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Objectives: Transjugular intrahepatic portosystemic shunt (TIPS) is adopted to treat refractory complications of portal hypertension, such as variceal bleeding and ascites. This study aimed to assess predictors of hepatic encephalopathy (HE) development and cumulative transplant-free survival after TIPS placement in patients with cirrhosis complicated by refractory ascites and major gastroesophageal bleeding., Materials and Methods: Sixty-three cirrhotic patients who underwent TIPS positioning as a secondary prophylaxis of major upper gastroesophageal bleeding (N=30) or to control refractory ascites (N=33) were enrolled., Results: After a median follow-up of 26 months following TIPS insertion, only 1/30 (3.3%) patients developed reoccurrence of bleeding. Complete control of refractory ascites was recorded in 19/23 (82.6%) patients. Within the first month after TIPS placement, 34/63 (53.9%) patients developed clinically significant HE, which was associated with the baseline presence of type 2 hepatorenal syndrome (P=0.022). At the end of 90 months of follow-up, 35 (55.6%) patients were alive, 12 (19.0%) patients underwent liver transplantation, and 16 (25.4%) patients died. Independent predictors of transplant-free survival were a model for end-stage liver disease score up to 15 (P<0.001), the absence of a history of spontaneous bacterial peritonitis (P=0.010) pre-TIPS, and no HE within 1 month post-TIPS (P=0.040)., Conclusion: TIPS insertion can be considered a safe and effective treatment in patients with cirrhosis and severe complications of portal hypertension that are not manageable with standard treatments. Interestingly, if confirmed in future studies, the history of spontaneous bacterial peritonitis pre-TIPS could be added to the model for end-stage liver disease score as a strong baseline predictor of post-TIPS mortality.

[This corrects the article DOI: 10.1371/journal.pone.0172159.].

Background: There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used., Aim: To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study., Methods: Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org)., Results: Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI., Conclusions: Based on these results, we can estimate that 30-44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from "dose adjustment/closer monitoring", in mild to moderate liver disease, to "the use is contraindicated" in severe liver disease.

Background: Hemolytic uremic syndrome (HUS) can be triggered by Shiga toxin producing Escherichia coli (STEC) infection or it can be defined as atypical HUS (aHUS) if it is related to uncontrolled complement activation. aHUS is characterized by a high incidence of recurrence after kidney transplantation, and it can also occur de novo in transplant recipients. Eculizumab is used both to prevent and to treat aHUS following kidney transplantation. In this paper, we report our centre experience and we present 4 cases of HUS in patients who underwent kidney transplantation., Methods: This is a single-center experience about HUS development in transplanted patients., Results: Patient 1 with end-stage renal disease (ESRD) due to STEC-HUS undergoing kidney transplantation without prophylactic therapy with eculizumab. Patient 2 with HUS secondary to an episode of diarrhea at 8 years old. After a slow progression to ESRD, she underwent kidney transplantation and she received prophylactic therapy with eculizumab due to the presence of anti-complement factor H antibodies. Patient 3 underwent pre-emptive living donor ABO-incompatible kidney transplantation and developed HUS secondary to antibody-mediated rejection. Patient 4 developed de novo HUS 16 years after kidney transplantation without a known cause., Conclusion: The correct diagnosis of HUS and the identification of the complement component alterations in case of aHUS are important parameters required to predict the risk of post-transplant recurrence of the disease. In the cases we reported, eculizumab has been found to be effective both to prevent and to treat aHUS following kidney transplantation., (© 2017 S. Karger AG, Basel.)

Unlabelled:  Background and rationale. Acoustic radiation force impulse (ARFI) is a non-invasive tool used in the evaluation of liver fibrosis in HCV positive immune-competent patients. This study aimed to assess the accuracy of ARFI in discriminating liver transplanted patients with different graft fibrosis severity and to verify whether ARFI, eventually combined with non-invasive biochemical tests, could spare liver biopsies. This prospective study included 51 HCV positive liver transplanted patients who consecutively underwent to annual liver biopsy concomitantly with ARFI and blood chemistry tests measurements needed to calculate several non-invasive liver fibrosis tests., Results: Overall ARFI showed an AUC of 0.885 in discriminating between patients without or with significant fibrosis (Ishak score 0-2vs. 3-6). Using a cut-off of 1.365 m/s, ARFI possesses a negative predictive value of 100% in identifying patients without significant fibrosis. AUC for Fibrotest was 0.848 in discriminating patients with Ishak fibrosis score 0-2 vs. 3-6. The combined assessment of ARFI and Fibro-test did not improve the results obtained by ARFI alone., Conclusion: ARFI measurement in HCV positive liver transplanted patients can be considered an easy and accurate non-invasive tool in identify patients with a benign course of HCV recurrence.

Background & Aims: The addition of protease inhibitors, boceprevir (BOC) or telaprevir (TRV), to peg-interferon and ribavirin (PR) increases the incidence of anaemia in patients with chronic hepatitis C virus (HCV) infection. Although genetic variants in inosine triphosphatase (ITPA) gene have been linked to the haemolytic anaemia induced by PR, the mechanism sustaining severe anaemia during triple therapy is still unknown. This study aims to elucidate the molecular mechanisms underlying anaemia in chronic HCV patients with combined therapy., Methods: We studied 59 patients with chronic HCV genotype-1: 29 treated with TRV/PR and 30 with BOC/PR. We evaluated biochemical and haematological parameters, red cell index at baseline, 4, 12, 16 and 24 weeks of treatment; in a subgroup, we performed functional studies: osmotic fragility, red cell membrane protein separation, mass spectrometry analysis, quantification of erythroid microparticles release. IL28B and ITPA polymorphisms were also evaluated., Results: We found early acute normochromic normocytic haemolytic anaemia (4-8 weeks) followed by a late macrocytic hypo-regenerative anaemia with inappropriate low reticulocyte count (12-24 weeks). Studies on red cells revealed: (i) presence of spherocytes; (ii) increased osmotic fragility; (iii) abnormalities in red cell membrane protein composition; (iv) reduced membrane-cytoskeleton stability; (v) increased release of erythroid microparticles. ITPA polymorphisms impacted only the early phase of anaemia., Conclusions: The bimodal pattern of anaemia in chronic HCV patients on triple therapy might be because of acquired spherocytic-like anaemia in the early phase, followed by hyporegenerative anaemia, most likely related to the combined effects of PR and TRV or BOC on erythropoiesis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitamin D serum levels seem to influence antiviral response in chronic hepatitis C. Vitamin D pathway is controlled by genes presenting functional single nucleotide polymorphisms (SNPs). Data regarding the association between these polymorphisms and the rate of sustained viral response (SVR) following antiviral treatment in chronic hepatitis C virus (HCV) infection are largely incomplete. Aim of this study was to evaluate if the carriage of different SNPs of these genes could influence the rate of SVR in patients treated with interferon plus ribavirin. Two hundred and six HCV positive patients treated with PEG-interferon plus ribavirin were retrospectively evaluated. Polymorphic loci rs7041 G>T and rs4588 C>A of the vitamin D transporter GC-globulin, rs10741657 G>A of the vitamin D 25 hydroxylase CYP2R1 and rs10877012 G>T of vitamin D 1-hydroxylase CYP27B1 were genotyped. A genetic model named VDPFA (vitamin D Pathway Functional Alleles) was constructed considering for each patient the sum (from 0 to 8), derived from every functional allele carried, associated with the achievement of SVR. Three groups were identified: those carrying ≤4 VDPFA (N=108), those carrying 5-6 VDPFA (N=78) and those carrying ≥7 VDPFA (N=20). Significant associations were found between the rates of SVR and the VDPFA value both in all (61/108, 53/78, 17/20, p=0.009) and in 1/4-5 HCV genotypes (17/56, 23/43, 6/8, p=0.003). Moreover in patients who don't achieve rapid viral response (RVR) SVR and VDPFA were found to be in stronger associations in all (12/55, 17/39, 7/9, p<0.001) and in 1/4-5 HCV genotypes (4/41, 12/31, 5/6, p=0.001). VDPFA value ≥7 could aid to select, among RVR negative difficult to treat 1/4-5 HCV genotypes, those achieving SVR. These observations could permit to extend the indication to adopt dual antiviral therapy beyond RVR positivity rule without reducing the chances of SVR.

Background: Pregnancy after kidney transplant has become possible thanks to the recent surgical and pharmacological breakthrough., Materials and Methods: We performed a retrospective study including all childbearing women transplanted in our centers after 1997. The following variables were analyzed: type of nephropathy, patient age when dialysis started, age at transplantation, time between dialysis and transplantation and between transplantation and baby birth. We also considered immunosuppressive therapy, type of delivery, baby weight, Apgar score, and mother and baby follow-up., Results: We followed up 13 pregnancies in 12 patients who were diagnosed with chronic pyelonephritis (n = 4), postpartum cortical necrosis (n = 1), immunoglobulin A GN (n = 4), diabetic nephropathy (n = 1), unknown nephropathy (n = 2). All patients received a cadaveric donor kidney. They were treated with calcium antagonists and alfamethyldopa for their high blood pressure. We observed 9 mother complications: nonnephrotic proteinuria (n = 1), urinary tract Infection (n = 1), pre-eclampsia (n = 4), internal placenta detachment (n = 1) and spontaneous abortions (n = 2); 4 fetal complications: IUGR (n = 2), acute distress respiratory syndrome (n = 1), Klinefelter syndrome (n = 1) and preterm births (n = 4). In 2 cases the child weight was lower when compared to the gestational age, and 5 babies were admitted to the neonatal intensive care unit. The mother's follow-up showed no acute rejection episodes. Breastfeeding was discouraged due to the transmission of immunosuppressive medications into breast milk. We did not observe significant disease upon child follow-up., Conclusion: Our data were in agreement with the literature confirming that pregnancy after kidney transplant though possible carries elevated risks. Patients therefore are referred to highly specialized centers where obstetricians, nephrologists, intensivists, and neonatologists provide surveillance and treatment., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Uremia has been implicated in increased oxidative stress (OS) and decreased monocyte HLA-DR expression in chronic kidney disease (CKD) patients. Thus, one would expect normalization of these parameters after successful kidney transplant (KTx). Our aim was to describe patterns of OS and HLA-DR expression after KTx and to explore the effect of renal function and different immunosuppression regimens. 30 KTx patients (20 male; 48 +/- 11 years) were enrolled and compared with 20 healthy controls. We measured advanced oxidation protein products (AOPP) and the percentage of monocytes expressing HLA-DR (%DR+) before (preKTx) and after KTx (on days 2, 30, 90, 180 and after 1 year). Compared to controls, patients had a higher preKTx AOPP (152.6 vs. 69.3 micromol/l; p < 0.001). AOPP decreased at 48 h after KTx, achieving values similar to controls. Thereafter, it increased again and remained significantly higher compared to controls, returning to preKTx levels at 90 days. Prior to KTx there was a trend for lower %DR+ in KTx patients compared to controls (96 vs. 98%; NS). Following KTx, patients had a lower %DR+ in the 1st month; then it gradually returned to preKTx levels during the 1st year; at no time did it reach a value similar to controls. Cyclosporine (CyA)-treated patients had a significantly higher AOPP (161.5 vs. 99.5 micromol/l; p = 0.03) and a lower %DR+ (91.7 vs. 96.4; p < 0.05) at 30 days than patients on tacrolimus (FK). Patients on mycophenolate mofetil (MMF) showed a low AOPP (106.9 vs. 168.1 micromol/l; p = 0.05) and a high %DR+ (96.7 vs. 88.2%; p = 0.001) than those on everolimus. After 3 months, CyA-treated patients had a non-significant increase in AOPP levels, whereas those on FK showed a decrease (p < 0.05) as did those treated with MMF (p < 0.05). Successful KTx reduced but did not normalize AOPP, suggesting ongoing OS, perhaps due to persistent mild renal dysfunction and the effects of immunosuppression. HLA-DR expression remained low after KTx, which may be a possible contributing factor to infectious complications after transplantation. Immunosuppressive agents appear to have diverse effects on OS and HLA-DR expression., ((c) 2008 S. Karger AG, Basel.)

Background: Solid organ transplanted patients have a three- to fourfold higher lifetime risk of developing a cancer than the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model., Methods: We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years., Results: During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.6 x 10,000 PY), and 22 of them developed a SPC (annual incidence: 3.9 x 10,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.8 x 10,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83-1.41)., Conclusions: This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy.

The regulation of the immunosuppressive therapy after kidney transplantation is the most complex aspect of the management of transplanted patients. Every day the transplant clinician is challenged by need to provide a sufficient immunosuppression to avoid or reduce the risk of rejection without exposing the patient to the risk of developing opportunistic infections or malignancy or toxic side effects. The safety and efficacy profile of immunosuppressive therapy is limited within a narrow therapeutic window whose borders are represented by two clinical conditions such as rejection and drug-related toxicity. The availability of several different drugs allows the clinicians to make multiple choices to individualize treatments according to the specific needs of a single patient. Pharmacokinetic monitoring of the immunosuppressive drugs is an important element in the management of these patients but cannot be considered as the unique driving factor and must be integrated with a careful surveillance and evaluation of all drug-related side effects.

Background: Pregnancy after kidney transplant has become possible thanks to recent surgical and pharmacological breakthroughs., Materials and Methods: We performed a retrospective study including all pregnant women transplanted in our center after 1997. The following variables were analyzed. The type of nephropathy, patient age when dialysis began, patient age at trans-plantation, the time between dialysis and transplantation and the time between transplantation and childbirth. Immunosuppressive therapy, type of delivery, baby's weight and Apgar score were also considered., Results: We followed four pregnancies in three patients who were, respectively, diagnosed with chronic pyelonephritis, post-partum cortical necrosis and immunoglobulin A (IgA) glomerulonephritis (GN). We observed complications in three cases and two pre-term births. In one case, the baby's weight at birth was lower when compared to the gestation age. We did not observe any significant disease in the baby's follow-up., Conclusions: We concluded that our data were in agreement with those in the literature confirming that pregnancy after kidney transplant, although possible, carries an elevated risk; and therefore, patients have to be referred to highly specialized centers.

Background: Patients undergoing kidney transplantation demonstrate a higher risk of developing cancer as the result of immunosuppressive treatment and concurrent infections., Methods: The incidence of cancer in a cohort of patients who underwent kidney transplantation between 1990 and 2000, and who survived the acute phase (10 days), was analyzed as part of the North Italy Transplant program., Results: A total of 3,521 patients underwent transplantation during a 10-year period in 10 of 13 participating centers; the length of follow-up after kidney transplant was 67.7+/-36.0 months. During the follow-up, 172 patients developed cancer (39 with Kaposi sarcoma, 38 with lymphoproliferative diseases, and 95 with carcinomas [17 kidney, 11 non-basal cell carcinoma of the skin, 10 colorectal, 8 breast, 7 gastric, 7 lung, 6 bladder, and 3 mesothelioma]). The average time to cancer development after transplant was 40.1+/-33.4 months (range 0-134 months). Twenty-four patients developed cancer within 6 months from the transplant (10 with carcinomas, 7 with Kaposi sarcoma, and 7 with lymphoproliferative diseases). Three patients demonstrated a second primary cancer. The average cancer incidence was 4.9%. The incidence of cancer was 0.01 per year. Independent determinants of cancer development were age, gender, and immunosuppressive protocol including induction. Ten-year mortality was significantly higher in patients with cancer (33.1%) than among patients without cancer (5.3%). The relative risk of death in subjects with cancer was 5.5 (confidence interval 4.1-7.4)., Conclusions: These preliminary data underline the importance of long-term surveillance of transplant recipients, choice of immunosuppressive treatment, and careful donor selection.

The experience and the current practice of a single center located in northern Italy is reported. The center of Vicenza is a self-standing nephrologic unit serving a population of about 300,000 individuals. The overall province counts approximately 800,000 individuals and some of them are referred to our center from peripheral hospitals for renal transplantation and/or particular pathologic conditions. The center offers an integrated approach to the treatment of uremia including hemodialysis (HD), peritoneal dialysis (PD), and renal transplantation. In HD and PD, the most peculiar aspect is the treatment personalization that leads to numerous types of applied therapies and technologies. The policy of the center is based on the belief that the nephrology team has a substantial influence on the outcomes of dialysis patients. A large number of treatment options are available. Special care is placed on the delivery of an adequate amount of dialysis, but the fractional clearance of urea in relation to volume (Kt/V) is seen as a prerequisite and other factors are considered important. Reduction in mortality and morbidity is largely dependent on beginning therapy early in the course of renal treatment. The attainment of appropriate hemoglobin concentrations, good nutrition, good control of calcium and phosphorus metabolism, lipids, and blood pressure, is considered of great importance. Beyond all these factors the time spent by the physician with the patient is considered one of the major factors influencing quality of care. The particularly low mortality of the center (6%/yr) may also be ascribed to a lower incidence of diabetes and other comorbidities., (Copyright 2001 by W.B. Saunders Company)

Aim: CMV antigenemia by direct pp65 antigen detection and quantification was monitored on a weekly basis during the first 3 months after kidney transplantation., Subjects and Methods: Preemptive therapy with ganciclovir was started according to the following criteria: any positive antigemia in CMV-NEG subjects, a single determination > or = 30 cell or a two fold increase of positive cells in two consecutive specimens in CMV-POS and continued until pp65 was cleared. Overall, 109 patients were monitored., Results: Among the 24 CMV-NEG patients, 13 (54%) developed a pp65 positive assay without symptoms and were treated. Ten patients remained CMV-infection free and one patient developed late onset (7 months) CMV disease (hepatitis). Among the 85 POS patients 15 (17%) developed a pp65 positive assay and were treated. Two of them developed CMV disease within 7 days of the onset of positive antigenemia and 13 were asymptomatic. The other 70 patients remained CMV-infection free. The interval between transplant and the onset of CMV infection was 39 +/- 13 days in the CMV-NEG group and 64 +/- 20 days in the CMV-POS group (p < 0.001). The peak antigenemia level was 193 +/- 175 cells in the CMV-NEG group and 55+/- 78 cells in the CMV-POS group (p < 0.001). The duration of treatment did not differ in the two groups (22 +/- 7days). A second course of therapy, due to a relapse of asymptomatic infection was performed in 11/13 (85%) treated CMV-NEG patients and in 2/15 (13%) treated CMV-POS patients., Conclusions: Among the total 28 treated patients, we observed only 6 episodes of mild creatinine increase and 9 episodes of mild neutropenia. In the overall population, we observed 8 systemic infections not related to CMV.

Central venous catheterization allows immediate and easy vascular access for hemodialysis. Accidental arterial puncture is the most frequent complication of central vein cannulation and may occur in up to 8% of cases with the classic Seldinger procedure. We compared the Seldinger technique which implies manual localization of the vascular access, and an ultrasound guided technique, to assess whether the latter is an improvement on the Seldinger procedure.

The endotoxin transfer across dialysis membranes has been investigated using specific in vitro circuits. Backdiffusion and backfiltration have been analyzed and most dialysis membranes have shown to be permeable to LAL positive substances. Synthetic membranes however display the better capacity of retention of these products despite their higher porosity and permeability. For such reason synthetic polysulfone ultrafilters are used as pyrogen filters to obtain ultrapure dialysate. We have investigated the characteristics of a polysulfone ultrafilter named Diaclean and manufactured by Amicon Ireland. The capacity of endotoxin retention has been investigated both in filtration and backfiltration modes on new and used ultrafilters. The capacity of endotoxin adsorption was investigated as well. Used ultrafilters appeared to maintain the retention capacity and the adsorption capacity up to 4 months of use. Only slight differences were noted from the baseline values (p = n.s.). The best adsorption capacity is always displayed by the outer layer of the membrane suggesting its best utilization in back filtration mode with tangential flow. No morphological changes were observed in the used membrane analyzed by scanning electron microscopy.

Objective: The evaluation of the efficacy, adequacy, clinical tolerance, and safety of a new bicarbonate continuous ambulatory peritoneal dialysis (CAPD) solution., Design and Patients: A 6-week cross-over clinical study in 6 stable CAPD patients was performed. After a control period (2 weeks) with a standard CAPD solution (lactate, 35 mmol/L), a two-chamber bag containing 34 mmol/L of bicarbonate was used for 4 weeks. A breakable valve divided the two chambers, one containing bicarbonate and the other calcium. The two solutions were mixed just before use, thus avoiding the calcium and magnesium carbonate precipitation., Results: No differences between control and study periods were found for blood urea nitrogen, creatinine, total proteins, albumin, total and ionized calcium, phosphate, sodium, potassium, chlorine, and hemoglobin. Blood bicarbonate significantly increased from 21.25 +/- 2.02 to 23.36 +/- 1.15 (p < 0.05) during the study. The peritoneal equilibration tests for urea nitrogen, creatinine, proteins, sodium, potassium, and glucose were slightly reduced during bicarbonate dialysate, but this effect was compensated for by a slight increase of ultrafiltration, thus keeping peritoneal clearances constant. Residual renal function did not change during the study. No side effects occurred during the bicarbonate period., Conclusion: A CAPD bicarbonate solution is effective in uremic acidosis correction, does not affect dialysis adequacy, is safe, and well tolerated.