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W2887781110 abstract "The Sandoz 5th Standalone Transplantation Meeting 2017 titled “Long Term Challenges Following Solid Organ Transplantation” was held on 27th to 28th of November in Nice, France, and was simultaneously live-streamed via an audiovisual link to delegates attending 2 satellite meetings in Sweden and Spain. Participants at each location had the opportunity for exchange of knowledge and experience through expert presentations, debate, questions and educational discussion. The meeting was co-chaired by Professor Christophe Legendre, Professor of Nephrology at the Paris Descartes University and Head of the Adult Nephrology and Transplantation Unit at Necker Hospital, France and Professor Richard Viebahn, Chairman of Surgery at Ruhr-University of Bochum and Universitätsklinikum Knappschaftskrankenhaus Bochum. Despite improvements in patient and graft survival rates after solid organ transplantation, balancing the benefits and adverse effects of immunosuppression (IS) to extend graft survival remains a challenge. Some of the most relevant issues surrounding the long-term management of solid organ transplant recipients were addressed at this year's meeting. The key areas covered were: ethical dilemmas in organ donation, graft and patient loss, risks of minimizing IS, malignancies in transplanted patients, and posttransplant monitoring for diabetes and nephrotoxicity. ETHICAL DILEMMA IN ORGAN DONATION: LIVING VERSUS DECEASED DONATION Why Be a Living Donor? Professor Ingela Fehrman-Ekholm, Sweden Most people donate organs for altruistic reasons,1 and the majority of living donations come from close family relatives and spouses of the recipient.2 When compared, spouses rather than family relatives are better informed about the risks of donation and they place a high value on the possible gains to the quality of their family life.1 In Sweden, during the 2000s, donation from living donors (LD) exceeded deceased donation, but recent data have shown a decline in living donation rates,3 a pattern also seen in the United States.4 The reason for this downward trend is not clear, but may be linked to a lack of confidence and indecision by the donor or physician and the strictness of the selection criteria for suitable donors.5 The risks to LDs after donation include a reported increased risk of end-stage renal disease (ESRD),6 although in a Norwegian study, the rate of ESRD was only 0.47% (9 of 1900 LDs).7 Non-ESRD risks, such as the development of type 2 diabetes (T2D) or hypertension (HT)8,9 and elevated risks of gestational HT and preeclampsia have also been noted.10 Psychiatric problems relating to donation, (eg, feeling moral duty to donate, being too young or the donation resulting in an unsuccessful donation) may also be experienced.11 Studies have shown that LDs generally live longer than nondonors.12 However, this is most likely due to a selection effect from choosing healthy individuals, but may also be linked to the improved long-term renal function of the remaining kidney.13,14 Prof. Fehrman-Ekholm explained that her personal experience supports the use of LDs and for many donors it is a “life project”. She advised that in LD programs, strict selection criteria should be adhered to, particularly with respect to younger donors, and where possible smokers or overweight/obese LDs should not be used. In Sweden yearly checks have also been introduced without cost for LDs to increase safety. Key Learning: Most people donate organs for altruistic reasons, and some consider donation to be a “life project.” Deceased Donation, Dr Núria Masnou, Spain The shortage of organs for transplantation is a global challenge. The Madrid Resolution on Organ Donation and Transplantation recommends a strategy of striving for self-sufficiency in organ donation using resources from within each country with the priority sources of organs being donation after brain death (DBD) and donation after circulatory death (DCD).15 Worldwide data demonstrates that countries with high deceased organ donation rates (>20 donors per million population per year) are mainly those who focused donation in DBD programs and have DCD programs as a complementary source of organs.16 Because of the highest potential number and better viability of organs available, the use of DBD has to become the standard. Raising the rate at which brain death is diagnosed would enable more potential donors to become actual donors. However, this creates a dilemma regarding the most appropriate management of a patient’s death—to finely balance the provision of a less invasive approach to end-of-life care versus a potentially more costly provision of intensive care until brain death occurs, but which increases the availability of transplantable organs.17,18 Ideally, organ donation should be accepted as a normal step in end-of-life care.16 However, health professionals confront difficult and potentially conflicting choices affected by cultural values, religious beliefs, legal regulations and medical practices regarding end-of-life care and death management.16 Sensitive decisions should be addressed early in the end-of-life care pathway, allowing loved ones to readjust their expectations to enable interventions that maximize organ donation potential. Key Learning: Organ donation should be accepted as a normal step in end-of-life treatment. GRAFT AND PATIENT LOSS: CURRENT FIGURES What About the Kidney? Professor Christophe Legendre, France The short-term outcomes of kidney transplantation have improved over the past 20 years, whereas long-term outcomes have only shown minimal improvements with recipients either dying with a functioning graft or suffering graft loss due to various complex causes (Figure 1).19FIGURE 1: Short and long-term graft attrition rates after kidney transplantation (1989-2014). Adapted with permission from Wekerle et al.19Early graft loss after kidney transplantation can occur due a number of reasons: vascular thrombosis,20,21 death with a functioning kidney,22 poor quality of donor kidney,20 disease recurrence,23 and antibody-mediated rejection (AMR).24 Early graft loss (within 30 days) is a major risk for recipient death, but long-term mortality is greater for patients remaining on the waiting list.20 Long-term outcomes after kidney transplantation are affected by multiple complex factors.25-27 Antibody-mediated rejection with donor-specific anti-HLA antibodies (DSAs) (often associated with nonadherence) is the main cause of graft dysfunction.28 Superimposed disease processes (polyomavirus-associated nephropathy, T cell–mediated rejection) and other factors (recurrence, medical) also play a role in graft dysfunction.27 Adverse effects, such as diabetes,29 infection, and cancer,30 counterbalance the prevention of rejection by IS. Immunosuppression strategies to reduce toxicities using mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, may allow reduction of calcineurin inhibitor (CNI) exposure without compromising safety or efficacy31,32 although the risk-benefit ratio has to be carefully balanced.33,34 Improvement of long-term function after kidney transplantation remains an unmet clinical need and is a challenge.35 Expectations for the future include improved HLA matching, biomarkers, immune monitoring, and drug development. These will improve individual decision making and treatment outcomes.19 Key Learning: AMR with DSAs is currently the main cause of graft dysfunction. What About the Liver? Professor Marina Berenguer, Spain The survival outcomes of liver transplant patients who live beyond 6 months have not changed since 2002.36 The causes of early and late mortality vary, with infection and intraoperative and perioperative causes accounting for most early deaths while malignancies, and cardiovascular (CV) causes together with renal failure account for more deaths after 1 year.36-38 Several factors affect the long-term outcomes of liver transplant recipients: recurrence of the primary disease leading to transplantation, particularly hepatitis C virus (HCV) recurrence and hepatocellular carcinoma (HCC), chronic kidney disease (CKD), CV disease, recurrence and de novo cancer.36-38 Direct-acting antiviral therapies for HCV infection have revolutionized the treatment of patients with chronic HCV infection. On the one hand, the proportion of patients on waiting lists for liver transplantation for decompensated HCV cirrhosis has significantly decreased over time (Figure 2).39 On the other hand, patients with recurrent HCV are now easily managed with these drugs leading to viral eradication in most infected recipients, this in turn, resulting in significant improved graft and patient outcome.40FIGURE 2: Reduction in liver transplant waiting lists in the era of HCV DAAs. A) Patients included (%) in the waiting list due to HCV-cirrhosis with or without HCC. B) HCV-patients delisted (%) from the waiting list. N = 1113 HCV-patients listed for liver transplantation from 1997-2016. DAA, direct-acting antiviral; HCC, hepatocellular carcinoma. Adapted with permission from Sáez-González et al.39Since the introduction of the MELD system for organ allocation, the prevalence of renal failure in liver transplant candidates is rising.41 A significant proportion of liver transplant recipients develop CKD in the long term and the risk of death increases exponentially when the glomerular filtration rate (GFR) is less than 30 mL/min per 1.73 m2.42 Renal failure, obesity, T2D, and HT are the main risk factors known to be associated with CV disease in patients after liver transplantation and remain poorly controlled.43,44 In addition, nonalcoholic fatty liver disease as an indication for liver transplantation is on the rise45 and is an independent risk factor of posttransplant renal dysfunction and CV disease.46 Adequate posttransplant management of CV risk factors together with individualization of IS may help to reduce the burden of these complications. Key Learning: Direct-acting antiviral therapies for HCV infection have revolutionized the treatment of patients with chronic HCV infection and thus the indications and outcome of liver transplantation for HCV-infected candidates. What About the Heart? Dr Luciano Potena, Italy Posttransplant survival of adult heart transplant recipients continues to improve.47 The first year after transplant represents the period with the highest risk of death with primary graft dysfunction (PGD) being the leading cause. A recent consensus classification of PGD endorsed by the International Society for Heart and Lung Transplantation defines PGD and aids identification of patients at major risk for early death and graft loss.48 Donor age, recipient DM, ischemic time, and postoperative dialysis are factors that predict nonrecovery from PGD. After the initial postoperative period, causes of graft loss include acute cellular rejection and AMR, and cardiac allograft vasculopathy (CAV). Diagnosis of rejection is still based mainly on pathology classification for acute cellular rejection and AMR. Several studies demonstrated the limitations of this approach, mainly related to low reproducibility rate of biopsy reading. Recently, microarray-based gene expression profiling of the biopsies has allowed improved precision of the diagnosis, opening novel potential scenarios for more selective and appropriate treatment.49 Cardiac allograft vasculopathy remains the major cause of late graft-related death. While uncertainty in the definition, of CAV remains an unmet need (Figure 3), diagnostic processes are in development through the combined use of coronary angiography and intravascular ultrasound imaging: the association of both techniques may allow identification of patients at risk of long-term CV events.50 These tools may enable a more accurate, personalized approach for clinicians to tailor current therapies to the needs of individual heart transplant recipients, such as targeted revascularization of aggressive therapeutic approach to limit CAV progression.51,52FIGURE 3: Features of CAV (left) versus native vascular disease (right). Abs, antibodies; CMV, cytomegalovirus (image created by author).Key Learning: PGD and CAV, respectively, are the major causes of early and late graft loss after heart transplantation. Diagnosis of acute rejection may be improved by using a molecular biology approach. Prognostic relevance of CAV may be assessed by combining angiography and intravascular ultrasound in a multiple imaging technique approach. HOW SAFE IS IT TO MINIMIZE IMMUNOSUPPRESSION? Kidney Transplantation Experience, Dr Lars Wennberg, Sweden Concerns about chronic CNI nephrotoxicity and other adverse effects of IS have driven development of regimens which aim to minimize the side effects of IS while preserving kidney graft function.53 Evolution of IS therapies such as mTOR inhibitors (everolimus and sirolimus [SRL]) and the selective T cell lymphocyte costimulation blocker, belatacept, have improved these regimens. The efficacy of IS strategies with mTOR inhibitors, with or without CNIs, in terms of renal and antiviral benefits, have been demonstrated in randomized controlled trials and confirmed in meta-analyses.53-56 Immunosuppression with belatacept versus CNIs has also been extensively studied, and long-term exposure to belatacept 7 years after transplantation demonstrated significantly higher patient and graft survival and mean estimated glomerular filtration rate versus cyclosporine (Figure 4).57FIGURE 4: Belatacept-based IS versus cyclosporine-based IS in kidney-transplant recipients. A, Kaplan-Meier curve for the composite end point of patient and graft survival. B, eGFR rate from Month 1-84. The eGFR was determined by repeated-measures modeling, with time as a categorical variable. Bars indicate 95% CIs. CI, confidence interval; eGFR, estimated glomerular filtration rate; MI, more intensive; LI, less intensive. Adapted with permission from Vincenti et al.57Immune-based biomarkers offer the potential for identifying patients at risk for graft rejection and individualizing therapy.58 Current therapies to reduce or eliminate DSAs are limited and ineffective in the most highly HLA-sensitized patients. IdeS is an IgG endopeptidase that reduces or eliminates DSAs and has been shown to permit HLA-incompatible transplantation in the majority of highly HLA-sensitized patients.59 Key Learning: Immune-based biomarkers offer the potential for identifying patients at risk for graft rejection and for individualizing therapy. Minimization of IS is possible in carefully selected and monitored patients. Liver Transplantation, Professor John O’Grady, UK Personalization and minimization of IS regimens in liver transplant recipients include60: Individual drug exposure versus total IS burden, Early CNI minimization or early withdrawal to improve renal function, Reduction of the long-term IS burden, Recognition of spontaneously occurring tolerance, Promotion of operational tolerance. There is evidence that conversion from CNI-based to mTOR inhibitor-based IS improves kidney function in patients with renal insufficiency after liver transplantation.61 However, there are drawbacks as seen in the spare-the-nephron trial where liver transplant recipients receiving mycophenolate mofetil (MMF) plus SRL had improved renal function, but also an increased risk of rejection.62 Although late acute rejection after liver transplantation continues to be a risk to patient and graft survival,63 chronic rejection has not been found in liver transplant recipients receiving low-dose CNIs, indicating that minimization or even cessation, of CNIs may be an achievable goal in the long-term for many liver graft recipients.64 An unintended consequence of minimizing IS is AMR. Although AMR is rare, it is recently being recognized more often as a cause of graft failure in liver transplant recipients. Markers of AMR include DSA in the serum, compatible histology, and positive C4d staining, although standardized criteria for diagnosis still need to be established.65 In liver transplantation, spontaneous tolerance is more frequent than in other solid organ transplantations due to the unique tolerogenic microenvironment of the liver. Operational tolerance is defined as successful IS withdrawal maintained for at least 1 year with stable graft function without evidence of histological rejection.66 There have been a number of studies of intentional drug withdrawal aiming at elucidating the mechanisms involved in the maintenance of the tolerant state.66-79 Within these studies, the rate of successful drug withdrawal varies between 5% and 60%, depending on how patients are selected (Table 1).TABLE 1: Prevalence of spontaneous operational tolerance in liver transplantation (1997-2014)Time since transplantation and age at transplantation are independently associated with the probability of being tolerant.66 Patients enrolled more than 10 years after transplantation had an 80% rate of successful withdrawal, whereas patients enrolled longer than 6 years after transplantation had a success rate of 38%.66 Biomarkers that predict tolerance in liver transplant recipients are being investigated, including γδ T cell subsets, CD25+, CD4+, regulatory T cells, and NK cells. These may potentially provide a means of prospectively selecting liver transplant patients who would benefit from IS withdrawal.80,81 The ongoing Liver Immunosuppression Free Trial is a prospective randomized marker-based trial designed to assess the clinical utility and safety of biomarker-guided IS withdrawal in liver transplantation.82 The Liver Immunosuppression Free Trial aims to validate a biomarker test of operational tolerance to stratify liver transplant recipients before withdrawing IS medication. Key Learnings: In liver transplantation, spontaneous tolerance is more frequent than in other solid organ transplantations and while the mechanism remains unclear, it is believed to be due to the unique tolerogenic microenvironment of the liver. Tolerance increases with the duration since transplantation, especially in older patients. A biomarker test of operational tolerance could help facilitate minimization strategies for maintenance IS. Heart Transplant Recipient, Dr Eric Epailly, France Increasing numbers of patients are surviving longer than 5 years after heart transplantation and conditions, such as CAV, malignancy, infection, acute rejection, and renal insufficiency have a major impact on heart transplantation outcomes.83 The International Society for Heart and Lung Transplantation (IHSLT) Registry data suggest that malignancy is the leading cause of death among long-term survivors of heart transplantation.83 The sequelae of IS, such as infection, malignancy, and renal insufficiency, indicate the need to minimize IS. Current guidelines recommend CNI-based therapy as a standard tool in IS protocols after heart transplantation and that MMF or mTOR inhibitors should be included, if they can be tolerated. The avoidance of steroids is an acceptable option.84 Although steroid withdrawal can be successfully achieved in some patients, the use of steroids minimization protocols after heart transplantation varies between centers.85,86 IHSLT data show that 63% and 81% of pediatric and adult heart transplant patients, respectively, are recorded as having received maintenance steroids at 1 year after transplantation.84 The feasibility of weaning steroids and MMF early after heart transplantation and maintaining patients solely on monotherapy with tacrolimus has been demonstrated.87 The possibility of introducing mTOR inhibitors to enable reduction or discontinuation of CNI therapy has been researched in various settings.88 The optimal time for conversion and the adequate reduction in CNI exposure remains to be defined, although very early CNI withdrawal should be avoided (Figure 5).11FIGURE 5: The optimal time for conversion and reduction in CNI exposure remains to be defined: CNI minimizing and CNI free protocols. BPAR, biopsy-proven acute rejection; EVR, everolimus. Adapted with permission from Deuse T, Bara C, Barten MJ, et al. The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation. Contemp Clin Trials.11Key Learning: Current guidelines recommend CNI-based therapy as the standard tool in IS protocols after heart transplantation and that MMF or mTOR inhibitors should be included, if they can be tolerated and could allow CNI sparing protocols without increased risk of AR. MALIGNANCIES Basic Science in Malignancies in Transplanted Patients, Dr Fritz Diekmann, Spain The incidence and risk of malignancy is high in solid organ transplant recipients compared with the general population. Malignancies may arise via donor transmission or be either preexisting or de novo malignancies.89 Non–IS-related risk factors for malignancies include older age, male gender and longer duration of dialysis. IS plays a key role in the development of posttransplant malignancies and each IS drug presents a distinct influence on cancer risk.89 The association between CNIs and risk of malignancy may be a result of systemic immune suppression and the local inhibition of DNA repair and apoptosis (Figure 6).90 The mTOR inhibitors exert various antioncogenic effects and have been shown to lower the occurrence of malignancies after transplantation.89 Studies show that a switch to everolimus or SRL may be beneficial after diagnosis of posttransplant Kaposi sarcoma.89FIGURE 6: Positive and negative effects of immunosuppressive therapies after transplantation. AZA, azathioprine; CSA, cyclosporine; Il-11, interleukin 11; TAC, tacrolimus; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor. Adapted with permission from Ajithkumar et al.89Registry data suggest that statin use, in addition to its lipid-lowering role, can be associated with improved cancer-free and overall survival after cardiac transplantation.91 Imunosuppression may promote viral replication, so transplant patients are vulnerable to viral infection or reactivation of latent infection.92 Viruses implicated in carcinogenesis include Epstein-Barr virus (EBV), human herpes virus 8 (HHV-8), human papillomavirus, hepatitis B virus, and HCV.92 The tumor microenvironment contains complex molecular and cellular components that may induce an immunosuppressive population of immune cells.93 The increased expression of the tumor suppressor p53 gene in tumors, and its ability to eliminate cancer cells by apoptosis is well established.93 Murine studies have demonstrated that p53 also suppresses tumor progression by other mechanisms, such as inhibition of mTOR pathway activation.94 A better understanding of the complex regulatory role p53 plays in tumor immunology may enable new approaches of targeting the p53 pathway to improve immunotherapy outcomes.94 Key Learning: IS plays a key role in the development of posttransplant malignancies and each IS drug presents a distinct influence on cancer risk. What Is the Evidence for Routine Screening? Dr Isabelle Binet, Switzerland Skin cancers are by far the most frequently occurring posttransplant malignancies and have a potentially serious impact on recipient outcome. Evidence from a cohort study of adult kidney recipients transplanted between 2005 and 2013 showed that pretransplant skin cancer was also associated with an increased risk of posttransplant malignancy, death and graft failure.95 Guideline recommendations for skin cancer screening are well defined and there is a consensus that the management of skin cancer is based on a structured screening process.96 The European Renal Best Practice guidelines for the prevention and treatment of skin cancer recommend the following steps: raising patient self-awareness, early referral of patients with premalignant lesions, complete removal of all skin cancers by a dermatologist, and close follow-up procedures.97 Ulrich et al98 recommend an interdisciplinary approach and use of screening algorithm that evaluates transplant candidates for a skin cancer risk factor-oriented assessment, followed by individually adjusted posttransplant aftercare with examination intervals between 3 and 12 months according to the risk stratification.98 Swiss clinical practice guidelines also recommend a multidisciplinary approach with pretransplant education, regular dermatological consultations starting before transplantation and exchange of information with the transplant team.99 Screening recommendations for nonskin malignancies in transplant candidates and transplant recipients generally extrapolates the recommendations of the general population. There is no randomized trial evidence in the transplant population and the clinical guidelines are variable (Table 2).100TABLE 2: Recommendations for screening for malignancies (other than skin) in transplant recipientsFurthermore the benefits-to-harms ratio of cancer screening is uncertain in people with chronic illness—factors include screening test accuracy, quality of life of having cancer, and cancer treatment effectiveness need to be evaluated and taken into account in order to develop an effective cancer screening program in transplant recipients.101 The clinical and economic consequences of cancer after kidney transplantation warrant efforts to improve pretransplant screening and management protocols before and after transplant.102 Key Learning: Screening for skin cancer should be a priority and guideline recommendations are well defined. Screening for nonskin cancer generally follows existing cancer screening recommendations from the general population. How to Manage IS in Cancer, Professor Dr Vedat Schwenger, Germany Transplant recipients have an increased risk of malignancies when compared with the general population.103 Prevention of posttransplant malignancies is a key goal in the follow-up of transplant recipients and screening is a strategic approach, although current guidelines for cancer screening in transplantation are not evidence based.96 The risk of posttransplant malignancies can be reduced with a careful management of IS therapy, although there are no standardized strategies. Considerations should include the risk of viral infection with EBV and HHV-8, which are known to be associated with posttransplant malignancies, and the duration and intensity of different IS regimens.104-107 Evidence suggests that mTOR inhibitors lower de novo malignancy risk compared with continuation on CNI-based IS, and this is particularly due to a reduced incidence of nonmelanoma skin cancer.108 It is known that the use of azathioprine is associated with a higher incidence of malignancies,109 whereas CNI withdrawal has no effect on malignancies.104 Posttransplant lymphoproliferative disease (PTLD) is a common malignant complication after transplantation and encompasses a spectrum of disorders that ranges from polyclonal lymphoid proliferations to malignancy (eg, non–Hodgkin B cell lymphoma). Most are of B cell origin, and most are driven by EBV infection (Figure 7).110 Posttransplant lymphoproliferative disease potentially develops in transplant recipients because IS drug therapy decreases the T cell response necessary to control primary EBV infection or reactivation of a latent EBV infection.111FIGURE 7: EBV serostatus and non–Hodgkin lymphoma in (A) kidney, (B) liver, and (C) heart transplants during 2000 to 2015. Collaborative Transplant Study (CTS) data. CTS graphs CTS-K-55609-0817, L-55609-817 and H-55609-817. Available from: http://www.ctstransplant.org/. Accessed December 12, 2017.110Reduction of IS is the first step in the management of PTLD.112,113 Patients with progressive PTLD may require additional rituximab therapy and cytotoxic chemotherapy, although the optimal treatment schedule is yet to be established. Surgery and radiotherapy may be used as adjunctive therapies. Future options will include more targeted therapy or precision medicine.111 There is evidence that mTOR inhibition can be effective in suppressing EBV-related malignancies. The PI3K-Akt-mTOR pathway is a frequently activated pathway in PTLD and has been analyzed as a potential target.111 Key Learning: The risk of posttransplant malignancies, particularly of skin cancers, can be reduced with a careful management of IS therapy although there are no standardized strategies. DIABETES OR NEPHROTOXICITY: PATIENT MONITORING Is CNI Nephrotoxicity Still Present? Professor Dr Dirk Kuypers, Belgium Chronic allograft nephropathy, characterized by progressive renal dysfunction accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes, and glomerulosclerosis is the main cause of kidney transplant failure despite improvements in IS.114 Early tubulointerstitial damage correlates with immunological factors, including severe acute rejection and persistent subclinical rejection with the addition of ischemia-reperfusion injury. Later damage is characterized by progressive de novo arteriolar hyalinosis, ischemic glomerulosclerosis, and further interstitial fibrosis associated with long-term CNI nephrotoxicity.114 The pathophysiology of chronic allograft nephropathy remains poorly understood and not all renal failure should be attributed to CNI-related nephrotoxicity as specific glomerular disease processes and vascular injuries may also be present.115-117 Combining conventional assessment with molecular analysis of kidney transplant has created a new understanding of transplant disease states and their outcomes.26 Antibody-mediated rejection, triggered in some cases by nonadherence, is a major cause of kidney transplant failure.26 Pathological changes in the renal graft precede functional changes. Glomerular expression profiling and transcriptome analysis may allow development of a predictive assay to identify allografts at risk of chronic damage early after transplantation that would enable early interventions to prevent progression of fibrosis in these patients.118 A 2016 study by O'Connell and colleagues identified a set of 13 genes in protocol allograft biopsies collected at 3 months after transplantation, which was independently predictive of the development of histological injury at 1 year.119,120 The predictive capacity of the gene set was superior to that of clinical indicators or routine histological parameters. The results suggest that those kidney transplant recipients who are at risk of allograft loss can be identified before the development of irreversible damage, thus offering the potential to modify therapeutic approaches before the onset of fibrosis (Figure 8 and Table 3).FIGURE 8: Results of the Genomics of Chronic Allograft Rejection (GoCAR) study by O’Connell and colleagues: Kaplan-Meier plot of time to allograft loss for patients from a publically available dataset (GSE21374)120 who were stratified into high-risk and low-risk groups according to the gene set risk score. HR, hazard ratio. Adapted with permission from O'Connell et al.119TABLE 3: Genes included in the prediction set by array probeIDDonor characteristics may also play a role in how a recipient graft responds to CNI-based IS therapies. The functional expression of genes (CYP3A5 and ABCB1) involved in CNI metabolism varies in human proximal tubule cells in the kidney and has implications for CNI disposition and risk of nephrotoxicity.121 Donor and recipient risk stratification for chronic allograft nephropathy seems a potential tool for optimization of IS therapy. Key Learning: Not all renal failure should be attributed to CNI related nephrotoxicity as specific glomerular disease processes and vascular injuries may also be present. Diabetes Posttransplant: One Common Enemy, Dr Martina Guthoff, Germany Type 2 diabetes is the most common cause of ESRD122 and limits access to transplantation mostly due to related comorbidities.123 The prevalence of T2D or prediabetes on kidney transplant waiting lists has been shown to be around 55%, with more than 1 third of patients investigated being previously undiagnosed.124 Posttransplantation diabetes mellitus (PTDM) defines diabetes after solid organ transplantation using the American Diabetes Association criteria for diabetes in stable transplant recipients under maintenance IS.125 The pathophysiological features of PTDM include insulin resistance and decreased ß-cell function whereas the latter is the predominant factor that will lead to manifest diabetes.126,127 Transplant recipients who develop PTDM are at increased risk of CV events and other events, including infections,128 reduced patient survival,129,130 impaired allograft outcome,131 and risk for death with a functioning graft.132 The reported incidence of PTDM is variable and ranges from 7% to 46%.29,44,133,134 Longitudinal data of glucose metabolism in patients after kidney transplantation indicate that substantial fluctuations between normal glucose tolerance, prediabetes and PTDM occur.135 Consequently, prediabetes has been identified as a key risk factor for PTDM throughout long-term follow-up and offers a window of opportunity for intervention. Other modifiable risk factors for developing PTDM, which are targets for intervention, include obesity and IS therapy.136,137 Both CNI and steroid therapy have established contributory roles to PTDM.138 In the HARMONY study, rapid steroid withdrawal after induction therapy for low immunological risk patients reduced PTDM.139 However, the long-term consequences of steroid withdrawal/avoidance remain unclear.140 Current 2014 consensus guidelines recommend no change or alteration to IS strategy for allograft recipients based on PTDM risk alone, because the risk of allograft injury outweighs the potential benefit of an improvement in glucose metabolism with regard to patient prognosis.125 Lifestyle interventions can be effective in reducing the risk of later PTDM both for patients on the waiting list and posttransplantation.141,142 At the time of transplantation, early basal insulin administration has been shown to be effective in lowering the risk of PTDM by reducing glucotoxicity to ß cells and preserving insulin secretion.143 Further long-term trials are needed to establish whether interventions to improve glucose metabolism result in reduced incidence of PTDM and patient outcomes after transplantation (Figure 9).FIGURE 9: Optimizing risk management for PTDM. Tx, transplantation. Management strategy based on the author's personal opinion.Key Learning: Prediabetes has been identified as a key risk factor for PTDM throughout long-term follow-up and offers a window of opportunity for intervention. CONCLUSIONS The Sandoz 5th Standalone Transplantation Meeting 2017 was held at Nice, France and simultaneously live-streamed to participants in Sweden and Spain. The meeting brought together key specialist experts to outline the long-term challenges in solid organ transplantation and stimulated vibrant and informative discussions, with delegates from each location sharing their knowledge and experience. Global Conclusion: The lack of donor organs available for transplantation continues to be a challenge. Tailoring IS therapies to the needs of each individual may help balance the benefits and adverse effects of IS to extend graft survival. Understanding the mechanisms involved in the induction of tolerance is a key area of research." @default.
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W2887781110 title "Long-term Challenges After Solid Organ Transplantation" @default.
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