Digital Home-Monitoring of Patients after Kidney Transplantation: The MACCS Platform

Kidney transplantation is the treatment of choice for patients with end-stage renal disease (ESRD) as it prolongs life, improves quality of life (QoL), and saves money and resources compared to maintenance dialysis^1,2. QoL is defined as the general well-being of individuals, and health-related QoL (HRQoL) is an assessment of how the individual's well-being may be affected over time by a disease, disability, or disorder³. Recently, QoL, HRQoL, and specific patient-reported outcomes were considered core outcome domains for kidney transplantation, which have become critically important to patients, health professionals, and regulatory agencies^4,5. Kidney transplant recipients (KTR) must change their lifestyle after transplantation, adhere to a complex medication schedule, and perform regular self-assessments⁶. The regular intake of immunosuppressive therapy is of utmost importance to ensure adequate drug blood levels⁷. Extremely low blood concentrations may result in under-immunosuppression, increasing the risk for rejection or the development of donor-specific antibodies (DSA). Acute rejections and DSA are major causes for graft loss. Extremely high blood concentrations of immunosuppressants may result in over-immunosuppression increasing the risk for drug-related side effects, infections, and malignancies. Therefore, strict adherence and regular control of laboratory values is necessary to adjust immunosuppressive therapy within a narrow therapeutic range.

Other frequent complications of immunosuppressive drugs include diabetes and hypertension, which can lead to costly hospitalizations and reduced QoL. To achieve better transplant survival, close monitoring and adherence are essential. Studies in the general population suggest that only ~50% of patients in the Western world are fully adherent to their medication schedule⁸. It has been suggested that approximately 20%-30% of graft losses in KTR are linked to non-adherence^9,10. There are many reasons for non-adherence including insufficient communication, misunderstanding, and forgetfulness¹¹. Key pillars for better adherence are good and clear communication and an unambiguous written medication plan¹⁰. Other important factors for adherence are an individually adapted explanation of the therapeutic concept and the understanding of medication and disease. Patient empowerment, which enables patients to better take care of their health, is the basis for better adherence and behavioral changes¹². Being adherent to medication and to a self-assessment plan is crucial for long-term success after kidney transplantation¹³.

The kidney transplant center at Charité cares for KTR from the metropolitan area of Berlin and Brandenburg. Many patients travel several hours for a consultation. Long travel times are an important problem in the care of KTR¹⁴, especially for elderly and frail patients, and also for those who have to manage a family and are working. Other hurdles are travel costs, inconvenience, and loss of working hours¹⁵. Therefore, the Berlin kidney transplant center and local nephrologists (physicians in private practice) share the care after kidney transplantation, which raises the problem of missing or incomplete information during a consultation. To minimize information loss, automatic and safe exchange of key data is needed¹⁶. However, to date, data have been stored in different data silos with no interoperability. Today, data exchange relies on telephone, letters, fax, or e-mails with limited data protection and is highly dependent on individuals. Thus, loss of information and incomplete data are common problems, and automatic, secure data exchange according to European (EU) General Data Protection Regulation (GDPR) remains a rare exception.

Several eHealth solutions have been suggested to support patients after transplantation to better utilize the potential of digitalization for the healthcare of this vulnerable patient group¹⁷. Early detection of complications allows early intervention by a telemedicine team, resulting in less severe complications, less hospitalizations, or a shorter length of hospital stay, as shown in other telemedicine projects^18,19,20,21. A high hospitalization rate is observed in the transplant population²². Approximately one-third of KTR are hospitalized annually with average costs of ~6,600 Euro per hospitalization. As a consequence, telemedicine-driven early interventions offer the opportunity to reduce hospitalizations and, by this means, reduce costs and improve QoL. One interesting target is to improve adherence, e.g., with the help of apps or telemedicine concepts. Due to the permanent availability of apps for smartphones, such apps can be included in interventions that aim to increase adherence. DeVito et al. demonstrated in a randomized controlled trial (RCT) that a user-centered app for lung transplant recipients with regular self-assessments, reminder function, remote vital sign monitoring, and an automatic decision support tool could improve adherence to therapy. But they did not observe significant differences regarding the 12-month hospitalization rate and mortality²³.

Schmid et al. conducted an RCT with a comprehensive telemedicine concept after kidney transplantation. They found a significantly higher adherence rate and a dramatic reduction in hospitalizations and costs^20,21. These results were confirmed by Lee et al. who reported significantly lower readmission rates within the first 90 days after liver transplantation than the standard of care with the use of additional telemedicine support through smart tablets¹⁹. Their telemedicine features consisted of using Bluetooth devices to remotely monitor vital signs, drug reminders, regular self-assessments, as well as access to educational sessions, text messaging and video conferencing tools. Better QoL, general health, and physical function were observed in patients in the telemedicine group. Adherence was excellent (86%) with respect to remote vital signs, but was only 45% for messaging or videoconferencing. However, not all studies could demonstrate positive effects of apps or eHealth solutions^17,19. Han et al. investigated an app with a medication reminder, intake documentation, and shared laboratory values, which also provided information about immunosuppressive therapy. They did not observe any significant difference in adherence between intervention and control groups in KTR, most likely due to high drop-out rates. In this RCT, only 47% used the app after 1 month²⁴.

The secure and interoperable MACCS platform for KTR was developed to address the limitations of current post-transplant care, namely the need for close monitoring, regular self-assessments, decreasing adherence, and loss of information between physicians. The platform enables patients to share vital signs, daily medication intake protocols, blood glucose, messages, and well-being with the transplant center via an app (see the Table of Materials). Well-being is captured by a simple question ("how are you feeling today?") and a 5-point Likert scale with different emojis (smileys) reflecting the current mood of the patient. In the transplant center, all data are stored directly in the electronic health record (EHR) called TBase²⁵. The EHR is tailored for the needs of transplanted patients, is used for regular post-transplant care, and automatically integrates all relevant data from the hospital, outpatient visits, and transplant-specific data such as donor data, ischemia times, and human leukocyte antigen mismatches. A telemedicine dashboard was implemented in the EHR for an easy review of incoming data by the telemedicine team.

The EHR is connected via a secure HL7 FHIR interface with an FHIR server (platform) outside the firewall of the transplant center, which transfers pseudonymized data from the transplant EHR (TBase) to the patient app. This allows the transplant center to send secure messages, laboratory data, and medication plans directly to the patient´s smartphone. Another important partner in the telemedicine project provides specialized software for local nephrologists and has a market share of ~65% in Germany (see the Table of Materials). The software connects to the HL7 FHIR server and allows direct communication between the transplant center and local nephrologists. The shared data include laboratory values, medical letters, test results, vital signs, and medication plans. With the use of an automatic data exchange, the platform aims to eliminate loss of information, as well as manual, incomplete, insecure, or late data transmission. By this means, workload is reduced, and time-consuming tasks and errors are eliminated to create significant efficiency gains. The platform also facilitates communication between physicians through an easy exchange of notes to prevent information gaps. Another advantage is the fact that data are transmitted directly into the software of the physicians to be used for daily routine. Thus, physicians only work with familiar software and do not need to use different software tools (Figure 1).

The concept of the project is GDPR-compliant, and all of the data are protected according to the highest European standards. Individual data are visible for approved medical personnel only. All information is encrypted and transferred according to HL7 FHIR standards. The patient can give and deny access rights to other physicians through the app and can cancel participation at any time. Data are transmitted only after written informed consent and after a complex onboarding process (digital inclusion process). It is important to mention that all services of the platform are offered as an additional service to patients, free of charge. Thus, patients can choose between regular care or regular care plus telemedicine services. The project started to enroll patients in February 2020, and the additional telemedicine services are supported by two large health insurance companies.

In summary, a comprehensive telemedicine platform for KTR was established. Initially, the German Federal Ministry of Economy and Energy (BMWi) funded the project as part of the open call "Smart Service World" to stimulate the growing number of smart services in healthcare. The basic concept is similar to other comprehensive telemedicine systems^{18,19,23,26,27}. Compared to most telemedicine concepts, the advantages of the platform include its interoperability through standardized HL7 FHIR interfaces and GDPR compliance. The platform has no specific hardware requirements. The apps are free of charge and allow straightforward and easy use. The possibility for an easy multi-channel communication with the telemedicine team might also increase the use of the app for home monitoring. Patients use their regular scale and blood pressure device at home, and no costly and complicated Bluetooth devices are needed. Another innovative feature of the platform is the direct involvement of local nephrologists. Patients are usually treated by a combination of tertiary kidney transplant centers and local nephrologists, who already know the patient from dialysis or predialysis times.

As patients frequently visit their local nephrologists, a comprehensive platform for KTR should also automatically incorporate the local nephrologists to prevent information gaps. Importantly, the platform also implements automatic safe data exchange and communication with local nephrologists, who can use their regular software and have a direct added benefit due to automatic data exchange with the transplant center. In contrast to similar eHealth solutions, the platform is fully integrated into the workflow of the transplant center and the local nephrologist. The platform also fully integrates the local nephrologist in the data exchange of key variables and provides extensive, safe, and easy communication tools for physicians and patients. The direct benefits for users should increase acceptance and reinforce regular use. Further improvements of the platform are under development, and after establishment of an advanced stable platform, a prospective RCT on KTR is planned to provide solid evidence for better outcomes and cost effectiveness.

The protocol follows the current guidelines of the ethics and data protection committees at Charité - Universitätsmedizin Berlin and is in compliance with current EU GDPR.

1. Perspective of the telemedicine team

1. Screening for patients
   NOTE: Key data of the project are provided in Table 1.
   1. Ask the nurse to screen incoming outpatients or patients on the ward for eligibility. Ask the telemedicine team (nurse and physician) to talk to patients in the outpatient clinic or on the ward about the content, data protection, and aim of the project.
   2. After agreeing, ensure that the patients provide written consent. Ensure that the nurse documents refusals and reasons for not participating and checks again with patients who need time for consideration.
2. Role of the nurse in the patient onboarding process
   1. Ask the patient to show his/her smartphone and support the patient in downloading the app from Apple Store or Play Store.
      ​NOTE: If the patient does not own an adequate smartphone, the telemedicine team provides a smartphone for the time of participation.
   2. Search for the patient in the transplant database (TBase).
      1. Click on the Onboarding into MACCS project button. Ensure that the patient registers on the registration web page with the initial login data automatically created by the transplant database.
      2. Ask the patient to create new login data and digitally confirm consent when redirected to the consent page. Ensure that the patient logs out of the registration page after the platform establishes a safe connection between the patient app and transplant EHR (TBase).
3. Patient training by the nurse
   1. Show where to find laboratory values and how these are presented; how to find the text messaging function and how to send a message; how to start a video consultation; how to find a medication plan and how to confirm medication intake; and check the current medication plan for correctness.
      ​NOTE: The current medication plan is transferred to the app automatically once the connection is established.
   2. Demonstrate how to submit vital signs, blood sugar, well-being status, and confirm or decline medication intake. Train the patient how to take the immunosuppressive drugs correctly, and how to measure the heart rate and blood pressure correctly.
   3. Set the patient's current body weight in the telemedicine dashboard by clicking on the Therapeutic Plan button, fill in Weight in kg, and click on Confirm Data.
   4. Define the therapeutic plan for home measurements with the patient and fill out the Frequency table in TBase.
      NOTE: The individual adherence plan is one part of adherence calculation and is documented in the dashboard.
   5. Discuss with the patients when to contact them in to remind them to forward data; encourage the patients to always call in case of medical or technical problems. Explain the working hours of the telemedicine team, morning hotline for urgent issues, and what to do in case of medical problems or emergencies during and after the regular working hours of the telemedicine team.
   6. Check whether data have been received the next day, and call patients to explain that the data have arrived and ask about any technical issues they may have faced.
4. Daily routine of the telemedicine team
   NOTE: Monday to Friday from 8 a.m. to 4 p.m. (Table 2). Outside regular working hours, the nephrologist-on-call has full access to the transplant database and the telemedicine dashboard. The telemedicine team consists of at least one experienced nurse for every 300 patients, and at least one experienced medical doctor for every 600 patients. One medical doctor is always on duty (Table 1). Currently, the telemedicine team consists of two nurses, three junior physicians, and four senior nephrologists.
   1. Daily routine of the nurses
      1. Start the day with a structured process in reviewing incoming vital signs in the telemedicine dashboard (Table 3). Filter patients according to their critical values as defined in Table 4 and, if necessary, call the patient or discuss the case with a physician from the telemedicine team.
      2. Review well-being data. Call patients if the well-being score is low or if it decreases by more than 2 points. Consult a physician of the telemedicine team if the reason for the decrease in well-being is critical. Review less critical, but suspicious values and, if necessary, discuss these cases with a physician from the telemedicine team.
      3. Control incoming medical messages and take action, if necessary. Document all calls and activities in the telemedicine dashboard chart.
      4. Identify patients who did not document data in the app as previously agreed. Call the patients and ask about potential technical problems as the reason for the missing data. If technical data transmission is working, remind the patient to regularly forward data as agreed.
      5. Answer incoming calls (on medical and technical questions) from patients and local nephrologists. Ask patients at regular intervals about satisfaction with the telemedicine service and usability of the app, and document this information, which is forwarded to the development team for evaluation and continuous improvement.
   2. Routine of the physicians on duty in the telemedicine center
      1. Review reports from the nurses on critical values, e.g., high blood pressure (acute onset or over longer periods). Contact the senior nephrologist of the transplant team, or the physician who saw the patient during the last inpatient stay in severe cases.
      2. Call the patient, take medical history, and give advice, e.g., how to measure the blood pressure correctly or advise on other medical problems. Follow the patient closely over the next days if a change of medication or an unclear situation has occurred.
      3. In severe cases, advise the patient to contact the local nephrologist for a visit, to go to the next emergency room, or to come to the kidney transplant center for follow-up.
      4. Contact the local nephrologist or emergency room upfront, if needed. Update the senior nephrologist at regular intervals and have a daily brief consultation with the team in the kidney transplant center on problematic cases. Document all contacts and activities in the telemedicine dashboard.
         ​NOTE: All physicians and nurses in the regular transplant service have full access to the transplant database, including all data in the telemedicine dashboard.
      5. Review reports from the nurse on non-adherent patients, analyze the type of non-adherence, and determine a procedure to improve adherence, together with the regular transplant team or local nephrologist. Aim to strengthen adherence through advice and telephone calls or video consultations.
      6. Contact a psychologist for behavior therapy to strengthen adherence, if necessary. Follow patients with documented non-adherence more closely. Provide regular feedback to the senior nephrologist and development team.

2. Perspective of local nephrologists

1. Training of local nephrologists by the telemedicine team
   1. Inform the local nephrologists about the project through letters, events, and congresses and offer central training courses and video courses.
   2. Make an appointment with local nephrologists for a training and onboarding visit. During the visit, explain the project in detail to the physicians and nurses, discuss data protection, and answer questions.
   3. Explain the contract to local nephrologists, who sign the contract with the transplant center with specified terms and conditions. Explain the technical onboarding process in detail, and provide assistance and documents on how to include patients in the project.
2. Onboarding process of patients by local nephrologists using the software system (Table of Materials)
   ​NOTE: Through a general update, all software users have the option to participate, and the current software version has a built-in functionality for a secure connection to the FHIR server.
   1. Select the patient participant in the software. Click on the MACCS button; after the local software opens an overlay window, click on Connect.
      NOTE: The local nephrologist can only include patients who are already participating and have gone through the onboarding process at the transplant center.
   2. After the local software generates login data (code and QR code), ask the patients to scan the QR code with their smartphones (or enter the code manually) and complete the onboarding process by clicking on the Data Sharing button to indicate agreement.
      NOTE: The platform now enables an automatic data exchange of pseudonymized data with the transplant center and the patient app.
   3. Review the data transferred from the transplant center in the local software system.
3. Interaction of the local nephrologists with the telemedicine team
   1. Call the telemedicine team if medical or technical problems occur. Ask the transplant center (including the transplant pathologist and senior transplant nephrologist) for telemedicine consultation to discuss the best therapy for the patient, if necessary.
   2. Attend a (virtual) training session, workshop, or onsite presentation.

3. Perspective of patients

1. Onboarding process
   ​NOTE: Onboarding of patients will take place with the help of the telemedicine team after explanation of the additional services of the project, data protection, and right to withdraw at any time.
   1. Listen to the telemedicine team and ask questions. Give signed consent and download the app with the help of the nurse.
   2. After receiving the initial login data from the nurse, change the login data, and confirm participation digitally. Enter the new login data into the app and push Sign in. After the app opens, enter the well-being status, and click on the Send button. Observe the buzzing sound and the confirmation sign (green banner showing Feedback sent).
   3. Measure the blood pressure, enter the data into the app, and push the Send button. Observe the buzzing sound and the green banner pop-up showing Vital Data Sent. Look at the Show History list and observe the table with all the values and transmission information.
   4. Open the Communication page and send a text message to the nurse. Start a video session by clicking on the Video button. Open the Lab Results page and look at recent laboratory data. Open the Medication page, scroll through the medication plan, and confirm medication intake. Set the alert function for timely medication intake.
   5. After the nurse explains how the medication plan can be forwarded and printed out, log out of the app.
2. Use of the app by patients at home
   1. Open the app and enter the vital signs. Look at laboratory values, medication plan, and confirm medication intake.
   2. Send a text message and perform a video consultation. Enter login data in the registration page and look at the consent page, where consent was given for data transfer to the local nephrologist, and where consent can be easily withdrawn.

In the first 5 months between February and July 2020, 172 KTR matched the inclusion criteria and were asked to participate (Table 1). Out of 172 participants, seven needed to borrow a smartphone (four did not own one, three needed a new one); all other patients owned a smartphone. The app does not need wireless access (Wi-Fi) as data can be transferred by mobile phone via regular telecommunication services, and 2/172 patients were equipped with a subscriber identity module (SIM) card for mobile data transfer. Thirty-three patients (19%) declined for various reasons (Figure 2). Some patients did not have Wi-Fi or mobile data and therefore, did not want to participate.

One patient was excluded due to poor cognitive function as they were unable to handle the app. However, one patient with severe visual impairment and one blind patient were successfully enrolled, and five patients participated with the help of their relatives. Two patients participated from abroad, although they do not have easy access to mobile data or Wi-Fi. They transfer data from time to time, when they visit friends with Wi-Fi access or go to Wi-Fi access points in town. In the end, 139 patients were finally enrolled. Of these, 8 patients (5.7%) withdrew, and 131 patients are still participating in the project. The demographic characteristics are shown in Table 5, and a first overview of incoming data is depicted in Table 6. In total, 29,089 entries were transmitted on 8,954 observation days from 131 active participating KTR, which resulted in 3.4 entries per day and per patient.

Figure 1: Data flow of the MACCS project. Abbreviations: EHR = electronic health record; MACCS = Medical Assistant for Chronic Care Service. Please click here to view a larger version of this figure.

Figure 2: Screening and drop-outs between February 28, 2020 and July 27, 2020. Please click here to view a larger version of this figure.

Table 1: Key information of the MACCS project. Abbreviations: MACCS = Medical Assistant for Chronic Care Service; KTR = kidney transplant recipients.

Table 2: Core features of telemedically supported case management.

Table 3: Priorization of tasks of telemedicine team and local nephrologists.

Table 4: Assessment of vital signs.

Table 5: Demographic and clinical characteristics of participating patients. Abbreviations: Min = minimum; Max = maximum; ADPKD = autosomal dominant polycystic kidney disease.

Table 6: Number of vital signs received during the observation period.

A comprehensive telemedicine platform was created to improve the care of KTR. The platform was readily accepted by patients with excellent participation in sending vital signs from home. To develop the platform and to provide these services to patients, extensive software engineering was necessary. Critical steps included (a) constant software development with the involvement of all stakeholders from the beginning, and (b) a comprehensive data protection concept, which was achieved with the help of a specialized law firm. This iterative process resulted in the release of several new versions of the different software components and apps, which were engineered toward a more patient-centered design. Key factors for the successful implementation of new features were close communication through weekly meetings, constant troubleshooting, involvement of the users, and quick problem-solving. During the initial development process, several workshops were organized with participation of all user groups (including patients) to find the best software design and to prioritize the most important features for a basic first version of the platform. In these workshops, patient engagement focused on acceptance issues, usability, identification of key features, and patient burden for documentation. Additional interviews with clinicians, local nephrologists, and patients helped to shape the project toward the needs of the different users. An extensive literature search provided additional insights¹⁷.

Interoperability is of crucial importance for future development, acceptance, and scalability. Therefore, the most advanced interoperability standard, namely, HL7 FHIR, was implemented. This allows further development in an open-source environment and the utilization of the large HL7 FHIR community for rapid adaptation of future needs (e.g., to integrate wearables or other apps) and a seamless integration into other eHealth solutions (e.g., EHR of hospitals and health insurance companies, different physicians' software) or a larger eHealth framework (e.g., GEMATIK, the future German patient health record). Another important feature of HL7 FHIR-derived communication is the availability of highest data privacy. An extensive data protection concept was developed based on informed consent and secure data transfer of only pseudonymized data according to strict EU GDPR. Because development of the platform takes place in a separate developer container, and researchers only have access to pseudonymized data on the replication server, regular developers and scientists have no access to the live system with patient data. The partner, who hosts the FHIR server, has access only to pseudonymized patient data. The key for pseudonymization is separated and transferred during the onboarding process to the patient app, where the patient can administer access rights. All servers with patient data are localized within the EU according to the latest GDPR. Thus, patient confidentiality is already protected by virtue of the platform design.

However, an app can only help if it is used, similar to drugs or other interventions in healthcare. Therefore, a simple and intuitive user experience in combination with regular reinforcement, e.g., through the telemedicine team is needed to ensure effective intervention. If patients feel that they benefit directly from the app (e.g., through additional communication services, ease of documentation, reminder function), they will use it more often. In this regard, patient empowerment, flexibility, adjustment to individual needs, and teaching are critical to achieve a constant and regular use of the app. As a consequence, constant assessment of use, acceptance, and attrition rates as well as a thorough analysis of problems is needed for a steady improvement of the platform to achieve the goal of better patient care. Last, but not least, the successful implementation of the platform relies on the "human factor", namely, the usability of the system, its effect on the workload, and the interaction of the telemedicine team with the patients as well as their local nephrologists. The platform is one of the first to include local physicians and thus enables a seamless treatment with all information on hand to the treating physician, irrespective of the location. The data exchange between physicians is facilitated by the high interoperability of the HL7 FHIR communication standard. The system allows all physicians to work with their regular software, with no need for additional software and passwords, which is a prerequisite for good acceptance. An extension of the platform to other individual healthcare providers such as pharmacists, physiotherapists, other medical specialties, or hospitals, is a goal for the near future.

Another important aspect was close communication with healthcare providers, who are strongly interested in digital pilot projects, which have the potential to save costs and improve outcomes. Because healthcare providers were part of the initial consortium, those discussions had already taken place in the early stages of the development process. As a consequence, a detailed analysis of healthcare costs after kidney transplantation and potential cost reductions were performed right from the beginning. It showed hospitalizations and premature graft loss, with return to dialysis being the most important cost factor in this patient group. Importantly, both factors also have direct adverse consequences on patients' QoL. It is obvious that fewer hospitalizations and graft losses are associated with cost reductions and at the same time, directly improve QoL. As non-adherence is an important factor for long-term graft survival, the concept aims to strengthen adherence through multiple ways, e.g., efficient communication, medication reminders, and better self-assessments. Ultimately, all these factors should help to assist in behavioral changes, to better detect health indicators, and empower the patient to better manage the chronic disease. Although educational and behavioral interventions to increase adherence are promising, the effect size seems small²⁸. Thus, multifaceted and individualized interventions for better empowerment of patients are important for better efficacy²⁹ and must eventually be combined with novel eHealth interventions^17,19,30. Similar to other comprehensive telemedicine projects^{18,19,21,23,26,27}, this should lead to improved adherence and a more timely detection of adverse events.

As demonstrated by another German group, such a comprehensive telemedicine project is cost-effective, may reduce hospitalizations, and prolong graft survival, and therefore avoid costly dialysis treatment²⁰. The group in Freiburg observed a dramatic 60% reduction in unplanned hospitalizations, resulting in a cost reduction of approximately 5,000 Euros in the first year after transplantation. Even when the authors accounted for the telemedicine costs, they could demonstrate cost savings of approximately 2,000 Euros per patient in the first year after transplantation. These assumptions are currently being evaluated by regular prospective assessments of key performance indicators such as adherence, rejection, development of DSA, graft loss, emergency room visits, and hospitalizations¹⁸. Based on the convincing evidence from other studies^18,19,20,21, two large German health insurance companies decided to support the MACCS project. Hopefully, more insurance companies will participate in the future. Ultimately, a prospective randomized trial is needed to demonstrate the effect of the telemedicine concept on patient adherence, QoL, hospitalizations, cost reductions, and long-term outcome.

A potential limitation is the fact that the platform depends on the willingness of the participants to regularly use the apps and ultimately integrate the apps into their daily routine. To achieve high acceptance, extensive educational sessions were established during the onboarding process, and new participants were called on the day after inclusion. Technical support is provided by the telemedicine team to patients who are not familiar with apps. Another limitation is the fact that the system relies on manual patient data entry, with the potential for typing errors. Patients may also get annoyed by having to repeatedly enter data into the app. Automatic data entry of vital signs with Bluetooth devices would improve data quality and comfort but adds complexity and costs. In the first version of the platform, complexity and costs were reduced by utilizing the patient´s own scale and blood pressure devices. In addition, the app was optimized for flexible manual data entry. Another inherent limitation is the fact that data entry of the patients has to be trusted, in particular, regarding the intake of their medication. However, the precise evaluation of true adherence is difficult, and concepts for adherence measurements, which rely on more technical solutions, are not yet standard.

In the future, it is planned to incorporate Bluetooth Internet of Things (IoT) devices for automatic and more precise data transfer. An interesting option to improve adherence is a Bluetooth-connected pillbox, which tracks the opening of a pillbox, but does not track the actual swallowing of a pill. Thus, similar to self-reporting, there is still uncertainty with regard to medication intake³¹. It is also possible to directly track swallowed pills, which are attached to a sensor. After activation in the stomach, the sensor transmits a signal to a smartphone via a patch attached to the belly. However, as the use of the patch was associated with discomfort, further research is needed to develop the system for routine care^32,33. At the end of the day, patients are responsible for their actions. The goal is not to perfectly track non-adherence, but instead to assist and empower patients for better adherence. The platform provides drug reminders, easy communication tools, information on the latest medication plan, laboratory values on the smartphone, a helpline, and a telemedicine team, and thereby creates an environment for maximal assistance to fulfill the tasks for optimal outcomes.

In the first version of the platform, the most important features, which were defined and prioritized with all stakeholders during a design and development process, were implemented. The focus was to incorporate features with a proven impact on adherence as well as those with high feasibility and medical relevance (e.g., medication reminder, medical messages, medication plan, laboratory values of highest interest). In addition, for automatic data transfer, the main pillar for successful implementation of such a transfer is the "human factor", namely, a competent telemedicine team, which has to train, support, and communicate with patients and local nephrologists. The constant communication with the telemedicine team motivates patients to stay in the project. To deal with all the incoming data and the high information load, the team developed a strictly structured daily schedule, focusing on the most urgent problems first. Furthermore, the telemedicine team is in close contact with the regular medical team involved in post-transplant care for an integrated care. Steady improvement of the telemedicine features with stepwise implementation of new features, according to the needs of the participants, is planned. Therefore, regular assessments of satisfaction and problems are of utmost importance, to define areas that need improvement.

As a next step during the current COVID-19 pandemic, a full integration of video consultations is planned. In a further step, a platform for educational purposes will be created, which can provide important content regarding transplantation and immunosuppression to patients in an easily accessible way. Other planned features for the patients are a better graphic display of vital signs and adherence as well as simple statistics for concise information and better illustration. In addition, expansion to other software systems to integrate other nephrologists and general practitioners is planned. The development of secure, web-based access would allow physicians to get access to patient data. Such web-based access could also serve as an emergency access for physicians to retrieve medical history and medical records through a temporarily activated emergency access to the platform. Another long-term goal is the development of a dashboard for antibiotic stewardship for better treatment of frequent urinary tract infections. Currently, a telemedicine unit within Charité is supervising patients and deciding, on a case-by-case basis, when patients reach critical thresholds. The additional workload requires additional manpower. Whether the additional tasks are performed by an increased healthcare team or by a separate telemedicine team is a matter of debate and depends on the local situation. However, extensive daily communication between all involved healthcare professionals and a structured therapeutic approach are essential for uniform and successful treatment.

Communication with patients is time-consuming and creates a high workload and may lead to "information overload". Thus, communication and the identification of the most critical patients are the bottlenecks in the current approach. The integration of novel artificial intelligence (AI)-driven technologies for automated communication on routine questions and automated detection of the most critical patients would reduce the workload of the telemedicine team and help focus on the most urgent cases. As monitoring is time- and cost-intensive, automated monitoring systems based on complex-event detection modules are key technologies to fuel the healthcare sector productivity in combination with individual risk predictions to focus limited resources on the most vulnerable patients. However, only approved AI components will be implemented after profound evaluation. Using the text interface of the existing patient app, automatic assessment of patient requests is planned so that urgent messages can be processed more quickly by medical staff. Noncritical patient requests as well as reminders and support can be provided by a chatbot component improving clinical workflow. Intelligent apps will be added to the open platform, e.g., for diabetic patients, as post-transplant diabetes is frequent and poor diabetic control affects long-term outcomes. Such apps may give personal advice to patients with regard to food intake and activity.

Another key feature of the platform in the future will be the connection with multiple IoT devices. Automatic data entry from IoT devices and wearables will reduce the burden for the patients to document data daily and will allow for a real-time analysis of patient activity, heart rate, and even electrocardiograms at home. Furthermore, point-of-care measurements with innovative laboratory devices may be added for home monitoring. To handle increased data volumes, Big Data and AI technologies are needed to detect critical situations, which would optimize the operational workflow of the telemedicine staff and lead to fewer patient constraints. In the end, such real-time analytics of IoT data streams and chat extractions will allow for a true real-time integrated decision making by using all of the data available from the patient (including medical history, patient record, IoT devices, and chat communications) and hence, for more timely identification of critical situations. The extension of the platform with educational content, personalized advice, and real-time information extracted from all available data sources will allow a more fine-grained overview of the patients' situation and automated warnings that will ease the tasks and workload of physicians and also allow for more patient-centered care through 24/7 communication and reminder functions. Such a system is also highly attractive for other conditions. Transferring the concept to other chronically ill patients and their particular requirements is being pursued.