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Non-classical Human Leukocyte Antigen (HLA)-E preferentially presents leader peptides derived from classical HLA-class I molecules. HLA-E can trigger opposed immune responses by interacting with inhibitory NKG2A or by activating NKG2C receptors on NK and T-cells. We studied the impact of HLA-E on renal allograft survival during acute cellular rejection. HLA-E expression was up-regulated in acute cellular rejection (ACR) biopsies (n=12) compared to biopsies from 13 renal allografts with no rejection-signs. HLA-E up-regulation was correlated with numbers of HLA-class I leader peptide mismatches (p=0.04). CD8+ and CD56+ infiltrating cells correlated with HLA-E expression (p0.0001 and p=0.0009, respectively). Activating NKG2C receptor dominated on effector cells in biopsies and peripheral blood during ACR potentially allowing HLA-E-mediated immune activation. Moreover, HLA-E expression correlated with deterioration in renal allograft function (p0.008) and reduced allograft survival (p=0.002). Our findings provide evidence that during renal allograft rejection HLA-E along with high numbers of mismatched HLA-class I leader peptides might represent additional targets for immune-activating responses.

Introduction Because of the shortage of available organs for renal transplantation, strategies enabling the safe use of organs from donors with potential chronic infections such as hepatitis C are necessary. The aim of this study was to analyze the outcome of renal transplant donation from hepatitis C virus (HCV)-positive donors. Methods Between September 2002 and May 2007, 51 kidneys (34 donors) reactive for HCV antibodies were further evaluated. Six kidneys (5 donors) were transplanted to 6 recipients with known chronic HCV infection. The remaining 29 donors underwent extended virological testing. Nine donors were HCV RNA positive and thus not suitable for HCV-negative patients. Twenty donors (21 kidneys) did not have detectable HCV RNA copies and were transplanted into 21 HCV-negative recipients. Clinical outcomes focusing on safety, allograft function, and de novo HCV infection in the recipient were collected. Results There were no de novo HCV infections detected in recipients who were HCV negative before transplantation. The extended virological donor screening did not have an impact on median cold ischemia time. Five-year graft survival was 75%. Discussion Organs from anti-HCV-reactive, nonviremic donors can be transplanted safely to HCV-negative recipients.

Approximately 70% of kidney transplant recipients are non-responders to conventional hepatitis B virus (HBV) vaccines. We examined whether Fendrix™, an HBV vaccine containing 3-O-desacyl-4'-monophosphoryl lipid A (MPL) as adjuvant, could induce HBV immunity in these patients and compared their vaccination efficacy with healthy controls tested previously by the same assays. We selected 35 kidney transplant recipients who had been vaccinated at least thrice against HBV but had never displayed anti-HBs antibodies. We re-assessed their anti-HBs antibody titres and further determined cellular HBV immunity by proliferation assay and interferon (IFN)-γ ELISpot. Seventeen recipients did neither display humoral nor cellular immunity and could be tested prior to and at month 1 after vaccination. Of note, HLA antigens associated with non-response to HBV vaccination (HLA-DRB1*03 and HLA-DQB1*02) were over-represented in these 17 recipients. At month 1 after a single vaccination with Fendrix™, we observed a significant increase in anti-HBs antibodies (P = 0.02). In seven of 17 recipients, we detected anti-HBs antibodies ≥10 IU/l (10-264), in four HBV-specific lymphocyte proliferation (stimulation index of 2.6-8.7) and in one specific IFN-γ responses (12 spots increment). The vaccination response to Fendrix™ was significantly higher (P = 0.035) than the response to HBVaxPro™ in young healthy controls. In summary, the results show that a single vaccination with Fendrix™ could already induce HBV-specific humoral and/or cellular responses in ten of 17 kidney transplant patients. Thus, Fendrix™ appears as an efficient vaccine in this patient cohort.

An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4+ T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA+ CD4+ T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4+CD25++CD127&minus, regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analysed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -12.0±4.2 mL·min-1·1.73m-2, P=0.005). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex.

Background Transplanting kidneys from deceased donors with hepatitis C virus (HCV) viremia has been controversial for some time. Direct-acting antiviral agents have been shown to be highly effective in treating HCV infection. We report our experience with transplanting kidneys from HCV-positive donors with detectable viremia into HCV-negative recipients, followed by early treatment with a sofosbuvir-based antiviral regimen. Methods Data were collected from seven HCV-negative recipients receiving kidneys from five deceased HCV-viremic donors. Before transplantation, all intentional transplanted recipients had given informed consent regarding the acceptance of an HCV-viremic kidney. Recipients were closely monitored after transplant with measurements of HCV viremia, liver and renal function, and trough levels of immunosuppressive drugs. Results Four donors were infected with HCV genotype 1; the other with HCV genotype 3a. HCV viremia was detectable in all seven renal transplant recipients within 3 days after transplant. After determination of HCV genotype, antiviral treatment with a sofosbuvir-based regimen (sofosbuvir/ledipasvir, n = 4; sofosbuvir/velpatasvir, n = 3) was initiated within a median of 7 days after transplantation and was continued for 8 to 12 weeks. For all recipients, viral load was below the level of detection at the end of treatment, and all exhibited a sustained virologic response 12 weeks later. All recipients exhibited normal liver enzyme activity at the end of treatment. Renal allograft function and trough levels of tacrolimus remained stable. Conclusions Early administration of a sofosbuvir-based regimen to HCV-negative recipients of kidneys from HCV-viremic donors is feasible and safe. The definition of an optimal therapeutic approach warrants further investigation.

Polyomaviruses, like the BK-polyomavirus (BKPyV), can cause severe pathologies in immunocompromised patients. However, since highly effective antivirals are currently not available, methods measuring the impact of potential antiviral agents are required. Here, a dual fluorescence reporter that allows the analysis of the BKPyV non-coding control-region (NCCR) driven early and late promoter activity was constructed to quantify the impact of potential antiviral drugs on viral gene expression via tdTomato and eGFP expression. In addition, by cloning BKPyV-NCCR amplicons which in this protocol have been exemplarily obtained from the blood-derived DNA of immunocompromised renal transplanted patients, the impact of NCCR-rearrangements on viral gene expression can be determined. Following cloning of the patient derived amplicons, HEK293T cells were transfected with the reporter-plasmids, and treated with potential antiviral agents. Subsequently, cells were subjected to FACS-analysis for measuring mean fluorescence intensities 72 h post transfection. To also test the analysis of drugs that have a potential cell cycle inhibiting effect, only transfected and thus fluorescent cells are used. Since this assay is performed in large T Antigen expressing cells, the impact of early and late expression can be analyzed in a mutually independent manner.

ZUSAMMENFASSUNGHarnwegsinfektionen gehören zu den häufigsten Infektionen im ambulanten Bereich und stellen auch die häufigsten nosokomialen Infektionen dar. Die typischen Symptome sind Schmerzen beim Wasserlassen (Algurie), häufiges Wasserlassen (Pollakisurie), imperativer Harndrang (Strangurie) und ggf. Hämaturie. Es wird eine unkomplizierte von einer komplizierten Harnwegsinfektion unterschieden, die sich im Keimspektrum und dadurch in der therapeutischen Strategie unterscheiden. Harnwegsinfekte bei Männern sollten in der Regel als komplizierte Infektionen eingeschätzt werden, da die Prostata mitbetroffen sein kann. Als Diagnostik stehen die Anamnese, die körperliche Untersuchung, die Urinuntersuchung durch Schnellstreifentest, die Mikroskopie und die Urinkultur zur Verfügung. Der häufigste Erreger von unkomplizierten Harnwegsinfektionen ist Escherichia coli, gefolgt mit Abstand von Staphylococcus saprophyticus, Proteus mirabilis und Klebsiella pneumoniae. Bei komplizierten Harnwegsinfektionen sollte der vorherige Erregernachweis berücksichtigt werden, wenn dieser bekannt ist. Bei einer akuten unkomplizierten Harnwegsinfektion ist eine orale kurzzeitige antimikrobielle Therapie empfohlen, um die klinischen Symptome rasch zu beenden. Die Dauer der Therapie orientiert sich am klinischen Verlauf.

Background After reactivation the BK-polyomavirus (BKPyV) associated nephropathy (PyVAN) is observed in 1–10% of renal transplant recipients, of which up to 80% undergo graft failure. BKPyV reactivation after renal transplantation was associated with donor-derived serotypes against which the recipient has no immunological protection. However, PyVAN risk assessment seroactivity testing is a time-consuming and cost intensive process. Objectives Since BKPyV serotypes can be attributed to distinct genotypes I to IV, in the present study we retrospectively analyzed whether a simple PCR-based BKPyV genotyping assay might be a fast and inexpensive method to assess the risk for PyVAN and transplant outcome already at early stages of BKPyV reactivation. Study design 56 patients who were renal transplanted and tested positive for BKPyV viremia were included into the study. The BKPyV-VP1-coding sequences were PCR-amplified, sequenced, and subjected to genotyping. For group specific analysis patients were grouped in genotype I (n = 46) and a second group including genotype II and IV (n = 10) and associated with their clinical outcomes. Results The most abundant genotype I was detected in 46 of 56 (82%) patients, however, in the genotype II and IV group PyVAN was twice as frequent as compared to the genotype I group 24 months after transplantation (8 of 10 (80%) vs. 17 of 46 (37%); p = 0.001). Accordingly, graft failure was significantly more frequent in the genotype II and IV group (3 of 10 (30%) vs. 2 of 46 (4%); p = 0.007). Conclusion PCR-based BKPyV genotyping might represent a fast and inexpensive method to assess the risk for PyVAN and transplant outcome already at early stages of BKPyV reactivation even if matched samples of the donor are not available.

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

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has a major impact on transplant recipients, with mortality rates up to 20%. Therefore, the effect of established messenger RNA (mRNA)-based SARS-CoV-2 vaccines have to be evaluated for solid organ transplant patients (SOT) since they are known to have poor responses after vaccination. We investigated the SARS-CoV-2 immune response via SARS-CoV-2 IgG detection in 23 renal transplant recipients after two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 following the standard protocol. The antibody response was evaluated once with an anti-SARS-CoV-2 IgG CLIA 15.8 +/− 3.0 days after the second dose. As a control, SARS-CoV-2 IgG was determined in 23 healthcare workers (HCW) and compared to the patient cohort. Only 5 of 23 (22%) renal transplant recipients were tested positive for SARS-CoV-2 IgG antibodies after the second dose of vaccine. In contrast, all 23 (100%) HCWs were tested positive for antibodies after the second dose. Thus, the humoral response of renal transplant recipients after two doses of the mRNA-based vaccine BNT162b2 (Pfizer-BioNTech, Kronach, Germany) is impaired and significantly lower compared to healthy controls (22% vs. 100%; p = 0.0001). Individual vaccination strategies might be beneficial in these vulnerable patients. OA Förderung 2021

Background. Due to its high sensitivity, the flow cytometry crossmatch (FCXM) has been described as valuable tool for identifying an optimal donor. We here focused on the impact of ABO incompatibility on FCXM results. Methods. We analyzed 29 ABO incompatible and 89 ABO compatible donor-recipient pairs (73 and 175 data sets, respectively) prior to living donor kidney transplantation. In all patients, lymphocytotoxic crossmatches for B and T cells were negative. Results. Recipients with blood group O (A to O and B to O) displayed significantly (P < 0.05) higher T-FCXM results than those with blood group A and B (A to B, B to A and AB to A), respectively. Donor-specific T-FCXM responses (Δ MFI values) were significantly higher (P < 0.05) in ABO incompatible vs. compatible pairs (ABO incompatible recipients with blood group O: 32 ± 6; with blood group A: 19 ± 7; with blood group B: 7 ± 4; recipients with ABO compatibility: 3 ± 2, respectively, data represent mean ± SEM). Consistent with the T-FCXM results donor-specific isohemagglutinins (IgG titers) were significantly higher in recipients with blood group O vs. A, both prior to rituximab treatment and plasmapheresis/immune adsorption (P = 0.004) and immediately prior to transplantation, i.e., after rituximab and antibody-depleting therapies (P = 0.04). Conclusions. ABO incompatibility was associated with higher T-FCXM responses, especially in recipients with blood group O. This finding has major impact on the interpretation of flow crossmatch results. Current cut-off values need to be reassessed in the ABO incompatible setting. This article is protected by copyright. All rights reserved.

Background Post-transplant function of suboptimal kidney grafts can be improved but not accurately predicted by hypothermic machine perfusion. Therefore, a new concept of ex situ pre-implantation machine perfusion with controlled rewarming up to subnormothermic temperatures was developed and evaluated. Methods Porcine kidneys (n= 6/ group) were retrieved before or 30 min after cardiac arrest of the donor and subjected to 18 hours of static cold storage. In some cases 90 min of machine controlled oxygenated rewarming (COR) was added thereafter. Functional integrity was evaluated in all kidneys by subsequent normothermic reperfusion in vitro. After supplementation of the preservation solution (Custodiol-N solution + 5g/L dextran 40) with 10mg/dL creatinine, ex situ renal function was assessed by monitoring urine output, urinary creatinine and creatinine clearance at 20°C. Functional integrity was evaluated in all kidneys by normothermic reperfusion. Results COR resulted in a more than twofold improvement of post reperfusion creatinine clearance, oxygen consumption and enzyme release upon reperfusion, when compared with static cold storage. Predictive discrimination between kidneys with good or impaired function upon reperfusion based on parameters during perfusion at 4°C was only moderate. This improved significantly at 20°C. Correlation with renal clearance upon reperfusion was weak for vascular resistance at 8° (r2=0.2) and 20°C (r2=0.41). Best correlation was found for clearance measurements at 20° (r2=0.81). Conclusion Reconditioning by controlled oxygenated rewarming up to 20°C improves renal function after reperfusion and can be utilized to assess graft integrity of pre-damaged donor kidneys. This article is protected by copyright. All rights reserved.

Die BK-Polyomavirus(BKPyV)-Reaktivierung nach Nierentransplantation fuhrt bei bis zu 10 % der transplantierten Patienten zu einer polyomavirusassoziierten Nephropathie (PyVAN), von denen bis zu 50 % einen Transplantatverlust erleiden. Der Hauptrisikofaktor der BKPyV-Reaktivierung ist die immunsuppressive Therapie durch einerseits die immunsuppressive Wirkung und andererseits direkte medikamentenabhangige Effekte auf die Virusreplikation. Bis heute existiert keine kausale Therapie der PyVAN. Diese Ubersichtsarbeit soll die aktuellen diagnostischen und therapeutischen Empfehlungen bei BKPyV-Reaktivierung nach Nierentransplantation darstellen. Ein sorgfaltiges Screening nach Nierentransplantation auf BKPyV eroffnet die Moglichkeit einer in Abhangigkeit von der Viruslast stehenden fruhzeitigen Anpassung der Immunsuppression. Durch die fruhzeitige Anpassung der Immunsuppression kann ein Fortschreiten der PyVAN verhindert werden und die Transplantatfunktion erhalten bleiben.

Elevated donor serum creatinine has been associated with inferior graft survival in kidney transplantation (KT). The aim of this study was to evaluate the impact of elevated donor serum creatinine on short and long-term outcomes and to determine possible ways to optimize the use of these organs. All kidney transplants from 01–2000 to 12–2012 with donor creatinine ≥ 2 mg/dl were considered. Risk factors for delayed graft function (DGF) were explored with uni- and multivariate regression analyses. Donor and recipient data were analyzed with uni- and multivariate cox proportional hazard analyses. Graft and patient survival were calculated using the Kaplan-Meier method. Seventy-eight patients were considered. Median recipient age and waiting time on dialysis were 53 years and 5.1 years, respectively. After a median follow-up of 6.2 years, 63 patients are alive. 1, 3, and 5-year graft and patient survival rates were 92, 89, and 89 % and 96, 93, and 89 %, respectively. Serum creatinine level at procurement and recipient’s dialysis time prior to KT were predictors of DGF in multivariate analysis (p = 0.0164 and p = 0.0101, respectively). Charlson comorbidity score retained statistical significance by multivariate regression analysis for graft survival (p = 0.0321). Recipient age (p = 0.0035) was predictive of patient survival by multivariate analysis. Satisfactory long-term kidney transplant outcomes in the setting of elevated donor serum creatinine ≥2 mg/dl can be achieved when donor creatinine is

Hintergrund Systemerkrankungen betreffen haufig die Niere und sind daher in der Nephrologie differenzialdiagnostisch zu berucksichtigen. Besondere Aufmerksamkeit gilt hierbei den Kollagenosen und Vaskulitiden, die renale Beteiligung ist bei diesen Erkrankungen prognoselimitierend.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell-dependent autoantibody production. Recently, a new B-cell subset was discovered that has a regulatory capacity. The aim of this study was to analyse regulatory B cells (Bregs) in SLE patients.Peripheral mononuclear blood cells (PBMCs) of 34 SLE patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and 21 healthy controls (HC) were included. PBMCs were stained for CD19, CD24, and CD38 and analysed by flow cytometry. In vitro stimulated PBMCs with CpG and restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin were investigated for IL-10(+) Bregs .The percentages of circulating CD19(+)CD24(hi)CD38(hi) cells in HC were not different those in from SLE patients. The percentages of IL-10(+) Bregs were significantly decreased in SLE patients, in particular those with lupus nephritis (LN), compared to HC. The proportion was independent of disease activity.This is the first study to demonstrate a decrease in IL-10-producing B cells in LN patients compared to HC, reflecting an impaired regulatory function.

Background: Graft versus host disease (GvHD) occurs in 20% of cases with patients having an MHC I matched bone marrow transplantation (BMT). Mechanisms causing this disease remain to be studied. Methods: Here we used a CD8+ T cell transgenic mouse line (P14/CD45.1+) and transgenic DEE mice bearing ubiquitously the glycoprotein 33-41 (GP33) antigen derived from the major lymphocytic choriomeningitis virus (LCMV) epitope to study mechanisms of tolerance in anti-host reactive CD8+ T cells after BMT. Results: We found that anti-host reactive CD8+ T cells (P14 T cells) were not negatively selected in the thymus and that they were present in wild type (WT) recipient mice as well as in DEE recipient mice. Anti-host reactive CD8+ T cells ignored the GP33 antigen expressed ubiquitously by host cells but they could be activated ex vivo via LCMV-infection. Lipopolysaccharides (LPS) induced transient cell damage in DEE mice bearing anti-host reactive CD8+ T cells after BMT, suggesting that induction of host inflammatory response could break antigen ignorance. Introducing the GP33 antigen into BM cells led to deletion of anti-host reactive CD8+ T cells. Conclusion: We found that after BMT anti-host reactive CD8+ T cells ignored host antigen in recipients and that they were only deleted when host antigen was present in hematopoietic cells. Moreover, LPS-induced immune activation contributed to induction of alloreactivity of anti-host reactive CD8+ T cells after BMT.

Background The novel coronavirus SARS-CoV-2 is associated with a severe respiratory manifestation, COVID-19, and presents a challenge for healthcare systems worldwide. Healthcare workers are a vulnerable cohort for SARS-CoV-2 infection due to frequent and close contact to patients with COVID-19. Study design Serum samples from 316 healthcare workers of the University Hospital Essen, Germany were tested for SARS-CoV-2-IgG antibodies. A questionnaire was used to collect demographic and clinical data. Healthcare workers were grouped depending on the frequency of contact to COVID-19 patients in high-risk-group (n = 244) with daily contact to known or suspected SARS-CoV-2 positive patients, intermediated-risk-group (n = 37) with daily contact to patients without known or suspected SARS-CoV-2 infection at admission and low-risk-group (n = 35) without patient contact. Results In 5 of 316 (1.6 %) healthcare workers SARS-CoV-2-IgG antibodies could be detected. The seroprevalence was higher in the intermediate-risk-group vs. high-risk-group (2/37 (5.4 %) vs. 3/244 (1.2 %), p = 0.13). Four of the five subject were tested negative for SARS-CoV-2 via PCR. One (20 %) subject was not tested via PCR since he was asymptomatic. Conclusion The overall seroprevalence of SARS-CoV-2 in healthcare workers of a tertiary hospital in Germany is low (1.6 %). The data indicate that the local hygiene standard might be effective.

Th17 cells are a distinct lineage of T-cells. These T-cells express IL-17A and the lineage-defining transcription factor RORγt. Th17 cells have a pivotal, physiological role in host defense against pathogens. These pro-inflammatory T-cells are also key players in autoimmunity and a pathogenic role has been demonstrated in several diseases such as rheumatoid arthritis or psoriasis. Recently, there is evidence that Th17 cells may drive renal inflammation and renal autoimmunity in anti-neutrophil-cytoplasmic-antibody-(ANCA)-vasculitis and systemic lupus erythematosus. The aim of this review is to discuss the possible involvement of Th17 cells in renal autoimmunity and its value for future therapeutic approaches.

Background The C5 complement inhibitor eculizumab is a first-line treatment in atypical haemolytic uraemic syndrome (aHUS). Therapy with eculizumab is associated with a highly increased risk for meningococcal infection. Therefore, vaccination is highly recommended before beginning treatment. Efficacy of quadrivalent meningococcal vaccines (MenACWY) in patients treated with the C5 complement inhibitor eculizumab in aHUS has not yet been determined. Methods Patients with aHUS received one dose of a MenACWY conjugate vaccine before eculizumab treatment commenced. Bactericidal titres against meningococcal serogroups A, C, W and Y were determined using baby rabbit complement in 25 patients. Results Full immune response to meningococcal vaccination was detected in five patients (20%), while seven patients (28%) showed no immune response in any of the tested serogroups. The remaining 13 patients showed incomplete immune response with proof of protective antibody titres for one to three serogroups without perceptible preference for any serogroup. Bactericidal titres after re-vaccination were available for 17 patients. Nine patients with incomplete immune response after first vaccinations showed protective antibody titres for all serogroups after re-vaccination. Kidney function had improved in >50% of patients at the time of re-vaccination compared with the time of first vaccination and immunosuppressive therapy was only applied to re-vaccinated patients following kidney transplantation. Conclusions Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal.

The interaction of major histocompatibility complex class I chain-related protein A (MICA) and its cognate activating receptor natural killer (NK) group 2 member D (NKG2D) receptor plays a significant role in viral immune control. In the context of kidney transplantation (KTx), cytomegalovirus (CMV) frequently causes severe complications. Hypothesizing that functional polymorphisms of the MICA/NKG2D axis might affect antiviral NK and T cell responses to CMV, we explored the association of the MICA-129 Met/Val single nucleotide polymorphism (SNP) (affecting the binding affinity of MICA with the NKG2D receptor), the MICA rs2596538 G/A SNP (influencing MICA transcription), and the NKG2D rs1049174 G/C SNP (determining the cytotoxic potential of effector cells) with the clinical outcome of CMV during the first year after KTx in a cohort of 181 kidney donor-recipients pairs. Univariate analyses identified the donor MICA rs2596538 G allele status as a protective prognostic determinant for CMV disease. In addition to the well-known prognostic factors CMV high-risk sero-status of patients and the application of lymphocyte-depleting drugs, the donor MICA rs2596538 G allele carrier status was confirmed by multivariate analyses as novel-independent factor predicting the development of CMV infection/disease during the first year after KTx. The results of our study emphasize the clinical importance of the MICA/NKG2D axis in CMV control in KTx and point out that the potential MICA transcription in the donor allograft is of clinically relevant importance for CMV immune control in this allogeneic situation. Furthermore, they provide substantial evidence that the donor MICA rs2596538 G allele carrier status is a promising genetic marker predicting CMV viremia after KTx. Thus, in the kidney transplant setting, donor MICA rs2596538 G may help to allow the future development of personal CMV approaches within a genetically predisposed patient cohort. OA Förderung 2018

Introduction Cytomegalovirus (CMV) infection is an uncommon but severe infection in patients with systemic lupus erythematosus (SLE) due to immunosuppressive therapy. Standard prophylaxis with antiviral agents or pre-emptive strategies to monitor viral load are not standard of care. The aim of the present study was to investigate the expression of coinhibitory molecules PD-1 and BTLA-4 on CMV specific T-cells in SLE-patients. Methods Sixteen SLE-patients and eight healthy controls were enrolled. Tweleve SLE patients were CMV IgG+, four were CMV IgG-. Peripheral blood was sampled and stimulated with CMV lysate, SEB or control serum in presence of anti-CD28/CD49d. After six hours of stimulation, CD154 expression was determined by flow cytometry on CD3 +T cells. The coinhibitory molecules PD-1 and BTLA were determined on activated CD154 +CD3+T cells. Symptomatic CMV infection was defined as CMV syndrome or tissue invasive disease. Asymptomatic CMV infection was defined as detectable CMV replication in peripheral blood and absence of signs indicating CMV syndrome/tissue invasive disease. Results PD-1 and BTLA-4 expression was not significantly different on CMV-specific CD154 +CD3+T cells in SLE-patients as compared to healthy controls. An analysis according to the CMV serostatus revealed a tendency to a decreased proportion of PD-1 +CD154+CD3+T cells in CMV IgG negative patients as compared to CMV IgG positive (24.9%±30.0% vs 35.5±11.5%, p=0.3). The BTLA-4 expression was significantly decreased on CD154 +CD3+T cells in CMV IgG negative patients as compared to CMV IgG positive (70.3%±31.7% vs 95.0±4.3%, p=0.01). Conclusion SLE-patients show a significant decreased expression of BTLA on CMV-specific T-cells. The coinhibitors PD-1 and BTLA usually promote T-cell suppression. Thus a decrease may prone to severe symptomatic infections.

Background Systemic lupus erythematodes (SLE) is an autoimmune disease where T-cell dependent B-cell activation plays a crucial role. Costimulatory marker promote and inhibit immune responses after ligation. Here we analysed the marker BTLA (CD272), PD-1 (CD279), HLA-DR and HVEM on peripheral cyctotoxic T-cells. Patients and methods 30 SLE-patients fulfilling the American College of Rheumatology (ACR) criteria fur SLE and 14 healthy controls (HC) were enrolled. Whole blood staining was performed and samples were analysed by multi-colour flow cytometry. Disease activity was assessed by SLEDAI. Renal involvement was defined as biopsy proven lupus nephritis. Results The expression of the costimulatory marker PD-1 is signifcantly increased on CD8 +T cells in SLE patients as compared to with healthy controls (31.3%±26.7% vs 15.63%±12.22%). We could not found a significant difference in the expression levels of the BTLA receptor on CD8 +T cells (72,24%±15.33 vs 72.66%±9,4%) in SLE patients as compared to with healthy controls. Also HLA-DR and HVEM was not significantly different expressed on CD8 +T cells in SLE. Conclusions The costimulytory maker PD-1 is upregualted on cytotoxic T-cells in SLE. Further investigations are needed to elucidate the functional role of this pattern.

Objectives Cytotoxic T-cells are a thought to play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) in particular in lupus nephritis. The aim of this study was to investigate the activation marker CD314 (NKG2D) and CD107a (LAMP-1) on cytotoxic CD8 +T cells in patients with systemic lupus erythematosus. Methods Peripheral blood of patients with systemic lupus erythematosus (n=30) and healthy controls (n=21) was stained with anti-CD8 (PB), -CD3 (Chrom Orange), -CD45RO (FITC), -CD197 (PE), -CD314 (APC), -CD107a (APC) antibodies and analysed by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated by immunohistochemistry and immunofluorescence for the presence of CD8 +C107a+cells. Patients disease activity was assessed by systemic lupus erythematosus disease activity index (SLEDAI). Results The percentages of CD314 +on CD8+T cells were not different between SLE-patients and healthy controls. The percentages of CD107a+on CD8+T cells were significantly decreased in SLE-patients as compared to healthy controls (40.2%±18.5% vs 47.9±15.0%, p=0.02). This was even more significant in SLE-patients with inactive disease. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+T cells mainly located in the peritubular infiltrates. Conclusions These results demonstrate that CD8 +T cells of patients with systemic lupus erythematosus have an altered activation status which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+suggests a role in the pathogenesis of lupus nephritis.

Objectives B-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterised by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus especially in patients with lupus nephritis. Methods Isolated peripheral blood mononuclear cells of patients with systemic lupus erythematosus (n=30) and healthy controls (n=21) were in vitro stimulated with CPG, IgG +IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. CD19 +B cells were analysed for intracellular Granzyme B expression by flow cytometry. Patients disease activity was assessed by systemic lupus erythematosus disease activity index (SLEDAI). Results The strongest stimulus for Granzyme B secretion of CD19 +B cells was IgG +IgM in presence of IL-21. Patients with systemic lupus erythematosus had a significant decreased percentage of Granzyme B+CD19+B cells. This could be shown in particular for patients with active disease and with lupus nephritis. Conclusions These data demonstrate that CD19 +B cells of patients with systemic lupus erythematosus are impaired to produce Granzyme B. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.

Background Assays detecting CMV-specific cell-mediated immunity (CMI) may support the current management of CMV infection in solid-organ transplant (SOT) recipients, by allowing a better risk assessment and adjusting antiviral treatment. Objectives The primary endpoint was the performance of two tests measuring CMV-specific interferon-gamma production, both approved for commercial use in clinical settings. Secondarily, we determined a cut-off for the cellular immune response, which protects against CMV reactivation/infection. Study design Thirty kidney transplant (KTx) patients were stratified according to their CMV-IgG status pre-transplantation (Tx) and were divided into two groups: pre-emptive (donor-/recipient+, donor+/recipient+) and prophylaxis (donor+/recipient−). An ELISpot (T-Track-CMV) was performed at month 1 post-Tx (pre-emptive group) and end of prophylaxis and one month thereafter (prophylaxis group). An ELISA (QuantiFERON-CMV) was performed every 2–4 weeks (pre-emptive) or monthly (prophylaxis), in parallel to the CMV viral load (PCR). Results A good positive agreement was obtained between the QuantiFERON-CMV or T-Track-CMV and the CMV-IgG (kappa = 0.839 and 0.824, respectively). A cut-off of 19.5 spot forming units (SFU)/200,000 lymphocytes for the T-Track-CMV IE-1 (AUC = 0.802, sensitivity 45%, specificity 100%) and 495 SFU/200,000 lymphocytes for the T-Track-CMV pp65 (AUC = 0.617, sensitivity 11%, specificity 100%) was defined to assess protection against reactivation. The QuantiFERON-CMV performed modestly (AUC = 0.477, cut-off 85.1 IU/ml). Conclusions The QuantiFERON-CMV and T-Track-CMV enable the functional assessment of CMV-specific CMI in KTx recipients. In combination with CMV viral load monitoring, T-Track-CMV results could stratify patients at risk of CMV reactivation/infection.

Background Reactivation of the BK-Polyomavirus (BKPyV) can cause a polyomavirus associated nephropathy in approx. 10% of kidney transplant recipients. In these cases, current therapy is based on the reduction of immunosuppression. Since BKPyV-transcription is driven by the Non-Coding-Control-Region (NCCR) we were interested whether NCCR-activity is affected by immunosuppressive agents. Methods Plasma samples from 45 BKPyV-positive patients after renal transplantation were subjected to PCR-analysis. NCCR-amplicons were cloned into a plasmid that allows the quantification of early and late NCCR-activity by tdTomato and eGFP expression, respectively. HEK293T-cells were transfected with the reporter-plasmids, treated with immunosuppressive agents, and subjected to FACS-analysis. In addition, H727-cells were infected with patient derived BKPyV, treated with mTOR-inhibitors, and NCCR activity was analysed using qRT-PCR. Results While tacrolimus and cyclosporine-A did not affect NCCR-promoter-activity, treatment with mTOR1-inhibitor rapamycin resulted in the reduction of early, but not late-NCCR-promoter-activity. Treatment with dual mTOR1/2 inhibitors (INK128 or pp242) led to significant inhibition of early, however, concomitantly enhanced late-promoter-activity. In BKPyV infected cells both rapamycin and INK128 reduced early expression, however, INK128 resulted in higher late-mRNA levels when compared to rapamycin treatment. Conclusions Our results demonstrate that mTOR1-inhibitors are able to reduce early-expression of wildtype and rearranged NCCRs, which might contribute to previously described inhibition of BKPyV-replication. Dual mTOR1/2-inhibitors, however, additionally might shift viral early into late-expression promoting synthesis of viral structural proteins and particle production.

Die Nierentransplantation ist die Therapie der Wahl bei terminaler chronischer Nierenkrankheit. Doch trotz enormer Fortschritte in der Transplantationsmedizin bleibt das Langzeittransplantatuberleben eingeschrankt. Hauptgrunde hierfur sind die nephrotoxischen und kardiovaskularen Nebenwirkungen der immunsuppressiven Therapie und die immer noch nicht gut beherrschbare akute oder chronische Abstosung. Es wurde eine selektive Literaturrecherche in der Datenbank Pubmed zur Identifikation neuer diagnostischer Methoden zur Erkennung und Einordnung akuter oder chronischer Abstosungen durchgefuhrt. Zusatzlich wurde nach neuen therapeutische Strategien zur Prophylaxe oder Behandlung akuter oder chronischer Abstosungsreaktionen gesucht. Ergebnisse Der diagnostische Goldstandard bleibt die histologische Sicherung anhand der BANFF-Kriterien. Eine therapeutische Option zur Verbesserung des Langzeittransplantatuberlebens durch Reduktion der Nebenwirkungen konnte die Einsparung von Steroiden sein. Ob die Einsparung an Steroiden das Langzeittransplantatuberleben verbessert, bleibt unklar. Allerdings lassen sich steroidinduzierte Komplikationen wie ein neu aufgetretener Diabetes mellitus verringern. Eine weitere Moglichkeit bietet hier die calcineurininhibitorfreie Immunsuppression mit Belatacept. Zur Behandlung der zellularen Abstosungsreaktion bleiben hochdosierte Steroide und Antithymozytenglobulin die Mittel der Wahl. Bei der antikorpervermittelten Abstosung werden die Plasmapherese und Immunglobuline eingesetzt. Die Evidenzlage der Therapeutika gegen eine akute und chronische Abstosungsreaktion bleibt enttauschend, und das therapeutische Portfolio ist sehr begrenzt. Neue Substanzen wie Tocilizumab oder die Blockierung von Kostimulationsfaktoren konnten dringend benotigte neue Therapiestrategien darstellen.

HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m(2), P < .001) or low CNI (difference 7.6 mL/min/1.73 m(2), P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m(2) and 10.1 mL/min/1.73 m(2), respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account.

Significance Akin to other physiological responses, immune functions can be modified in humans through associative conditioning procedures as part of a learned placebo response. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. In the present study, we demonstrate in renal transplant patients who were already receiving immunosuppressive treatment that learned immunosuppressive placebo responses increased efficacy of immunosuppressive medication. These data demonstrate that behavioral conditioning of drug responses may be a promising tool that could be used as a placebo-based dose-reduction strategy in an ongoing immunopharmacological regimen, the aim being to limit unwanted drug adverse effects and to improve treatment efficacy., Patients after organ transplantation or with chronic, inflammatory autoimmune diseases require lifelong treatment with immunosuppressive drugs, which have toxic adverse effects. Recent insight into the neurobiology of placebo responses shows that associative conditioning procedures can be employed as placebo-induced dose reduction strategies in an immunopharmacological regimen. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. Thus, 30 renal transplant patients underwent a taste-immune conditioning paradigm, in which immunosuppressive drugs (unconditioned stimulus) were paired with a gustatory stimulus [conditioned stimulus (CS)] during the learning phase. During evocation phase, after patients were reexposed to the CS, T cell proliferative capacity was significantly reduced in comparison with the baseline kinetics of T cell functions under routine drug intake (ƞp2 = 0.34). These data demonstrate, proof-of-concept, that learned immunosuppressive placebo responses can be used as a supportive, placebo-based, dose-reduction strategy to improve treatment efficacy in an ongoing immunopharmacological regimen.

Introduction and aim. Procalcitonin is widely used as a biomarker to distinguish bacterial infections from other etiologies of systemic inflammation. Little is known about its value in acute liver injury resulting from intoxication with paracetamol.Material and methods. We performed a single-center retrospective analysis of the procalcitonin level, liver synthesis, liver cell damage and renal function of patients admitted with paracetamol-induced liver injury to a tertiary care children’s hospital. Children with acute liver failure due to other reasons without a bacterial or fungal infection served as the control group. Twelve patients with acute paracetamol intoxication and acute liver injury were compared with 29 patients with acute liver failure.Results. The procalcitonin levels were higher in children with paracetamol intoxication than in patients with acute liver failure without paracetamol intoxication (median 24.8 (0.01-55.57) ng/mL vs. 1.36 (0.1-44.18) ng/mL; p < 0.005), although their liver and kidney functions were better and the liver cell injury was similar in both groups. Outcome analysis showed a trend towards better survival without transplantation in patients with paracetamol intoxication (10/12 vs. 15/29). Within each group, procalcitonin was significantly correlated with alanine aminotransferase and aspartate aminotransferase but was not correlated with the International Normalized Ratio or paracetamol blood levels in the paracetamol group. In conclusion, paracetamol intoxication leads to a marked increase in procalcitonin serum levels, which are significantly higher than those seen in acute liver failure.Conclusion. The underlying mechanism is neither caused by infection nor fully explained by liver cell death alone and remains to be determined.

BACKGROUND: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio

This report describes how donor- and recipient-derived immunity was influenced by immunosuppressive treatment of ABO incompatibility (rituximab and immunoadsorption/plasmaphereses) in the long-term. We present an 8-year course of Hepatitis B virus (HBV) immunity, isohemagglutinins and B cell numbers. Whereas cellular HBV immunity was transferred from the HBV vaccinated donor (blood group A1) to the HBV naïve recipient (blood group 0), humoral HBV specific immune transfer was lacking. Starting at month 17 after transplantation, the recipient was vaccinated six times against HBV. Anti-HBs did not appear until the sixth vaccination at month 44. Immunoadsorption prior to transplantation reduced anti-A1 IgG titers from 256 to 2. Titers after transplantation remained low (⩽64). B cell numbers were below standard values up to month 26, then normalized and exceeded normal values from year 7 to 8 post transplantation. In conclusion, donor-derived B cell immunity was lost but recipient-derived immunity persisted after ABO incompatible transplantation.

Background/Aim ANCA-associated (AAV) vasculitis is an autoimmune small-vessel vasculitis and may be associated with accelerated atherosclerosis as suggested by current literature. Antibodies against oxidized lipoproteins (OxLDL) and phosphorylcholine (Pc) protect from atherosclerosis. This study characterizes these antibodies in AAV. Methods Pc- and anti-OxLDL antibodies were determined in sera of 39 AAV patients and 44 healthy controls (HC). Intima-media thickness (IMT, carotids) and pulse wave velocity (PWV, A. femoralis) were measured. Results Pc-/OxLDL IgM antibodies were significantly reduced in AAV. IMT and PWV were negatively associated with anti-Pc antibodies in HC only. Conclusion Atheroprotective anti-Pc/anti-OxLDL antibodies are significantly reduced in AAV possibly explaining accelerated atherosclerosis in vasculitis patients.

The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs, which are typically employed in the field of organ transplantation. Both drugs have narrow therapeutic indices, highly variable pharmacokinetics, and are associated with severe adverse effects. In current clinical routine, the dose finding of CNIs is based on the measurement of their blood concentrations. However, this method is limited in its ability to determine the biological impact of the drug. Alternative monitoring strategies, focusing on the pharmacodynamics of CNIs, could help to personalize drug dosing and optimize the treatment with CNIs. Therefore, we analyzed the relationship between pharmacokinetic and pharmacodynamic of the CNIs CsA (n = 9) and Tac (n = 8) in stable renal transplant patients during a 12-h dosing period. We observed a significant decrease in the drug-blood concentration during the course of the day and in parallel a significant recovery of T cell function. In addition, our data document that analysis of intracellular interleukin (IL)-2 production and determination of the IL-2 release are accurate parameters for monitoring the pharmacodynamics of CNIs.

Die Nierenbeteiligung ist bei systemischen Autoimmunerkrankungen wie z.B. der ANCA-Vaskulitis haufig. Das akute Nierenversagen (ANV) limitiert die Prognose des Patienten und muss rechtzeitig erkannt werden. Das ANV verlauft jedoch symptomarm und daher stehen haufig zunachst extra-renale Krankheitssymptome im Vordergrund. Zur Beurteilung einer Nierenbeteiligung sind die Retentionsparameter, vor allem aber die Urinanalyse von Bedeutung. Die Nierenbiopsie ist das Verfahren der Wahl zur Bestatigung der Diagnose. Die Behandlung muss auf die Krankheitsschwere der ANCA-Vaskulitis abgestimmt sein und in Fallen mit schwerem Organversagen mussen extrakorporale Verfahren wie die Plasmapherese erwogen werden. Die immunsuppressive Erhaltungstherapie is notwendig um Rezidive zu verhindern und die Patienten mussen engmaschig uberwacht werden, um renale Krankheitsaktivitat fruhrzeitig zu erkennen.

BACKGROUND Immunosuppressive therapy with mammalian target of rapamycin inhibitors (mTORi) requires maintenance of an effective inhibition of the alloimmune response, whereas reducing drug-related nephrotoxicity. Therapeutic monitoring is based on mTORi trough levels, which do not necessarily reflect biologic effects on the PI3K-Akt-mTOR pathway and hence may often result in under-immunosuppression or over-immunosuppression. METHODS Phosphorylation of p70S6 kinase was studied by phosphoflow cytometry and by Western blot in both peripheral blood monocyte cells and CD3+ T cells of renal transplant recipients (RTX) receiving tacrolimus (n=34) or cyclosporine A (CsA) (n=24) or an mTORi (n=26). 16 healthy age-matched volunteers served as a control group. To clarify whether p70S6K activity is varying among CD4(+) T-cell subsets, cell sorted CD4(+)CD25(hi) regulatory T cells (Tregs) and CD4(+)CD25- T cells were analyzed for p70S6K phosphorylation. RESULTS Simultaneous analysis of p70S6K phosphorylation by phosphoflow cytometry and Western blot showed high correlation in peripheral blood mononuclear cells of renal transplant patients (r=0.91, P

The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients.Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 × 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 × 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over ≥14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D-]/R+).The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared with preemptive group experienced a CMV infection or disease up to month 84 (11.5%; 95% confidence interval [95% CI], 6.8-17.8%] vs 39.7%; 95% CI, 31.9-48.0%; P0.0001 and 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.002). Incidences of graft loss (7.4% vs 8.6%), death (9.5% vs 11.3%), rejection (29.1% vs 28.5%), and renal function (estimated glomerular filtration rate [mean ± SD]: 58.2 ± 26.3 vs 59.9 ± 25.7 mL/min per 1.73 m) were not significantly different between prophylaxis and preemptive treatment. Tolerability was comparable between groups.Prophylaxis was more effective than the preemptive approach, applying a low-intense surveillance protocol in preventing CMV infection and disease in intermediate-risk patients. Both strategies were similarly effective in preventing graft loss and death under the conditions of this long-term trial with a threshold of 400 copies/mL for initiation of anti-CMV treatment.

The expression modulation of the immunosuppressive non-classical Human leukocyte antigen-G (HLA-G) molecule and its soluble isoforms is an immune evasion strategy being deployed by cytomegalovirus (CMV). The +3142 C>G single nucleotide polymorphism (SNP) located within the 3′ untranslated region (3′UTR) is of crucial importance for the regulation of HLA-G expression. Therefore, we analyzed the influence of the +3142 C>G HLA-G SNP on the occurrence of CMV infection in a cohort of 178 living-donor kidney recipients and their 178 corresponding donors. In addition, soluble HLA-G (sHLA-G) levels were quantified before and after transplantation. The presence of the HLA-G +3142 CC genotype in recipients, but not donors of our cohort as along with elevated sHLA-G levels (≥ 6.1 ng/mL) were associated with higher susceptibility to CMV infection after transplantation. Our results provided evidence that i) HLA-G is implicated in the establishment of CMV after living-donor kidney transplantation and ii) recipient HLA-G +3142 CC genotype and sHLA-G concentration levels could represent important predictive risk markers for CMV infection.

Cytomegalovirus (CMV) causes serious complications among solid organ transplant recipients. We report the positive correlation between the presence of the HLA-E*01:03 allele in living-donor kidney recipients and CMV reactivation during the first year after transplantation. Thus, HLA-E genotyping may help identify CMV replication-prone patients who require individualized patient-based CMV management.

Backround Pneumocystis jirovecii pneumonia (PCP) is an opportunistic fungal infection that is associated with a high morbidity and mortality in immunocompromised individuals. In this study, we analysed the microbiome of the lower respiratory tract from critically ill intensive care unit patients with and without pneumocystosis. Methods Broncho-alveolar fluids from 65 intubated and mechanically ventilated intensive care unit patients (34 PCP+ and 31 PCP- patients) were collected. Sequence analysis of bacterial 16S rRNA gene V3/V4 regions was performed to study the composition of the respiratory microbiome using the Illumina MiSeq platform. Results Differences in the microbial composition detected between PCP+ and PCP- patients were not statistically significant on class, order, family and genus level. In addition, alpha and beta diversity metrics did not reveal significant differences between PCP+ and PCP- patients. The composition of the lung microbiota was highly variable between PCP+ patients and comparable in its variety with the microbiota composition of the heterogeneous collective of PCP- patients. Conclusions The lower respiratory tract microbiome in patients with pneumocystosis does not appear to be determined by a specific microbial composition or to be dominated by a single bacterial species. Electronic supplementary material The online version of this article (10.1186/s12890-017-0512-5) contains supplementary material, which is available to authorized users.