weight heparin (LMWH) in terms of anticoagulation, platelet activation and lipid metabolism, we selected 54 patients who had been on 4-hour hemodialysis three times weekly for at least 12 months, without bleeding disorders or dyslipidemic diseases. 28 were on hemodialysis with Polysulfone low-flux, 26 were on hemodiafiltration with Polysulfone high-flux. All patients underwent EPO. Methods: During the first 18 months, we administered SH 1,500 IU on starting dialysis and 1,500 ± 500 IU in continuous intradialytic infusion per session. In the following 18 months, we administered LMWH 64.6 IU/kg on starting dialysis in a single arterious bolus. We assessed aPTT, anti-factor Xa activity, TAT and FPA, β-TG and PF4. Blood samples were taken monthly at times 0, 30, 60, 180 and 240 min, as well as 1, 4 and 20 h after dialysis end. Predialysis cholesterol, HDL, LDL, triglycerides and lipoprotein(a) were checked monthly. Results: During both LMWH and SH sessions no clotting or major bleeding complications were observed. APTT with LMWH was lower than that found with SH (p &lt; 0.001); aFXa using LMWH was higher than when using SH (p &lt; 0.001); TAT and FPA were lower in LMWH sessions (p &lt; 0.01) than in SH sessions. We also detected lower β-TG (p &lt; 0.05) and PF4 levels (p &lt; 0.05) using LMWH than using SH. As regards lipids, we only observed a significant decrease in triglycerides after 18 months of LMWH treatment. Conclusions: Routine use of LMWH during hemodialysis affords a safe and effective alternative to SH, and causes reduced platelet activation.Copyright © 2002 S. Karger AG, Basel

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.

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.

A new coated anionic exchange resin for blood purification specifically designed to remove phosphates was experimentally employed in animals. 3 pigs, in which uremia had been surgically induced, underwent 6 extracorporeal hemoperfuslon sessions (2 per pig) with a cartridge containing 100 gr of resin.The phosphate clearance proved satisfactory, values being 120 ml/min after 10' and around 80 ml/min after 2 hours. The biocompat ibility of the resin and of the coating membrane was satisfactory. The negligible variation in pH and plasma bicarbonate during all sessions confirmed the low absorption by the tested resin of other blood anions competing with phosphate.

Biocompatibility of charcoal hemoperfusion was studied in a group of 15 uremic patients, evaluating the effects of long-term treatment on some structural and functional parameters of circulating lymphocytes: in vivo distribution of T-cell subsets; surface T3, T4 and T8 antigen expression, in vivo and in vitro DNA synthesis. A comparative analysis was performed with patients on conventional dialysis using cuprophan membranes.

This paper reports the Authors' 8 year experience in the clinical use of charcoal hemoperfusion as a means to reduce the weekly time of treatment in chronic uremic patients. Two different programmes were applied. Programme A (34 patients) which involved substituting the 3 procedures per week of standard dialysis (4 hours duration each) by 2 procedures of combined hemodialysis and hemoperfusion, again of 4 hours duration each. Programme B (18 patients) which involved substituting the 3 procedures per week of 4 hours duration by 3 procedures of 3 hours each, 2 of combined hemodialysis and hemoperfusion, 1 of conventional dialysis. The net weekly reduction was 33% for Programme A and 25% for Programme B. The efficacy of the two Programmes was evaluated by clinical, hematochemical, nutritional and instrumental parameters.

Charcoal hemoperfusion has long been used in chronic uremia as an adjunct or substitute for conventional hemodialysis.In this study a regular combination of hemoperfusion and hemodialysis was used to cut down the weekly substitutive sessions from 3 to 2. Ten RDT patients were treated with the reduced-time schedule for 5–56 weeks. Clinical and metabolic conditions remained stable in all patients and no sign of inadequate treatment appeared. Long-term charcoal hemoperfusion was confirmed to be a safe and risk-free procedure. No change in platelets, white cells, red cells, fibrinogen and other hematochemical parameters were detected.

The capacity of activated charcoal to remove toxins from the blood is well established. Its poor biocompatibility, inability to remove urea, electrolytes and water, and high cost have so far been the major objection to a wider use of charcoal with chronic uremic patients.The availability of a charcoal coated by a new highly hydrophilic methacrylate based membrane enabled us to keep 18 uremic patients on a combined hemodialysis-hemoperfusion schedule for 4–52 weeks. Investigations concerned patients in whom relapsing signs of uremia occurred despite technically adequate dialysis, and other cases where dialysis was both technically and clinically adequate. In the first group of patients, the conbined programme led to an improvement of the dialysis resistent clinical signs, while certain positive metabolic effects were also observed. In the second group, the hemodialysis-hemoperfusion treatment allowed a reduction of about 30% in time of treatment per week.Tolerance of the new coated charcoal was good throughout treatment in terms both of biocompatibility and of side effects.

A simple mathematical model of the intradialytic relationship between natraemia and dialysate sodium concentration is presented. The model includes a bicompartmental description of sodium, urea and fluid kinetics and an algebraic characterization of diffusive/convective mass-transfer across the dialysis membrane. Its ability to provide realistic responses has been validated comparing model predictions by a priori parameter tuning against quantities measured during in vivo sessions with both constant and variable dialysate sodium concentration. A quantitative analysis of model predictions indicates that the mean deviation between data calculated by the model and those measured in vivo is 1.32 mEq/l for sodium and 0.76 mmol/l for urea, values which do not greatly exceed the measurement errors of current instruments. The model's predictive capacity thus proves reliable. The ability of the model to calculate the amount of sodium removed and the time course of intra-extracellular volumes during the dialysis session makes it possible to forecast the patient's clinical tolerance to a given sodium dialysate concentration.

Aim Kidney transplantation with ureteral duplication may represent a doubled risk factor in terms of ureteral stenosis or necrosis with urinary leakage usually from the site of ureteroneocystostomy. The incidence of complete duplication is very low at 0.19%. We report a kidney with ureteral duplication in the specific setting of multiorgan transplantation since it could be considered a adjunctive risk factor for urological complications.Methods The recipient was a 67-year old man, suffering from terminal renal insufficiency. He was also affected by HCV-related cirrhosis. The patient had been waiting for the combined transplantation for 27 months and in the last two months his hepatic function dramatically worsened. The donor was a 53-year old man who died of non-traumatic subarachnoid hemorrhage. Good HLA compatibility was observed between donor and recipient. During harvest both kidneys presented a complete ureteral duplication. So the ureters were freed together with a wide cuff of periureteral tissue and dissected distally. No vascular abnormalities were noted during the removal of either kidney. The grafts were flushed with University of Wisconsin solution and stored in the same solution.Results The liver was reperfused after 9 hours of cold ischemia. Subsequently the kidney was vascularized after 15 hours of cold ischemia. Urine production occurred immediately after revascularization. Two separated ureteroneocystostomies with a single antireflux technique were performed. Cyclosporine and steroids were given. Post-operative course was uneventful and liver and kidney function were normal. The 7-day cystography was normal. The 6, 12, 24 month ultrasonographies showed no signs of hydronephrosis or hydroureter. After 28 months renal cancer was diagnosed and the patient underwent a right nephrectomy. The liver-kidney recipient had excellent hepatic and renal function for 84.7 months. He died of malignancy from de novo tumor.Conclusions On the basis of this experience, a kidney with an ureteral duplication, while rare, can be satisfactorily used also in combined liver-kidney transplantation.