eHealth in transplantation

eHealth ("electronic" Health) is a new field in medicine that has the potential to change medical care, increase efficiency, and reduce costs. In this review, we analyzed the current status of eHealth in transplantation by performing a PubMed search over the last 5 years with a focus on clinical studies for post-transplant care. We retrieved 463 manuscripts, of which 52 clinical reports and eight randomized controlled trials were identified. Most studies were on kidney (n = 19), followed by liver (n = 10), solid organ (n = 7), bone-marrow (n = 6), and lung transplantation (n = 6). Eleven articles included adolescents/children. Investigated eHealth features covered the whole spectrum with mobile applications for patients (n = 24) and video consultations (n = 18) being most frequent. Prominent topics for patient apps were self-management (n = 16), adherence (n = 14), symptom-reporting (11), remote monitoring of vital signs (n = 8), educational (n = 7), and drug reminder (n = 7). In this review, we discuss opportunities and strengths of such new eHealth solutions, the implications for successful implementation into the healthcare process, the human factor, data protection, and finally, the need for better evidence from prospective clinical trials in order to confirm the claims on better patient care, potential efficiency gains and cost savings

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination

Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination–specific humoral and cellular immunity in kidney transplant recipients

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor-treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses. counts and relative frequencies of spike receptor binding domain-specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27(++)CD38(+) plasmablasts. Whereas overall proportions of spike-reactive CD4(+) T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67(+) and in vivo-activated programmed cell death 1-positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients

Performance of a minimally invasive uncalibrated cardiac output monitoring system (Flotrac™/Vigileo™) in haemodynamically unstable patients

Bei 25 kritisch kranken Patienten der interdisziplinären internistischen Intensivstation der Charité Campus Benjamin Franklin wurde im Rahmen einer Pilotstudie das minimalinvasive hämodynamische FloTrac™/Vigileo™-Monitoringsystem der Firma Edwards Lifesciences im Vergleich zum semiinvasiven PiCCO™-System der Firma Pulsion Medical Systems evaluiert. Das Patientengut wurde konsekutiv ausgewählt. Das heißt, es wurden Patienten eingeschlossen, die eine klinische Indikation für das erweiterte hämodynamische Monitoring mittels des PiCCO™-Systems besaßen und bereits über einen suffizienten radialarteriellen Zugang verfügten. Es erfolgte der Vergleich der radialarteriell mittels FloTrac™/Vigileo™-System abgeleiteten Blutdruckwerte mit den femoralarteriell abgeleiteten Blutdruckwerten des PiCCO™-Systems und der Vergleich der HZV-Werte der transpulmonalen Thermodilution und kontinuierlichen Pulskonturanalyse des PiCCO™-Systems mit denen der arteriellen Pulskonturanalyse des FloTrac™/Vigileo™-Systems patientenbezogen zu unterschiedlichen Zeitpunkten. Die zu den Messzeitpunkten verabreichte Katecholamintherapie ging in die Betrachtungen mit ein. In die statistische Auswertung wurden 25 Patienten mit insgesamt 324 Wertepaaren eingeschlossen. Ziel der Untersuchung war es die Messgenauigkeit des FloTrac™/Vigileo™-Monitoringsystems mit der des PiCCO™- Systems zu vergleichen. In der vorliegenden Studie zeigte sich, dass das FloTrac™/Vigileo™-System das HZV sowohl im Vergleich zur transpulmonalen Thermodilution als auch zur kontinuierlichen Pulskonturanalyse des PiCCO™-Systems unterschätzte. Ein prozentualer Fehler von 51,7% bis 62,6% für alle HZV-Werte, der in Anlehnung an das Konzept zur Beurteilung neuer HZV- Methoden von Critchley und Critchley deutlich über dem Schwellenwert von +/- 30% für die klinische Akzeptanz einer neuen Methode liegt [108], wurde errechnet. Ursächlich könnte dem zum einen die Unterschätzung des zentralen arteriellen Blutdruckes durch die periphere radialarterielle Blutdruckmessung des FloTrac™/Vigileo™-Systems zugrunde liegen. Im Vergleich der radialarteriell mittels FloTrac™/Vigileo™-System und femoralarteriell mittels PiCCO™-System abgeleiteten Blutdruckwerte zeigte sich in Bezug auf den systolischen Blutdruck kein statistisch signifikanter Unterschied, jedoch der diastolische als auch der arterielle Mitteldruck waren über die A.radialis abgeleitet signifikant niedriger. In einer Subgruppenanalyse, die den Einfluss der radial- und femoralarteriellen Blutdruckdifferenzen auf die ermittelten HZV-Werte untersuchte, zeigte sich, dass sowohl die bias als auch der percentage error der ermittelten HZV-Werten des FloTrac™/Vigileo™-Systems verglichen mit denen der transpulmonalen Thermodilution/kontinuierlichen Pulskonturanalyse des PiCCO™-Systems bei einem Mitteldruckunterschied > 5 mmHg signifikant anstiegen. Die Ursache für die Unterschätzung der HZV-Werte durch das FloTrac™/Vigileo™-System könnte zum anderen auch im Algorhythmus des FloTrac™/Vigileo™-Systems begründet sein. So zeigte sich, dass das FloTrac™/Vigileo™-System angeschlossen an den femoralerteriellen Katheter des PiCCO™-Systems einen dem PiCCO™-System vergleichbaren Blutdruckwert anzeigte, jedoch die bias und die limits of agreement der HZV-Werte denen mittels FloTrac™/Vigileo™-System an der Radialarterie ermittelten Werten glichen. Bei 315 der insgesamt 324 Messungen wurden in der vorliegenden Studie zur Kreislaufstabilisierung Katecholamine, speziell Noradrenalin in vasopressorischer Dosis, eingesetzt. Eine Subgruppenanalyse, die Patienten mit hoher und Patienten mit niedriger Noradrenalindosis einschloss, ergab bei beiden Gruppen keine Unterschiede in der bias der HZV-Werte. Analog diesem zeigte sich in Übereinstimmung mit der Literatur die Zuverlässigkeit der Pulskonturanalyse bei Änderungen der globalen Hämodynamik unabhängig von den Katecholamindosen. Allerdings war der percentage error größer bei der Patientengruppe mit höherer Noradrenalindosis, welches eine Beeinflussung der peripherarteriellen Pulskonturanalyse des FloTrac™/Vigileo™-Systems durch Katecholamine vermuten lässt. In der Analyse des Einflusses der Noradrenalindosis auf die jeweiligen Mitteldruckunterschiede zwischen A.radialis und A.femoralis ergab sich eine negative Korrelation. In einer Subgruppenanalyse, die den Einfluss der Noradrenalintherapie bei Patienten mit einer Noradrenalindosis <0,1µg/kg/min und bei Patienten mit einer Noradrenalindosis > 0,1µg/kg/min verglich, war ein signifikanter Unterschied in der Differenz der über die A.femoralis und A.radialis abgeleiteten Blutdruckmittelwerte nachweisbar. Unter Berücksichtigung der erhobenen Daten und in Anlehnung an das entwickelte Konzept zur Beurteilung einer neuen HZV- Messmethode von Critchley und Critchley kann auch die neue Softwareversion des minimalinvasiven hämodynamischen FloTrac/Vigileo-Monitoringsystems nicht als Alternative für die kontinuierliche HZV-Messung mit dem PiCCO™-System auf einer Intensivstation empfohlen werden. Anhand der vorliegenden Daten ist jedoch ersichtlich, dass eine Trendbeurteilung der HZV-Veränderungen mittels des FloTrac™/Vigileo™-Systems möglich scheint. Ein Einsatz dieses minimalinvasiven Monitoringsystems in präklinischen Bereichen beziehungsweise in Rettungsstellen, die aufgrund der Invasivität beziehungsweise Komplexität der derzeit verfügbaren Verfahren kaum Möglichkeiten zum erweiterten hämodynamischen Monitoring haben, wäre damit in Situationen, in denen weniger der Absolutwert des jeweiligen Herzzeitvolumens eine Rolle spielt, vorstellbar.Background: Early haemodynamic assessment is of particular importance in the evaluation of haemodynamically compromised patients, but is often precluded by the invasiveness and complexity of the established cardiac output (CO) monitoring techniques. The FloTrac™/Vigileo™ system allows minimally invasive CO determination based on the arterial pressure waveform derived from any standard arterial catheter, and the algorithm underlying CO calculation was recently modified to allow a more precise estimate of aortic compliance. Methods: Using the new software, we studied 25 haemodynamically unstable patients who had a radial artery catheter and underwent invasive haemodynamic monitoring with the PiCCO™ system. PiCCO™-derived transpulmonary thermodilution and pulse contour CO (reference-CO) were compared with the CO values obtained with the FloTrac™/Vigileo™ system (AP-CO). Reported CO values are indexed to body surface area. Agreement between reference-CO and AP-CO recorded during routine clinical care was assessed using Bland–Altman statistics. Results: Overall bias between the reference-CO and the AP-CO (n=324) was 0.68 litre min–1 m–2 with a high percentage error of ± 58.8% (95% limits of agreement ± 1.94 l min–1 m–2). There was a significant difference (P<0.001) between the radial and the femoral mean arterial pressures, and bias was significantly larger for a mean pressure difference of >5 mm Hg (0.93 vs 0.57 litre min–1 m–2, P=0.032). No connection was found between the norepinephrine dose and the CO agreement. Conclusions: Despite the updated algorithm, AP-CO still showed a limited agreement with the reference-CO and systematically underestimated the CO so that the method is not suitable to replace invasive CO monitoring at present

Treatment effect of mTOR-inhibition on tissue composition of renal angiomyolipomas in tuberous sclerosis complex (TSC).

Tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML) have a high lifetime risk of acute bleeding. MTOR-inhibitors are a promising novel treatment for TSC-AML, however adequate response to therapy can be difficult to assess. Early changes in MRI signal may serve as a novel early indicator for a satisfactory response to mTOR-inhibitor therapy of AML.Thirty-eight patients with the definite diagnosis of tuberous sclerosis receiving everolimus therapy and n = 19 patients without specific therapy were included. 1.5 Tesla MRI was performed including sequences with a selective fat suppression. Patients were investigated prior to the initiation of therapy (baseline) and after 0.05) and size (p>0.05) were measured in the control group.mTOR inhibitor therapy in TSC patients results in an early and pronounced fatty transformation of AMLs on MRI. Fatty transformation could represent a novel early indicator of response to therapy in this patient collective

Low Seroprevalence of SARS-CoV-2 Antibodies during Systematic Antibody Screening and Serum Responses in Patients after COVID-19 in a German Transplant Center

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 denotes a global health issue. Data regarding COVID-19 incidence in kidney transplant recipients (KTR) are sparse. From 19 March to 19 May 2020, we performed a systematic screening for COVID-19 in KTR. Tests included serum analysis for SARS-CoV-2 antibodies using S protein-based immunofluorescence, anti-SARS-CoV-2 S1 immunoglobulin G (IgG) and immunoglobulin A (IgA) enzyme-linked immunosorbent assays (ELISA), and/or quantitative reverse transcription polymerase chain reaction (qRT-PCR) from nasal-throat swabs. Outpatient serum samples from KTR with PCR confirmed COVID-19, and swab samples from recipients (+donors) undergoing kidney transplantation were analyzed. Out of 223 samples from outpatients, 13 patients were positive with solely anti-SARS-CoV-2-IgA and 3 with both anti-IgA and anti-IgG. In total, 53 patients were symptomatic in the past, but positive results could be found in both symptomatic and asymptomatic patients. After an in depth analysis using immunofluorescence and neutralization tests in 2 KTR, recent COVID-19 infection remained highly suspicious. Apart from outpatient visits, only 5 out of 2044 KTR were symptomatic and tested positive via PCR, of which 4 recovered and one died. All patients showed seroconversion during the course of the disease. This study demonstrated a low seroprevalence in a German KTR cohort, and seroconversion of IgA and IgG after COVID-19 could be demonstrated. Effective containment strategies enabled us to continue our transplant program

Everolimus in de novo kidney transplant recipients participating in the Eurotransplant senior program: Results of a prospective randomized multicenter study (SENATOR).

Early conversion to everolimus was assessed in kidney transplant recipients participating in the Eurotransplant Senior Program (ESP), a population in whom data are lacking. The SENATOR multicenter study enrolled 207 kidney transplant recipients undergoing steroid withdrawal at week 2 post-transplant (ClinicalTrials.gov [NCT00956293]). At week 7, patients were randomized (1:2 ratio) to continue the previous calcineurin inhibitor (CNI)-based regimen with mycophenolic acid (MPA) and cyclosporine or switch to a CNI-free regimen with MPA, everolimus (5-10 ng/mL) and basiliximab at weeks 7 and 12, then followed for 18 weeks to month 6 post-transplant. The primary endpoint was estimated GFR (eGFR). At week 7, 77/207 (37.2%) patients were randomized (53 everolimus, 24 control). At month 6, eGFR was comparable: 36.5±10.8ml/min with everolimus versus 42.0±13.0ml/min in the control group (p = 0.784). Discontinuation due to adverse events occurred in 27.8% of everolimus-treated patients and 0.0% of control patients (p = 0005). Efficacy profiles showed no difference. In conclusion, eGFR, safety and efficacy outcomes at month 6 post-transplant showed no difference between groups. The everolimus group experienced a higher rate of discontinuation due to adverse events. However, the high rate of non-randomization is highly relevant, indicating this to be a somewhat unstable patient population regardless of treatment

Fatty transformation of angiomyolipoma in TSC patients after initiation of mTOR inhibitor therapy.

<p><b>A</b>: Example of a large AML at the central part of the right kidney in a 33 year-old female TSC patient. <b>A1</b>: At baseline a heterogeneous AML with a mixed-signal on the T2 fat saturated MR sequence (solid arrows) could be visualized. Slow flowing blood in a small vessel (dotted arrows) appears hyperintense on the fat saturated sequence. The unaffected “healthy” kidney tissue is also visualized with a hyperintense signal (*). <b>A2</b>: 2.5 months following the initiation of the mTOR inhibitor therapy a reduction in the overall signal of the AML on the T2 fat saturated sequence can be visualized. The vessel, which was visible at baseline (A1: dotted line) cannot be delineated anymore. Additionally, a reduction of size of the AML can be visualized. This case represents a good example of how difficult it can be to clearly quantify a size reduction in a heterogenous AML following the initiation of mTOR therapy. <b>B</b>: Example of a AML at the caudal part of the right kidney in a 45 year-old male TSC patient. <b>B1</b>: At baseline a heterogeneous relatively bright angiomyolipoma could be visualized on the T2 fat saturated sequence (arrows). The unaffected “healthy” kidney tissue is visualized with a homogenous hyperintense signal on the T2 fat saturated sequence (*). <b>B2</b>: 3 to 6 months following the initiation of the mTOR inhibitor therapy, a clear reduction in the signal on the T2 fat saturated sequence as well as in the size of the angiomyolipoma is visualized. The signal of the healthy kidney tissue does not change following the initiation of the therapy (*). MRI: Magnetic Resonance Imaging. Fatsat: Fat saturated. Scale bar: 1.5 cm.</p

Signal changes in magnetic resonance imaging with selective fat suppression in TSC patients following the initiation of mTOR inhibitor therapy.

<p>Patients were investigated at baseline and after 0–3 months, 3–6 months and 18–24 months of mTOR inhibitor therapy. Additionally, a control collective of TSC patients without mTOR inhibitor therapy was investigated. A pronounced and significant reduction of the mean contrast to noise ratio (CNR) was already observed in the early group within the first three months. In the control group, no reduction of the mean CNR value was observed. Error bars indicate the standard deviation. P-values generated from linear mixed model statistical analysis (* p<0.01, *** p<0.0001); CNR: Contrast to noise ratio.</p