How Long Does It Take to Acquire Mastery of Performance in Laparoscopic Living Donor Nephrectomy? A Center-Based and Surgeon-Based Operative Time CUSUM Analysis.

BACKGROUND: The safety of laparoscopic donor nephrectomy (LDN) has been widely documented, but its challenging learning curve (LC) requires an insightful assessment to expand its application. The aim of this study was to evaluate LC of LDN in a high-volume transplant center. METHODS: Three hundred forty-three LDNs performed from 2001 to 2018 were evaluated. CUSUM analysis based on the operative time was used to assess the number of cases required to reach mastery in the technique for both the entire surgical team and for the 3 main surgeons considered separately. Analysis of association between demographics, perioperative characteristics, and complications within the different LC phases was conducted. RESULTS: Mean operative time was 228.9 minutes. Mean length of stay was 3.8 days and mean warm ischemia time (WIT) was 170.8 seconds. Surgical and medical complication rates were 7.3% and 6.4%, respectively. The CUSUM-LC showed a requirement of 157 cases (for surgical team) and 75 cases (for single surgeons) to reach competence in the procedure. Patient baseline characteristic showed no differences among the LC phases. Compared with the initial LC phase, hospital stay was significantly lower at the end of the LC whereas WIT results were longer in the LC descendent phase. CONCLUSIONS: This study confirms the safety and efficacy of LDN, with a low rate of complications. This analysis suggests that about 75 procedures are required to reach competence and 93 cases to achieve mastery level of skill for a single surgeon. It can be hypothesized that, in a high-volume transplant enter, the time to guarantee training in LDN is compatible with the duration of a clinical fellowship.

DNA Methylation - and Telomere - Based Biological Age Estimation as Markers of Biological Aging in Donors Kidneys.

The biological age of an organ may represent a valuable tool for assessing its quality, especially in the elder. We examined the biological age of the kidneys [right (RK) and left kidney (LK)] and blood leukocytes in the same subject and compared these to assess whether blood mirrors kidney biological aging. Biological age was studied in n = 36 donors (median age: 72 years, range: 19-92; male: 42%) by exploring mitotic and non-mitotic pathways, using telomere length (TL) and age-methylation changes (DNAmAge) and its acceleration (AgeAcc). RK and LK DNAmAge are older than blood DNAmAge (RK vs. Blood, p = 0.0271 and LK vs. Blood, p = 0.0245) and RK and LK AgeAcc present higher score (this mean the AgeAcc is faster) than that of blood leukocytes (p = 0.0271 and p = 0.0245) in the same donor. TL of RK and LK are instead longer than that of blood (p = 0.0011 and p = 0.0098) and the increase in Remuzzi-Karpinski score is strongly correlated with kidney TL attrition (p = 0.0046). Finally, blood and kidney TL (p < 0.01) and DNAmAge (p < 0.001) were correlated. These markers can be evaluated in further studies as indicators of biological age of donor organ quality and increase the usage of organs from donors of advanced age therefore offering a potential translational research inkidney transplantation.

Telemedicine monitoring in the follow-up of kidney transplant recipients: consensus indications from an Italian panel of surgeons and nephrologists after the COVID-19 experience.

The quality of follow-up has clearly emerged as a key factor for long-term kidney graft survival. Currently, many clinics are facing difficulties in delivering optimal surveillance because of the increased number and complexity of kidney transplant recipients, and because of the COVID-19 pandemic. Additional ways of performing follow-up visits are needed and telemedicine has emerged as a tool to strengthen patient care intensity. Six Italian transplant surgeons and nephrologists convened via teleconference to develop a consensual model of video visits for the follow-up of kidney transplant recipients. Issues discussed were: profile of eligible patients; assessments that can be carried out; video visit organization and medical professionals involved; supporting tools and implementation. The video visit was consensually recognized as the most relevant for the follow-up of kidney transplant recipients. Eligible patients should have basic electronic devices and the skills to correctly use them and be in clinically stable condition. With the exception of physical and instrumental examination, and kidney biopsy, all other assessments are feasible during a video visit and can be implemented by specific training and use of supporting tools. The video visit model is simple and adaptable to most transplant patients. It is not intended to replace face-to-face examinations, but is an additional tool for improving the intensity of follow-up of kidney transplant recipients, which can be integrated into current monitoring protocols.

Advantages of Using a Web-based Digital Platform for Kidney Preimplantation Biopsies.

BACKGROUND: In the setting of kidney transplantation, histopathology of kidney biopsies is a key element in the organ assessment and allocation. Despite the broad diffusion of the Remuzzi-Karpinski score on preimplantation kidney biopsies, scientific evidence of its correlation to the transplantation outcome is controversial. The main issues affecting the prognostic value of histopathology are the referral to general on-call pathologists and the semiquantitative feature of the score, which can raise issues of interpretation. Digital pathology has shown very reliable and effective in the oncological diagnosis and treatment; however, the spread of such technologies is lagging behind in the field of transplantation. The aim of our study was to create a digital online platform where whole-slide images (WSI) of preimplantation kidney biopsies could be uploaded and stored. METHODS: We included 210 kidney biopsies collected between January 2015 and December 2019 from the joint collaboration of the transplantation centers of Padua and Verona. The selected slides, stained with hematoxylin and eosin, were digitized and uploaded on a shared web platform. For each case, the on-call pathologists' Remuzzi grades were obtained from the original report, together with the clinical data and the posttransplantation follow-up. RESULTS: The storage of WSI of preimplantation kidney biopsies would have several clinical, scientific, and educational advantages. The clinical utility relies on the possibility to consult online expert pathologists and real-time quality checks of diagnosis. From the perspective of follow-up, the archived digitized biopsies can offer a useful comparison to posttransplantation biopsies. In addition, the digital online platform is a precious tool for multidisciplinary meetings aimed both at the clinical discussion and at the design of research projects. Furthermore, this archive of readily available WSI is an important educational resource for the training of professionals. CONCLUSIONS: Finally, the web platform lays the foundation for the introduction of artificial intelligence in the field of transplantation that would help create new diagnostic algorithms and tools with the final aim of increasing the precision of organ assessment and its predictive value for transplant outcome.

Kidney Autotransplantation for Renal Artery Aneurysm: Case Series and a Systematic Review.

OBJECTIVES: Renal artery aneurysm (RAA) is a rare vascular disease. Kidney autotransplantation (KAT) is the treatment option when endovascular approach is not available. However, the evidence on KAT for RAA is mostly limited to small case series or reports. Here, we describe our 2 center experience of KAT for RAA, and provide the results of our systematic literature review to evaluate the outcomes. METHODS: A retrospective 2 center study was conducted in patients undergoing KAT for RAA between 2010 and 2018. Moreover, a systematic review was performed on medical databases to evaluate the outcomes of KAT for RAA. RESULTS: Nine patients were surgically treated at our institutions: eight with laparoscopic nephrectomy (LN), and 1 with open followed heterotopic KAT. All RAAs were ex-vivo reconstructed, and in 3 cases a vein graft was used for reconstruction. There were 2 postoperative major complications including 1 graft loss. In the systematic review, 102 studies with 355 patients were included. In 35 patients (9.9%) a minimal invasive approach was performed. The incidence of postoperative major complications and graft loss was 9.4% and 4.1%. CONCLUSIONS: Our experiences showed that laparoscopic approach for nephrectomy followed heterotopic KAT was feasible with good postoperative outcomes. KAT is an effective treatment for RAA when endovascular approach is not feasible for interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration.

[Perioperative strategies: taking care of the elderly patient with severe advanced comorbidities needing acute surgery.] / Strategie perioperatorie: presa in carico dell'anziano con gravi comorbilità e fase avanzata di malattia con patologia chirurgica acuta.

In the common clinical practice the perioperative risk assessment of an acute surgical patient with advanced chronic comorbidities is carried out independently by surgeon and anesthesiologist, usually in two different steps. While the surgeon evaluates the risk mainly in relation to the surgical outcome, the perioperative risk assessment regarding the weight of the coexisting medical condition on the quality of recovery in the short- mid- and long-term is all about the anesthesiologist evaluation. When frailty and/or comorbidities are so serious that will make surgery seem futile, the patient's assessment on one hand, and the decisions regarding the further clinical waypoint on the other, have to be discussed firstly between surgeons and anesthesiologists before being shared with the patients and their relatives. This is mostly true in the event of an emergency surgical procedure. In regard, a consensus conference attended by a panel of experts respectively from the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) and the Italian Society of Surgery (SIC) was called for developing a shared clinical pathway aimed to select the best care option - operative vs palliative - in the best interest of the surgical patient with advanced chronic comorbidities, in emergency or elective condition. After two years, the panel of experts developed a position paper recommending, in case of potentially futile surgery, to assess the patient verifying two coexisting conditions ("Two Steps method"): Palliative Performance Scale <50%, and at least one of the following general clinical criteria: 1) more than one hospital admission within the last 12 months; 2) hospital admission from or awaiting admission to long-term care facilities, home care service, hospice; 3) chronic renal failure requiring weekly dialysis sessions; 4) home oxygen use and/or non-invasive ventilation. Under these conditions, the surgeon together with the anesthesiologist can share with the patient and/or his relatives the decision between palliative surgery or palliative care taking into account his wishes and preferences.

Outcome and quality of life of patients with augmented bladder or urinary diversion after kidney transplantation.

OBJECTIVE: The aim of the study was to assess results and quality of life after kidney transplant in adult patients with previously bladder augmentation or urinary diversion due to significant lower urinary tract dysfunction. MATERIALS AND METHODS: This cross-sectional study examines the outcome of 19 renal allografts transplanted in patients with augmented bladder or urinary diversion over a ten years period; moreover we submitted SF36 questionnaire to evaluate quality of life of these patients and compared the results with the general population. RESULT: Between January 1, 2005 and 31 December 2015 we performed 19/1093 renal transplantations in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling. Current post-transplant follow-up was 47 months (range 18-188). No patient developed any episode of acute or chronic rejection. Mean serum creatinine after one year from transplant was 102 umol/L. Overall survival is 94.8% at the end of follow-up and graft survival is 89.6%. No significant differences emerged between patients undergoing transplant with lower urinary tract dysfunction and patients without, regarding to recurrent urinary tract infection. There was not statistically significant difference for vitality (p = 0.8088) and mental health (p = 0.8668). CONCLUSIONS: Presence of a previously augmented bladder or other lower urinary tract dysfunction treated in kidney transplant patients doesn't worsen the final outcome. Mental health and the vitality of these patients are similar to the general population.

Kidney exchange strategies: new aspects and applications with a focus on deceased donor-initiated chains.

Kidney paired donation (KPD) is a valuable way to overcome immunological incompatibility in the context of living donation, and several strategies have been implemented to boost its development. In this article, we reviewed the current state of the art in this field, with a particular focus on advanced KPD strategies, including the most recent idea of initiating living donor (LD) transplantation chains with a deceased donor (DD) kidney, first applied successfully in 2018. Since then, Italy has been running a national programme in which a chain-initiating kidney is selected from a DD pool and allocated to a recipient with an incompatible LD, and the LD's kidney is transplanted into a patient on the waiting list (WL). At this stage, since the ethical and logistic issues have been managed appropriately, KPD starting with a DD has proved to be a feasible strategy. It enables transplants in recipients of incompatible pairs without the need for desensitizing and also benefits patients on the WL who are allocated chain-ending kidneys from LDs (prioritizing sensitized patients and those on the WL for longer).

[Pulse pressure variation guided fluid therapy during kidney transplantation: a randomized controlled trial]. / Reposição de volume orientada pela variação da pressão de pulso durante transplante renal: estudo randomizado controlado.

PURPOSE: Kidney transplantation is the gold-standard treatment for end stage renal disease. Although different hemodynamic variables, like central venous pressure and mean arterial pressure, have been used to guide volume replacement during surgery, the best strategy still ought to be determined. Respiratory arterial Pulse Pressure Variation (PPV) is recognized to be a good predictor of fluid responsiveness for perioperative hemodynamic optimization in operating room settings. The aim of this study was to investigate whether a PPV-guided fluid management strategy is better than a liberal fluid strategy during kidney transplantation surgeries. Identification of differences in urine output in the first postoperative hour was the main objective of this study. METHODS: We conducted a prospective, single blind, randomized controlled trial. We enrolled 40 patients who underwent kidney transplantation from deceased donors. Patients randomized in the PPV Group received fluids whenever PPV was higher than 12%, patients in the Free Fluid Group received fluids following our institutional standard care protocol for kidney transplantations (10mL.kg-1.h-1). RESULTS: Urinary output was similar at every time-point between the two groups, urea was statistically different from the third postoperative day with a peak at the fourth postoperative day and creatinine showed a similar trend, being statistically different from the second postoperative day. Urea, creatinine and urine output were not different at the hospital discharge. CONCLUSION: PPV-guided fluid therapy during kidney transplantation significantly improves urea and creatinine levels in the first week after kidney transplantation surgery.

Pulse pressure variation guided fluid therapy during kidney transplantation: a randomized controlled trial / Reposição de volume orientada pela variação da pressão de pulso durante transplante renal: estudo randomizado controlado

Abstract Purpose: Kidney transplantation is the gold-standard treatment for end stage renal disease. Although different hemodynamic variables, like central venous pressure and mean arterial pressure, have been used to guide volume replacement during surgery, the best strategy still ought to be determined. Respiratory arterial Pulse Pressure Variation (PPV) is recognized to be a good predictor of fluid responsiveness for perioperative hemodynamic optimization in operating room settings. The aim of this study was to investigate whether a PPV guided fluid management strategy is better than a liberal fluid strategy during kidney transplantation surgeries. Identification of differences in urine output in the first postoperative hour was the main objective of this study. Methods: We conducted a prospective, single blind, randomized controlled trial. We enrolled 40 patients who underwent kidney transplantation from deceased donors. Patients randomized in the "PPV" group received fluids whenever PPV was higher than 12%, patients in the "free fluid" group received fluids following our institutional standard care protocol for kidney transplantations (10 mL.kg-1. h-1). Results: Urinary output was similar at every time-point between the two groups, urea was statistically different from the third postoperative day with a peak at the fourth postoperative day and creatinine showed a similar trend, being statistically different from the second postoperative day. Urea, creatinine and urine output were not different at the hospital discharge. Conclusion: PPV guided fluid therapy during kidney transplantation significantly improves urea and creatinine levels in the first week after kidney transplantation surgery.

Resumo Objetivo: Transplante renal é o tratamento padrão-ouro na doença renal em estágio terminal. Embora diferentes variáveis hemodinâmicas, tais como pressão venosa central e pressão arterial média, têm sido usadas para orientar a estratégia de reposição volêmica durante a cirurgia, a melhor estratégia ainda não foi determinada. A Variação da Pressão de Pulso (VPP) durante o ciclo respiratório é reconhecida como um bom preditor da resposta à infusão de volume para otimização hemodinâmica perioperatória no centro cirúrgico. O objetivo do estudo foi estudar se a estratégia de reposição de volume orientada por VPP é melhor do que a estratégia liberal de reposição de volume durante cirurgia de transplante renal. O principal objetivo do estudo foi identificar diferença no débito urinário na primeira hora do pós-operatório. Método: Realizamos estudo prospectivo, unicego, randomizado, controlado. Incluímos 40 pacientes submetidos a transplante renal de doador cadáver. Pacientes randomizados para o Grupo VPP receberam volume quando a VPP estava acima de 12%, e os pacientes no Grupo Reposição Liberal receberam volume de acordo com o nosso protocolo institucional padrão de assistência para transplante renal (10 mL.kg-1.h-1). Resultados: O débito urinário foi semelhante em todos os tempos nos dois grupos, a ureia foi estatisticamente diferente a partir do terceiro dia do pós-operatório com pico no quarto dia do pós-operatório e a creatinina apresentou tendência semelhante, tornando-se estatisticamente diferente a partir do segundo dia do pós-operatório. Ureia, creatinina e débito urinário não estavam diferentes na alta hospitalar. Conclusões: A terapia orientada por VPP durante transplante renal melhorou de forma significativa os níveis de ureia e creatinina na primeira semana pós-transplante renal.

Everolimus in kidney transplant recipients at high cardiovascular risk: a narrative review.

Kidney transplant recipients (KTRs) are at increased risk of cardiovascular (CV) morbidity and mortality, and side effects induced by immunosuppressive therapy may be a major contributor to this risk, together with traditional CV risk factors. Many strategies have been considered in order to reduce CV risk in KTRs, such as steroid and/or calcineurin inhibitor (CNI) minimization, but current data are inconclusive. The introduction of mammalian target of rapamycin (mTOR) inhibitors, the cornerstone of CNI minimization, in the immunosuppressive protocol may reduce both the incidence and severity of CNI-associated side effects; however, whether this strategy has an impact on CV risk after kidney transplantation needs to be evaluated. To this end, a panel of Italian experts in the field of transplantation was convened in a series of meetings to assess the current literature on the potential of the mTOR inhibitor everolimus as a cardioprotective agent. This narrative review summarizes the panel's round-table discussions and provides recommendations for CV risk management in KTRs.

Immune activation, immune senescence and levels of Epstein Barr Virus in kidney transplant patients: Impact of mTOR inhibitors.

Post-transplant lymphoproliferative disorders (PTLD) represent a severe complication in transplanted patients and Epstein-Barr Virus (EBV) is the main driver. Besides immunodepression, immune activation/chronic inflammation play an important role in both virus reactivation and expansion of EBV-positive B cells. The aim of this study was to assess the impact of immunosuppressive strategies on factors involved in the PTLD's pathogenesis. 124 kidney transplanted patients were enrolled in this study: 71 were treated with mycophenolic acid (MPA) and 53 treated with mTOR inhibitor (mTORi), both in combination with different doses of calcineurin inhibitor. At the time of the transplant (T0), profile of inflammation/immune activation and immune senescence didn't differ between the two groups, but after one year of treatment (T1) markers were significantly higher in MPA-treated patients; their immunosenescence process was supported by the greater erosion of telomeres despite their younger age. Percentages of activated B cells and levels of EBV-DNA significantly increased in MPA-treated patients, and at T1 were significantly higher in MPA- than in mTORi-treated patients. Overall, these findings indicate that mTOR inhibitors constrain the inflammation/immune activation and senescence status, thus reducing the expansion of EBV-infected B cells and the risk of virus-associated PTLD in kidney transplant recipients.

Lower Urinary Tract Symptoms in Kidney Transplant Recipients and Timing of Treatment With TURP: Impact on Renal Graft Survival and Function.

BACKGROUND: With the aging of recipients of renal transplantation (RT) one of the emerging issues is the incidence of low urinary tract symptoms (LUTS), which may have negative consequences on the graft survival and function. The aim of our study was to assess the influence of LUTS and the treatment with transurethral resection of the prostate (TURP) on the outcome of RT. MATERIALS AND METHODS: We collected data from men over 55 who underwent RT at our center from January 2007 to December 2016. We analyzed the incidence of LUTS; the rate of treatment with TURP; the eGFR (estimated glomerular filtration rate) at 6 months and 1, 3, and 5 years from transplantation; and graft survival. RESULTS: Fifty-five patients out of 268 experienced LUTS, and 19 of them had a bladder outlet obstruction (BOO). Patients experiencing BOO had a significantly higher hazard ratio (HR) of graft failure (HR 5.7, CI 1.56-21.4) compared to the other recipients. Of the 18 patients treated with TURP, 10 received the procedure within 6 months from the LUTS onset. They had a significantly absolute eGFR improvement at 6 months from the intervention (+14.25 mL/min ± 8.10) compared to the patients treated later (-8.4 mL/min ± 14.43). DISCUSSION: We showed the negative effects of LUTS on kidney graft function and survival. Although TURP is the standard therapy for such an issue, the best timing for it still has to be defined. Our experience supports the need for an early treatment of the LUTS for promoting the outcome of the RT.

Evidence-based practice: Guidance for using everolimus in combination with low-exposure calcineurin inhibitors as initial immunosuppression in kidney transplant patients.

The mammalian target of rapamycin (mTOR) inhibitor, everolimus, in combination with reduced-exposure calcineurin inhibitor (CNI), has been demonstrated in clinical trials to have comparable efficacy in low-to-moderate immunological risk kidney transplant recipients to the Standard of Care, mycophenolic acid (MPA) in combination with standard-exposure CNI. Current treatment guidelines consider mTOR inhibitors to be a second-line therapy in the majority of cases; however, given that everolimus-based regimens are associated with a reduced rate of viral infections after transplantation, their wider use could have great benefits for kidney transplant patients. In this evidence-based practice guideline, we consider the de novo use of everolimus in kidney transplant recipients. The main outcomes of our consideration of the available evidence are that: 1. Everolimus, in combination with reduced-exposure CNI and low dose steroids, is a suitable regimen for the prophylaxis of kidney transplant rejection in the majority of low-to-moderate immunological risk adult patients, with individualized management; 2. Induction with either basiliximab or rabbit anti-thymocyte globulin is an effective therapy for kidney transplant recipients when initiating an everolimus-based, reduced-exposure CNI regimen; and 3. An individualized approach should be adopted when managing kidney transplant recipients on everolimus-based therapy.

Deceased Donor-initiated Chains: First Report of a Successful Deliberate Case and Its Ethical Implications.

BACKGROUND: It has been suggested that deceased donor kidneys could be used to initiate chains of living donor kidney paired donation, but the potential gains of this practice need to be quantified and the ethical implications must be addressed before it can be implemented. METHODS: The gain of implementing deceased donor-initiated chains was measured with an algorithm, using retrospective data on the pool of incompatible donor/recipient pairs, at a single center. The allocation rules for chain-ending kidneys and the characteristics and quality of the chain-initiating kidney are described. RESULTS: The benefit quantification process showed that, with a pool of 69 kidneys from deceased donors and 16 pairs enrolled in the kidney paired donation program, it was possible to transplant 8 of 16 recipients (50%) over a period of 3 years. After obtaining the approval of the Veneto Regional Authority's Bioethical Committee and the revision of the Italian National Transplant Center's allocation policies, the first successful case was completed. For the recipient (male, aged 53 y), who entered the program for a chain-initiating kidney with a Kidney Donor Risk Index of 0.61 and a Kidney Donor Profile Index of 3%, the waiting time was 4 days. His willing donor (female, aged 53 y) with a Living Kidney Donor Profile Index of 2, donated 2 days later to a chain-ending recipient (male, aged 47 y) who had been on dialysis for 5 years. CONCLUSIONS: This is the first report of a successfully completed, deliberate deceased donor-initiated chain, which was made possible after a thorough assessment of the ethical issues and the impact of allocation policies. This article includes a preliminary efficacy assessment and describes the development of a dedicated algorithm.

Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies.

The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35).

Interleukin-27 is a potential marker for the onset of post-transplant malignancies.

Background: Malignancies represent the third leading cause of post-transplant mortality worldwide. The main challenge for transplant physicians is a timely diagnosis of this condition. The aim of the study was to identify a soluble diagnostic marker for monitoring the development of post-transplant malignancies. Methods: This is a multicentre, observational, perspective, case-control study. We enrolled 47 patients with post-transplant solid neoplasia. As a control group we employed 106 transplant recipients without a history of neoplasia and matched them with cases for the main demographic and clinical features. We investigated the transcriptomic profiles of peripheral blood mononuclear cells from kidney graft recipients with and without post-transplant malignancies enrolled in two of the participating centres, randomly selected from the whole study population. Microarray results were confirmed by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in the remaining patients from the same transplant centres and validated in a further independent group enrolled in two different transplant centres. Results: We identified 535 differentially expressed genes comparing patients with and without post-transplant malignancies (fold change ≥2.5; false discovery rate <5%). The cancer pathway was closely related to gene expression data, and one of the most down-regulated genes in this pathway was interleukin-27 (IL-27), a cytokine regulating anti-tumour immunity. Quantitative PCR and ELISA confirmed the microarray data. Interestingly, IL-27 plasma levels were able to discriminate patients with post-transplant neoplasia with a specificity of 80% and a sensitivity of 81%. This observation was confirmed in an independent set of patients from two different transplant centres. Conclusions: Our data suggest that IL-27 may represent a potential immunological marker for the timely identification of post-transplant neoplasia.

Correction: Effects of immune suppression for transplantation on inflammatory colorectal cancer progression.

At the time of publication, the html version of this paper contained an error; the authors Imerio Angriman and Lucrezia Furian were not tagged as equally contributing authors. This has now been fixed in the html version of the paper, the PDF was correct at the time of publication.

Effects of immune suppression for transplantation on inflammatory colorectal cancer progression.

BACKGROUND: Ulcerative colitis patients and transplant recipients are at risk for colorectal cancer. Here, we show that immunosuppressive regimens for kidney transplants are associated with the progression of ulcerative colitis-related carcinogenesis. METHODS: We describe the case of a patient diagnosed with colorectal cancer in ulcerative colitis while on immunosuppressive therapy for a kidney transplant. The immunological microenvironment of the cancer and its mutational status were analyzed, and a mouse colon cancer model was created to replicate the unique clinical conditions. AOM/DSS mice were randomized into seven experimental groups that received different immunosuppressants and an untreated control group to assess the frequencies of adenocarcinoma and high-grade dysplasia. Histopathology, immunohistochemistry, and flow cytometry were also performed on the harvested mouse colons. RESULTS: All mice treated with an immunosuppressive regimen developed at least an adenoma, and several of those receiving anti-CD3, anti-CD8, and mycophenolate mofetil also developed adenocarcinomas. In contrast, mice receiving rapamycin did not develop adenocarcinomas, and the extent of high-grade dysplasia in those mice was similar to that in control mice. CONCLUSIONS: Patients with pre-neoplastic conditions, such as ulcerative colitis, who are undergoing a solid organ transplant might benefit from the use of mTOR inhibitors given their intrinsic anti-tumor properties.

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using in vitro human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes (CXCL11, CCL4, MS4A7, MS4A6A, and FCGR3A) indicative of endothelial activation, IFNγ response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; P=0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; P=0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition.