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Beyond Survival in Solid Organ Transplantation: A Summary of Expert Presentations from the Sandoz 6th Standalone Transplantation Meeting, 2018

Legendre, Christophe MD1; Viebahn, Richard MD, PhD2; Crespo, Marta MD, PhD3; Dor, Frank MD, PhD, FEBS(Hon), FRCS4,,5; Gustafsson, Bengt MD, PhD, FEBS6; Samuel, Undine MD7; Karam, Vincent PhD8; Binet, Isabelle MD9; Aberg, Fredrik MD, PhD6,,10; De Geest, Sabina PhD, RN11,,12; Moes, Dirk Jan A. R. PharmD, PhD13; Tonshoff, Burkhard MD14; Oppenheimer, Fredrico MD15; Asberg, Anders PhD16,,17,,18; Halleck, Fabian MD19; Loupy, Alexandre MD, PhD20; Suesal, Caner MD21

Author Information
doi: 10.1097/TP.0000000000002846
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INTRODUCTION

Transplantation medicine is a rapidly evolving field and over the last years there has been substantial progress in organ exchange strategies. Organ exchange helps improve transplantation opportunities for patients in special groups, such as highly immunized or high urgent (HU) patients. It also ensures that organs that have no suitable recipient in the country of donation can be made available for transplantation elsewhere.

The goal of transplantation is to not only ensure patient survival but also offer improved health and a good balance between the functional efficacy of the graft and their physical and psychological well-being to patients. Encouraging higher levels of patient engagement and personalizing communications may enhance long-term posttransplant care. The meeting thus encompassed a range of topics around a patient-centered approach in transplantation with consideration of the following issues: quality of life (QoL) beliefs and behaviors; medication adherence; optimization of follow-up; and personalized medicine.

ORGAN TRANSPLANTATION IN EUROPE: FACTS AND TRENDS

In 2015, 5746 organ transplants were performed in France within 47 transplant centers at university hospitals.1 Diversification of donor type has led to the overall expansion of the donor pool which has been linked to the utilization of older donors or those with comorbidities. The introduction of the Kidney Allocation System created a new policy for organ allocation at national level.

The Kidney Allocation System objectives were to:

  • Keep existing National Priorities unchanged
  • Introduce a Unified Allocation Score (UAS), applied locally for one kidney and nationally for the other
  • Replace regional borders by a Gravity Model, introducing an interaction between UAS and shipping time

In France, the UAS has improved transplant access and HLA matching in young adults. The allocation of 1 of the 2 kidneys to local teams enables a link between retrieval and transplant and limits the travel of the graft, but contributes to regional disparities in organ allocation.

In Spain, the success in solid organ transplantation lies in the development of good practice in the process of organ donation as the result of a specific organizational approach around the process of deceased donation. The approach incorporates: a coordinated transplant network at national, regional, and hospital levels2; designated coordinator profiles; the National Transplant Organization supporting, among others, sharing programs for the sickest patients, highly sensitized or pair exchange for incompatible living donation; a quality assurance program3; training and education; a positive media relationship; and appropriate hospital reimbursement. During recent years, a plan to continue growing was designed, focusing on 5 areas: intensive care to facilitate organ donation; consideration of expanded and nonstandard criteria donors; improvement of donation after circulatory death (specially controlled circulatory death); incorporation of special surgical techniques; and encouragement of living donation.4 In 2017, Spain had the highest number of solid organ transplant (SOT) procedures per million population (pmp) in the world and there were 46.9 donors from 188 hospitals authorized for donation and 113 transplant procedures pmp.5 That is, 5257 SOTs were performed in 43 hospitals in a country with 46 570.000 inhabitants, thus reducing waiting lists.

There are 51 transplant centers in the United Kingdom, and during 2016, 72.1 total transplant procedures pmp were performed.6 Over the last 10 years, there has been a 24% decrease in waiting lists, 57% increase in transplants (all organs), and 75% increase in deceased organ donors.

The UK Living Kidney Sharing Scheme was established in 2012 to guide the sharing of donated kidneys across the United Kingdom.7 It includes paired or pooled donation and donor chains initiated by nondirected (unspecified) donors.

A new strategy “Taking Organ Transplantation to 2020: A UK strategy” aims to continue improvements in the UK transplant rate and provides a series of calls to action to enable the United Kingdom to match world-class performance in organ donation and transplantation.8

International cooperation enables additional organ sharing opportunities. The European Network for Collaboration on Kidney Exchange Programmes is a program supported by COST to develop strategies to implement a collaborative KEP to allow organs to be exchanged between countries.9

Scandiatransplant is the organ exchange organization for Denmark, Finland, Iceland, Norway, Sweden, and Estonia.10 During 2017, the Scandiatransplant total deceased donor transplantation rate was 18.5 pmp.

Scandiatransplant serves as collaborative platform through specialized working and advisory groups to facilitate best practice recommendations and policies optimizing retrieval, allocation, and transplantation of organs.10 Guidelines for each organ type are updated regularly. For example, 2017 rules regarding liver exchange and payback state that 72 hours after an HU call, every center has an obligation to offer available livers for the recipient center.

Other guidelines include the Scandia Transplant Accepted Mismatch Programme and the Scandia Transplant kidney Exchange Programme.

Eurotransplant—which was founded in 1967—facilitates patient-oriented allocation and cross-border exchange of deceased donor organs in Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands, and Slovenia, serving a population of around 136 million inhabitants. On January 1, 2018, there were 14 733 patients registered on the active organ waiting list, of which 10 768 were newly registered during 2017. In 2017, 6636 organ transplants from deceased donors were performed (Figure 1).11 Of all organs made available, 26.1% were exchanged cross-border, which benefits specific patient groups such as HU or highly immunized patients and pediatric patients, as well as smaller countries because of their inherently limited donor and recipient pool.

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FIGURE 1.:
Euro-transplant facts and figures. Reproduced with permission from: https://www.eurotransplant.org/cms/mediaobject.php?file=ET+factsheet+January+20185.pdf (accessed November 2018).11

During the last 20 years, the median age of the donors has risen. In 1990, it was between 30 and 40 years. Almost 30 years later, the donors are around 20 years older.12 The age of patients on the waiting list is also rising.

Organs are not yet matched according to gender. However, with some organs, for example, thoracic organs, it is more likely that an organ with the same gender is transplanted. This is related to the need to match the height and weight of the donor with that of the recipient.

Key Learning: Waiting time for organs remains an issue in many countries. Initiatives to develop or expand cross-border exchange of donor organs can help ensure better use of the available donor organs.

QoL: DISCREPANCIES BETWEEN BELIEFS AND BEHAVIORS

Victim of its success, the number of SOTs performed each year increases constantly.13 As a result, the cumulative number of individuals living long-term with a functional graft is dramatically growing. Thus, the SOT professionals shift their attention from acute to long-term management. Patients differ from healthcare professionals in their assessments of “symptom bother” and impact on QoL. Therefore, patient-reported measures of physical, psychological, and social functioning are useful tools to complement clinical outcome measures.

The lack of consensus about how to define QoL is a limitation when measuring QoL outcomes in transplantation. The World Health Organization uses a multidimensional definition describing health related (HRQoL) as not only the absence of disease but also the presence of physical, mental, and social well-being.14 HRQoL may also be defined as a state of well-being based on 2 components, including the ability to perform daily activities that reflect physical, psychological, and social well-being and the patient’s satisfaction with his level of functioning, control of his illness, and symptoms related to his treatment.15,16

There is a lack of consensus in transplantation regarding the choice of instruments used to measure QoL as well as their validation and translation for use across different countries. Generic instruments such as the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) are commonly used, although condition-specific instruments have been developed for transplant recipients and are considered to be more efficient at measuring QoL changes.17-20

Historically, the methodology used for assessment of long-term outcome in transplantation recipients has had its limitations. Despite the availability of many cohorts of organ transplantation, most studies are limited to the first year posttransplant, are cross-sectional rather than longitudinal, involve small number of patients, are not validated and translated instruments, and have no comparisons with general population.21

In recent years, the importance of assessing of QoL after transplantation has received better recognition, as evidenced by the increasing number of trials including QoL outcome measures. However, there are few longitudinal studies (Figure 2) and little empirical research in SOT on patients’ judgment about what they value in relation to their QoL.

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FIGURE 2.:
Frequency of publications in SOT identified in the PubMed database (1970–2018) with QoL measures as described in the title. QOL, quality of life; SOT, solid organ transplant; Tx, treatment.

Key Learning: The use of QoL outcome measures can help inform long-term management of transplant recipients, along with clinical data. There is currently much variation in the methodology used for assessment of QoL after transplantation. Longitudinal studies using condition-specific QoL instruments are required.

Patients benefit psychologically and socially from transplantation as well as physically. Patient-centered analysis of QoL, such as assessment of mood status22 and sleep quality23 and disease-specific HRQoL,24 can provide useful insights to help improve recipient QoL after transplantation. Contextual inquiry methodology, using home visits, allows a more in‐depth understanding of the “reality” of daily life and has demonstrated that patients find implementation of healthcare strategies difficult.25

Before transplantation, patients may overestimate the scale of QoL improvements, and those low in optimism are vulnerable to distress as a result of their high expectations.26 Unmet lifestyle expectations after liver transplantation may lead to increased stress, which affects QoL long term.27 Preoperative health may impact expectations for posttransplant QoL. In a study of HRQoL after lung transplant, expectations for HRQoL in patients without chronic lung allograft dysfunction were met, while those with chronic lung allograft dysfunction experienced HRQoL that was better than or at least similar to that expected—an example of the so-called “disability paradox.”28 Feeling adequately informed and having high optimism has a positive influence on posttransplant QoL, while limitations in ability to work or perform recreational activities, severe complications during hospital stay, unfulfilled expectations, and distress are all negative determinants for posttransplant QoL.27,28

The Pictorial Representation of Illness and Self Measure is a simple visual tool to measure illness burden and may be used to explore levels of suffering and help identify patients at a higher risk of psychological disorders through the self-illness separation distance (Figure 3).29

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FIGURE 3.:
The Pictorial Representation of Illness and Self Measure tool. Adapted with permission from Kabar et al.29

Patient health beliefs and perceived barriers may influence the likelihood of engaging in health promoting behavior after transplantation. There is a need for education programs to be targeted and population specific. In a Korean study, less than half (~47%) of kidney transplant patients received the influenza vaccination despite recommendations to take it.30 Beside cues to action, perceived barriers, perceived benefits, and perceived severity all play a role in the health belief model. In another study, although ~35% transplant patients reported being unaware of the risk of skin cancer, education about the risk did not lead to less sun exposure, even in patients with skin tumors, emphasizing the educational gap.31

In Switzerland, as in other countries, increased collaboration and involvement of patients in research is requested by policy and funding agencies. A greater patient involvement should lead to better understanding about beliefs and behaviors and what matters to transplant recipients. The European Patients’ Academy provides patients with education and training to increase their capability to understand and contribute to medical research and development.32

Key Learning: Feeling adequately informed and having high optimism has a positive influence on posttransplant QoL. Targeted and population specific education programs are needed to support health promoting behavior after transplantation.

The benefits of transplantation across organ type on the QoL of patients after transplantation is well established in a number of studies and meta-analyses (Figure 4).33-35 The greatest improvements are seen for general QoL and physical functioning. Less consistent improvements are found for the psychosocial or mental components, but in many cases, psychosocial QoL is good already pretransplant.30,36 Although QoL improves after transplantation, transplant recipients continue to have significant deficits compared with healthy controls.37 Disease-specific symptoms may improve posttransplant, but the side effects of immunosuppressive medications can worsen other symptoms (nausea, tremors, headaches, and excess appetite).38 However, there is a paucity of randomized trial data on the effect of different immunosuppression regimens on QoL.39

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FIGURE 4.:
Meta-analysis: QoL after kidney transplantation. Adapted with permission from Landreneau et al.35 QoL, quality of life.

Patients deriving the greatest QoL benefits are those in the poorest pretransplant condition.34 However, there remains a significant proportion of patients for whom transplantation brings poor QoL outcomes with deterioration in physical functioning and psychosocial outcomes.40 For example, a high pretransplant body mass index has been shown to hinder the improvement in physical QoL after liver transplantation.41 Fatigue is chronic problem after liver transplantation, and fatigue severity is associated with sleep quality, anxiety, and depression.42

The long-term pattern of QoL after transplantation shows an increasing proportion of patients experiencing relevant symptoms and a general worsening of QoL over time.43 Structured intervention programs and psychological assistance addressing these symptoms, as well as long-term patient follow-up and individualization of immunosuppression therapies, are needed to enhance the QoL-benefit from transplantation.44-47 QoL of the patient’s caregiver appears relevant as it may impact posttransplant outcomes,48 which calls for increased caregiver involvement after transplantation.

Key Learning: Greater benefits are experienced in the general and physical functioning domains than the psychosocial domain of QoL after transplantation. The long-term pattern of QoL after transplantation shows a general worsening of QoL over time.

MEDICATION ADHERENCE IN SOT

Adherence to medications is defined as the process by which patients take their medication as prescribed. Adherence consists of 3 interrelated yet separate phases: initiation, implementation, and persistence.49Initiation refers to taking the first dose of a prescribed drug. For immunosuppressants, this happens typically in the hospital. Implementation refers to “the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen from initiation until the last dose is taken.” Persistence is the third phase, and discontinuation (nonpersistence) happens when patients stop taking their medicine on their own initiative. Nonadherence refers to noninitiation, suboptimal implementation (eg, late, skipped, extra, or reduced doses or drug holidays), or discontinuation (nonpersistence). Medication nonadherence in transplantation has been defined as deviation from the prescribed medication regimen sufficient to adversely influence the regimen’s intended effect.50 Nonadherence to immunosuppressants is considered clinically meaningful if there is >5% deviation from the dosing schedule.51

The choice of an adherence measurement method requires careful consideration of (1) the phase of adherence (initiation, implementation, persistence), (2) the context (routine clinical care, trial setting, cohort studies/registries), (3) the purpose of adherence measurement (observational and/or interventional), (4) user perspective in view of preference and usability of the adherence measure, and (5) the type of data that are collected (reliability and accuracy as well as rich or sparse data). In the absence of a gold standard for medication adherence measurement, available methods for assessing adherence to immunosuppressants can be positioned along 2 intersecting axes: (1) reliable to biased assessments and (2) sparse to rich sampling (Figure 5).52

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FIGURE 5.:
Medication adherence methods. Adapted with permission from Vrijens and Urquhart.52

Results from therapeutic drug monitoring (TDM) assays are a fairly reliable yet sparse assessment that is routinely applied in transplant care and can be used to calculate the Medication Level Variability Index as an indicator for nonadherence.53 The use of therapeutic monitoring using dried blood spot sampling enriches the assay method as more frequent assessment can be performed while patients are in the home settings, although further studies are needed to define its clinical utility as an adherence measure in transplantation.54 Medication adherence self-report questionnaires (eg, Immunosuppressant Therapy Adherence Scale, Simplified medication adherence questionnaire, BAsel Adherence to Immunosuppressive Medication Scale) are less reliable and result in scarce data collection, yet can be easily implemented in routine care to assess medication adherence as the fifth vital sign.55

The most reliable and rich adherence measurement is the use of electronic monitoring devices,56 admittedly an indirect method, as ingestion is not proven. However, a specific type, the Ingestible Sensor System, allows direct assessment of the ingestion of oral medications and thus adherence assessment. This system has been tested in a transplant as well as a psychiatric population.57 The latter was Abilify MyCite, a pill with a built-in sensor for adherence monitoring linked to a digital health feedback system used in clinical trials.58 Usability and implementation issues limit their use in routine practice settings. Importantly, electronic monitoring systems allow visualization of adherence medication dynamics and feedback loops to the patient including tailored behavioral interventions can be established, which have proven to be a most efficacious intervention for improvement of adherence in transplant and nontransplant populations.59,60 Thus, the use of digital reminder technology based on electronic monitoring has potential to help facilitate adherence and individualize medication in an integrated approach.

Key Learning: Medication adherence is crucial for successful long-term outcomes after transplantation and needs therefore to be considered as the fifth vital sign in transplant care. Adherence assessment methods vary in view of degree of reliability and from rich to sparse data collected.

Tailoring Immunosuppression Therapy

TDM is an important tool to optimize therapy with immunosuppressive drugs that have a narrow therapeutic window, poor correlation between dosage and blood concentration, and high inter-patient variability in pharmacokinetics. TDM involves the measurement of drug blood concentrations in terms of area-under-the-blood concentration versus time curve (AUC) or trough levels.61

Analytical measures to determine blood concentrations may differ in sensitivity and specificity and subsequently have variable performance. This variability can potentially lead to clinically relevant differences in dose adjustments.62 In a study of renal transplant patients, the specificity and sensitivity of liquid chromatography-tandem mass spectrometry outperformed fluorescence polarization immunoassay for clinical drug monitoring for everolimus.62

There are a number of factors that contribute to patient variability in drug response, which include: demographics (age, gender, race and bodyweight), comorbidities (diabetes, cardiovascular), organ functioning (intestine, liver, kidney, cardiovascular system), co-medication, nutrition, smoking, and compliance to drug therapy.

Calcineurin inhibitors (CNIs) show large variability in pharmacokinetic and pharmacodynamic pathways. Genetic variants in proteins involved in the CNI metabolic pathway can contribute to differences in the efficacy and toxicity of CNIs.63 Much of the inter-individual variability in tacrolimus (Tac) pharmacokinetics is explained by the presence of a single nucleotide polymorphism resulting in the absence of a functional CYP3A5 protein.64 Information about the CYP3A5 genotype can be used to individualize the initial dose of Tac and subsequent TDM can improve treatment outcomes.

Measurement of exposure for drugs, such as mycophenolic acid, with a variable pharmacokinetic profile remains a challenge.65 The most informative measure for true drug exposure is the AUC, which requires multiple concentration markers for an accurate calculation but is laborious and inconvenient for the patient. Ctrough monitoring is widely used for TDM, as it is easy to obtain and requires only a single sample; however, the correlation between Ctrough and AUC is not optimal for every immunosuppressive drug.66,67 A limited sampling strategy with or without dried blood spots measurements combined with Bayesian estimation using a population pharmacokinetic model may offer a practical alternative to Ctrough for the prediction of drug exposure.65

Computational population pharmacokinetic software packages are available to estimate the AUC using a limited sampling strategy based on a compartmental population pharmacokinetic model and have been shown to be clinically useful. They may provide a simple, flexible method to tailor immunosuppression.68,69

Key Learning: TDM is an important tool to optimize therapy, and the most informative measure is the AUC. A population pharmacokinetic computational software package using a limited sampling strategy may provide a simple method to tailor therapy for every patient.

Adherence Improvement in Pediatric Transplantation

Adolescent age at transplant is an independently significant risk factor for worse long-term graft survival in all major pediatric SOT types.70

Developing interventions to optimize adherence to medication is challenging, and even when medication is taken as recommended there are no guarantees of graft survival. Nonadherence is difficult to measure accurately and the reasons for nonadherence are complex and difficult to address (Figure 6).71,72 Randomized trials that investigate multicomponent interventions incorporating socioeconomic-, treatment‐, condition‐, and patient‐related factors are needed.71

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FIGURE 6.:
Five dimensions of adherence. Adherence to long-term therapies: evidence for action. WHO 2003. Adapted with permission from Sabaté et al.72 WHO, World Health Organization.

Pilot studies investigating the implementation of a peer mentoring program,73 group meetings,74 and daily phone reminders75 in adolescent transplant recipients have shown promise and warrant further evaluation.

The 2018 randomized Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial investigated a multicomponent adherence-promoting intervention that included a combination of electronic adherence monitoring and feedback, problem-solving skills training, goal setting, and technology-based adherence support found that this approach improved adherence compared with the control group, who received no feedback on adherence data.56 The impact of improved adherence on graft outcomes requires further investigation.

A 2018 systematic review of adherence interventions in transplant recipients concluded adherence interventions are largely ineffective in improving transplant outcomes and recommend that interventions concentrate on nonadherent patients, use direct measures of adherence to guide the interventions, and employ strategies that engage nonadherent patients.76

Assessment of barriers to adherence (forgetting, difficulty swallowing pills, side effects, health literacy, complex regimens, etc) using a standardized automated clinic-based system as part of routine posttransplant care is feasible in the clinical care of pediatric kidney transplant patients. It also provides an opportunity for healthcare professionals to interact with patients and caregivers to optimize adherence.77

Key Learning: Adolescent age at transplant is an independently significant risk factor for worse long-term graft survival in all organ transplant types. Interventions should be guided by direct measures and concentrate on nonadherent patients.

HOW TO OPTIMIZE THE FOLLOW-UP IN ORGAN TRANSPLANTATION

Optimize Resources: Hospital Structure and Organization

Due to the increase in the prevalence of patients with a functioning graft requiring long-term follow-up,78 transfers of posttransplant care from the transplant center to another institution are increasingly required.79 Transfers may occur early (<6 mo) or later (>6 mo) after transplant and should be considered when the patient has established clinical stability (Table 1).

T1
TABLE 1.:
Parameters defining stability for transfer of care of kidney transplant recipients

The follow-up of transplant recipients requires the expertise of a diverse team of medical professionals (physicians, transplant nurses, administrators, radiologists, nutritionists, etc), facilities (transplant centers, local, regional, and national reference centers, laboratories, pharmacies), and support services. Ensuring adequate long‐term posttransplant follow‐up with an established treatment plan and monitoring protocol for patients is crucial.80 It has been shown that adverse drug events may be associated with a significant increase in the risk of hospital readmission after kidney transplant and subsequent graft loss.81

Medical transfer records with the relevant patient transplant reports should be interconnected and linked to the receiving transplant center to ensure that the full documentation is provided, and the center is prepared to care for the patient on arrival. Telehealth technologies used to share medical information in the delivery of clinical care may be used to integrate data from databases and communicate with patients using smartphone apps and texts and Web portals.82

Key Learning: Transfers of posttransplant care from the transplant center to another institution are increasingly required. Transfer should be considered when the patient has established clinical stability. Telehealth technologies used to share medical information in the delivery of clinical care show promise for the management of long‐term posttransplant follow‐up.

Home Monitoring of Kidney Transplant Patients

Tac dose adjustment managed using Tac trough concentrations to compensate for changing pharmacokinetics with time after transplantation remains a challenge. A nonparametric population pharmacokinetic model was developed that could be used in the BestDose clinical dose optimization software package.83 The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates and showed satisfactory predictive performance in an external cohort of renal transplant recipients. In a prospective single-center study, computer-assisted dose individualization was compared with conventional dosing in renal transplant recipients and found to improve target concentration achievement of Tac (Figure 7).84 The computer software is applicable as a clinical dosing tool to optimize Tac exposure and may potentially improve long-term outcomes. Future developments to improve the workflow and quality of the data collected are underway.

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FIGURE 7.:
Mean percentages of Tac concentrations within the target range per wk after transplantation for the Computer Group and Control Group (left) and observed tacrolimus trough concentrations in the Computer Group and Control Group over time after transplantation (right). Adapted with permission from Størset et al.84 CI, confidence interval; Tac, tacrolimus.

Key Learning: The development of computer software based on a nonparametric population pharmacokinetic model can be applied as clinical dosing tool to optimize Tac exposure in renal transplant patients.

Drug Self-management

The need for an interconnected treatment for chronically ill patients with modern communication technology is recognized. A real-time and bidirectional communication within a single platform could facilitate optimized drug dosing and close surveillance.

The Medical Allround-Care Service Solution is a new patient-centered smart electronic healthcare service platform that is in development with partners from research, industry, health insurance companies, patient organizations, and healthcare service providers.85 The project aims to connect patients with their treating physicians and focuses on improving the safety of patients after kidney transplants. Patient data collected using Apps on patient smartphones are integrated with data from other medical services and hospital systems and used provide personalized real-time therapy.

Telemedical supported case management with the goal of optimizing posttransplant aftercare has been shown to improve adherence versus standard care in a randomized controlled trial in renal transplant recipients (N = 46).86 The prevalence of nonadherence over the 1-year study period was 17.4% in the intervention group versus 56.5% in the standard aftercare group (P = 0.013).

Communication is essential for good treatment; however, access to expert knowledge for patients living in rural areas or suffering from a rare disease can be difficult and have severe consequences. The Digital Allround Care Ecosystem incorporates an ecosystem of connected services across the healthcare system.87 Data collected from patients, nephrologists, physicians, pharmacists, nurses, and clinics are integrated on a communication platform. Doctors can monitor patient progress and patients can review treatment plans and ask questions on the same interface (Figure 8).

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FIGURE 8.:
Connected services and easy communication in a healthcare system. Image created by Dr. Fabian Halleck.

Key Learning: Real-time and bidirectional communication within a single platform can integrate data to facilitate optimized drug dosing and personalized real-time therapy.

PERSONALIZED MEDICINE

Algorithm Decisions

A personalized approach to transplant medicine requires converting large volumes of multidimensional data into meaningful clinical decisions and requires robust risk stratification models, which are currently lacking in the transplant field.88

In the past years, attention has been given to define surrogate endpoints that might aid therapeutic interventions, clinical trials, and clinical-decision making. The development of the Integrative Box (iBox) system (clinical trial.gov: NCT03474003) aims to enable transplant clinicians to predict individual risk of allograft loss and offer them the possibility to personalize clinical management and treatment for their patients. The iBox also aims to be a data driven composite surrogate endpoint in kidney transplantation and generalized and transportable across transplant centers.

The iBox initiative consists in deriving prognostic algorithms utilizing large and deep phenotyped cohort of kidney recipients from the Paris Transplant Group. The goal of iBox algorithms is to integrate large-scale data, combining traditional factors and biomarkers candidates to represent the complex spectrum of risk predicting parameters and ultimately provide clinicians with an easy ready-to-use interface for calculating estimated allograft survival based on individual data.

The iBox initiative involves 10 centers in Europe and the US with different medical and allocation systems, 3 randomized control trials and a variety of clinical scenarios and subpopulations, and a dynamic design allowing risk assessment at different time points after transplantation (Figure 9).

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FIGURE 9.:
The iBox system (image created by Alexandre Loupy). iBox, integrative box.

Key Learning: The iBox system aims to enable transplant clinicians to predict individual risk of allograft rejection and transplant loss and offer them the possibility to personalize clinical management and treatment for their patients.

How Should We Use CTS Data?

The Collaborative Transplant Study (CTS) is an international voluntary study in the field of human organ transplantation with the support of >400 transplant centers in 42 countries.89 Since 1982, data sets on 700 000 kidney, heart, lung, liver, and pancreas transplants have been collected which can provide invaluable insights into transplantation-related problems.

Data may be uploaded by participating centers using questionnaires or electronic forms or by using the CTS “TaXi” software. There are >2700 graphs based on analysis of CTS data on the CTS homepage which can be searched for by key word or term (Figure 10). Participants are able to analyze their own center’s data online.

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FIGURE 10.:
Collaborative Transplant Study (2019). Introduction [Online]. Available at www.ctstransplant.org/public/introduction.shtml (accessed 14 June 2019). CTS, Collaborative Transplant Study.

The strengths of CTS data include:

  • Large patient numbers for survival analysis
  • Real-life data
  • Inclusion of patients at high risk
  • Allows analysis of complex factors, rare events, and success of new procedures
  • Long observation time
  • Enables observation of secondary effects

The CTS conducts various prospective and retrospective studies on research topics. These include research on immunosuppressive drugs, graft loss, patient survival, HLA antibodies, organ allocation, and posttransplant malignancies. Results are reported in regular publications and newsletters by the CTS team to provide up-to-date knowledge. Support is provided for participants who wish to undertake research projects with CTS data.

Finally, the CTS provides high quality serological and molecular HLA-typing reagents and kits for antibody testing to study participants at self-cost.

Key Learning: The CTS holds data sets on >700 000 transplant recipients, and >2700 graphs based on analysis of CTS data are presented on its homepage, which can provide invaluable insights into transplantation-related problems.

SUMMARY

Initiatives to develop cross-border exchange of donor organs are important to make better use of available organs. Adherence behavior influences the long-term outcomes of transplantation and is a key target for intervention in posttransplant care. The development of computer software and integrated healthcare systems are increasingly used to improve monitoring, dosing, and communication between physicians and patients in real time.

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