Nephrological Complications in Hemoglobinopathies: SITE Good Practice.

BACKGROUND: Hemoglobinopathies, among which thalassemic syndromes (transfusion-dependent and non-transfusion dependent thalassemias) and sickle cell disease (SCD), are the most widespread monogenic diseases worldwide. Hemoglobinopathies are endemic and spread-out all-over Italy, as result of internal and external migration flows. Nowadays, the increase therapeutic options associated to the general aging of patients with hemoglobinopathies related to the improvement in clinical management, contribute to the abnormalities in kidney function going from blood and urine test alterations to chronic kidney disease and end stage renal disease. METHODS: Here, we carried out a revision of the literature as panel of recognized experts in hemoglobinopathies with the consultancy and the revision of two nephrologists on kidney alteration and kidney disease in patients with TDT, NTDT and SCD. This is part of the action of the Italian society for the study of thalassemia and hemoglobinopties (SITE). The purpose of this "good practice (GP)" is to provide recommendations for follow-up and therapy for the management of kidney alterations in patients with TDT, NTDT and SCD. The literature review covers the period 1.1.2016 to 31.12.2022. In consideration of the rarity of these diseases, the analysis was extended from 5 to 7 years. Moreover, in the absence of relevant scientific papers in the identified time frame, we referred to pivotal or population studies, when available. Finally, in the absence of evidence-based data from prospective and randomized trials, the authors had to refer to expert opinion (expert consensus) for many topics. RESULTS: We generated question and answer boxes to offer a friendly consultation, using color code strategy and focused answers. CONCLUSIONS: The present GP will help in improving the clinical management, and the quality of care of patients with hemoglobinopathies.

Histocompatibility assessment in hematopoietic stem cell transplantation: recommendations from the Italian Association of Immunogenetics and Biology of Transplantation (Associazione Italiana di Immunogenetica e Biologia dei Trapianti - AIBT).

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is significantly influenced by the degree of HLA histocompatibility between donor and recipient. To provide shared indications for required histocompatibility testing and interpretation before HSCT, the Italian Society for Immunogenetics and Transplantation Biology (Associazione Italiana di Immunogenetica e Biologia dei Trapianti [AIBT]) gathered members and created a working group to discuss and develop recommendations for histocompatibility assessment in HSCT.After a review of the literature and multiple panel discussions, AIBT developed up-to-date recommendations for the resolution levels of HLA typing, histocompatibility definitions of patients and donors, importance of anti-HLA antibodies, and significance of NK alloreactivity, which are reported in this document. These recommendations have been shared with the Italian Group for Bone Marrow Transplantation (Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali emopoietiche e terapia cellulare [GITMO]) and the Italian National Center for Transplantation (Centro Nazionale Trapianti [CNT]). Notably, the increased use of HLA-mismatched transplantation (i.e., mismatched unrelated, haploidentical) in recent years has made these indications even more relevant for the standardization and improvement of quality of care.This document represents a useful instrument for health care workers involved in the field of HSCT, enhancing synergy with transplant physicians and enabling greater optimization of the available resources.

Management of the Sickle Cell Trait: An Opinion by Expert Panel Members.

The number of individuals with the sickle cell trait exceeds 300 million worldwide, making sickle cell disease one of the most common monogenetic diseases globally. Because of the high frequency of sickle cell disease, reproductive counseling is of crucial importance. In addition, unlike other carrier states, Sickle Cell Trait (SCT) seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and complications during pregnancy and surgery. This expert panel believes that increasing knowledge about these clinical manifestations and their prevention and management can be a useful tool for all healthcare providers involved in this issue.

A survey on preoperative autologous blood donation policy in bone marrow stem cell donors in Italy.

BACKGROUND: The high safety of homologous blood components, together with the introduction of the Patient Blood Management strategy, has led to the progressive abandonment of preoperative autologous blood donation (PAD) in surgery. Furthermore, recent scientific publications provide evidence about the non-usefulness of PAD in the collection of hematopoietic stem cells (HSC) from bone marrow (BM), also in consideration of harvest procedure safety. Nevertheless, no conclusive studies have been published yet. MATERIALS AND METHODS: Blood Establishments (BE) and Bone Marrow Collection Centers (BMCC) participated in a specific qualitative survey proposed by Italian National Blood and Transplant centers with the support of the relevant Italian Scientific Societies. The survey aimed at evaluating the policy adopted for PAD in related and unrelated adult HSC donors in Italy during the period 2018-2020. RESULTS: Forty-one BE corresponding to 37 BMCC filled in the questionnaire. Of 830 BM donors, 661 (80%) underwent 1063 PAD (mean 1.6 PAD/donor). The remaining 169 donors (20%) underwent BM harvest without PAD. No serious adverse events were reported for either donor group. In the case of ineligibility of donors for the PAD program, due to low hemoglobin values, 7/10 centers shifted donors to peripheral blood stem cell collection and three centers chose a different donor. Remarkably, only 51% of the PAD units requested were eventually transfused during the BM harvest process. Finally, the iron support policy among centers was heterogeneous. DISCUSSION: The results of this survey show that PAD is heterogeneously applied in Italian BMCC, as in other countries. However, all BMCC except two are willing to adopt a Patient Blood Management strategy as an alternative approach to adult related and unrelated BM donor harvests.

Rapid increase in neuroinvasive West Nile virus infections in humans, Italy, July 2022.

As in 2018, when a large West Nile virus (WNV) epidemic occurred, the 2022 vector season in Italy was marked by an early onset of WNV circulation in mosquitoes and birds. Human infections were limited until early July, when we observed a rapid increase in the number of cases. We describe the epidemiology of human infections and animal and vector surveillance for WNV and compare the more consolidated data of June and July 2022 with the same period in 2018.

Risk factors of extraneural spreading in astrocytomas and oligodendrogliomas in donors with gliomas: A systematic review.

BACKGROUND: Patients with a history of primary brain tumors can be eligible for organ donation under extended criteria. The risk assessment of tumor transmission via organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade. Previous surgeries, chemo-/radiotherapy, and ventriculo-peritoneal shunt placement can lead to a disruption of the blood-brain barrier, concurring to an increase in the transmission risk. AIM: To investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas. METHODS: We searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligodendrogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade, the elapsed time from the diagnosis to the onset of metastases, sites and number of metastases, prior surgeries, prior radiotherapy and/or chemotherapy, ventriculo-atrial or ventriculo-peritoneal shunt placement, and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion. Statistical analysis was performed using R software. Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed using χ 2 and Fischer exact test. The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and: (1) Localization of metastases; (2) The occurrence of intracranial recurrences; and (3) The occurrence of multiple metastases. RESULTS: Data on a total of 157 patients were retrieved. The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas. Respectively, 19% and 39% of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy. The most frequent metastatic sites were bone, bone marrow, and lymph nodes. The lungs and the liver were the most commonly involved visceral sites. There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy. Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra- central nervous system spread. CONCLUSION: A long follow-up time does not exclude the presence of extraneural metastases. Therefore, targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.

Organ donation from patients with a rare disease is often safe: the italian guidelines.

Although a disease is defined as rare when it has a prevalence of less than 1:2000, the overall prevalence of rare diseases in the population is greater than 1%. Among potential organ donors, a similar frequency is observed. To date, guidelines have not been established, and operational decisions have been made empirically, case- by-case, based on the experience and expertise of clinicians. For this reason, the Italian Superior Health Council (CSS) has appointed a working Group to address "patients with a rare disease as potential organ donors," with the aim of devising recommendations for the management of transplant cases in which the donors have a rare disease. This group evaluated 493 diseases (10% of all rare diseases, including over 95% of patients with a rare disease) to deliver a technical report dealing with the suitability of organ donation and transplantation, with a focus on the organs most frequently used, including kidney, liver, heart, lung, and pancreas. This work has made it clear that a rare disease "per se" does not contraindicate organ donation at all. Indeed, in donors affected by a rare disease, almost 80% of the organs are suitable for transplantation, approximately 7% are unsuitable, and approximately 14% are suitable as non-standard with an acceptable risk.

The Regulatory Approach for Faecal Microbiota Transplantation as Treatment for Clostridioides difficile Infection in Italy.

Faecal microbiota transplantation (FMT) is regarded as an efficacious treatment for recurrent C. difficile infection. Unfortunately, widespread patient access is hindered by regulatory hurdles, which are the primary barriers to incorporating FMT into clinical practice. At the European and International level, there is no uniform perspective on FMT classification, and a coordinated effort is desirable to solve this regulatory puzzle. In this communication, we report the regulatory principles and the implementation approach for FMT application in Italy. Our experience suggests that the EU Tissue and Cell Directives are suited to ensure safe and efficient FMT for C. difficile management, especially through extensive high-quality donor selection and full traceability maintenance.

The Italian National Faecal Microbiota Transplantation Program: a coordinated effort against Clostridioides difficile infection.

Clostridioides (previously Clostridium) difficile infection (CDI) is a common cause of antibiotic-associated diarrhea, whose symptoms range from mild diarrhea to life-threatening pseudomembranous colitis. CDI is characterized by significant recurrence rate following initial resolution and recurrent C. difficile infection (rCDI) represents an onerous burden for the healthcare systems. Conventional antibiotic-based approaches are generally used for the treatment of rCDI but the effective therapy remains elusive. Recently, the faecal microbiota transplantation (FMT) has emerged as an alternative therapeutic strategy against rCDI, with high treatment success rate. In 2018, the Italian National FMT Program was launched, with the aim to provide high quality standards in FMT application to adults with rCDI not responding to antibiotic therapy. Here, we sketch out the key characteristics and the progress of the Italian National FMT Program during the COVID-19 pandemic.

The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy.

BACKGROUND: Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients' quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort. RESULTS: To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002-2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. CONCLUSIONS: This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.

Discovered cancers at postmortem donor examination: A starting point for quality improvement of donor assessment.

BACKGROUND: clinical and imaging investigations allow a detailed assessment of an organ donor, but a quota of cancer still elude detection. Complete autopsy of donors is even less frequently performed, due to economic issues and increasing availability of high-quality imaging. The aim of this study is to gather evidence from the literature on donor malignancy discovered at autopsy following organ donation and to discuss the utility and limitations of autopsy practice in the field of transplantation. METHODS: A systematic search according to PRISMA guidelines was carried out in Pubmed and Embase databases until September 2020 to select articles with reporting of cancer discovered in a donor at postmortem examination. Cancer discover in not-transplant setting were excluded. A descriptive synthesis was provided. RESULTS: Of 7388 articles after duplicates removal, 56 were included. Fifty-one studies reported on complete autopsy, while 5 dealt only with limited autopsy (prostate and central nervous system). The number of autopsies ranged between 1 and 246 with a total of 823 autopsies performed. The most frequent cancer discovered at autopsy was lymphoma (n = 13, 15%), followed by renal cell carcinoma (RCC) (n = 11, 13%), non-small cell lung cancer (NSCLC) (n = 10, 11%), melanoma (n = 10, 11%), choriocarcinoma (n = 6, 7%) and glioblastoma (GBM) (n = 6, 7%). CONCLUSIONS: Lymphoma and melanoma are still difficult-to-detect cancers both during donor investigation and at procurement, whilst prostate cancer and choriocarcinoma are almost always easily detected nowadays thank to blood markers and clinical examination. There have been improvements with time in pre-donation detection procedures which are now working well, particularly when complete imaging investigations are performed, given that detection rate of CT/MRI is high and accurate. Autopsy can play a role to help to establish the correct donor management pathways in case of cancer discover. Furthermore, it helps to better understand which cancers are still eluding detection and consequently to refine guidelines' assessment procedures.

Incidence and outcome of SARS-CoV-2 infection on solid organ transplantation recipients: A nationwide population-based study.

Since February 21 2020, when the Italian National Institute of Health (Istituto Superiore di Sanità-ISS) reported the first autochthonous case of infection, a dedicated surveillance system for SARS-CoV-2-positive (COVID+) cases has been created in Italy. These data were cross-referenced with those inside the Information Transplant System in order to assess the cumulative incidence (CI) and the outcome of SARS-COV-2 infection in solid organ transplant recipients (SOTRs) who are assumed to be most at risk. We compared our results with those of COVID+ nontransplanted patients (Non-SOTRs) with follow-up through September 30, 2020. The CI of SARS-CoV-2 infection in SOTRs was 1.02%, higher than in COVID+ Non-SOTRs (0.4%, p < .05) with a greater risk in the Lombardy region (2.89%). The CI by type of organ transplant was higher for heart (CI 1.57%, incidence rate ratio [IRR] 1.36) and lower for liver (CI 0.63%, IRR 0.54). The 60-day CI of mortality was 30.6%, twice as much that of COVID+ Non-SOTRs (15.4%) with a 60-day gender and age adjusted odds ratio (adjusted-OR) of 3.83 for COVID+ SOTRs (95% confidence interval [3.03-4.85]). The lowest 60-day adjusted-OR was observed in liver SOTRs (OR 0.46, 95% confidence interval [0.25-0.86]). More detailed studies on disease management and evolution will be necessary in these patients at greater risk of COVID-19.

HLA and AB0 Polymorphisms May Influence SARS-CoV-2 Infection and COVID-19 Severity.

BACKGROUND: SARS-CoV-2 infection is heterogeneous in clinical presentation and disease evolution. To investigate whether immune response to the virus can be influenced by genetic factors, we compared HLA and AB0 frequencies in organ transplant recipients and waitlisted patients according to presence or absence of SARS-CoV-2 infection. METHODS: A retrospective analysis was performed on an Italian cohort composed by transplanted and waitlisted patients in a January 2002 to March 2020 time frame. Data from this cohort were merged with the Italian registry of COVID+ subjects, evaluating infection status of transplanted and waitlisted patients. A total of 56 304 cases were studied with the aim of comparing HLA and AB0 frequencies according to the presence (n = 265, COVID+) or absence (n = 56 039, COVID-) of SARS-CoV-2 infection. RESULTS: The cumulative incidence rate of COVID-19 was 0.112% in the Italian population and 0.462% in waitlisted/transplanted patients (OR = 4.2; 95% CI, 3.7-4.7; P < 0.0001). HLA-DRB1*08 was more frequent in COVID+ (9.7% and 5.2%: OR = 1.9, 95% CI, 1.2-3.1; P = 0.003; Pc = 0.036). In COVID+ patients, HLA-DRB1*08 was correlated to mortality (6.9% in living versus 17.5% in deceased: OR = 2.9, 95% CI, 1.15-7.21; P = 0.023). Peptide binding prediction analyses showed that these DRB1*08 alleles were unable to bind any of the viral peptides with high affinity. Finally, blood group A was more frequent in COVID+ (45.5%) than COVID- patients (39.0%; OR = 1.3; 95% CI, 1.02-1.66; P = 0.03). CONCLUSIONS: Although preliminary, these results suggest that HLA antigens may influence SARS-CoV-2 infection and clinical evolution of COVID-19 and confirm that blood group A individuals are at greater risk of infection, providing clues on the spread of the disease and indications about infection prognosis and vaccination strategies.

Donor-Transmitted Cancers in Transplanted Livers: Analysis of Clinical Outcomes.

The risk of transmission of malignancy from donor to recipient is low. However, this occurrence has dramatic consequences. Many reports of donor-derived cancers in liver transplant recipients have been published, but they have not been systematically summarized into a lucid and unified analysis. The present study is an attempt to provide clarity to this unusual but clinically important problem. We systematically reviewed all patient reports, patient series, and registries published on cancer transmission events through the end of December 2019. We identified a total of 67 publications with 92 transmission events. The most frequently transmitted cancers were lymphomas (30; 32.6%), melanomas (8; 8.7%), and neuroendocrine tumors (8; 8.7%). Most of the melanomas were metastasizing, whereas most of the lymphomas were localized to the graft. The median time to cancer diagnosis after transplantation was 7 months, with 78.1% of diagnoses established in the first year. Melanoma carried the worst prognosis, with no recipients alive at 1 year after cancer diagnosis. Lymphoma recipients had a better outcome, with more than 75% surviving at 2 years. A metastatic cancer carries a worse prognosis for recipients, and recipients with localized cancer can benefit from the chance to undergo transplantation again. The findings confirm the need to pay attention to donors with a history of melanoma but also suggest the need for a more careful evaluation of groups of donors, such as those dying from cerebral hemorrhage. Finally, recipients of organs from donors with cancer should be carefully followed to detect potential transmission.

Physical activity and renal function in the Italian kidney transplant population.

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.

Donor-transmitted cancer in kidney transplant recipients: a systematic review.

The transmission of cancer from a donor organ is a rare event but has important consequences. Aim of this systematic review was to summarize all the published evidence on cancer transmission in kidney recipients. We reviewed published case reports and series describing the outcome of recipients with donor-transmitted cancer until August 2019. A total of 128 papers were included, representing 234 recipients. The most common transmitted cancers were lymphoma (n = 48, 20.5%), renal cancer (42, 17.9%), melanoma (40, 17.1%), non-small cell lung cancer (n = 13, 5.6%), neuroendocrine cancers comprising small cell lung cancer (n = 11, 4.7%) and choriocarcinoma (n = 10, 4.3%). There was a relative lack of glioblastoma and gastrointestinal cancers with only 6 and 5 cases, respectively. Melanoma and lung cancer had the worst prognosis, with 5-years overall survival of 43% and 19%, respectively; while renal cell cancer and lymphomas had a favorable prognosis with 5-years overall survival of 93 and 63%, respectively. Metastasis of cancer outside the graft was the most important adverse prognostic factor. Overall reporting was good, but information on donors' cause of death and investigations at procurement was often lacking. Epidemiology of transmitted cancer has evolved, thanks to screening with imaging and blood tests, as choriocarcinoma transmission have almost abolished, while melanoma and lymphoma are still difficult to detect and prevent.

The COVID-19 outbreak in Italy: Initial implications for organ transplantation programs.

The spread of Coronavirus Disease 2019 (COVID-19) has already reached a pandemic dimension within a few weeks. Italy has been one of the first countries dealing with the outbreak of COVID-19, and severe measures have been adopted to limit viral transmission. The spread of COVID-19 may have several implications in organ transplant activity that physicians should be aware of. The initial experience gained during the COVID-19 outbreak shows that around 10% of infected patients in Italy need intensive care management to overcome the acute respiratory distress syndrome. Due to the exponential rise of infected patients we are now facing an actual risk of saturation of intensive care unit (ICU) beds. A restriction in the number of ICU beds available for both donors and transplant recipients may unfavorably influence the overall donation activity, and eventually lead to a reduced number of transplants. Preliminary Italian data show that a 25% reduction of procured organs has already occurred during the first 4 weeks of COVID-19 outbreak. This underlines the need to closely monitor what will be further happening in ICUs due to the COVID-19 spread in the attempt to preserve transplant activity, especially in Western countries where deceased donors represent the major organ resource.

Rare Disease Patients as Potential Organ Donors.

BACKGROUND: Rare diseases (RDs) are a heterogeneous group of pathologies, which, when present in a donor, with their anatomic or functional deficiencies, may put the recipient at risk. The aim of our work is to analyze the incidence of RDs in our donors to support transplant experts in the evaluation of these organs. METHODS: We retrospectively assessed the incidence of RDs in donors from July 2017 to June 2019, along with the risk attributed, the number of transplanted organs, and the follow-up results of the recipients. RESULTS: Over a 24-month period, we had 19 donors with RDs. Of those, the organs of 4 donors were rejected before the risk assessment, the organs of 4 other donors were deemed an unacceptable risk, the organs of 4 more donors were rejected by transplant centers, and the organs of 7 donors were accepted with 16 organs ultimately transplanted (2 hearts, 3 livers, and 11 kidneys). Three of the recipients died of causes not related to the RDs. Thirteen of the recipients are still alive with a functioning organ with an average follow-up of 9 months. CONCLUSIONS: Although the evaluation of the results is influenced by the limited follow-up period, the use of donors with RDs has proved safe. One of the critical issues encountered in the evaluation process was the impossibility of carrying out genetic and histologic investigations for each organ in urgency. Moreover, the heterogeneity of RDs and the lack of solid literature data require, for the purpose of assessing the level of risk, a specific assessment of individual cases. To overcome these limitations, a group of experts was set up at the Superior Health Council, who drafted a reference document, which allowed for the assessment of the suitability and risk level of donors with the most frequent RDs.