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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.

The worldwide pandemic outbreak due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has created unprecedented challenges for public health services. Lombardy, region of the Northern Italy, has been the first area in the Western world whose organs and tissues procurement programs have had to face the virus pandemic emergency. We retrospectively collected and analyzed data about cardiovascular tissues (CT) in 2019 and in 2020. We aimed to describe the rapid evolution of SARS-CoV-2 regulation laws for tissue donor’s selection and harvesting from February 2020 until January 2021. As expected the number of CT donors in 2020 was significantly lower than those of 2019 (66 vs. 99, p value 0.02). The total number of CT collected from donors have been 254 in 2019 and 206 in 2020 (p 0.28). Femoral arteries were the most required vascular tissues (55.5% in 2019 and 40% in 2020). Fifty-five and forty-eight pulmonary valves were implanted in 2019 and 2020, respectively. No differences were found for the types of CT requests between the 2 years. The median age of receivers of vascular tissues was 69.6 ± 14.6 years in the 2019 and 63.3 ± 14.9 years in 2020 (p

Donations after circulatory death (DCD) are still challenging in Italy because of prolonged ischemia time (tWIT) due to the law and logistical issues. This cohort study was primarily aimed at assessing the association between successful transplantation and DCD types in the North Italy Transplant program. Adjusted risk ratios (RR) and 95% confidence intervals (CIs) for type III versus type II DCD were estimated using a Poisson regression model with a robust error variance. All consecutive DCD between 2008 and 2020 were included. Among 142 DCD, 102 were eligible for liver donation, and 96 were proposed: 68/69 (99%) and 28/33 (85%) type III and II DCD, respectively. Sixty-nine livers were recovered, 51/68 (75%) from type III and 18/28 (64%) from type II DCD, respectively (RR: 1.18; 95% CI: 0.87-1.60). After ex-vivo perfusion, 50/68 (74%) and 14/28 (50%) livers from type III and type II DCD were transplanted (RR: 1.49; 95% CI: 1.01-2.19). The estimate decreased after further controlling for tWIT (RR: 1.11; 95% CI: 0.55-2.24). Five patients (7.8%) experienced a PNF, 3/50 and 2/14 from type III and type II DCD, respectively. Type III DCD livers were more likely to be transplanted than type II. Warm ischemia time might explain this difference.

Donation after circulatory death (DCD) allows expansion of the donor pool. We report on 11 years of Italian experience by comparing the outcome of grafts from DCD and extracorporeal membrane oxygenation (ECMO) prior to death donation (EPD), a new donor category. We studied 58 kidney recipients from DCD or EPD and collected donor/recipient clinical characteristics. Primary non function (PNF) and delayed graft function (DGF) rates, dialysis need, hospitalization duration, and patient and graft survival rates were compared. The estimated glomerular filtration rate (eGFR) was measured throughout the follow-up. Better clinical outcomes were achieved with EPD than with DCD despite similar graft and patient survival rates The total warm ischemia time (WIT) was longer in the DCD group than in the EPD group. Pure WIT was the highest in the class II group. The DGF rate was higher in the DCD group than in the EPD group. PNF rate was similar in the groups. Dialysis need was the greatest and hospitalization the longest in the class II DCD group. eGFR was lower in the class II DCD group than in the EPD group. Our results indicate good clinical outcomes of kidney transplants from DCD despite the long “no-touch period” and show that ECMO in the procurement phase improves graft outcome, suggesting EPD as a source for pool expansion.

Background The risk of disease transmission from nonstandard risk donors (NSRDs) is low, and outcomes are similar or better relative to transplants performed with standard criteria donors. However, NSRDs have posed new ethical challenges to the informed consent (IC) process. Based on the shared decision-making model, coinciding with the 3 main timings of the IC process ([1] pretransplant assessments and waiting list registration, [2] time on the waiting list, and [3] time of the organ offer), we put forward a model (3-T Model) to summarize the knowledge on IC for NSRDs and to deliver conceptual and practical support to transplant providers on this emergent issue. Methods We searched PubMed and analyzed data from our area to provide evidence and ethical arguments to promote standardization of the timing of patient information, degree of patient participation, and disclosure of donor risk factors throughout the 3 stages of the time continuum leading to the potential acceptance of NSRDs. Results Each of the 3 timings carries special ethical significance and entails well-defined duties for transplant providers relative to patient involvement and information of the benefits and risks associated with NSRDs. Based on our framework, experience, and interpretation of the literature, we put forward a list of recommendations to combine standardization (ie, timing, content, and degree of patient participation) and individualization of IC. Conclusions The 3-T Model may enable the prevention of physicians' arbitrariness and the promotion of patient-centered care. Future studies will assess the effectiveness of the 3-T Model in transplant clinical practice.

The transformation of the walls in the city of Nola between the fifteenth and sixteenth centuriesThe study relating to the town walls of Nola (a city near Naples) is one of the most interesting among those about the Neapolitan military architecture between the fifteenth and sixteenth centuries. The building phases of the defensive walls allow us to retrace two main moments of the Renaissance military architecture. It is to say, from the original and most ancient example of a puntoni struts fortifications, about which we can relate thanks to the precious and detailed Ambrogio Leone de Nola’s description made at the beginning of 1500, to the renewed defensive rampart body designed by el comendador Luis Escrivà during the Toledian period. A thorough recon of the iconographic sources, the regarding of the specialistic historiography, the contemporary theoretical assumptions and, most of all, a thorough recon of the still visible traces in the urban fabric and those emerged during the recent archeological investigations enable us to propose a structured theory about the building of the walls of Nola.

Introduction The interest in health-related quality of life (HR-QoL) has increased in the past few years. Aim The aim of this study was to evaluate the HR-QoL before and after transplantation in solid organ recipients referred to the North Italy Transplant program. Material and Methods This cross-sectional study was performed between 2010 and 2011. All consecutive recipients on the waiting list for liver, heart, or kidney transplantation were included and compared to all consecutive transplanted patients at 6 and 24 months of follow-up after transplantation. The HR-QoL was evaluated with the 36-item Short Form Health Survey (SF–36) and the Profile of Mood States (POMS). Questionnaires were self-reported anonymously. Descriptive statistical analyses were performed. Results Four hundred eleven patients were interviewed: 146 patients (35.5%) were on the waiting list, 137 (33.3%) were transplanted 6 months before the interview, and 128 (31.1%) were transplanted 24 months before the interview. Patients on the waiting list had a lower SF–36 score for all items than did transplanted patients after both 6 and 24 months. According to POMS results, patients on the waiting list had a higher prevalence of depression, tension, anger, fatigue, and confusion than did transplanted patients. Conclusions Patients on the waiting list showed a worse quality of life compared to patients after transplantation as demonstrated by SF–36 and POMS results. These findings should be confirmed in a cohort study.

The purpose of this study was to assess the safety and the clinical outcome associated with organ transplantation from increased infectious risk donors (IRD). We retrospectively identified all adult deceased IRD referred to the Nord Italia Transplant program coordinating center from November 2006 to November 2011. All potential donors were screened for social risk factors that may increase the risk of donor-derived infection with human immunodeficiency (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). All recipients were followed monthly for the first 6 months post-transplant. A total of 86 potential IRD were identified during the study period. Three hundred and seventy-nine organs from IRD were offered to the transplant centers, but only 185 (48.8%) were used for transplantation. Organs from IRD were transplanted into 174 recipients. The complete follow-up data were available for 152 of 174 (87.3%) recipients. During a mean follow-up of 11.7 months (median 12; range 2.4-12), no transmission of HIV, HBV, or syphilis was documented by serology and nucleic acid testing (NAT) testing. Two patients transplanted with organs from HCV-RNA-positive donors, as expected, developed post-transplant HCV infection. In conclusion, the use of organs from IRD was associated with a safe increase in the transplant procedures in our country.

Nella medicina dei trapianti l’etica del rapporto medico-paziente si estende in modo peculiare a più soggetti “deboli”: i soggetti in lista d’attesa, i familiari dei donatori deceduti, i donatori viventi. L’applicazione coerente e sistematica dei principi etici dei trapianti rappresenta forse l’elemento più critico di tutto il sistema donazione-trapianto. In Italia, il processo donazione-trapianto, sia da donatore cadavere, sia da donatore vivente, sta vivendo un’evoluzione, regionale e nazionale, che tocca le modalità di applicazione di principi fondanti quali l’equità di accesso alle cure ed il rispetto dell’autodeterminazione dei soggetti coinvolti nella donazione e nel trapianto. Nell’esperienza della Comunità dei Trapianti del NITp (Nord Italia Transplant), il coinvolgimento degli esperti di etica ha portato alla “Carta dei Principi”, modello positivo di connubio tra etica e trapianti. Il ricorso alla consulenza etica viene oggi visto, in prospettiva, come un valore aggiunto che assicura l’indipendenza di valutazione di un parte terza rispetto ad alcune scelte critiche della rete regionale e nazionale trapianti nei confronti dei “pazienti” e dei loro familiari. ---------- In transplant medicine, ethics of doctor-patient relationship extends particularly to more “weak” subjects: subjects on the waiting list, the families of deceased donors, living donors. The consistent and systematic application of the ethical principles of transplantation is perhaps the most critical element of the whole system donation-transplantation. In Italy, the cadaveric donation- transplantation process, both from cadaveric and living donor, is undergoing an evolution, at regional and national levels, touching on detailed rules for the application of principles such as equality of access to care and respect for the self-determination of stakeholders. In the experience of the NITp’s transplant community, the involvement of Ethics experts led to the “Chart of principles”, a good match between ethics and clinical transplants. Ethics consultation is seen, ultimately, as an added value that ensures the independence of evaluation by a third party in the light of some critical choices of regional and national transplant network towards the “patients” and their family members.

The imbalance between patients on waiting list and organ availability is the core problem for the transplantation community and search for strategies to increase the number of donors is still the priority of all transplant organizations. North Italy Transplant program (NITp), the first italian transplant organization, was founded in 1972 and during 40-year activity 10229 donors have been used and 30573 organ transplants have been performed. In NITp, the identification of key steps to expand the donor pool and continous education programs, not only on the procurement side but also dedicated to all professionals involved in the donation-transplantation process, have allowed to reach these results.

Metformin is a drug increasingly used in the treatment of diabetic patients. In addition to its hypoglycemic effect, it reduces vascular risk and does not determine an increase in body weight. Compared to the older molecule, phenformin, metformin possesses a lower risk of induction of severe lactic acidosis in the general diabetic population. On the other hand, metformin must be used with caution in patients with kidney damage. In patients with a glomerular filtration rate (GFR) below 30 ml/min, the use of metformin is also associated with a high risk of lactic acidosis. The assessment of glomerular filtration rate using MDRD or CKD-EPI formulas allows the clinician to identify patients potentially at risk. All subjects with normal renal function treated with metformin for years are at risk of suddenly developing lactic acidosis during episodes of acute worsening renal function. We report a case of lactic acidosis in association with acute kidney injury (AKI).

Background: The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response. Methods: Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients. Results: Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤1 T allele (56.1%) to tacrolimus-treated patients carrying ≤1 T allele (44.7%) to patients carrying ≥2 T alleles (25.0%, p=0.0009). Conclusions: Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying

Two novel human leucocyte antigen (HLA) class I alleles have been identified in two Italian individuals. HLA-B*27:07:02 is identical to HLA-B*27:07:01 except for a nucleotide substitution at position 846 (A->G) resulting in a silent mutation. HLA-B*35:206 differs from the most similar allele, HLA-B*35:08:01, because of a single base mutation at position 149 (G->C) causing an aminoacidic change at codon 26 from Gly to Ala.

Summary Here we describe the molecular modelling of the new variant HLA-B*35:132. This allele shows one mismatch with B*35:01:01:01 in exon 3 at position 575 where a T is substituted by a C, which implies an amino acidic change from Leucine to Proline. This seems not to alter the molecular structure and not to compromise the HLA complex and T-cell receptor interaction.

Background The immune rejection has been anticipated as one of the major causes of allograft aortic valve (AAV) degeneration. The purpose of this study was to prospectively serially measure the magnitude and evolution of the recipient anti-HLA class I antibody response up to 6 years from AAV implant and to correlate serologic data with valve performance by means of a concurrent echocardiographic survey. Methods Cryopreserved AAVs were obtained from multiorgan HLA-typed donors. Nineteen patients younger than 50 years (mean age, 43.3 ± 8 years) were prospectively studied. After successful surgery, all AAV recipient underwent at 3 and 6 months and each year postoperatively (mean follow-up, 71.9 months) concomitant serum sample collection and two-dimensional transthoracic echocardiography. The presence of anti-HLA antibodies was tested against a panel of lymphocytes obtained from 30 blood donors. Results Progressive structural valve deterioration was seen in 6 patients (31.5%) of whom 4 (21%) were reoperated. All pretransplant recipients sera were panel-reactive antibody negative. Seventeen patients (89.4%) demonstrated significant panel-reactive antibody levels, which peaked at 6 months postoperatively, declined from 6 to 24 months, and slowly decreased afterward. In 14 of 19 cases (73.6%) donor-specific HLA antibodies were identified. A strong immunization (6-year persistence of panel-reactive antibody > 70% and peak panel-reactive antibody > 80%) was detected in 31.5% and 36.8% of recipients, respectively. Strong immunization was found to be significantly associated with progressive structural deterioration. Conclusions The immune reaction after cryopreserved AAV implantation is a peculiar long-lasting response occurring in the majority of recipients younger than 50 years of age. An association between a sustained and pronounced immunization and an aggressive AAV degeneration was observed.

The offer of liver transplantation to many patients affected by liver failure is limited by organ shortage. Clinical application of human-based liver cell therapies, such as bioartificial liver and hepatocyte transplantation, might support liver transplantation, allowing more patients to be treated and decreasing mortality in the waiting list. The development of a standardized method of hepatocyte isolation is a mainstay for large-scale application of liver cell therapy. The aim of this study is to analyze retrospectively a 2-year experience of human hepatocyte isolation from livers rejected from transplantation at organ harvesting, performed on a national basis in Italy. All the livers judged unsuitable for transplantation were considered for hepatocyte isolation. Macrosteatosis greater than 60% was the most common reason of refusal, followed by nonviral cirrhosis. Fifty-four organs were used. Human hepatocyte isolation resulted in more that 7 million liver cells/g of tissue digested with 73% 14% viability. Steatotic organs gave better results in terms of cell yield than cirrhotic livers. Isolated hepatocytes were able to perform specific liver functions, and evidence of factor IX and albumin messenger RNA (mRNA) production was reported when cells were plated in culture. Modifications of the traditional method of hepatocyte isolation, aimed at reducing ischemia-reperfusion damage and improving post-isolation cell conditions, showed improvements in post-isolation viability. In conclusion, we show that it is possible to use the vast majority of livers not suitable for transplantation on a national basis for human hepatocyte isolation, obtaining a large amount of viable functioning human hepatocytes that might be used for cell transplantation and therapy. (Liver Transpl 2003;9:506-512.) B

Solid organ transplantation during the past 30 years has developed from an experimental procedure into routine clinical practice. The current repertoire of immunosuppressive agents has made a major contribution to transplant survival; however, problems in different areas still need to be overcome. Several gene polymorphisms are supposed to influence immunosuppressive therapy and susceptibility to rejection. Therefore, a priority of transplant biologists is to estimate individual patient risk and to characterise the genetic profile of patients in need of a transplant in order to optimise the use of a scarce resource such as organs from cadaver donors, and to avoid serious drug-induced adverse effects. Polymorphisms in genes encoding tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-6, IL-10, interferon-gamma (IFNgamma), transforming growth factor-beta (TGFbeta) and thiopurine S-methyltransferase (TPMT) can have significant effects on an individual's risk of rejection, as well as their ability to tolerate immunosuppressive therapy. Genotyping of known polymorphisms in these genes may in the future contribute to our ability to individualise immunosuppressive therapy in organ transplant recipients.

Donor organ procurement is a world-wide problem. In Italy it is particularly so and the reasons for this are investigated. An overall increase in the number of donors has been noted in 1994 and the first 8 months of 1995, and ways of continuing this encouraging trend should be pursued by improvements in education, legislation, and hospital organization.