Monitoring of gene expression in tacrolimus-treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study.

AIMS: Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections. METHODS: NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colony-stimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids. RESULTS: Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs. 10%, P = .01). CONCLUSIONS: NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients. Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment.

Pharmacokinetics of Daclatasvir, Sofosbuvir, and GS-331007 in a Prospective Cohort of Hepatitis C Virus-Positive Kidney Transplant Recipients.

BACKGROUND: Limited data exist on the pharmacokinetic profile of novel direct-acting antivirals in kidney transplant recipients. Daclatasvir is primarily eliminated through the biliary route and sofosbuvir through the renal route; here, we report the pharmacokinetic profile of combined treatment with these compounds in a prospective study of hepatitis C virus (HCV)-positive kidney transplant recipients (EudraCT: 2014-004551-32). METHODS: In this study, plasma samples of 16 HCV-positive kidney transplant recipients receiving daclatasvir and sofosbuvir were collected at 4 time points at days 1, 7, 14, 21, 56, and 84 after start of treatment. Inclusion criteria were stable graft function and an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m. Daclatasvir, sofosbuvir, and GS-331007 (inactive metabolite of sofosbuvir) plasma concentrations were determined using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. RESULTS: All patients showed a rapid virological response with HCV RNA below the detection limit 21 days after the start of therapy (medium time to viral clearance). No difference of the areas under the concentration-time curve (AUC) of daclatasvir, sofosbuvir, and GS-331007 was observed between patients with an eGFR below or ≥60 mL/min. For GS-331007, no relevant changes of trough levels were observed over time. Mean GS-331007 trough levels were 339.5 ± 174.9 ng/mL in patients with an eGFR ≥60 mL/min and 404.3 ± 226 ng/mL in patients with an eGFR <60 mL/min at day 7 (P = 0.52). At day 84, GS-331007 trough levels were 357.8 ± 200.8 and 404.2 ± 70.2 ng/mL in patients with an eGFR ≥60 mL/min and in patients with an eGFR <60 mL/min, respectively (P = 0.51). The accumulation ratios of renally eliminated GS-331007 for AUC and Cmax did not significantly differ between the 2 eGFR groups at day 7. CONCLUSIONS: An impaired eGFR (30-60 mL/min) does not lead to a dose accumulation of daclatasvir, sofosbuvir, and GS-331007. This study provides the rationale for future studies investigating the pharmacokinetic profile of sofosbuvir-based HCV treatment in kidney transplant recipients with an eGFR <30 mL/min.

A prospective study of daclatasvir and sofosbuvir in chronic HCV-infected kidney transplant recipients.

BACKGROUND: Only a few prospective trials exist regarding the use of novel direct-acting antiviral agents (DAAs) in kidney transplant recipients (KTR) with chronic hepatitis C virus (HCV) infection. METHODS: This prospective single-center trial evaluated treatment with daclatasvir (DCV) and sofosbuvir (SOF) over 12 weeks in 16 adult chronic HCV infected KTR and eGFR > 30 ml/min/1.73m2. Primary endpoint was sustained virological response 12 weeks after end of therapy (SVR12). Beside baseline liver biopsy, hepatic function and glucose metabolism were regularly assessed. RESULTS: Four of 16 study patients had previously failed interferon-based HCV treatment. Liver biopsy showed mostly moderate fibrosis score before therapy with DCV/SOF was initiated at a median of 10.3 years after transplantation. In total, 15 of 16 KTR achieved SVR12. One patient showed early viral relapse because of resistance-associated variants (RAVs) in the HCV NS5A region. Rescue treatment with SOF/velpatasvir/voxilaprevir resulted in SVR12. DAAs treatment led to significant improvement of liver metabolism and glucose tolerance accompanied with no therapy-associated major adverse events and excellent tolerability. CONCLUSIONS: Our study demonstrates safety, efficacy and functional benefit of DCV/SOF treatment in KTR with chronic HCV infection. We provide data on rescue strategies for treatment failures due to present RAVs and amelioration of hepatic function and glucose tolerance. TRIAL REGISTRATION: Registry name: European Clinical Trials Register; Trial registry number (Eudra-CT): 2014-004551-32 , Registration date: Aug 28th 2015.

Bioavailability and costs of once-daily and twice-daily tacrolimus formulations in de novo kidney transplantation.

The use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.

Simultaneous determination of mycophenolate and its metabolite mycophenolate-7-o-glucuronide with an isocratic HPLC-UV-based method in human plasma and stability evaluation.

OBJECTIVES: Mycophenolic acid (MPA) is an immunosuppressive agent which is commonly used in a fixed dose regime in solid organ transplantation. For clinical trials and therapeutic drug monitoring measuring plasma concentrations is necessary. Also, stability issues have to be addressed. METHODS: We describe an isocratic, RP-based HPLC-UV method for simultaneous determination of MPA and its major metabolite Mycophenolic acid 7-o Glucuronide (MPAG) in human plasma. Pre-analytics included protein precipitation with acetonitrile. The method was validated according to EMA/FDA guidelines. Patient lithium-heparin plasma and blood was used for evaluation of short-term (72 hours at room temperature = RT) and long-term stability (2 years at -80 °C) without acidification. RESULTS: Linearity was assessed in the concentration range of 0.5-40.0 µg/mL for MPA and 5.0-350.0 µg/mL for MPAG, respectively. For MPA coefficient of variation was <7.0% (lower limit of quantification = LLOQ: 10.8%), for MPAG <9.6% (LLOQ: 10.6%). Bias ranged between -1.9 and +1.5% for MPA and for MPAG between -4.3 and -0.3%. The method showed agreement with a reference method for both analytes. MPA remained stable for 7 h (-1.6 to +8.4% change to the initial concentration) and MPAG for 24 h (-1.8 to -11.5% change) at RT in lithium heparin blood. After 2 years of storage at -80 °C MPA, MPAG concentrations and 95% CIs remained within ±15% of the initial value. CONCLUSION: The presented assay is applicable for clinical studies. Blood samples were stable for 7 hours at RT and plasma for 2 years stored at -80 °C.

No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study.

AIMS: Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug-drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration-time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy. METHODS: In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC0-12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1-2 g day(-1) ) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined. RESULTS: MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml(-1) mg(-1) [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml(-1) mg(-1) (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml(-1) mg(-1) (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml(-1) mg(-1) (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min-max: 0.5-10.0)] than EC-MPS intake alone [3 h (1.5-12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5-5.0)] ± pantoprazole [1.0 h (0.5-6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found. CONCLUSION: Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired.

Pretransplant virtual PRA and long-term outcomes of kidney transplant recipients.

Virtual panel-reactive antibodies (vPRA) have been implemented to gauge sensitization worldwide. It is unclear how it associates with long-term outcomes, and its correlation with peak (pPRA) or actual (aPRA) has not been studied. We retrospectively reviewed data from 18- to 65-year-old kidney-only transplant patients during 1.1.1996-31.7.2011 in our center. PRAs were calculated based on solid-phase techniques. Of the 726 qualified cases, regardless of the PRA type, sensitized patients (PRA > 5%) had more females and previous transplant. Highly sensitized (HS, PRA > 50%) had longer waiting time, lower transplant rate, less living donor, more delayed graft function, and acute rejection. The conformity between vPRA and pPRA in HS was 75%, 57% between pPRA and aPRA. Forty-three percent (61/142) patients whose pPRA was >5% had no detectable aPRA and maintained similar outcomes as sensitized patients. Multivariate analysis showed consistently lower death-censored graft survival in HS defined by vPRA [HR 2.086 (95% CI 1.078-4.037), P < 0.05] and pPRA [HR 2.139 (95% CI 1.024-4.487), P < 0.05]. Both vPRA and pPRA provided reliable way estimating sensitization and predicting long-term graft survival, while aPRA might underestimate true sensitization. vPRA might be the most objective parameter to gauge sensitization.

A randomized trial of intensified vs. standard dosing for enteric-coated mycophenolate sodium in de novo kidney transplant recipients: results at 1 year.

In a 6-month prospective, openlabel, multicenter study, 128 de novo kidney transplant patients receiving cyclosporine (CsA) and steroids were randomized to an intensified regimen of enteric-coated mycophenolate sodium (EC-MPS) or to a standard EC-MPS regimen to Week 6 posttransplant, after which the regimen was identical. In a follow-up study to Month 12 post-transplant (49 intensified regimen, 52 standard regimen), the reduced rate of BPAR observed at Month 6 (intensified regimen 3.2%, standard regimen 16.9%, p = 0.016) was maintained at Month 12 (4.8% vs. 18.5%, p = 0.026). Estimated GFR (Cockcroft-Gault) at Month 12 was comparable in the intensified group (mean (SD) 54.8 (22.9) ml/min) vs. the standard group (mean (SD) 57.5 (23.6) ml/min, p = 0.83). The incidence of adverse events and serious adverse events at Month 12 was similar in both treatment groups, although adverse events with a suspected relation to study drug were reported in 69.8% and 50.8% of patients in the intensified and standard regimen groups, respectively (p = 0.032). Infections and hematological parameters were similar between groups. In conclusion, an early regimen of intensified EC-MPS with CsA and steroids achieves a low rate of BPAR over the first year after kidney transplantation with similar renal function to a standard regimen, and without a clinically relevant impact on safety.

Effects of mycophenolic acid alone and in combination with its metabolite mycophenolic acid glucuronide on rat embryos in vitro.

Mycophenolic acid (MPA) is an immunosuppressive agent that acts as a selective, non-reversible inhibitor of the enzyme inosine-5'-monophosphate dehydrogenase (IMPDH). Malformations have been described in children after maternal exposure to mycophenolate. However, the causal link is unclear in most cases because women had been treated with a combination of drugs and birth defects may have other causes. Therefore, it is important to study the action of this drug and its main metabolite on embryonic tissue. We studied the teratogenic potential of MPA and its major metabolite, the mycophenolic acid glucuronide (MPAG) in the rat whole-embryo culture. A total of 147 day 9.5 embryos were cultivated for 48 h in the standard medium containing 85 % serum. We tested MPA at concentrations of 0.1; 0.25; 0.5; 0.75 mg/l (0.31; 0.78; 1.56; 2.34 µM) and MPA glucuronide at concentrations of 3; 10; 30; 100 mg/l (6.04; 20.14; 60.43; 201.43 µM). Both substances are highly protein bound, and MPA glucuronide might displace MPA from protein binding. Therefore, we examined whether the effects of MPA can be enhanced when studied in combination with the glucuronide. Furthermore, the focus was on additional endpoints to the standard evaluation of cultivated embryos, such as development of cranial nerves [trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X)] after staining with an antibody against 2H3 neurofilament. Ultrastructural changes were evaluated by electron microscopy. At a concentration of 0.75 mg MPA/l medium, all embryos showed dysmorphic changes. Embryos exposed to 0.25 mg MPA/l medium showed impaired development of nerves, and at 0.1 mg/l, no effects were detectable. Concentration-dependent ultrastructural changes, such as signs of apoptosis, were found by electron microscopy. The examination of the metabolite in this assay showed that at a concentration of 100 mg MPAG/l, the embryos exhibited distinct malformations. This is probably caused by MPA, which was detectable at 0.6 % in the material used for our experiments. The combination of the parent compound (0.03; 0.1; 0.25 mg/l) with its metabolite MPAG (3 mg/l) did not cause enhanced toxicity under our experimental conditions. IMPDH, the target enzyme of MPA, could be detected in rat embryos on day 9.5 of embryonic development as well as at the end of the culture period 48 h later. In summary, MPA impairs embryonic development at low, therapeutically relevant concentrations, but the glucuronide does not exhibit such a potential. Activity of MPA is not enhanced by MPAG.

Immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix(®)) in renal transplant recipients.

BACKGROUND: In the course of the influenza A H1N1 pandemic, transplanted patients were recommended to receive vaccination. In the present study, we evaluated the immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix®) in renal allograft recipients. METHODS: Sixty patients and 22 healthy controls participated in a prospective observational study and received a single dose of Pandemrix®. H1N1 antibody titres as well as anti-HLA antibodies were determined before and after vaccination. In 19 patients, a booster vaccination was performed and the outcome of all vaccinated renal allograft recipients (n = 107) in our clinic was reviewed. RESULTS: Two out of sixty patients had an elevated influenza A H1N1 titre before vaccination. Of the remaining 58 patients, only 20/58 (34.5%) developed a protective immune response in contrast to 20/22 (91%) of the control group. After booster vaccination, a protective titre was present in 8/19 (42%) of patients. Of the 107 patients, 6 (5.6%) developed new donor-specific HLA antibodies after vaccination. CONCLUSIONS: These data suggest that Pandemrix® does not provide a protective immune response in the majority of kidney transplant recipients. Therefore, for new vaccines, efficacy as well as safety profiles should be evaluated in this subgroup of patients.

Non-invasive imaging of living kidney donors: intraindividual comparison of multislice computed tomography angiography with magnetic resonance angiography.

BACKGROUND: Evaluation of vascular variants is crucial for donor assessment prior to living kidney transplantation. Both contrast-enhanced (CE) magnetic resonance angiography (MRA) and multislice computed tomography (MSCT) are currently used for imaging living kidney donors. Aim of this study was the comparison of the accuracy of MSCT angiography and CE-MRA for the assessment of renal vascular anatomy. METHODS: Prospective study at a university transplant center including 65 potential living kidney donors. Pre-operative imaging by MSCT angiography and CE-MRA was correlated with the findings of laparoscopic donor nephrectomy in 48 donors. RESULTS: MSCT detected significantly more patients and more kidneys with accessory arteries than CE-MRA (p < 0.05). MSCT and CE-MRA performed similarly in identifying venous and ureteral abnormalities. The overall sensitivity, specificity, and accuracy for identifying accessory arteries were 85%/97%/94% for MSCT and 54%/97%/85% for CE-MRA. The sensitivity, specificity, and accuracy for the identification of supernumerary veins were 67%/95%/92% for MSCT and 67%/98%/94% for CE-MRA, respectively. CONCLUSION: We found MSCT angiography to be more sensitive and accurate than CE-MRA in the detection of supernumerary arteries prior to living donor nephrectomy.

Predictors of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Patients: Baseline Characteristics, Immunosuppression, and the Role of IMPDH Monitoring.

Immunosuppression increases the risk of severe coronavirus disease 2019 (COVID-19). Morbidity and mortality of this disease in kidney transplant patients are higher than in the general population. As the vaccination response of transplant patients is weak, serological monitoring was performed. In this cohort study, we analyzed the determinants of vaccination response. All patients had no history of COVID-19. With anti-spike IgG monitoring, 148 responders and 415 non-responders were identified. We compared both groups using multivariate analyses of the cohort and a sub-cohort of mycophenolic-acid-treated patients. We investigated the influence of patient characteristics, immunosuppression, and erythrocyte inosine monophosphate dehydrogenase (IMPDH) activity. In responders, the time after transplantation was longer (13.5 vs. 8.5 years), the glomerular filtration rate was higher (56.9 vs. 47.8 mL/min/1.73 m2), and responders were younger (53.0 vs. 57.4 years). Heterologous vaccination was more effective than homologous vaccination. Calcineurin inhibitors plus mycophenolate reduced the seroconversion rate. No seroconversion was observed in belatacept patients. In mycophenolate-treated patients, IMPDH activity was a significantly better predictor of response than mycophenolate dose (AUC 0.84 vs. 0.62, p < 0.001). Immunosuppression strongly affects vaccine response. Modifications to immunosuppression should be considered in order to facilitate this response. Erythrocyte IMPDH activity can be used to guide mycophenolate treatment.

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.

Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations.

OBJECTIVES: We investigated the pharmacokinetic and pharmacogenetic implications of conversion from a twice-daily (P-Tac) to a once-daily (A-Tac) tacrolimus (Tac) formulation. METHODS: We analyzed Tac levels in a cohort of 41 renal transplant patients with a stable graft function over a period of 1 year before and after conversion. RESULTS: After conversion, the patients had, on average, significantly lower Tac trough and dose-normalized trough levels (14%, P=0.0004 and 23%, P=0.001, respectively) despite similar doses. CYP3A5*3/*3 patients (n=27) required significantly lower Tac doses with both the formulations to reach Tac target levels (P-Tac 39%, P=0.011; A-Tac 36%, P=0.003) compared with *1/*3 patients (n=13). Interestingly, after the conversion, mean Tac trough levels and dose-normalized trough level remained almost constant in *1/*3 patients, but decreased significantly in *3/*3 patients (16%, P=0.001 and 25%, P=0.006). CONCLUSION: This study provides further evidence that the CYP3A5*1/*3 polymorphism significantly impacts Tac pharmacokinetics. Moreover, we show for the first time a pharmacogenetic effect on two different Tac formulations, as Tac trough levels of *3/*3 patients declined significantly after conversion to identical A-Tac doses.

TBase - an Integrated Electronic Health Record and Research Database for Kidney Transplant Recipients.

TBase is an electronic health record (EHR) for kidney transplant recipients (KTR) combining automated data entry of key clinical data (e.g., laboratory values, medical reports, radiology and pathology data) via standardized interfaces with manual data entry during routine treatment (e.g., clinical notes, medication list, and transplantation data). By this means, a comprehensive database for KTR is created with benefits for routine clinical care and research. It enables both easy everyday clinical use and quick access for research questions with highest data quality. This is achieved by the concept of data validation in clinical routine in which clinical users and patients have to rely on correct data for treatment and medication plans and thereby validate and correct the clinical data in their daily practice. This EHR is tailored for the needs of transplant outpatient care and proved its clinical utility for more than 20 years at Charité - Universitätsmedizin Berlin. It facilitates efficient routine work with well-structured, comprehensive long-term data and allows their easy use for clinical research. To this point, its functionality covers automated transmission of routine data via standardized interfaces from different hospital information systems, availability of transplant-specific data, a medication list with an integrated check for drug-drug interactions, and semi-automated generation of medical reports among others. Key elements of the latest reengineering are a robust privacy-by-design concept, modularity, and hence portability into other clinical contexts as well as usability and platform independence enabled by HTML5 (Hypertext Markup Language) based responsive web design. This allows fast and easy scalability into other disease areas and other university hospitals. The comprehensive long-term datasets are the basis for the investigation of Machine Learning algorithms, and the modular structure allows to rapidly implement these into clinical care. Patient reported data and telemedicine services are integrated into TBase in order to meet future needs of the patients. These novel features aim to improve clinical care as well as to create new research options and therapeutic interventions.

Inosine 5'-Monophosphate Dehydrogenase Activity for the Longitudinal Monitoring of Mycophenolic Acid Treatment in Kidney Allograft Recipients.

BACKGROUND: Mycophenolic acid (MPA) is a standard immunosuppressant in organ transplantation. A simple monitoring biomarker for MPA treatment has not been established so far. Here, we describe inosine 5'-monophosphate dehydrogenase (IMPDH) monitoring in erythrocytes and its application to kidney allograft recipients. METHODS: IMPDH activity measurements were performed using a high-performance liquid chromatography assay. Based on 4203 IMPDH measurements from 1021 patients, we retrospectively explored the dynamics early after treatment start. In addition, we analyzed the influence of clinically relevant variables on IMPDH activity in a multivariate model using data from 711 stable patients. Associations between IMPDH activity and clinical events were evaluated in hospitalized patients. RESULTS: We found that IMPDH activity reflects MPA exposure after 8 weeks of constant dosing. In addition to dosage, body mass index, renal function, and coimmunosuppression affected IMPDH activity. Significantly lower IMPDH activities were found in patients with biopsy-proven acute rejection as compared to patients without rejection (median [interquartile range]: 696 [358-1484] versus 1265 [867-1618] pmol xanthosine-5'-monophosphate/h/mg hemoglobin, P < 0.001). The highest IMPDH activities were observed in hospitalized patients with clinically evident MPA toxicity as compared to patients with hospitalization not related to MPA treatment (1548 [1021-2270] versus 1072 [707-1439] pmol xanthosine-5'-monophosphate/h/mg hemoglobin; P < 0.001). Receiver operating characteristic curve analyses underlined the usefulness of IMPDH to predict rejection episodes (area, 0.662; confidence interval, 0.584-0.740; P < 0.001) and MPA-associated adverse events (area, 0.632; confidence interval, 0.581-0.683; P < 0.001), respectively. CONCLUSIONS: IMPDH measurement in erythrocytes is a novel and useful strategy for the longitudinal monitoring of MPA treatment.

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

The MACCS (Medical Assistant for Chronic Care Service) platform enables secure sharing of key medical information between patients after kidney transplantation and physicians. Patients provide information such as vital signs, well-being, and medication intake via smartphone apps. The information is transferred directly into a database and electronic health record at the kidney transplant center, which is used for routine patient care and research. Physicians can send an updated medication plan and laboratory data directly to the patient app via this secure platform. Other features of the app are medical messages and video consultations. Consequently, the patient is better-informed, and self-management is facilitated. In addition, the transplant center and the patient's local nephrologist automatically exchange notes, medical reports, laboratory values, and medication data via the platform. A telemedicine team reviews all incoming data on a dashboard and takes action, if necessary. Tools to identify patients at risk for complications are under development. The platform exchanges data via a standardized secure interface (Health Level 7 (HL7), Fast Healthcare Interoperability Resources (FHIR)). The standardized data exchange based on HL7 FHIR guarantees interoperability with other eHealth solutions and allows rapid scalability to other chronic diseases. The underlying data protection concept is in concordance with the latest European General Data Protection Regulation. Enrollment started in February 2020, and 131 kidney transplant recipients are actively participating as of July 2020. Two large German health insurance companies are currently funding the telemedicine services of the project. The deployment for other chronic kidney diseases and solid organ transplant recipients is planned. In conclusion, the platform is designed to enable home monitoring and automatic data exchange, empower patients, reduce hospitalizations, and improve adherence, and outcomes after kidney transplantation.

The 'blood group O problem' in kidney transplantation--time to change?

BACKGROUND: Patients with blood group O have disadvantages in the allocation of deceased donor organs in the Eurotransplant Kidney Allocation System and fewer ABO-compatible living donors. In order to investigate the consequences of this dilemma, we analysed the outcome of patients with blood group O in our transplantation programme. METHODS: A single-centre analysis of 1186 waitlisted patients for first deceased donor kidney transplantations between 1996 and 2008 was performed, and the mechanisms of blood group-dependent differences for graft and recipient outcome were assessed. RESULTS: Median follow-up time until death or end of observation for all waitlisted patients was 66 months (range, 0-158 months) and for 589 recipients of a kidney graft was 61 months (range, 0-158 months). Patients with blood group O had significantly longer waiting times for deceased donor kidney grafts, compared to non-group O recipients (median waiting time, 85 vs 59 months). As a consequence, blood group O patients had an increased risk for death without transplantation (13.1% for O patients vs 9.6% for non-O patients; P < 0.05). Despite a good human leukocyte antigen match, graft outcome tended to be worse in O recipients; 14.1% (95% CI, 8.2-19.9%) of all O kidneys from deceased donors were transplanted into non-O recipients, leading to the accumulation of O recipients on the waiting list. CONCLUSIONS: The export of blood group O donor kidneys to other blood groups leads to longer waiting times, to a higher death rate and to accumulation of blood group O patients on the waiting list, which will further aggravate the problem in the future. Our results should prompt further research on the issues associated with blood group O. Current allocation systems and living donor kidney exchange programmes should be re-evaluated to address this problem.

Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients.

AIMS: Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients. METHODS: PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks. RESULTS: Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r(2)= 0.812; IMPDH r(2)= 0.833). MPA AUC(0-12) of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC(0-12) 28 microg*h ml(-1) (7-45) vs. 40 microg*h ml(-1) (16-130), P < 0.01), MPA AUC(0-12) of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC(0-12) 65 microg*h ml(-1) (range 37-130) vs. 37 microg*h ml(-1) (range 7-120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC(0-12)) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC(0-12) 43 nmol*h mg(-1) protein h(-1)[range 12-67) vs. 75 nmol*h mg(-1) protein h(-1) (range 15-371), P < 0.01]. CONCLUSIONS: Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC(0-4) and IMPDH AEC(0-4) in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC(0-12) from 30 to 60 microg*h ml(-1) seems to be appropriate in renal allograft recipients.

Target enzyme activity as a biomarker for immunosuppression.

Pharmacokinetic drug monitoring has been used for many years to relate immunosuppressant dose to drug exposure in vivo. However, this conventional therapeutic drug monitoring of blood immunosuppressant levels may not necessarily predict the pharmacologic effects on immune cells. The direct determination of target enzyme activity (eg, calcineurin activity, inosine-5'-monophospahte dehydrogenase [IMPDH] activity, p70S6 kinase) may help to better assess the individual response to the immunosuppressant. However, its use is limited by the difficulties of the assay systems, which did not allow yet the prospective assessment of these enzymes in larger patient cohorts with the establishment of validated pharmacodynamic drug monitoring. The most progress regarding a robust and reproducible test system has been achieved with the determination of IMPDH activity as a specific pharmacodynamic parameter of mycophenolic acid activity. This recently validated and standardized assay allows the investigation of IMPDH activity in larger clinical studies. Although the determination of target enzyme activity, eg, by the determination of IMPDH activity, holds promise for a more individualized therapy in transplant medicine, more studies are needed to prospectively validate this approach.