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Seroconversion after COVID-19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an increasing threat to these patients. In this observational cohort study, we measured anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age-matched healthy controls. In addition, vaccine-induced neutralization of SARS-CoV-2 wild-type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live-virus assay. After a third vaccine dose, anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p < 0.001). Vaccine-induced cross-neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti-S1 IgG, surrogate neutralizing, and/or anti-RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p < .001 for all)., Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Straus Program; Heidelberg Faculty of Medicine Physician Scientist Program; German Federal Research Network Applied Surveillance and Testing (BFAST); Network University Medicine; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis

Background and objectives: antibody response after severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) vaccination is impaired in kidney transplant recipients. Emerging variants, such as B.1.617.2 ( d), are of particular concern because of their higher transmissibility and partial immune escape. Little is known about protection against these variants in immunocompromised patients. Design, setting, participants, and measurements: in this prospective two-center study, antispike 1 IgG and surrogate neutralizing antibodies were measured in 173 kidney transplant recipients and 166 healthy controls with different vaccination schedules. In addition, different SARS-CoV-2 epitope antibodies from 135 vaccinated kidney transplant recipients were compared with antibodies in 25 matched healthy controls after second vaccination. In 36 kidney transplant recipients with seroconversion, neutralization against B.1.1.7 ( a), B.1.351 ( b), and B.1.617.2 ( d) was determined on VeroE6 cells and compared with neutralization in 25 healthy controls. Results: kidney transplant recipients had significantly lower seroconversion rates compared with healthy controls. After the second vaccination, antispike 1, antireceptor-binding domain, and surrogate neutralizing antibodies were detectable in 30%, 27%, and 24% of kidney transplant recipients, respectively. This compares with 100%, 96%, and 100% in healthy controls, respectively (P,0.001). Neutralization against B.1.1.7 was detectable in all kidney transplant recipients with seroconversion, with a median serum dilution that reduces infection of cells by 50% of 80 (interquartile range, 80-320). In contrast, only 23 of 36 (64%) and 24 of 36 (67%) kidney transplant recipients showed neutralization against B.1.351 and B.1.617.2, respectively, with median serum dilutions that reduce infection of cells by 50% of 20 (interquartile range, 0-40) and 20 (interquartile range, 0-40), respectively. Neutralization against different variants was significantly higher in healthy controls (P,0.001), with all patients showing neutralization against all tested variants. Conclusions: seroconverted kidney transplant recipients show impaired neutralization against emerging variants of concern after standard two-dose vaccination., Dietmar Hopp Stiftung; German Federal Research Network Applied Surveillance and Testing; Network University Medicine; fightCOVID@DKFZ Initiative; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis; Lessons to Get Prepared for Future Pandemics; Heidelberg Faculty of Medicine Rahel Goitein-Strauss Program; Heidelberg Faculty of Medicine Physician Scientist Program

Introduction: donor-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 a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). Methods and analysis: sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. Ethics and dissemination: ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings. Trial registration number NCT05365672., Preparation of the study was funded by the Federal Ministry of Education and Research, Berlin, Germany (FKZ 161B0560A, 161B0560B, and FKZ 031B0560A, 031B0560B), and TolerogenixX GmbH, Heidelberg, Germany (N/A). Conduct of the study is funded by TolerogenixX GmbH (N/A).

HLA matching and avoidance of unacceptable mismatches are important aspects in the selection of donors for solid organ transplantation. The impact of HLA-DPB1 incompatibility on the outcomes of kidney transplantation is not fully understood. We investigated a potential effect of mismatching for HLA-DPB1 at allele, eplet, or Terasaki epitope (TerEp) level on the formation of de novo donor-specific antibodies (dnDSA) and also asked whether polymorphisms associated with HLA-DPB1 expression level may influence dnDSA induction. Furthermore, we analyzed the correlation between graft survival and HLA-DPB1 mismatches defined by different approaches. A cohort of 366 patients who received a kidney transplant at the Heidelberg University Hospital, Germany, with availability of pre- and post-transplant HLA antibody results by single antigen testing as well as of donor and recipient HLA-DPB1 high-resolution typing were analyzed retrospectively. Susceptibility to increased HLA-DPB1 expression was predicted by the linked dimorphism rs9277534 A/G of the HLA-DPB1 gene. Neither HLA-DPB1 mismatches at allele, eplet or TerEp level nor exposure to donor's high HLA-DPB1 expression were significantly associated with the risk of developing dnDSA against HLA-DPB1. However, HLA-DPB1 eplet and TerEp mismatches had a significant negative impact on graft survival (p < 0.001 and p = 0.003, respectively). Matching for HLA-DPB1 at epitope instead of allele level appears to have potential to improve graft survival in kidney transplantation.

Background The Identification of B cell subsets with regulatory functions might open the way to new therapeutic strategies in the field of transplantation, which aim to reduce the dose of immunosuppressive drugs and prolong the graft survival. CD25 was proposed as a marker of a B-cell subset with an immunosuppressive action termed Bregs. The effect of CD19 + CD25 + Bregs on graft function in renal transplant recipients has not yet been elucidated. We investigated a potential impact of CD19 + CD25 + Bregs on renal graft function as well as a possible interaction of CD19 + CD25 + Bregs with peripheral Tregs in healthy controls, end-stage kidney disease patients (ESKD), and renal transplant recipients. Moreover, we aimed to investigate the association of CD19 + CD25 + Bregs with serum IL-10, TGF-ß1, and IFN-γ in the same study groups. Method Thirty-one healthy controls, ninety renal transplant recipients, and eighteen ESKD patients were enrolled. We evaluated the CD19 + CD25 + Bregs and Treg absolute counts. Next, we investigated CD19 + CD25 + Bregs as predictors of good graft function in multiple regression and ROC analyses. Finally, we evaluated the association between CD19 + CD25+ Bregs and serum IL-10, TGF-ß, and IFN-γ. Results ESKD patients and renal transplant recipients showed lower counts of CD19 + CD25+ Bregs compared to healthy controls (p p = 0.02). In these patients, higher CD19 + CD25+ Bregs were independently associated with higher Treg counts (unstandardized B = 2.8, p = 0.004). In ROC analysis, cut-offs for CD19 + CD25 + Breg counts and serum TGF-ß1 of 0.12 cell/μl and 19,635.4 pg/ml, respectively, were shown to provide a good sensitivity and specificity in identifying GFR ≥ 30 ml/min (AUC = 0.67, sensitivity 77%, specificity 43%; AUC = 0.65, sensitivity 81%, specificity 50%, respectively). Finally, a significant positive association between CD19 + CD25+ Bregs and TGF-ß1 was shown in renal transplant recipients (r = 0.255, p = 0.015). Conclusions Our findings indicate that higher counts of CD19 + CD25+ Bregs are independently associated with better renal function and higher absolute Treg counts in renal transplant recipients.

Kidney insufficiency and immunosuppression are well established contributors of tumor development, both before and after kidney transplantation. Patients with pre-transplant malignancies (PTM) are at risk of tumor recurrence and of the development of an unrelated tumor after transplantation. In this retrospective study of a German patient cohort, we analyzed 1089 patients that underwent kidney transplantation to determine the frequency, recurrence rate and overall survival of patients with pre-existing tumors across a 10-year period. PTM were found in 5.79% of the patients and appeared at a mean time of 7.39 (SD 6.8) years before transplantation. The tumors were most frequently of urologic (41.43%) origin, followed by malignancies of the skin (25.71%) and gynecologic tumors (10%). Tumor recurrence was observed in one case (1.6%) where the patient died of metastatic spinocellular carcinoma. Patients with pre-existing malignancies had a statistically significantly worse overall survival compared to transplant recipients without tumors (HR = 2.71, 95% CI 1.49–4.969). However, these differences could be entirely ascribed to the age (HR = 1.06, 95% CI 1.04–1.08) and gender (HR = 1.67, 95% CI 1.11–2.52) of the patients. We found that there was no difference in cancer-specific mortality or posttransplant cancer rate between patients with and without pre-existing malignancies (HR = 0.94, 95% CI 0.21–4.26).

Main problem: soluble urokinase plasminogen activator receptor (suPAR) is an immunological risk factor for kidney disease and a prognostic marker for cardiovascular events.Methods: we measured serum suPAR levels in a total of 1,023 kidney transplant recipients either before (cohort 1, n = 474) or at year 1 after transplantation (cohort 2, n = 549). The association of suPAR levels and all-cause and cardiovascular mortality was evaluated by multivariable Cox regression analysis.Results: the highest suPAR tertile compared to the two lower tertiles had a significantly higher risk of all-cause mortality in both cohorts separately (cohort 1: hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.20-3.08, p = 0.007; cohort 2: HR = 2.78, 95% CI 1.51-5.13, p = 0.001) and combined (n = 1,023, combined HR = 2.14, 95% CI 1.48-3.08, p < 0.001). The association remained significant in the subgroup of patients with normal kidney function (cohort 2: HR = 5.40, 95% CI 1.42-20.5, p = 0.013). The increased mortality risk in patients with high suPAR levels was attributable mainly to an increased rate of cardiovascular death (n = 1,023, HR = 4.24, 95% CI 1.81-9.96, p < 0.001). Conclusion: a high suPAR level prior to and at 1 year after kidney transplantation was associated with an increased risk of patient death independent of kidney function, predominantly from cardiovascular cause., NA

After solid-organ transplantation, reactivation of the cytomegalovirus (CMV) is often observed in seronegative patients and associated with a high risk of disease and mortality. CMV-specific T cells can prevent CMV reactivation. In a phase 1 trial, CMV-seronegative patients with end-stage renal disease listed for kidney transplantation were subjected to CMV phosphoprotein 65 (CMVpp65) peptide vaccination and further investigated for T-cell responses. To this end, CMV-specific CD8+ T cells were characterized by bulk T-cell-receptor (TCR) repertoire sequencing and combined single-cell RNA and TCR sequencing. In patients mounting an immune response to the vaccine, a common SYE(N)E TCR motif known to bind CMVpp65 was detected. CMV-peptide-vaccination-responder patients had TCR features distinct from those of non-responders. In a non-responder patient, a monoclonal inflammatory T-cell response was detected upon CMV reactivation. The identification of vaccine-induced CMV-reactive TCRs motifs might facilitate the development of cellular therapies for patients wait-listed for kidney transplantation.

Lymphatic complications after kidney transplantation (KTx) are associated with morbidities such as impaired wound healing, thrombosis, and organ failure. Recently, a consensus regarding the definition and severity grading of lymphoceles has been suggested. The aim of the present study was to validate this classification method. All adult patients who underwent KTx between December 2011 and September 2016 in our department were evaluated regarding lymphoceles that were diagnosed within 6 months after KTx based on the recent definition. Patients with lymphoceles were categorized according to the classification criteria, and clinical outcomes were compared between the groups. In our department, a total of 587 patients underwent KTx between 2011 and 2016. Lymphoceles were detected after KTx in 90 patients (15.3%). Among these patients, 24 (26.6%) had grade A lymphoceles, 14 (15.6%) had grade B, and 52 (57.8%) had grade C. The median duration times of intermediate care (IMC) and hospital stay were significantly higher among patients with grade C lymphoceles than they were among patients with grade A and B lymphoceles. Significantly more patients with grade C lymphoceles were readmitted to the hospital for treatment. The recently published definition and severity grading of lymphoceles after KTx is an easy-to-use and valid classification system, which may facilitate the comparison of results from different studies on lymphoceles after KTx.

Chronic kidney failure (KF) provokes the development of immune senescent CD8

Monitoring of donor-specific HLA antibodies (DSA) has become part of the clinical routine in kidney transplantation. This paper gives a brief overview on data from the Collaborative Transplant Study (CTS) and the Heidelberg Transplant Center on the clinical relevance of post-transplant DSA monitoring in patients undergoing renal transplantation. The obtained findings underline the importance of DSA monitoring in the post-operative course in immunologically high-risk patients and patients with deterioration of graft function. Especially in patients with a pre-activated immune system, a gap in the immunosuppressive therapy appear to lead to persistence, reappearance or de novo occurrence of strong, complement-activating DSA, resulting in severe antibody-mediated rejection (AMR) and, without timely intervention, in AMR-related graft loss.

Because of the current organ shortage, ABO-incompatible (ABOi) transplantations have been increasingly performed in recent years. The results seem comparable to those of compatible transplantations, but there have also been reports of increased side effects possibly because of the desensitization therapy. To address an increase in severe infectious complications, we compared the outcomes of 48 ABOi transplant recipients to outcomes of 96 matched ABO-compatible (ABOc) controls transplanted at Heidelberg University Hospital from August 2005 to April 2018. Over a follow-up period of 8 years, ABOi transplant recipients had comparable graft and patient survival as well as graft function compared with ABOc patients. T-cell-mediated and antibody-mediated rejections were not different between groups. In ABOi transplant recipients, urosepsis (22.9% vs. 8.5%; P = 0.019) and pneumonia with opportunistic pathogens (8.3% vs. 1.0%, P = 0.025) appeared more frequently. As a consequence, a significantly higher number of deaths from infection have been observed after ABOi transplantations (6.3% vs. 0%, P = 0.010). High-titer recipients (isoagglutinin titer of ≥1:256) showed a higher incidence of BK virus replication and postoperative bleeding complications. ABO-incompatible transplantations can be performed with results that are not different from results after ABOc transplantations. However, an increased rate of serious infectious complications must be taken into account.

A successful transition of renal transplant recipients from pediatric to adult care requires a structured, need-adapted and multidisciplinary approach to preserve renal graft function during this critical period of life. In this article we present our clinical protocol for transition from pediatric to adult care, which we developed on the basis of the International Society of Nephrology (ISN)/International Pediatric Nephrology Association (IPNA) consensus guidelines influenced by our own experience. This transition program was established in our center in July 2017. The entire transition process is structured and accompanied by a transition key worker (social worker). From 12 years of age we train pediatric renal transplant recipients in medical knowledge, self-management skills and networking with self-help groups. The training is adapted to the individual patient‘s intellectual ability, lasts about 10 years and takes place with increasing intensity. Repeatedly we perform standardized informational interviews and check patient’s knowledge of transplant-related topics. Psychosocial and educational issues are evaluated concomitantly. The actual transfer takes place in a pediatric-adult-transition clinic. Relevant medical and psychosocial aspects are discussed and the future treatment regimen is established. The date of transfer is adapted to the individual patient’s need; it varies between 18 and 24 years of age. In periods of increased risk for non-adherence the transfer is postponed to intensify the efforts for training and assistance. After transfer a standardized evaluation of each individual patient takes place focusing on medical and psychosocial issues and on satisfaction with the transition process. Collection of these data is still in progress and will be analyzed systematically at a later stage in order to evaluate the impact of this new transition program on the stability of transplant function. That analysis might serve as a basis for negotiations about refunding with health insurance companies.

BACKGROUND Living 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 AND METHODS We 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. RESULTS The 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. CONCLUSIONS This 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.

IntroductionGaps still exist regarding knowledge on regulatory cells in transplant recipients. We studied the phenotypic patterns of CD4+, CD8+CD28- Tregs, and CD19+IL-10+ Bregs in the blood of healthy controls (HC), end-stage kidney disease patients (ESKD), early and late stable renal transplant recipients (Tx), and transplant recipients with steroid-treated acute cellular rejection 1 week–3 months after successful treatment. We also investigated the relationship between immunosuppressive drugs and the aforementioned regulatory cells in transplant recipients.MethodsWe recruited 32 HC, 83 ESKD, 51 early Tx, 95 late Tx, and 9 transplant patients with a recent steroid-treated acute cellular rejection. Besides CD19+IL-10+ Bregs, we analyzed absolute and relative frequencies of CD4+CD25+CD127-Foxp3+ Tregs and CD8+CD28- Tregs and their expression of IL-10, TGF-ß, IFN-g, and Helios.ResultsWe found a negative correlation between absolute CD4+CD25+CD127-Foxp3+ Treg and relative CD19+IL-10+ Breg frequencies in early Tx recipients (r=-0.433, p=0.015, n=31). In that group, absolute CD4+CD25+CD127-Foxp3+ Tregs were negatively associated with steroid dose and tacrolimus trough levels (r=-0.377, p = 0.021, n=37; r=-0.43, p=0.033, n=25, respectively), opposite to IL-10+ Bregs, whose frequency apparently was not negatively affected by potent immunosuppression early posttransplant. We found also lower CD4+CD25+CD127-Foxp3+ Tregs in patients treated with basiliximab or rATG as compared with ESKD patients (p=0.001 and p <0.001, respectively). No difference in absolute IL-10+ Bregs could be detected among these 3 patient groups. Early Tx recipients showed lower CD4+CD25+CD127-Foxp3+ Tregs within 3 months of antibody induction than after 3 months (p = 0.034), whereas IL-10+ Bregs showed higher relative counts during the first 3 months post antibody induction than after 3 months (p = 0.022). Our findings suggest that IL-10+ Bregs decrease with time posttransplantation independent of the effect of antibody induction and dose of other immunosuppressive drugs.ConclusionThese findings suggest that CD19+IL-10+ Bregs and CD4+CD25+CD127-Foxp3+ Tregs behave in opposite ways during the early posttransplant period, possibly due to a predominant negative impact of high doses of immunosuppressants on Tregs. CD19+IL-10+Bregs do not seem to be suppressed by antibody induction and early potent immunosuppression with chemical drugs.

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.

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-gamma, 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

The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy.Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres.Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention.A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.La incidencia de complicaciones linfáticas tras el trasplante renal (post-kidney-transplantation lymphatic, PKTL) varía considerablemente en la literatura. Esto se debe en parte a que no se ha establecido una definición universalmente aceptada. Este estudio tuvo como objetivo proponer una definición aceptable para las complicaciones PKTL y un sistema de clasificación de la gravedad basado en la estrategia de tratamiento. MÉTODOS: Se realizó una búsqueda sistemática de la literatura relevante en MEDLINE y Web of Science. Se logró un consenso para la definición y la clasificación de gravedad de las PKTL entre veinte centros de trasplante de alto volumen.En 32 de los 87 estudios incluidos se definía la linforrea/linfocele. Sesenta y tres artículos describían como se trataban las PKTL, pero ninguno calificó la gravedad de las mismas. La definición propuesta para la linforrea fue la de un débito diario superior a 50 ml de líquido (no orina, sangre o pus) a través del drenaje o del orificio cutáneo tras su retirada, más allá del 7º día postoperatorio del trasplante renal. La definición propuesta para linfocele fue la de una colección de líquido de tamaño variable adyacente al riñón trasplantado, tras haber descartado un urinoma, hematoma o absceso. Las PKTL de grado A fueron aquellas con escaso impacto o que no requirieron tratamiento invasivo; las PKTL de grado B fueron aquellas que precisaron intervención no quirúrgica y las PKTL de grado C aquellas en que fue necesaria la reintervención quirúrgica. CONCLUSIÓN: Se propone una definición clara y una clasificación de gravedad basada en la estrategia de tratamiento de las PKTLs. La definición propuesta y el sistema de calificación en 3 grados son razonables, sencillos y fáciles de comprender, y servirán para estandarizar los resultados de las PKTL y facilitar las comparaciones entre los diferentes estudios.

IntroductionPeritoneal fenestration is an effective preventive method for reducing the rate of lymphatic complications in kidney transplantation (KTx). The size of the fenestration plays an important role in its effectiveness. A large peritoneal window is no longer indicated, due to herniation and difficulties in performing biopsies. Small preventive fenestration is effective but will be closed too early. The aim of this study is to evaluate whether metal clips around the edges of a small fenestration result in optimal effects with minimum fenestration size.Methods and analysisThis trial has been initiated in July 2019 and is expected to last for 2 and a half years. All patients older than 18 years, who receive kidneys from deceased donors, will be included. The kidney recipients will be randomly allocated to either a control arm (small fenestration alone) or an intervention arm (small fenestration with clipping). All fenestrations will be round, maximum 2 cm, and close to the kidney hilum. Clipping will be performed with eight metal clips around the peritoneal window (360°) in every 45° in an oblique position. The primary endpoint is the incidence of symptomatic post-KTx lymphatic complications, which require interventional treatment within 6 months after KTx. Secondary endpoints are intraoperative and postoperative outcomes, including blood loss, operation time, severity grade of lymphocele/lymphorrhea and relative symptoms.Ethics and disseminationThis protocol study received approval from the Ethics Committee of the University of Heidelberg (Registration Number S-318/2017). A Standard Protocol Items: Recommendations for Interventional Trials checklist is available for this protocol. The results will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberClinicalTrials.gov Registry (NCT03682627).

BACKGROUND: Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor. METHODS: In this phase I trial, patients received either 1.5 × 10(6) MICs per kg BW on day –2 (n = 3, group A), or 1.5 × 10(8) MICs per kg BW on day –2 (n = 3, group B) or day –7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360. RESULTS: MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 10(10) donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19(+)CD24(hi)CD38(hi) transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature. CONCLUSION: MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs. TRIAL REGISTRATION: EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220. FUNDING: Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.

Contains fulltext : 226016.pdf (Publisher’s version ) (Closed access) In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether

Background The clinical outcome and health-related quality of life (HRQoL) of living kidney donors is mostly not detrimental, but some donors experience impairment after donation. Gender-specific effects of living kidney donors was evaluated. Methods Clinical outcome was assessed in living kidney donors and HRQoL was obtained by self-reporting validated test systems as the Multidimensional Fatigue Inventory (MFI-20), the Short Form 36 (SF-36), and the Patient Health Questionnaire (PHQ-9). Results Two hundred and eleven (211) living renal donors were evaluated (female 62.2%). Response rate was 80.8%. In both genders, a decrease of renal function of 26% was observed after donation. De novo antihypertensives were introduced in 28.3% of women and 36.5% of men. HRQoL was comparable in female and male donors, except for mental HRQoL, which was lower in 51- to 60-year-old female donors, compared to age-matched male donors and to the female general population. Female donors aged 40–59 years demonstrated more fatigue than the age-matched general population. A low mental HRQoL (MCS; SF-36) was associated with higher values for fatigue (General Fatigue Score; MFI-20) in both genders. Multiple regression analysis detected the General Fatigue score of the MFI-20 questionnaire and depression identified by the PHQ-9 score as independent variables predicting MCS of the SF-36 in both genders. Lower age at time of donation contributed to a lower MCS in female donors. Conclusions Overall, HRQoL in living kidney donors exceeds that of the general population. Inferior mental health status and fatigue seem to be a problem, especially in middle-aged female donors, but not in all female donors. Psychological evaluation pre donation and psychological support post donation are required. Electronic supplementary material The online version of this article (10.1186/s12882-018-1187-8) contains supplementary material, which is available to authorized users.

Premature aging of both CD4+ regulatory T (Treg) and CD4+ responder‐T (Tresp) cells in patients with end‐stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T‐cell populations are released from the thymus as inducible T‐cell co‐stimulator‐positive (ICOS +) and ICOS − recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS + and ICOS − RTE Treg/Tresp cells into ICOS + CD31− or ICOS − CD31− memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS + and ICOS − Treg cells in co‐culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS + RTE Treg/Tresp cells and ICOS − RTE Treg cells through CD31+ memory Treg/Tresp cells into CD31− memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS − RTE Tresp cells showed an increased differentiation via ICOS − mature naive (MN) Tresp cells into CD31− memory Tresp cells. Thereby, the ratio of ICOS + Treg/ICOS + Tresp cells was not changed, whereas that of ICOS − Treg/ICOS − Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS + and ICOS − RTE Tresp cells proceeded, whereas that of ICOS + RTE Treg cells ceased and that of ICOS − RTE Treg cells switched to an increased differentiation via ICOS − MN Treg cells. Consequently, the ratios of ICOS + Treg/ICOS + Tresp cells and of ICOS − Treg/ICOS − Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance‐inducing differentiation of ICOS + and ICOS − Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long‐term renal replacement therapy.

Steunstichting ESOT A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors.

A new immune monitoring tool which assesses the expression of nuclear factor of activated T cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE).Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months.In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-RE was 13.1 ± 9.1%. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 ± 2.0 m/s vs 0.4 ± 1.4 m/s, P0.001). Infections occurred more often in the standard group compared with the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months of follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell glomerular filtration rate: 68.5 ± 17.4 mL/min vs 57.2 ± 19.0 mL/min; P = 0.009).NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.

Lymphocele is a common complication following kidney transplantation (KTx). We aimed to evaluate the preventive effect of peritoneal fenestration during KTx in reducing lymphocele. From January 2001, the data of all KTx were prospectively gathered in our digital data bank. From 2008, preventive peritoneal fenestration was performed as a routine procedure for all patients with KTx. Between 2001 and 2008, 579 KTx were performed without preventive peritoneal fenestration. To compare the results between with and without peritoneal fenestration, the same number of patients after 2008 (579 patients) was included in this study. The pre-, intra-, and postoperative data of the patients in these two groups were analyzed and compared, especially regarding the postoperative different types of lymphocele formation. The mean recipient age was 52.6 ± 13.8, and 33.7% of the patients were female. Type C lymphocele was significantly lower in the group with preventive fenestration (5.3% vs. 8.8%, p = 0.014 for 31/579 vs. 51/579). Peritoneal dialysis and implantation of the kidney in the left fossa were independently associated with a higher rate of type C lymphocele (OR 2.842, 95% CI 1.354–5.967, p = 0.006 and OR 3.614, 95% CI 1.215–10.747, p = 0.021, respectively). The results of this study showed that intraoperative preventive peritoneal fenestration could significantly reduce type C lymphocele.

Antiprogrammed cell-death protein 1 (PD-1) antibodies have revolutionized therapy of metastatic melanoma and other tumors, but some subgroups of patients such as immunosuppressed patients after solid-organ transplantation, have regularly been excluded from clinical studies. We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as these checkpoint inhibitors have become therapeutic standard in a variety of tumors other than melanoma.

AimsMicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients. MethodsEighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR-155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1(st) week and the 1(st), 2(nd), 3(rd) and 6(th) months post-transplantation. ResultsEight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve=0.875; P=0.046) and CXCL10 (area under the curve=0.865; P=0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73pgml(-1), with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function. ConclusionsThe regular early post-transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers.

The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors is intended to assist medical professionals who evaluate living kidney donor candidates and provide care before, during and after donation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach and guideline recommendations are based on systematic reviews of relevant studies that included critical appraisal of the quality of the evidence and the strength of recommendations. However, many recommendations, for which there was no evidence or no systematic search for evidence was undertaken by the Evidence Review Team, were issued as ungraded expert opinion recommendations. The guideline work group concluded that a comprehensive approach to risk assessment should replace decisions based on assessments of single risk factors in isolation. Original data analyses were undertaken to produce a “proof-in-concept” risk-prediction model for kidney failure to support a framework for quantitative risk assessment in the donor candidate evaluation and defensible shared decision making. This framework is grounded in the simultaneous consideration of each candidate's profile of demographic and health characteristics. The processes and framework for the donor candidate evaluation are presented, along with recommendations for optimal care before, during, and after donation. Limitations of the evidence are discussed, especially regarding the lack of definitive prospective studies and clinical outcome trials. Suggestions for future research, including the need for continued refinement of long-term risk prediction and novel approaches to estimating donation-attributable risks, are also provided. In citing this document, the following format should be used: Kidney Disease: Improving Global Outcomes (KDIGO) Living Kidney Donor Work Group. KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. Transplantation. 2017;101(Suppl 8S):S1–S109.

The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication. Areas covered: The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone. Expert opinion: CNI sparing regimens are well-established. Complete CNI avoidance after kidney transplantation was often associated with impaired graft survival until the approval of the co-stimulation blocker belatacept for de novo immunosuppression after kidney transplantation. Concerns still exist with respect to severe T-cell-mediated rejection episodes in the early phase after transplantation. Thus, a triple drug regimen with CNI, mycophenolic acid and steroids still represents the gold-standard of immunosuppressive therapy. Alternative substances expand the possibilities of tailoring individual immunosuppression for different indications such as biopsy-proven CNI toxicity, polyoma virus BK nephropathy or CNI-triggered thrombotic microangiopathy. However, a change of the immunosuppressive therapy must always be balanced against each patient´s individual immunological risk in order to address the importance of chronic antibody-mediated rejection driven by donor specific antibodies (DSA).

Despite preventive methods, lymphoceles frequently form following kidney transplantation (KTx), with an incidence of 0.6%-51%. Here, we summarize the current strategies for preventing and managing this complication, and describe the approach used in our department. Rapid diagnosis and early treatment of lymphoceles through a well-defined approach can prevent or reduce the risk of organ loss. Diagnosis can be made by ultrasound, computed tomography, or magnetic resonance imaging and laparoscopic fenestration is the current therapy of choice when non-surgical methods fail. Preventive methods should be performed pre-, intra-, and post-operatively. A peritoneal fenestration at the end of KTx seems to be a reasonable method for preventing lymphocele formation.

Refinement of immunosuppressive strategies has led to further improvement of kidney graft survival in recent years. Currently, the main limitations to long-term graft survival are life-threatening side effects of immunosuppression and chronic allograft injury, emphasizing the need for innovative immunosuppressive regimens that resolve this therapeutic dilemma. Several cell therapeutic approaches to immunosuppression and donor-specific unresponsiveness have been tested in early phase I and phase II clinical trials in kidney transplantation. The aim of this overview is to summarize current cell therapeutic approaches to immunosuppression in clinical kidney transplantation with a focus on myeloid suppressor cell therapy by mitomycin C-induced cells (MICs). MICs show great promise as a therapeutic agent to achieve the rapid and durable establishment of donor-unresponsiveness in living-donor kidney transplantation. Cell-based therapeutic approaches may eventually revolutionize immunosuppression in kidney transplantation in the near future.

Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (Csubtrough/sub) and peak concentrations (Csubpeak/sub) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (Esubtrough/sub) and at peak levels (Esubpeak/sub) were determined by qRT-PCR. The pharmacodynamic concentration producing the half-maximum effect (CEsub50/sub) and the Hill coefficient (H) were estimated from Esubtrough/suband from Esubpeak/sub. Ten stable kidney transplant recipients on triple immunosuppression with prednisolone, mycophenolate, and tacrolimus were analyzed. Median age was 58 years, median time since transplant was 84 months, and median serum creatinine was 249 µmol/L. The immunosuppressive effect on NFAT-regulated genes at trough concentrations was 38% (Esubtrough/sub), and the effect at peak concentrations was 59% (Esubpeak/sub) of maximum immunosuppression (Esubmax/sub). The pharmacodynamic parameters of the action of tacrolimus were estimated with the Hill coefficient H at 1.5 and the CE50 at 6.7 ng/mL. Accordingly, the pharmacodynamic threshold concentration was estimated at 0.9 ng/mL and the ceiling concentration at 48 ng/mL, indicating a wide span between target trough and peak levels. The low Hill coefficient indicates concentration-dependent pharmacodynamics of tacrolimus on NFAT transcripts. Therefore, the extension of the administration interval to 24 hours is not likely to jeopardize the immunosuppressive effect of the prolonged-release tacrolimus preparations. .

Purpose The widening gap between demand and supply of organs for transplantation provides extraordinary challenges for ethical donor organ allocation rules. The transplant community is forced to define favorable recipient/donor combinations for simultaneous kidney-pancreas transplantation. The aim of this study is the development of a prognostic model for the prediction of kidney function 1 year after simultaneous pancreas and kidney transplantation using pre-transplant donor and recipient variables with subsequent internal and external validation. Methods Included were patients with end-stage renal failure due to diabetic nephropathy. Multivariable logistic regression modeling was applied for prognostic model design with retrospective data from Hannover Medical School, Germany (01.01.2000–31.12.2011) followed by prospective internal validation (01 Jan. 2012–31 Dec. 2015). Retrospective data from another German transplant center in Kiel was retrieved for external model validation via the initially derived logit link function. Results The developed prognostic model is able to predict kidney graft function 1 year after transplantation ≥ KDIGO stage III with high areas under the receiver operating characteristic curve in the development cohort (0.943) as well as the internal (0.807) and external validation cohorts (0.784). Conclusion The proposed validated model is a valuable tool to optimize present allocation rules with the goal to prevent transplant futility. It might be used to support donor organ acceptance decisions for individual recipients. Electronic supplementary material The online version of this article (10.1007/s00423-018-1712-z) contains supplementary material, which is available to authorized users.

In recent studies, semi-selective compared to antigen-specific immunoadsorption (IA) columns showed comparable effectiveness in anti-A/B antibody removal before incompatible living donor kidney transplantation. Semi-selective columns allow a greater number of IA treatments at lower costs. They are also capable of removing potentially harmful human leukocyte antigen alloantibodies. Nevertheless, additional plasma exchange treatments are often necessary to reach the preoperative target titer, most likely due to an inadequate anti-A/B IgM antibody depletion.We compared the effectiveness of immunoglobulin and anti-A/B antibody reduction by different semi-selective (Therasorb Ig-flex, Therasorb Ig-omni5, Immunosorba) and antigen-specific (Glycosorb) IA columns during the desensitization of 63 ABO-incompatible living donor kidney transplant candidates with a total of 375 IA treatments. Fifty-three patients were eventually transplanted.Total IgM reduction during the first IA treatment was significantly greater with the Therasorb Ig-omni5 compared to the Therasorb Ig-flex (mean: -71.3 vs -41.6; p = 0.001) or Immunosorba columns (mean: -71.3 vs -42.8; p = 0.03). During a median of 5.5-6 pre-transplant IA treatments, Therasorb Ig-flex and Therasorb Ig-omni5 columns were equally effective in the reduction of total IgM while both showed superior IgM reduction compared to the Immunosorba columns (Therasorb Ig-flex, mean: -81.2 vs -72.2; p = 0.01; Therasorb Ig-omni5, mean: -88.2 vs -72.2; p = 0.02). IgG reduction was not significantly different between groups. Likewise, anti-A/B IgM antibody reduction (titer Saline) during the first IA treatment was significantly greater with the Therasorb Ig-omni5 compared to the Therasorb Ig-flex (mean titer reduction: -1.9 vs -1.1; p = 0.02) and tended to be greater than with Immunosorba or Glycosorb columns. During a median of 5-6 pre-transplant IA treatments, overall anti-A/B IgM antibody reduction was significantly greater when IA was performed with the Therasorb Ig-flex (mean titer reduction: -3.8 vs -1.3; p 0.001) or Therasorb Ig-omni5 (mean titer reduction: -4.3 vs -1.3; p = 0.01) compared to the Immunosorba columns with no differences compared to the Glycosorb columns. Again, anti-A/B IgG antibody reduction (titer Coombs) was not significantly different between groups.The semi-selective Therasorb Ig-omni5 device offers potential advantages in reducing total IgM as well as anti-A/B IgM antibodies.

Context Studies on the surgical outcome in living kidney donors mainly report perioperative complications with short follow-up. Objective The objectives of this study are to evaluate the long-term surgical outcome in living kidney donors and to identify donors with an increased risk for a complicated postoperative course. Basic Procedures A prospectively collected database of 496 living kidney donors at the Department of General, Visceral, and Transplantation Surgery of the Ruprecht Karls University Heidelberg was retrospectively analyzed in a retrospective, observational single-center study. Results The median follow-up time was 37 months. The perioperative severe complication (Clavien-Dindo IIIb) rate was 2.8%, the early postoperative (PO) severe complication rate (1-3 months post operation) was 0.7%, and the late PO severe complication rate (> 3 months post operation) was 8.4%. In multivariate analyses, male sex was associated with higher overall perioperative complication rate (odds ratio [OR], 1.930; P = .005) as well as higher rate of late PO complications (OR, 2.243; P = .014). An increased body mass index was associated with a higher late and severe (Clavien-Dindo ≥ IIIb) PO complication rate (OR, 1.107; P = .009 and OR, 1.105; P = .008, respectively). Conclusions and Relevance Long-term surgery-associated severe complications occur in 8.4% of kidney donors. Older age is associated with an increased operative time, greater intraoperative blood loss, and longer PO hospital stay. Male donors and donors with an increased body mass index have a higher risk for a complicated PO course after kidney donation. Within a shared decision-making process before living kidney donation, special awareness should be brought to these facts.

BACKGROUND The pre-procurement pancreas suitability score (P-PASS) and the pancreas donor risk index (pDRI) are established predictive scores for graft survival and patient outcome following pancreatic transplantation. This retrospective study aimed to evaluate the predictive value of P-PASS and pDRI following simultaneous pancreas and kidney (SPK) transplantation, or pancreas after kidney (PAK) transplantation, and the clinical impact of donor-specific factors on the postoperative graft and recipient outcome at a single transplant center. MATERIAL AND METHODS The study included 105 patients who underwent SPK (n=104) or PAK (n=4) between 2000 and 2017. Donor-specific and recipient-specific parameters were recorded. Kaplan-Meier analysis and Cox regression analysis were used to assess the outcome after transplantation. RESULTS Overall, the mean 1-year and 5-year pancreas graft survival and patient survival rates were 78.7% and 93.2%, and 76.9% and 90.0%, respectively. The postoperative outcome in patients with a P-PASS score of

The Epstein-Barr virus (EBV) induces B-cell proliferation with high efficiency through expression of latent proteins and microRNAs. This process takes place in vivo soon after infection, presumably to expand the virus reservoir, but can also induce pathologies, e.g. an infectious mononucleosis (IM) syndrome after primary infection or a B-cell lymphoproliferation in immunosuppressed individuals. In this paper, we investigated the growth characteristics of EBV-infected B-cells isolated from transplant recipients or patients with IM. We found that these cells grew and withstood apoptosis at highly variable rates, suggesting that the expansion rate of the infected B-cells widely varies between individuals, thereby influencing the size of the B-cell reservoir and the ability to form tumors in infected individuals. All viruses investigated were type 1 and genetically close to western strains. EBV-infected B-cells expressed the transforming EBV latent genes and microRNAs (miRNAs) at variable levels. We found that the B-cell growth rates positively correlated with the BHRF1 miRNA levels. Comparative studies showed that infected B-cells derived from transplant recipients with iEBVL on average expressed higher levels of EBV miR-BHRF1 miRNAs and grew more rapidly than B-cells from IM patients, suggesting infection by more transforming viruses. Altogether, these findings suggest that EBV infection has a highly variable impact on the B-cell compartment that probably reflects the genetic diversity of both the virus and the host. It also demonstrates the unexpected finding that B-cells from different individuals can grow at different speed under the influence of the same virus infection.