German Transplant Centers Research Articles

Does Timepoint of Surgical Procedure Affect the Outcome in Simultaneous Pancreas-Kidney Transplantation? A Retrospective Single-Center Analysis over 20 Years.

Background: Sleep deprivation and disturbances in circadian rhythms may hinder surgical performance and decision-making capabilities. Solid organ transplantations, which are technically demanding and often begin at uncertain times, frequently during nighttime hours, are particularly susceptible to these effects. This study aimed to assess how transplant operations conducted during daytime versus nighttime influence both patient and graft outcomes and function. Methods: simultaneous pancreas-kidney transplants (SPKTs) conducted at the University Hospital of Leipzig from 1998 to 2018 were reviewed retrospectively. The transplants were categorized based on whether they began during daytime hours (8 a.m. to 6 p.m.) or nighttime hours (6 p.m. to 8 a.m.). We analyzed the demographics of both donors and recipients, as well as primary outcomes, which included surgical complications, patient survival, and graft longevity. Results: In this research involving 105 patients, 43 SPKTs, accounting for 41%, took place in the daytime, while 62 transplants (59%) occurred at night. The characteristics of both donors and recipients were similar across the two groups. Further, the rate of (surgical) pancreas graft-related complications and reoperations (daytime 39.5% versus nighttime 33.9%; p = 0.552) were also not statistically significant between both groups. In this study, the five-year survival rate for patients was comparable for both daytime and nighttime surgeries, with 85.2% for daytime and 86% for nighttime procedures (p = 0.816). Similarly, the survival rates for pancreas grafts were 75% for daytime and 77% for nighttime operations (p = 0.912), and for kidney grafts, 76% during the day compared to 80% at night (p = 0.740), indicating no significant statistical difference between the two time periods. In a multivariable model, recipient BMI > 30 kg/m2, donor age, donor BMI, and cold ischemia time > 15 h were independent predictors for increased risk of (surgical) pancreas graft-related complications, whereas the timepoint of SPKT (daytime versus nighttime) did not have an impact. Conclusions: The findings from our retrospective analysis at a big single German transplant center indicate that SPKT is a reliable procedure, regardless of the start time. Additionally, our data revealed that patients undergoing nighttime transplants have no greater risk of surgical complications or inferior results concerning long-term survival of the patient and graft. However, due to the small number of cases evaluated, further studies are required to confirm these results.

Smart Conditioning with Venetoclax-Enhanced Sequential FLAMSA + RIC in Patients with High-Risk Myeloid Malignancies

Up to 50% of patients with high-risk myeloid malignancies die of relapse after allogeneic stem cell transplantation. Current sequential conditioning regimens like the FLAMSA protocol combine intensive induction therapy with TBI or alkylators. Venetoclax has synergistic effects to chemotherapy. In a retrospective survey among German transplant centers, we identified 61 patients with myeloid malignancies that had received FLAMSA-based sequential conditioning with venetoclax between 2018 and 2022 as an individualized treatment approach. Sixty patients (98%) had active disease at transplant and 74% had genetic high-risk features. Patients received allografts from matched unrelated, matched related, or mismatched donors. Tumor lysis syndrome occurred in two patients but no significant non-hematologic toxicity related to venetoclax was observed. On day +30, 55 patients (90%) were in complete remission. Acute GvHD II°–IV° occurred in 17 (28%) and moderate/severe chronic GvHD in 7 patients (12%). Event-free survival and overall survival were 64% and 80% at 1 year as well as 57% and 75% at 2 years, respectively. The off-label combination of sequential FLAMSA-RIC with venetoclax appears to be safe and highly effective. To further validate these insights and enhance the idea of smart conditioning, a controlled prospective clinical trial was initiated in July 2023.

Bacterial and Bacteriophage Consortia Are Associated with Protective Intestinal Immuno-Modulatory Metabolites in Allogeneic Stem Cell Transplantation Patients

The human microbiome is a predictor of clinical outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungi and viruses as well as intestinal microbiota-derived metabolites are involved. However, it is still unclear how dynamic shifts in these three kingdoms contribute to the production of intestinal metabolites, how metabolites are impacted by graft-versus-host disease (GvHD) or antibiotics and whether they are associated with clinical outcome. We report the two-year follow-up of a prospective, observational, longitudinal cohort of allo-SCT patients (n=78) at two German transplantation centers that combined three-kingdom (bacteria, fungi, viruses) analysis of intestinal microbial communities with targeted metabolomics ( Figure 1). Using Multi-omics factor analysis (MOFA), we uncovered a functional microbiome signature of bacteria from the Lachnospiraceae and Oscillospiraceae families and their associated bacteriophages, which correlated with the production of immuno-modulatory metabolites (IMMs) including short-chain fatty acids (SCFAs), branched-chain fatty acids (BCFA), metabolites associated with induction of type-I IFN signaling (IIMs) and immuno-modulatory secondary bile acids ( Figure 2). We established an Immuno-modulatory Metabolite Risk Index (IMM-RI) consisting of five index IMMs, which was associated with improved survival, less transplant-related mortality and reduced relapse rate. Onset of gastrointestinal GvHD and exposure to antibiotics significantly impacted intestinal levels of protective IMMs. Using whole shotgun metagenomic sequencing, we observed that in IMM-RI low-risk patients, sustained production of protective IMMs was associated with a high abundance of microbial SCFA biosynthesis pathways, specifically butyric acid via butyryl-CoA:acetate CoA-transferase (BCoAT). Through genome assembly from viral metagenomic sequencing data, we detected two distinct bacteriophages which encoded BCoAT as an auxiliary metabolic gene. They were more abundant in IMM-RI low-risk patients and positively correlated with intestinal butyric acid levels, suggesting that these bacteriophages may modulate bacterial metabolite biosynthesis. Our study identifies a specific microbiome signature associated with protective IMMs that could improve fecal microbiota transplantation (FMT) donor selection and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies for cancer patients.

COVID-19 Outcomes in Kidney Transplant Recipients in a German Transplant Center.

Kidney transplant recipients (KTRs) show higher morbidity and mortality from COVID-19 than the general population and have an impaired response to vaccination. We analyzed COVID-19 incidence and clinical outcomes in a single-center cohort of approximately 2500 KTRs. Between 1 February 2020 and 1 July 2022, 578 KTRs were infected with SARS-CoV-2, with 25 (4%) recurrent infections. In total, 208 KTRs (36%) were hospitalized, and 39 (7%) died. Among vaccinated patients, infection with the Omicron variant had a mortality of 2%. Unvaccinated patients infected with the Omicron variant showed mortality (9% vs. 11%) and morbidity (hospitalization 52% vs. 54%, ICU admission 12% vs. 18%) comparable to the pre-Omicron era. Multivariable analysis revealed that being unvaccinated (OR = 2.15, 95% CI [1.38, 3.35]), infection in the pre-Omicron era (OR = 3.06, 95% CI [1.92, 4.87]), and higher patient age (OR = 1.04, 95% CI [1.03, 1.06]) are independent risk factors for COVID-19 hospitalization, whereas a steroid-free immunosuppressive regimen was found to reduce the risk of COVID-19 hospitalization (OR = 0.51, 95% CI [0.33, 0.79]). This suggests that both virological changes in the Omicron variant and vaccination reduce the risk for morbidity and mortality from COVID-19 in KTRs. Our data extend the knowledge from the general population to KTRs and provide important insights into outcomes during the Omicron era.

Control and care structures at transplant centers for patients with ethyltoxic cirrhosis while waiting for a liver transplant: A qualitative survey of practitioners.

The aim of this study was to record the current care and control structures in place for patients with ethyltoxic liver cirrhosis while being prepared for a liver transplant (LTX) at German transplant centers. In addition, it was also intended to analyze the associated barriers as well as the view of the practitioners on ways to improve care of this patient group. In an exploratory descriptive qualitative design, 11 interviews with practitioners from 10 of the 22 German LTX centers were conducted and analyzed using qualitative content analysis. There were considerable differences in the care and control structures in place at the LTX centers. Addiction therapy counseling or treatment were not integrated into the treatment concept at all centers. Structural barriers arose from insufficient funding and staffing. Practitioners recommended expansion of treatment options as well as standardizing treatment concepts. The results of our study point to a need for action both in the area of the structures of the individual LTX centers and overall at the system level. Taking into account current standards of addiction medicine, our results could serve as a basis for the development of treatment concepts and recommendations for optimizing standard care before LTX.

The dual role dilemma of liver transplantation health care professionals

BackgroundSimilar to many other countries, in Germany patients with alcohol-related liver disease are obliged to prove their abstinence before being accepted on a waitlist for liver transplantation. Health care professionals (HCPs) must both treat patients and ensure that patients have proven their abstinence. The aim of this exploratory study was to develop a deeper understanding of how HCPs deal with this dual role.MethodsThe study used semi-structured interviews as the source of data. 11 healthcare professionals from ten of the 22 German transplant centers were interviewed. After transcription, a qualitative content analysis was performed.ResultsWe found that these HCPs faced an ethical dilemma, as they must balance the roles of being both a treatment provider (the therapist role) and an assessor (the monitoring role). To solve this dilemma, the strategy seems to be a tendency for the HCPs to take on one dominant role amongst these two roles. HCPs who prefer to take on the therapist role seem to feel burdened by the 6-month abstinence rule and the obligation to monitor their patients. HCPs who prefer to take on the monitoring role tend to have negative assumptions about the patients. HCPs also reported the impression that patients perceive HCPs as more involved in monitoring and less open to the therapeutic role. From this it can be deduced that current regulations and structures lead both to stress for HCPs and to suboptimal therapy for those affected.ConclusionsThe results showed that current transplantation guidelines can have a negative impact on both patient care and the burdens on the HCPs. From our point of view, there are various changes that could be made to the current clinical practice that would help solve this dilemma. For instance, integrating other assessment criteria that are more closely adapted to the health status trajectory and psychosocial background of the individual patient would be both possible and would lead to improvements in practice.

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients

BackgroundGraft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients.MethodsThe EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period.DiscussionC/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022.Trial registrationThis trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020–000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20–1842-112.

The Tacrolimus Concentration/Dose Ratio Does Not Predict Early Complications After Kidney Transplantation.

Early-on post kidney transplantation, there is a high risk of graft rejection and opportunistic viral infections. A low tacrolimus concentration/dose (C/D) ratio as a surrogate marker of fast tacrolimus metabolism has been established for risk stratification 3months post-transplantation (M3). However, many adverse events occurring earlier might be missed, and stratification at 1month post-transplantation (M1) has not been investigated. We retrospectively analyzed case data from 589 patients who had undergone kidney transplantation between 2011 and 2021at three German transplant centers. Tacrolimus metabolism was estimated by use of the C/D ratio at M1, M3, M6, and M12. C/D ratios increased substantially during the year, particularly between M1 and M3. Many viral infections and most graft rejections occurred before M3. Neither at M1 nor at M3 was a low C/D ratio associated with susceptibility to BKV viremia or BKV nephritis. A low C/D ratio at M1 could not predict acute graft rejections or impaired kidney function, whereas at M3 it was significantly associated with subsequent rejections and impairment of kidney function. In summary, most rejections occur before M3, but a low C/D ratio at M1 does not identify patients at risk, limiting the predictive utility of this stratification approach.

Risk factors and characteristics influencing humoral response to COVID-19 vaccination in patients after allogeneic stem cell transplantation.

Vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is approved and recommended for immunocompromised patients such as patients after allogeneic stem cell transplantation (allo-SCT). Since infections represent a relevant cause of transplant related mortality we analyzed the advent of immunization to SARS-CoV-2 vaccination in a bicentric population of allogeneic transplanted patients. We retrospectively analyzed data of allo-SCT recipients in two German transplantation centers for safety and serologic response after two and three SARS-CoV-2 vaccinations. Patients received mRNA vaccines or vector-based vaccines. All patients were monitored for antibodies against SARS-CoV2-spike protein (anti-S-IgG) with an IgG ELISA assay or an EIA Assay after two and three doses of vaccination. A total of 243 allo-SCT patients underwent SARS-CoV-2 vaccination. The median age was 59 years (range 22-81). While 85% of patients received two doses of mRNA vaccines, 10% had vector-based vaccines and 5% received a mixed vaccination. The two vaccine doses were well tolerated with only 3% patients developing a reactivation of graft versus host disease (GvHD). Overall, 72% of patients showed a humoral response after two vaccinations. In the multivariate analysis age at time of allo-SCT (p=0.0065), ongoing immunosuppressive therapy (p= 0.029) and lack of immune reconstitution (CD4-T-cell counts <200/μl, p< 0.001) were associated with no response. Sex, intensity of conditioning and the use of ATG showed no influence on seroconversion. Finally, 44 out of 69 patients that did not respond after the second dose received a booster and 57% (25/44) showed a seroconversion. We showed in our bicentric allo-SCT patient cohort, that a humoral response could be achieve after the regular approved schedule, especially for those patients who underwent immune reconstitution and were free from immunosuppressive drugs. In over 50% of the initial non-responders after 2-dose vaccination, a seroconversion can be achieved by boostering with a third dose.

Human Leucocyte Antigen–Matching Can Improve Long Term Outcome of Renal Allografts from Donors Older Than 75 Years

BackgroundRenal transplantation is the therapy of choice for kidney failure. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys ≥65 years to recipients of the same age group considered a regional allocation with short cold ischemia (CIT) but not human-leukocyte-antigen (HLA)-matching. The acceptance of organs aged ≥75 years is also still controversial within the ESP. MethodsIn a multicenter approach, 179 kidney grafts ≥75 years (mean donor age 78 years) that were transplanted in 174 patients in 5 German transplant centers were analyzed. The primary focus of the analysis was long-term outcome of the grafts and the impact of CIT, HLA matching, and recipient related risk factors. ResultsThe mean graft survival was 59 months (median 67 months) with a mean donor age of 78.3 ± 2.9 years. Grafts with 0 to 3 HLA-mismatches had a significantly better overall graft survival compared to grafts with ≥4 mismatches (69 months vs 54 months; P = .008). The mean CIT was short (11.9 ± 5.3 hours) and had no impact on graft survival. ConclusionRecipients receiving a kidney graft from donors aged ≥75 years can benefit from nearly 5 years of survival with a functioning graft. Even minimal HLA matching may improve long term allograft survival.

Presence of Measurable Residual Disease in NPM1 Positive AML in Remission Pre-Transplant Does Not Impact on Survival after Allogeneic Hematopoietic Stem Cell Transplantation

Due to their biological and clinical features, acute myeloid leukemia (AML) with Nucleophosmin-1 (NPM1) gene mutations represents a distinct entity within the WHO classification 2022. As per ELN classification, they are mainly categorized either as favorable or intermediate-risk disease, and as such patients are referred for allogeneic hematopoietic stem cell transplantation (allo-HSCT) at disease relapse, during CR1 or, less frequently, due to primary refractoriness. However, even when transplanted, relapse remains the most common cause of treatment failure. Besides conditioning intensity, presence of measurable residual disease (MRD) at time of allo-HSCT has recently been shown to be associated with an increased risk of relapse post-transplant. Yet, the reported effect might vary according to genetic and immunophenotypic diversity of the disease, transplant setting and MRD technology used. Here, we aim to determine the impact of NPM1 presence assessed via qPCR on post allo-HSCT outcomes. This retrospective study included adult AML patients harboring an NPM1 mutation (NPM1mut) who received a first allo-HSCT between January 2011 and January 2022 at four German transplant centers. NPM1 mutation status was assessed at diagnosis, and monitored throughout the treatment course by qPCR. NPM1 MRD monitoring was performed as previously described (Papadaki et al., 2009, sensitivity of 10−6). MRD status pre-transplant was correlated with outcome. There were no restrictions regarding donor type or conditioning intensity We identified 161 adult AML patients with available pre-transplant MRD status. Median age of the entire cohort was 55 years (21-75). The majority of patients (86%) had cytogenetically normal AML and presented in hematologic remission (CR1, CR2) (69%) at time of allo-HSCT. Whereas NPM1mut was measurable in all patients with active disease, 85/111 (77%) patients in remission had either NPM1mut persistence after antecedent induction/consolidation therapy (n=68) or molecular relapse (n=17). Conditioning intensity used was RIC in 57, MAC in 12, sequential-RIC in 88 and sequential-MAC in 4 patients. Most patients (n=90) were transplanted from matched unrelated donor (matched related: n=37, haploidentical: n=34), using preferentially PBSCs as graft source (n=146). At a median follow-up of 28 months (3-127), the estimated probability of OS and LFS at 2 years was 63% and 55%, respectively. When patients are stratified into groups with active disease, vs NPM1+CR vs NPM1- CR, 2-year OS and LFS show a significant difference (45% vs. 73% vs. 71%; p=0.002 and 55% vs. 62% vs. 67% p=0.005, respectively). Yet, if considering only patients in remission, no survival difference according to NPM1-MRD status at transplantation was detected (OS, p=0.49 and LFS, p=0.33). Likewise, cumulative incidence of relapse at 2 years was 44%, 15% and 17% (p=0.001); however among remission patients there was no significant difference between MRD+ and MRD- patients before allo-HSCT (p=0.96). CI of NRM at 1-year was 14%, 18% and 8% for non-CR, NPM1+ CR and NPM1- CR patients (p=0.9). Intriguingly, MRD positivity as assessed per qPCR at time of transplant did not impact on post-transplant outcome in our cohort of NPM1 positive AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Individualised immunosuppression with intravenously administered donor-derived modified immune cells compared with standard of care in living donor kidney transplantation (TOL-2 Study): protocol for a multicentre, open-label, phase II, randomised controlled trial

IntroductionDonor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in...

Body Mass Index Thresholds and the Use of Bariatric Surgery in the Field of Kidney Transplantation in Germany

BackgroundObesity in the recipient is linked to inferior transplant outcome. Consequently, access to kidney transplantation (KT) is often restricted by body mass index (BMI) thresholds. Bariatric surgery (BS) has been established as a superior treatment for obesity compared to conservative measures, but it is unclear whether it is beneficial for patients on the waiting list.MethodsA national survey consisting of 16 questions was sent to all heads of German KT centers. Current situation of KT candidates with obesity and the status of BS were queried.ResultsCenter response rate was 100%. Obesity in KT candidates was considered an important issue (96.1%; n = 49/51) and 68.6% (n = 35/51) of departments responded to use absolute BMI thresholds for KT waiting list access with ≥ 35 kg/m2 (45.1%; n = 23/51) as the most common threshold. BS was considered an appropriate weight loss therapy (92.2%; n = 47/51), in particular before KT (88.2%; n = 45/51). Sleeve gastrectomy was the most favored procedure (77.1%; n = 37/51). Twenty-one (41.2%) departments responded to evaluate KT candidates with obesity by default but only 11 (21.6%) had experience with ≥ n = 5 transplants after BS. Concerns against BS were malabsorption of immunosuppressive therapy (39.2%; n = 20/51), perioperative morbidity (17.6%; n = 9/51), and malnutrition (13.7%; n = 7/51).ConclusionsObesity is potentially limiting access for KT. Despite commonly used BMI limits, only few German centers consider BS for obesity treatment in KT candidates by default. A national multicenter study is desired by nearly all heads of German transplant centers to prospectively assess the potentials, risks, and safety of BS in KT waitlisted patients.Graphical abstract

High Mortality of COVID-19 Early after Allogeneic Stem Cell Transplantation: A Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group

Recipients of allogeneic stem cell transplantation (alloSCT) are at high risk for contracting infectious diseases with high morbidity and mortality. Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that can lead to severe pneumonia and acute respiratory distress syndrome, with a potentially fatal outcome. In this retrospective study conducted on behalf of the German Cooperative Transplant Study Group, we aimed to analyze risk factors, disease course, and outcomes of COVID-19 in patients who underwent alloSCT. AlloSCT recipients who became infected with SARS-CoV-2 at German and Austrian transplant centers between February 2020 and July 2021 were included. Classification of COVID-19 severity into mild, moderate-severe, or critical disease and division of the course of the pandemic into 4 phases were done according to the German Robert Koch Institute. The main endpoint was overall mortality at the end of follow-up. We further analyzed the need for treatment in an intensive care unit (ICU) and the severity of disease. Risk factors were evaluated using univariate and multivariate analyses, and survival analysis was performed using Kaplan-Meier method. The study cohort comprised 130 patients from 14 transplant centers, with a median age at diagnosis of COVID-19 of 59 years (range, 20 to 81 years) and a median interval between alloSCT and COVID-19 of 787 days (range, 19 to 8138 days). The most common underlying diseases were acute myeloid leukemia (45.4%) and lymphoma (10.8%). The majority of patients (84.9%) were infected in the later phases of the pandemic; 20.8% had moderate-severe disease, 12.3% had critical disease, and 19.2% were treated in an ICU. After a median follow-up of 127 days, overall mortality was 16.2%, 52.0% among patients treated in an ICU. Risk factors for mortality in multivariate analysis were active disease (odds ratio [OR], 4.46), infection with SARS-CoV-2 ≤365 days after alloSCT (OR, 5.60), age >60 years (OR, 5.39), and ongoing immunosuppression with cyclosporine (OR, 8.55). Risk factors for developing moderate-severe or critical disease were concurrent immunosuppression (OR, 4.06) and age >40 years (OR, 4.08). Patients after alloSCT exhibit a substantially increased mortality risk after COVID-19 infection compared with the normal population, without considerable improvement over the course of the pandemic. Risk factors include age, early infection post-alloSCT, and active immunosuppression. Further studies are needed to improve prevention and treatment in this high-risk patient group.

Results of the prospective multicenter SoLKiD cohort study indicate bio-psycho-social outcome risks to kidney donors 12 months after donation

The outcome after living kidney donation was assumed to be comparable to that of the general population. However, recent register studies reveal negative changes in kidney function, quality of life and fatigue. Avoiding methodological issues of previous studies, the Safety of the Living Kidney Donor (SoLKiD) cohort study analyzed the outcome of donors in a multicenter and interdisciplinary fashion. Donor data were collected pre-donation and two-, six- and 12-months post-donation in 20 German transplantation centers. Primary parameters were kidney function, quality of life, and fatigue. Secondary endpoints were blood pressure, hemoglobin, hemoglobin A1c, body mass index, depression and somatization. Parameters were analyzed with non-parametric statistical tests and a mixed model regression for changes in time, their clinical relevance and interaction encompassing 336 donors with mean age of 52 years. Most of the physical secondary parameters, depression, and quality of life showed little or no changes and regained their pre-donation level. Kidney function decreased significantly with a 37% loss of glomerular filtration rate and an increase of donors with chronic kidney disease stage 3 from 1.5% pre-donation to about 50%. Donors consistently showed increased fatigue and somatization. Mental fatigue increased from 10.6% to 28.1%. The main influencing factors for decreased kidney function and increased fatigue were their respective pre-donation levels, and donor age for kidney function and subject stress level in fatigue. Thus, our study showed that a significant number of donors developed clinically relevant changes in physical and mental health and emphasizes the urgent need to inform potential donors about these risks.

Donor Genetic Determinant of Thymopoiesis rs2204985 Impacts Clinical Outcome after Single HLA Mismatched HSCT

Introduction: A common genetic variant within the TCRA-TCRD locus has been recently identified as a predictive factor of thymic function and T cell repertoire diversity (Clave et al., 2018). Specifically it was shown in a mouse model that transplantation of rs2204985 AA human hematopoietic stem cells (HSC) into immunodeficient mice led to lower thymocyte counts and poorer TCR diversity. T cell mediated pathways are known to play a significant role in immunological processes affecting HSCT outcome like GvL, GvH and infection. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated HSCT.Methods: The study included 2,016 adult patients with hematologic malignancies who received their first unrelated (10/10 or 9/10 HLA matched) graft between 2000 and 2013 in a German transplant center. Patients with refractory disease at time of transplantation were excluded from the analysis. Both donors and patients were retrospectively genotyped for the TCRA-TCRD rs2204985 polymorphism by next generation sequencing using a validated protocol on an Illumina Miseq platform. Overall survival (OS), disease free survival (DFS), relapse (RI), non-relapse mortality (NRM), acute GvHD (aGvHD) and chronic GvHD (cGvHD) were evaluated; p<0.05 was considered significant and donor rs2204985 GG/AG genotype was set as reference vs the AA genotype. Stratification for diagnosis was performed and a backward stepwise model finding approach was used to select variables related to a given outcome with a threshold of 0.10 for retention in the model.Results: The rs2204985 genotype frequencies found in both patients and donors were in line with those previously reported for Caucasian populations indicating a codominance of the two alleles (i.e. A and G). Regarding the impact of this genetic variation on outcome, multivariate analysis of the combined cohort indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations, therefore subanalysis on account of HLA incompatibility was performed. Analysis in the subgroup of single HLA mismatched cases (n=624) revealed that donor AA genotype associated with markedly inferior OS (55.1% vs 70.6%, p=0.004, Fig. 1) and DFS (47.6% vs 63.4%, p=0.002, Fig. 2) one year after HSCT as compared to the donor AG/GG genotypes. These results were confirmed in the corresponding multivariate models (OS HR: 1.48, p=0.003; DFS HR: 1.50, p=0.001) which are visually displayed as forest plots in Fig. 3 and Fig 4, respectively. The adverse effect of donor AA genotype on survival appears to be driven by a combined higher risk of RI (1Y after HSCT: 29.3% vs 18.3%, p=0.048; HR: 1.38, p=0.035) and NRM (1Y after HSCT: 28.6% vs 19.9%, p=0.043; HR: 1.38, p=0.042) as shown by both the univariate and multivariate analyses for the two respective endpoints. No association was found between donor rs2204985 genotype and risk of acute or chronic GvHD. The donor rs2204985 genotype had also no significant impact on any outcome endpoint in the 10/10 HLA matched subgroup. Last, no significant interactions were observed between this variable and the other adjusted covariates in the multivariate models.Conclusion: To our knowledge this is the first study to date investigating the potential effect of donor's genotype regarding a common genetic variant within the TCRA-TCRD locus on the outcome of patients receiving unrelated HSC grafts. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely affect the outcome of HSC transplanted patients and should therefore be avoided. It is of note that one in four unrelated donors of Caucasian origin is expected to carry the AA genotype. A weaker relapse and -presumably- infection control, especially in the early post-transplantation period, due to compromised T cell reconstitution as a result of the unfavorable donor AA genotype may account for these findings. Confirmatory studies in larger independent cohorts are warranted before final conclusions are drawn. [Display omitted] DisclosuresPlatzbecker: Geron: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria. Sala: Celgene/BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Kroeger: Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Hertenstein: Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; BMS: Honoraria. Schrezenmeier: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria; Novartis: Honoraria; Apellis: Honoraria; Sanofi: Honoraria.

The Multicentre, Double-Blinded, Placebo-Controlled Clinical-Trial (Pre-GvHD) for Prediction and Pre-Emptive Treatment of Acute GvHD

Allogeneic stem cell transplantation (HSCT) is a curative treatment for adult patients with hematologic malignancies, but is limited by severe, life-threatening complications such as acute graft-versus-host disease (aGvHD). We have developed a proteomic urine pattern “aGvHD_MS17”, consisting of 17 differentially excreted peptides, capable to predict aGvHD grade II or more (1, 2). In 2008, a multicenter, randomized, placebo-controlled, double blind clinical trial (Pre-GvHD) was initiated testing aGvHD_MS17 for prediction of aGvHD and to initiate pre-emptive therapy using prednisolone 2-2.5mg/kg.Patients and Methods:Eleven German transplant-centres contributed 267 patients. Urine was collected weekly from day +7 to +35 and on days +50 and +80 (all +/-3 days) frozen, shipped to Hannover and analyzed using capillary electrophoresis coupled on-line to mass spectrometry (CE-MS) within 72h as described (1). aGvHD_MS17 was considered positive, when the dimensionless classification factor (CF) was +0.1 or more. Eight patients were excluded from analyses, either due to no medication (n=5) or protocol violations (n=3) and 92 were randomized according to the positivity of aGvHD-MS17 to receive either prednisolone (2-2.5mg/kg, n=44) or placebo (n=48) for 5 days followed by a taper for 19 days, if no aGvHD occurred. The remaining 167 patients formed the observation group according to pattern negativity.About half of the patients had acute leukemia (placebo group: n=24/48 (50%), prednisolone group: n=21/44 (50%); observation group: n= 91/167 (54%)) and were in complete remission/chronic phase (CR/CP) (placebo n=23/48 (47%), prednisolone n=27/44 (61%) and observation n=68/167 (41%). The majority was transplanted from matched donors (placebo: n=42/48 (87%); prednisolone: n=37/44 (84%); observation: 146/167 (87%), using reduced intensity conditioning regimens (RIC; 64%), and a calcineurin-inhibitor based GvHD-prophylaxis with MTX or MMF).Results:Prospective and blinded evaluation of aGvHD_MS17 revealed that the first analysis time point (day +7; range: 2-17) most accurately predicted aGvHD grade II or more with a sensitivity of 87% and a specificity of 81% prior to clinical signs with a CF of +0.1 (2). Patients with samples positive for aGvHD_MS17 in the early analyses time points had a 21-fold higher risk to develop aGvHD grade II or more ((p<0.0001), Figure 1). By day +28 the predictive value of aGvHD_MS17 was lost. Confounding factors were conditioning with RIC-protocols and early death after HSCT. Patients with one sample positive for aGvHD_MS17 had a 3-fold higher risk to die, 35% of those died prior to day +500, compared to only 10% of the patients with negative samples. Analysis of pre-emptive therapy using prednisolone revealed that the incidence and severity of acute GvHD was not significantly different between the placebo and prednisolone arm suggesting that prednisolone 2-2.5mg/kg was insufficient to prevent aGvHD in this setting. Further analyses of aGvHD according to organ manifestation are ongoing. The occurrence of aGvHD after a positive proteomic pattern test in the placebo group of this trial was lower than in the previous pilot study. Possible reasons include different patient populations (pilot study: 18% of patients transplanted in relapse; current trial: only 4% transplanted in relapse, increasing the risk to develop aGvHD), different intestinal decontamination and GvHD prophylaxis protocols. The frequency of adverse and serious adverse events was not higher in the prednisolone arm than the placebo arm. No specific safety risk of the pre-emptive therapy with prednisolone was identified.Conclusions:Taken together our results indicate that pre-emptive treatment of imminent aGvHD based on proteomic-pattern-diagnostic with prednisolone 2-2.5mg/kg appears to be safe, but did not influence severity or incidence of aGvHD grade II or more. The prospective evaluation of aGvHD_MS17 confirms the highly reproducible results in the early analysis time points (day +7 to +21) for prediction of aGvHD (day +7; range 2-17). Patients with aGvHD_MS17 positive samples have a 21-fold risk to develop severe GvHD (grade II-IV). Moreover, patients with one sample positive for aGvHD_MS17have a 3-fold increased risk of death by day +500 after HSCT.(1) Blood 2007 :109(12):5511-9.(2) Leukemia, 2014: , 28(4):842-52 [Display omitted] DisclosuresJochen:Mosaiques GmbH: Employment. Schmid:Jazz: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; MoilMed: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Bethge:Miltenyi Biotech GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding. Raad:Mosaiques GmbH: Employment. Durban:Mosaiques GmbH: Employment.

Shift in Living Kidney Donor Demographics Over the Past 50 Years in a German Transplant Center

BackgroundLiving kidney donors may face health risks after donation. Age, sex, body mass index, comorbidities, and relationship to the recipient have an impact on lifetime living kidney donor risk. In view of a changing landscape in renal transplantation with increasing organ shortages, the selection criteria for potential donors may have changed over time.Material/MethodsWe investigated donor demographics and outcomes in a cohort of 760 living kidney donors who donated from 1967 to 2016 at the transplant center in Heidelberg, Germany.ResultsThe living kidney donor age increased from 34.9±11.5 to 53.2±10.2 years, with 11.4% donors aged 65 years in the period from 2011 to 2016. The number of donors with comorbidities at the time of donation increased. The percentage of donors with a history of obesity, hypertension, smoking, and a family history of kidney disease enlarged to 18.6%, 36.1%, 37.0%, and 9.1%, respectively. De novo hypertension was a common problem in more than half of the donors at long-term follow-up, and donor renal function decreased about 30 mL/mi/1.73 m2.ConclusionsThis detailed analysis of living kidney donor demographics over the last 50 years detected an increased proportion of donors with higher age and comorbidities today. Careful donor selection, regular follow-up visits, and systematic donor registries are required to further improve donor outcomes.

Implementation of Palliative Care in Clinical Practice in German Units for Allogeneic Stem Cell Transplantation: A Nationwide Survey.

Allogeneic stem cell transplantation (alloSCT) is a curative therapy for otherwise fatal diseases, however it is associated with a considerable morbidity and mortality. In consequence, it can be assumed that a considerable percentage of patients would benefit from high-quality palliative care (PC) during their course of disease. To assess the standard of PC in German transplant centers, a questionnaire was sent out to all German centers recognized from the EBMT membership list and the annually ZKRD report (n = 52). The response rate was not as high as expected with n = 27 (51,9%), even after reminding by phone calls or by e-mails. In brief, palliative care after allogeneic stem cell transplantation shows a wide variation in Germany. This is true for structures, processes and measures. A national standard for SCT-patients has not been established so far and there are no pre-conditions concerning palliative care after alloSCT for a certification by the EBMT according the JACIE standards. There is a considerable need for a crosslinking of alloSCT with PC. Clear standards should be established by the scientific societies concerning personnel, structure and processes.

Coronavirus Disease 2019 Associated Risk Score, Behavior, and Symptom Prevalence in German Transplant Recipients

BackgroundTransplant recipients are prone to developing severe infections because of immunosuppression. Therefore, studying the manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients is of particular importance. MethodsOne hundred twelve transplant patients consecutively visiting the outpatient department of 2 German transplant centers were included in this study after providing written informed consent. The patients were interviewed about coronavirus disease 2019 (COVID-19) symptoms and history. Nasopharyngeal swabs were analyzed by SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR). SARS-CoV-2 IgG and IgA were measured concomitantly in patient sera by enzyme-linked immunosorbent assay. ResultsThe risk of severe COVID-19 according to 2 recent scores differed among the analyzed patients. All patients were well educated about their presumed higher risk of a severe COVID-19 and described performing self-isolation wherever possible. Nevertheless, 20 patients reported contact with someone suspected of having COVID-19 or who tested positive shortly thereafter (18%). Despite this relatively high exposure, no clinically relevant case of COVID-19 was reported. Though SARS-CoV-2 IgG and IgA were found in 3 patients (3%); 2 patients were asymptomatic and only 1 had mild COVID-19 symptoms and positive RT-PCR 4 weeks earlier. There were no occult SARS-CoV-2 infections, as demonstrated by negative PCR tests. ConclusionDespite the high exposure level, the incidence of COVID-19 remained very low. Because of the differences in COVID-19 risk, balancing risk exposure and quality of life should be recommended.