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BackgroundIn immunosuppression after transplantation, several multi-drug approaches are used, involving calcineurin inhibitors (CNI: tacrolimus-TAC or cyclosporine-CsA), antimetabolites (antiMs), mammalian target of rapamycin inhibitors (mTORis), and corticosteroids. However, data on immunosuppressive therapy by organ and its space–time variability are lacking.MethodsAn Italian multicentre observational cohort study was conducted using health information systems. Patients with incident transplant during 2009–2019 and resident in four regions (Veneto, Lombardy, Lazio, and Sardinia) were enrolled. The post-transplant immunosuppressive regimen was evaluated by organ, region, and year.ResultsThe most dispensed regimen was triple-drug therapy for the kidneys [tacrolimus (TAC) + antiM + corticosteroids = 41.5%] and heart [cyclosporin + antiM + corticosteroids = 36.6%] and double-drug therapy for liver recipients (TAC + corticosteroids = 35.4%). Several differences between regions and years emerged with regard to agents and the number of drugs used.ConclusionA high heterogeneity in immunosuppressive therapy post-transplant was found. Further studies are needed in order to investigate the reasons for this variability and to evaluate the risk–benefit profile of treatment schemes adopted in clinical practice.

Background Acute kidney injury (AKI) represents a frequent complication after orthotopic liver transplantation (OLT). This study aimed to evaluate early postoperative AKI incidence during the first 72 h after OLT, perioperative risk factors, and AKI impact on survival. Methods From January 2011 to December 2013) 1681 patients underwent OLT in 19 centers and were enrolled in this prospective cohort study. Results According to RIFLE criteria, AKI occurred in 367 patients, 21.8% (R: 5.8%, I: 6.4%, F: 4.8%, L: 4.8%). Based on multivariate analysis, intraoperative risk factors for AKI were: administration of 5-10 RBCs (OR 1.8, 95%CI 1.3-2.7), dopamine use (OR 1.6, 95%CI 1.2-2.3), post-reperfusion syndrome (OR 1.5, 95%CI 1.0-2.3), surgical complications (OR 2.0, 95% CI 1.3-3.0), and cardiological complications (OR 2.2, 95%CI 1.2-4.0). Postoperative risk factors were: norepinephrine (OR 1.4, 95%CI 1.0-2.0), furosemide (OR 4.2, 95% CI 3.0-5.9), more than 10 RBCs transfusion, (OR 3.7, 95%CI 1.4-10.5), platelets administration (OR 1.6, 95% CI 1.1-2.4), fibrinogen administration (OR 3.0, 95%CI, 1.5-6.2), hepatic complications (OR 4.6, 95%CI 2.9-7.5), neurological complications (OR 2.4, 95%CI 1.5-3.7), and infectious complications (OR 2.7, 95%CI 1.8-4.3). NO-AKI patients' 5 years survival rate was higher than AKI patients (68.06, 95% CI 62.7-72.7 and 81.2, 95% CI 78.9-83.3, p Conclusions AKI still remains an important risk factor for morbidity and mortality after OLT. Further researches to develop new strategies aimed at preventing or minimizing post-OLT AKI are needed.

Background The well-documented benefits of physical activity (PA) are still poorly characterized in long-term kidney transplant outcome. This study analyzed the impact over a 10-year follow-up of PA on graft function in Italian kidney transplant recipients (KTRs). Methods Since 2002, the Italian Transplant-Information-System collected donor and recipient baseline and transplant-related parameters in KTRs. In 2015, ‘penchant for PA’ (PA ≥ 30-min, 5 times/week) was added. Stable patients aged ≥18 years at the time of first-transplantation were eligible. KTRs with at least 10-year follow-up were also analyzed. Mixed-effect regression models were used to compare eGFR changes over time in active versus non-active patients. Results PA information was available for 6,055 KTRs (active 51.6%, non-active 48.4%). Lower penchant for PA was found in overweight and obese patients (OR = 0.84; OR = 0.48, respectively), in those with longer dialysis vintage (OR = 0.98 every year of dialysis), and older age at transplant. Male subjects showed greater penchant for PA (OR = 1.25). A slower decline of eGFR over time was observed in active KTRs compared to non-active, and this finding was confirmed in the subgroup with at least 10-year follow-up (n = 2,060). After applying the propensity score matching to reduce confounding factors, mixed-effect regression models corroborated such better long-term trend of graft function preservation in active KTRs. Conclusions Penchant for PA is more frequent among male and younger KTRs. Moreover, in our group of Italian KTRs, active patients revealed higher eGFR values and preserved kidney function over time, up to 10-years of follow-up.

The 759 cases of brain death declaration (BDD [Italian law, 6 hours of observation time]) that occurred in 190 Italian intensive care units (ICUs) between May and September 2012 were studied to quantify carbapenem-resistant gram-negative bacteria (CR-GN) isolated in organ donors, to evaluate adherence to national screening guidelines, and to identify risk factors for CR-GN isolation. Mandatory blood, bronchoalveolar lavage, and urine cultures were performed on the BDD day in 99% of used donors. Because results were rarely made available before transplant, >20% of transplants were performed before obtaining any microbiological information, and organs from 15 of 22 CR-GN cases were used. Two (lung-liver) of the 37 recipients died, likely because of donor-derived early CR-GN sepsis. ICU stay >3 days (odds ratio [OR] = 7.49, P = .004), fever (OR = 3.11, P = .04), age

Background The national protocol for the handling of high-urgency (HU) liver organ procurement for transplant is administered by the Italian National Transplant Center. In recent years, we have witnessed a change in requests to access the program. We have therefore evaluated their temporal trend, the need to change the access criteria, the percentage of transplants performed, the time of request satisfaction, and the follow-up. Methods We analyzed all the liver requests for the HU program received during the 4-year period of 2014 to 2017 for adult recipients (≥18 years of age): all the variables linked to the recipient or to the donor and the organ transplants are registered in the Informative Transplant System as established by the law 91/99. In addition, intention to treat (ITT) survival rates were compared among 4 different groups: (1) patients on standard waiting lists vs (2) patients on urgency waiting lists, and (3) patients with a history of transplant in urgency vs (4) patients with a history of transplant not in urgency. Results Out of the 370 requests included in the study, 291 (78.7%) were satisfied with liver transplantation. Seventy-nine requests (21.3%) have not been processed, but if we consider only the real failures, this percentage falls to 13.1% and the percentage of satisfied requests rises to 86.9%. The average waiting period for liver transplantation (LT) is 1.7 days and most requests (74%) are met in less than 24 hours, if we consider the hours between the registration of the request and the donor reporting . The percentage of late retransplantations is 2.1%. The clinical indication for HU-LT that appears to improve over time is hepatic artery thrombosis (82.5%). The overall 1-year patient survival is 68.3%. The overall 1-year graft survival, performed on all the patients, is 89% and all the indications for HU-LT appear to go well over time with an average survival rate greater than 85%. Conclusions The indications for HU-LT are changing according to the changes in the hepatologic field in recent years. The centralized management of requests has proven to be successful in optimizing responses. Urgent LT is confirmed to be lifesaving in its timeliness.

In order to bridge the gap between available organs and patients needing transplants, donor selection criteria for donors are increasingly being extended; the possibility of using organs from nonstandard risk donors has been introduced in many countries. This clearly poses considerable ethical issues that should be analyzed and taken into consideration by the competent bodies and institutions. In this article, we illustrate the Italian situation regarding the possibility of using organs from anti-hepatitis C virus (HCV) and HCV RNA-positive donors (anti-HCV+ve) in negative recipients (healthy subjects who have never come into contact with the hepatitis C virus) in light of the availability of new direct-acting antiviral drugs (DAAs) for hepatitis C treatment. We discuss the motivations behind the both favorable opinions of the Ethics Committee of the Italian National Institute of Health (Istituto Superiore di Sanita) and the Italian National Bioethics Committee (Comitato Nazionale per la Bioetica) discussing the main implications from an ethical point of view.

Objectives A prospective cohort study was conducted in Italy in order to describe the microbiologic aspects of colonization/infection by carbapenemase-producing Enterobacteriaceae (CPE) in donors and recipients of lung and liver transplants and the possible CPE transmission from donors to recipients. Methods Between 15 January 2014 and 14 January 2015, all recipients of solid organ transplants (SOT) at ten lung and eight liver transplantation centres and the corresponding donors were enrolled. Screening cultures to detect CPE were performed in donors, and screening and clinical cultures in recipients with a 28-day microbiologic follow-up after receipt of SOT. Detection of carbapenemase genes by PCR, genotyping by multilocus sequence typing, and pulsed-field gel electrophoresis and whole-genome sequencing were performed. Results Of 588 screened donors, 3.4% were colonized with CPE. Of the liver first transplant recipients (n = 521), 2.5% were colonized before receipt of SOT and 5% acquired CPE during follow-up. CPE colonization was higher in lung first transplant recipients (n = 111, 2.7% before SOT and 14.4% after SOT). CPE infections occurred in 1.9% and 5.3% of liver or lung recipients, respectively. CPE isolates were mostly Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae belonging to CG258. Three events of donor–recipient CPE transmission, confirmed by whole-genome sequencing and/or pulsed-field gel electrophoresis, occurred in lung recipients: two involving K. pneumoniae sequence type 512 and one Verona integron-encoded metallo-β-lactamase (VIM)-producing Enterobacter aerogenes. Conclusions This study showed a low risk of donor–recipient CPE transmission, indicating that donor CPE colonization does not necessarily represent a contraindication for donation unless colonization regards the organ to be transplanted. Donor and recipient screening remains essential to prevent CPE transmission and cross-infection in transplantation centres.

Introduction Antivirals direct acting (DAA) for hepatitis C virus (HCV) have brought a revolution in the field of transplantation. It is likely to think that in the future patients on the waiting list for liver transplantation (LT) will no longer be registered for HCV-related cirrhosis but for liver disease from other causes. On the eve of this change, we show a snapshot of the Italian waiting list for LT. Methods From October 1, 2012 to September 30, 2013, we estimated the total number of patients on the liver waiting list as intention to treat (ITT), the number of incident cases, and the delistings, particularly in the HCV positive (HCV+) population. Gender, median age, etiology and prognosis of liver disease, presence of hepatocellular carcinoma (HCC), reason for delisting, mean waiting time for LT, and rate of death on waiting list were evaluated. Results In the time period, there were 517 new patients who were HCV+ (median age, 53 years): 255 (49.3%) mono-infected with HCV, 236 (45.7%) co-infected with HCV and hepatitis B virus (HBV), 11 (2.1%) co-infected with HCV and human immunodeficiency virus (HIV), and 15 (2.9%) co-infected with HCV, HBV, and HIV. The median model for end-stage liver disease (MELD) score at listing was 17 and HCC was present in 206 (39.8%) cases. HCV+ patients delisted were 442 (61.9%), 355 (80.3%) for LT. The mean waiting time to transplantation was 1.9 months; the percentage of death was 7.6%. Conclusions This snapshot of the waiting list for LT in the year before the advent of DAA drugs will allow us to assess whether and how they will change the waiting list for LT when we start to look at the impact of new therapies on the waiting list.

Background In 2005 the Italian Medicines Agency (AIFA) started a program on independent research on drugs, with the aim to promote clinical research in areas of limited commercial interest. For 3 years (2005–2007) an area of the program was reserved to studies in the field of rare diseases. There is a concern that public funding of research may be wasted. We investigated the outcome of the program. Methods We conducted a cohort study on the projects that were funded by the AIFA in the area of rare diseases. The outcomes were the proportion of published studies, time to publication, impact factor of the publishing journals and relevance for clinical practice. We retrieved published articles through a literature search in peer reviewed biomedical journals indexed by Pubmed. We used the Kaplan–Meier method to estimate the cumulative probability of publication by time from project starting to publication. Results During the period 2005–2007, 62 projects were funded in the area of rare diseases. Most of the studies (n 39; 63 %) had a randomized design and in 22 (35 %) the control group received an active treatment. For 39 studies (63 %) we retrieved a publication in a peer reviewed journal. The median time to publication was 74 months and, at the maximum period of follow up (109 months), the cumulative probability of publication reached 77 %. The median impact factor was 5.4 (range 1.4–52.4). Considering the clinical relevance, more than 30 % of the published articles presented conclusive findings; an additional 10 % of the studies reached potential breakthrough findings. Conclusions Even though it takes time to set up and conduct a funding program for independent research on drugs, the results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0420-4) contains supplementary material, which is available to authorized users.

Introduction Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. Methods To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) ± other drugs ± radiotherapy according to surgical stage and histology. Results Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during pre-operative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6–180 days using supportive therapy only. Conclusions (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patients. Med. Pediatr. Oncol. 29:245–251, 1997. © 1997 Wiley-Liss, Inc.

Background and aims: Vitamin D deficiency is a well-known risk for hip fracture, and vitamin D insufficiency is so frequent in the elderly that population-wide preventive intervention would be useful. The objective of the study was to evaluate the efficacy of vitamin D bolus on hip fracture incidence in elderly women. Methods: All women aged >65 years registered at Health District 20 of the Regione Veneto, Italy, were eligible for this quasi-experimental, prospective community intervention study. A vial containing 400,000 IU vitamin D{in2} (Ostelin 800, Teofarma, Italy) was offered for oral administration to all women in the winters of 2000–2001 and 2001–2002. The only exclusion criteria for treatment were age and gender, and the control group included women who did not participate in the Health District initiative. Analysis of hip fracture incidence was carried out for 4 years, from 1999 to 2002. Patients with incident hip fracture were identified as soon as they were admitted to one of the 3 hospitals of the health district and interviewed regarding their participation in the vitamin D preventive intervention program. In 120 of the women (age range 68–90 years), serum concentrations of 25-OH vitamin D were measured from October to June, both before and 1 and 4 months after vitamin D administration. Results: 23,325 and 24,747 women received the vitamin D bolus during winters 2000–2001 and 2001–2002 respectively, i.e. 45–47% of eligible women. The proportion of women who accepted the bolus declined with advancing age, from 50–55% in women aged 60–70 years to 22–26% in those aged >90 years. The two-year intervention on the community decreased the incidence of fracture by 10% (p=0.050) in comparison with the previous two years. The age-adjusted risk reduction (RR) of hip fracture during 2001 and 2002 in women who had received vitamin D, with respect to women who had not, decreased by 17% (p=0.056) and 25% (p=0.005) respectively. The RR was considerably greater and statistically significant over both 2001 and 2002 in the cohort aged >75 years. 25-OH vitamin D concentrations, in the subset of women in whom it was measured, rose significantly (p