Long-term Challenges After Solid Organ Transplantation
2018-08-16

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 rate of successful whereas patients enrolled longer than 6 years after transplantation had a rate of that predict tolerance in liver transplant recipients are being T cell T and These may potentially a of liver transplant patients who would from IS The Liver Immunosuppression is a randomized trial to the clinical and safety of IS withdrawal in liver The Liver Immunosuppression to a of operational tolerance to liver transplant recipients IS Key In liver transplantation, spontaneous tolerance is more frequent than in other solid organ transplantations and while the remains it is to be due to the unique tolerogenic microenvironment of the liver. increases with the since transplantation, in patients. A of operational tolerance help minimization strategies for maintenance IS. Heart Dr France of patients are longer than years after heart transplantation and such as CAV, infection, acute and renal insufficiency have a major on heart transplantation The International Society for Heart and Lung Transplantation data that is the leading cause of death long-term of heart The of IS, such as infection, and renal indicate the need to minimize IS. Current CNI-based as a in IS after heart transplantation and that or mTOR inhibitors should be they can be The of is an Although withdrawal can be in some patients, the use of minimization after heart transplantation varies between data that and of and adult heart transplant patients, respectively, are as maintenance at 1 year after The of and early after heart transplantation and patients on with has been The of mTOR inhibitors to enable reduction or of CNI has been in various The time for conversion and the reduction in CNI exposure remains to be although early CNI withdrawal should be (Figure The time for conversion and reduction in CNI exposure remains to be CNI minimizing and CNI acute Adapted with permission from et The A trial to the use of after heart transplantation. Learning: Current CNI-based as the in IS after heart transplantation and that or mTOR inhibitors should be they can be and allow CNI without increased risk of in in Dr Spain The and risk of is high in solid organ transplant recipients with the may via donor or be either or de novo risk factors for malignancies include age, and longer of IS a key role in the development of posttransplant malignancies and each IS drug a on The association between CNIs and risk of may be a of immune and the of and (Figure The mTOR inhibitors various effects and have been shown to the of malignancies after Studies that a to or SRL may be after diagnosis of posttransplant and effects of therapies after transplantation. factor vascular Adapted with permission from et data that in to can be associated with improved and survival after cardiac may viral transplant patients are to viral infection or of in include virus virus hepatitis and The microenvironment complex molecular and cellular that may an population of immune The increased expression of the gene in and to eliminate by is studies have demonstrated that also by other such as of mTOR A better of the complex role in may enable of the to improve Key Learning: IS a key role in the development of posttransplant malignancies and each IS drug a on What the for Dr are by the most occurring posttransplant malignancies and have a potentially on recipient from a of adult kidney recipients transplanted between and that was also associated with an increased risk of posttransplant death and graft for are defined and there is a consensus that the management of is based on a The Renal for the prevention and treatment of the patient early of patients with of by a and close et an approach and use of that transplant candidates for a risk by posttransplant with between and months to the risk clinical also a approach with transplantation and exchange of with the transplant for malignancies in transplant candidates and transplant recipients generally the of the There is randomized trial evidence in the transplant population and the clinical are (Table 2: for for malignancies than in transplant the ratio of is in people with chronic include quality of of and treatment need to be and account in to develop an in transplant The clinical and of after kidney transplantation to improve and management and after Key Learning: for should be a priority and are for generally from the to IS in Professor Dr recipients have an increased risk of malignancies when with the of posttransplant malignancies is a key goal in the of transplant recipients and is a approach, although current for in transplantation are not evidence The risk of posttransplant malignancies can be with a management of IS although there are standardized should include the risk of viral infection with and which are known to be associated with posttransplant malignancies, and the and of IS that mTOR inhibitors de novo risk with on CNI-based IS, and this is particularly due to a of is known that the use of is associated with a higher of whereas CNI withdrawal has effect on Posttransplant disease is a after transplantation and a of that from to (eg, cell Most are of cell and most are driven by infection (Figure Posttransplant disease potentially in transplant recipients IS drug the T cell to primary infection or of a and in and heart during to and of IS is the first step in the management of Patients with may and although the treatment is to be Surgery and may be as will include more targeted or precision There is evidence that mTOR can be in The is a in and has been as a potential Key Learning: The risk of posttransplant malignancies, particularly of can be with a management of IS although there are standardized PATIENT CNI Professor Dr allograft nephropathy, by renal dysfunction by chronic vascular and is the main cause of kidney transplant failure improvements in Early with acute rejection and rejection with the of is by de novo ischemic and associated with long-term CNI The of chronic allograft remains poorly and not renal failure should be to nephrotoxicity as glomerular disease processes and vascular may also be with molecular of kidney transplant has created a of transplant disease and their Antibody-mediated in some by is a major cause of kidney transplant in the renal graft expression profiling and may allow development of a to at risk of chronic early after transplantation that would enable early interventions to of in these A by and a of in allograft biopsies at months after transplantation, which was independently of the development of histological at 1 The of the gene was to that of clinical or histological The that those kidney transplant recipients who are at risk of allograft loss can be the development of thus the potential to therapeutic the of (Figure and of the of by and Kaplan-Meier of time to allograft loss for patients from a who were and to the gene risk Adapted with permission from et 3: included in the by may also play a role in how a recipient graft to CNI-based IS The expression of and involved in CNI varies in in the kidney and has for CNI and risk of Donor and recipient risk for chronic allograft a potential for of IS therapy. Key Learning: renal failure should be to CNI related nephrotoxicity as glomerular disease processes and vascular may also be Dr 2 diabetes is the most cause of and to transplantation due to related The prevalence of or on kidney transplant waiting lists has been shown to be with more than 1 of patients being diabetes defines diabetes after solid organ transplantation using the criteria for diabetes in stable transplant recipients maintenance The of include and decreased function whereas the is the factor that will to recipients who develop are at increased risk of CV and other patient allograft and risk for death with a functioning The reported of is and from to data of in patients after kidney transplantation indicate that between normal tolerance, and has been as a key risk factor for long-term and a of opportunity for risk factors for which are for include and IS CNI and have to In the study, withdrawal after for low risk patients However, the long-term of remain Current consensus or to IS strategy for allograft recipients based on risk the risk of allograft the potential of an in with to patient interventions can be in the risk of both for patients on the waiting list and the time of transplantation, early has been shown to be in the risk of by to and preserving long-term trials are to interventions to improve in of and patient outcomes after transplantation (Figure risk management for transplantation. strategy based on the personal Learning: has been as a key risk factor for long-term and a of opportunity for The Sandoz 5th Standalone Transplantation Meeting 2017 was held at Nice, France and simultaneously live-streamed to in Sweden and Spain. The meeting together key to the long-term in solid organ transplantation and and with delegates from each location their knowledge and The lack of donor organs for transplantation continues to be a challenge. IS therapies to the needs of each individual may help balance the benefits and adverse effects of IS to extend graft survival. the mechanisms involved in the of tolerance is a key of