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Background Norovirus (NoV) infection frequently progresses to chronic disease after kidney transplant (KTx). This study aims to assess potential risk factors helping to determine patients at risk of chronic NoV infection and to analyse the effect of NoV on allograft outcome. Additionally, we assessed the effectiveness of intravenous immunoglobulin (IVIg) therapy for chronic NoV infection. Methods The study enrolled 60 KTx patients requiring hospitalization because of NoV infection. Clinical parameters, severity of NoV infection and potential risk factors were evaluated. Outcome parameters were clinical symptoms, rehospitalizations, persistent shedding of virus and effects on allograft function. Results Patients were divided into 2 groups: 29 had acute NoV infection only, 31 progressed to chronic NoV infection. Chronic NoV infection was defined as a recurrence of clinical symptoms plus redetection of NoV in stool. Lymphocyte-depleting induction therapy and diabetes mellitus were independent risk factors for chronic infection. For patients with chronic NoV infection, length of stay in hospital was significantly prolonged (p= 0.024). Allograft function remained impaired in the chronic NoV group 6 and 12 months after initial admission.IVIg was administered to 18 patients with chronic NoV infection. No further clinical symptoms of NoV infection occurred in 13 (72%) of these patients. However, NoV was still detectable in stool specimens from 10 (77%) of these patients. Conclusions Chronic NoV infection is associated with reduced allograft function. Administration of IVIg to patients with chronic NoV infection seems beneficial in achieving freedom from clinical symptoms, despite limited effects on shedding of virus.

Malina Grube,1 Frank Weber,2 Anna Lena Kahl,3 Andreas Kribben,1 Nils Mülling,1 Walter Reinhardt1 1Department of Nephrology, University Hospital Essen, Essen, Germany; 2Department of General-, Visceral- and Transplantation Surgery, Section of Endocrine Surgery, University Hospital Essen, Essen, Germany; 3Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Essen, GermanyCorrespondence: Nils MüllingDepartment of Nephrology, University Hospital Essen, Hufelandstr. 55, Essen, 45147, GermanyEmail nils.muelling@uk-essen.deBackground: The period after parathyroidectomy (PTx) in dialysis patients is characterized by periods of severe hypocalcemia. This study aims to investigate the effect of high doses of active vitamin D immediately after PTx on the development of hypocalcemia.Materials and Methods: We retrospectively reviewed 111 patients with secondary hyperparathyroidism receiving subtotal PTx between 2010 and 2019. A high dose group “HDG” (n = 67) receiving 12 μg alfacalcidol in combination with 8.550 mg calcium acetate per day, which was then adapted according to lab values, was compared with a low dose group “LDG” (n = 44) receiving up to 4 μg alfacalcidol per day. The laboratory values were recorded up to ten weeks postoperatively.Results: The assumed drops in parathyroid hormone (PTH) and calcium were observed in both groups after PTx. We observed significantly lower calcium values in the LDG between days 4 and 18 postoperatively than in the HDG (p < 0.001). The proportion of severe hypocalcemia after PTx (total calcium < 1.5 mmol/l) in the HDG was 8.5% on day 1 and 47% on day 4 in the LDG. Intravenous calcium requirements were significantly lower in the HDG (7.6%) than in the LDG (45.7%; p = 0.001).Conclusion: The period after PTx in dialysis patients is characterized by an expected drop in PTH and calcium within the first days. Ongoing high turnover is observed in the 2nd and 3rd week after PTx. Administering high doses of alfacalcidol combined with calcium acetate diminishes the episodes of severe hypocalcemia and the need for intravenous calcium.Keywords: secondary hyperparathyroidism, hungry bone disease, parathyroidectomy, vitamin D, dialysis, CKD stage 5

Kidney disease is an important public health problem. Both acute kidney injury (AKI) and chronic kidney disease have been well defined and classified, leading to improved research efforts and subsequent management strategies and recommendations. For those patients with abnormalities in kidney function and/or structure who meet neither the definition of AKI nor chronic kidney disease, there remains a gap in research, care, and guidance. The term acute kidney diseases and disorders, abbreviated to acute kidney disease (AKD), has been introduced as an important construct to address this. To expand and harmonize existing definitions and to ultimately better inform research and clinical care, Kidney Disease: Improving Global Outcomes (KDIGO) organized a consensus workshop. Multiple invitees from around the globe, representing both acute and chronic kidney disease researchers and experts, met virtually to examine existing data, and discuss key concepts related to AKD. Despite some remaining unresolved questions, conference attendees reached general consensus on the definition and classification of AKD, management strategies, and research priorities. AKD is defined by abnormalities of kidney function and/or structure with implications for health and with a duration of ≤3 months. AKD may include AKI, but, more importantly, also includes abnormalities in kidney function that are not as severe as AKI or that develop over a period of >7 days. The cause(s) of AKD should be sought, and classification includes functional and structural parameters. Management of AKD is currently based on empirical considerations. A robust research agenda to enable refinement and validation of definitions and classification systems, and thus testing of interventions and strategies, is proposed.

Background: Oral cladribine is an approved disease-modifying drug for the treatment of relapsing multiple sclerosis. In controlled clinical trials as well as in post marketing safety assessments, autoimmune conditions have not yet been reported as a specific side effect of cladribine. Objective and Results: Here, we report a case of anti-glomerular basement membrane antibody-mediated glomerulonephritis that occurred shortly after the fourth cladribine treatment cycle. Conclusion: Neurologists should be attentive to the development of secondary autoimmunity in cladribine-treated patients.

Background Severe thromboembolic events are one of the major complications associated with COVID-19 infection, especially among critically ill patients. We analysed ROTEM measurements in COVID-19 patients with a severe disease course and in patients with severe sepsis. Methods In this study, data obtained by extended analysis of haemostasis with standard laboratory tests and thromboelastometry of 20 patients with severe course of COVID-19 were retrospectively analysed and compared with similar data from 20 patients with severe sepsis but no COVID-19. Results The thromboelastometry values obtained from 20 sepsis patients contained a maximum clot firmness above the normal range but among COVID-19 patients, hypercoagulability was much more pronounced, with significantly higher maximum clot firmness (FIBTEM: 38.4 ± 10.1 mm vs. 29.6 ± 10.8 mm; P = 0.012; EXTEM: 70.4 ± 10.4 mm vs. 60.6 ± 14.8 mm; P = 0.022). Additionally, fibrinogen levels were significantly higher among COVID-19 patients (757 ± 135 mg/dl vs. 498 ± 132 mg/dl, P P = 0.013). Seven of 20 COVID-19 patients experienced thromboembolic events, whereas no patient in the sepsis group experienced such events. Conclusions ROTEM analysis showed significantly different pathological findings characterized by hypercoagulability and fibrinolysis shutdown among COVID-19 patients with a severe disease course compared to patients with severe sepsis. These abnormalities seem to be associated with thromboembolic events.

Background The single-nucleotide polymorphism CYP3A5 rs776746 is related to a reduction in the metabolizing activity of the CYP3A5 enzyme. Persons carrying at least one copy of the wild-type allele, defined as CYP3A5 expressers, exhibit higher clearance and lower trough concentrations of tacrolimus than homozygous nonexpressers, and this difference may affect alloimmunization and allograft function. Methods We retrospectively studied 400 kidney transplant recipients treated with a tacrolimus-based immunosuppression regimen to detect CYP3A5 genotype, de novo formation of human leukocyte antigen (HLA) antibodies and donor-specific antibodies (DSA), and clinical outcome up to 5 years after transplant. Results We found that 69 (17%) of the 400 patients were CYP3A5 expressers. During the first 3 years after transplant, CYP3A5 expressers tended to have lower tacrolimus trough levels than non-expressers, even though their tacrolimus dosage was as much as 80% higher. De novo DSAs were found more frequently in CYP3A5 expressers than in nonexpressers (13/69 [19%] vs. 33/331 [10%], p = 0.02). De novo DSA-free survival rates (p = 0.02) were significantly lower for expressers than for nonexpressers. CYP3A5 genotype had no effect on allograft failure, but CYP3A5 expressers exhibited a significantly higher frequency of antibody-mediated rejection. CYP3A5 expresser status was an independent risk factor for the development of de novo DSAs (relative risk, 2.34, p= 0.01). Conclusions Early detection of CYP3A5 expressers, enabling genotype-based dose adjustment of tacrolimus immediately after renal transplant, may be a useful strategy for reducing the risk of de novo DSA production and antibody-mediated rejection.

BACKGROUND HTK-N was developed based on the traditional HTK preservation solution, resulting in stronger protection against reactive oxygen species as well as better tolerance to hypothermia and ischemia. Aim of the present study was to compare HTK-N to HTK in clinical kidney transplantation demonstrating safety and non-inferiority. METHODS We performed a randomized controlled single blinded clinical phase II trial in patients undergoing living donor kidney transplantation. After retroperitoneoscopic nephrectomy kidneys were either perfused and stored with classical HTK solution or the new HTK-N solution. Primary endpoint was the glomerular filtration rate (eGFR according to CKD EPI) 3 months after transplantation. Secondary endpoints included graft and patient survival beside others. RESULTS The study included 42 patients, of which 22 were randomized in the HTK-N group and 20 in the HTK group. The primary end point showed a mean eGFR of 55.4 ± 14.0 ml/min/1.73m2 in the HTK group compared to a GFR of 57.2 ± 16.7 ml/min/m2 in the HTK-N group (p = 0.72). Regarding secondary endpoints, there were no apparent differences. Posttransplant graft and patient survival was 100%. CONCLUSION This study is the first clinical application of HTK-N for kidney preservation and demonstrates non-inferiority compared to HTK in the setting of living donor kidney transplantation. This article is protected by copyright. All rights reserved.

Cardiovascular complications are the leading causes of morbidity and mortality in patients with end-stage renal disease. The risk profile very often contributes to their death while on the waiting list. Most studies have been carried out in older patients with end-stage renal disease, reflecting the general dialysis population. The aim of this study was to analyze the risk profile in young patients with advanced chronic kidney disease on the kidney transplant waiting list.This was a retrospective, single-center study of 748 patients on the kidney transplant waiting list at the University Hospital Essen, Germany. Clinical and laboratory parameters were collected between 2015 and 2016.Of 748 patients (62% male), the median age was 48 years. Hypertension, coronary heart disease, and diabetes mellitus were the leading comorbidities, and their frequency rose significantly with age. Their median laboratory values did not differ significantly depending on age except for albumin. Hyperuricemia was quite common in our population with a prevalence of about 75% in women and 50% in men throughout all age groups. A total of 26.6% of the patients between 18 and 35 years of age had advanced anemia (hemoglobin 10 g/dL), and thus they were affected most frequently. Elevated C-reactive protein serum levels were observed in 37.2% of the patients. Regarding the lipid profile, we observed that HDL cholesterol was within the normal range in only among 51.9% of men and 44.3% of women.Cardiovascular risk factors are quite common in our cohort and affect young patients similarly.

Background and Aims Arterial hypertension is one of the most common diseases of the cardiovascular system worldwide and is still the cause of most deaths in Germany. Data on interactions of the endothelin-system with the renin-angiotensin- and the sympathoadrenergic system in the regulation of systemic hemodynamics in humans are lacking. In our present investigation we study the effects of Endothelin A-, Alpha1- and Angiotensin II-type-1-receptor antagonization on the systemic pressor effects of intravenous Endothelin-1-application in young, healthy men. In addition, we analyzed the effects of the genetic variations of the GNB3 C825T-polymorphism on hemodynamic changes. GNB3 825CT/TT-allele-carriers are considered to have a higher risk for multiple diseases with structural, vascular degeneration, such as arterial hypertension, diabetes mellitus and obesity. Method 21 healthy male volunteers were included in this double- blind, randomized, placebo-controlled cross-over study and were studied on four days. Endothelin-1 (ET-1) (0.5, 1, 2.5, 5 ng/kg/min for 20 min each) was given intravenous 2.0 hours after oral application of either placebo or Doxazosin, 3.5 hours after oral application of Candesartan (Candesartan 8 mg) or in the presence of a continuous infusion of the ET-A-selective antagonist BQ123 (60 μg/min). Blood pressure (BP) and heart rate (HR) were recorded and total peripheral resistance (TPR) was measured using impedance cardiography. ET-1-dose-response curves were analyzed with ANOVA. Data are presented as mean ± SD. Since we suspected an effect of the GNB3 C825T-polymorphism we divided the overall collective into 2 sub-collectives according to the GNB3 C825T-genotypes (n = 21, GNB3 825CC: n = 10, GNB3 825CT/TT: n = 11). Our analyses considered the overall collective and compared the sub-collectives intraday and interday. Results ET-1 increased systolic blood pressure (SBD) (p ≤ 0,01), diastolic blood pressure (DBD) and mean arterial pressure (MBP) as well as total peripheral resistance (TPR) (each p ≤ 0,001) with decreasing heart rate (HR5) (p ≤ 0,05). Elevation of blood pressure existed in both sub-collectives (GNB3 825CC: SBD & MBD: p ≤ 0,01, DBP & TPR: p ≤ 0,05, GNB3 825CT/TT: DBD, MBD & TPR: p ≤ 0,01, SBP p ≤ 0,05). Antagonization of ETA-receptors reversed the effect in the overall collective as well as in the sub-collectives. Both, Doxazosin, as well as Candesartan led to a decrease in blood pressure, however, dose-response relationship was influenced more by doxazosin (DBD: p ≤ 0,001, MBD: p ≤ 0,01) than by candesartan (all values: p > 0,05). For both drugs, blood pressure and TPR remained elevated under maximum ET-1-application compared to baseline measurement. Blood pressure dependent heart rate changes were observed in the overall collective and in GNB3 825CC-allele-carriers under sole ET-1-therapy (p ≤ 0.05) (Fig. 1). Candesartan reversed the effect of ET-1 on the sub-collectives (p > 0.05). GNB3 825CT/TT-allele-carriers showed no reduction in heart rate under ET-1-application, but with accompanying candesartan therapy (p ≤ 0.01) (Fig. 2). The genotype collectives thus behaved oppositely to the drugs in this respect. Conclusion In summary, ET-1 increased systolic, diastolic and mean arterial blood pressure as well as systemic vascular resistance. Doxazosin, Candesartan and BQ123 led to a decrease in blood pressure. Blood pressure and TPR remained elevated under maximum ET-1 application plus Candesartan or Doxazosin. The heart rate changes of the genotype-separated sub-collectives were opposite when ET-1 was administered compared to ET-1 and Candesartan.

The objective of this registry is to collect data on real-life treatment conditions for patients for whom multiple organ dialysis with Advanced Organ Support (ADVOS) albumin hemodialysis is indicated.This registry was performed under routine conditions and without any study-specific intervention, diagnostic procedures, or assessments. Data on clinical laboratory tests, health status, liver function, vital signs, and examinations were collected (DRKS-ID: DRKS00017068). Mortality rates 28 and 90 days after the first ADVOS treatment, adverse events and ADVOS treatment parameters, including treatment abortions, were documented.This analysis was performed 2 years after the first patient was included on January 18, 2017. As of February 20, 2019, 4 clinical sites in Germany participated and enrolled 118 patients with a median age of 60 (IQR: 45, 69) of whom 70 were male (59.3%). Patients had a median SOFA Score of 14 (IQR: 11, 16) and a predicted mortality of 80%. The median number of failing organs was 3 (IQR: 2, 4).Four hundred twenty nine ADVOS treatments sessions were performed with a median duration of 17 hours (IQR: 6, 23). A 5.8% of the ADVOS sessions (25 of 429) were aborted due to device related errors, while 14.5% (62 of 429) were stopped for other reasons. Seventy nine adverse events were documented, 13 of them device related (all clotting, and all recovered without sequels).A significant reduction in serum creatinine (1.5 vs 1.2 mg/dl), blood urea nitrogen (24 vs 17 mg/dl) and bilirubin (6.9 vs 6.5 mg/dl) was observed following the first ADVOS treatment session. Blood pH, bicarbonate (HCO3-) and base excess returned to the physiological range, while partial pressure of carbon dioxide (pCO2) remained unchanged. At the time of the analysis, 28- and 90-day mortality were 60% and 65%, respectively, compared to an expected ICU-mortality rate of 80%. SOFA score was an independent predictor for outcome in a multivariable logistic regression analysis.The reported data show a high quality and completion of all participating centers. Data interpretation must be cautious due to the small number of patients, and the nature of the registry, without a control group. However, the data presented here show an improvement of expected mortality rates. Minor clotting events similar to other dialysis therapies occurred during the treatments. CA extern

T follicular helper (TFH) cells are a heterogeneous subset of immunocompetent T helper (TH) cells capable of augmenting B cell responses in lymphoid tissues. In transplantation, exposure to allogeneic tissue activates TFH cells increasing the risk of the emergence of de novo donor-specific HLA-antibodies (dnDSA). These can cause antibody-mediated rejection (AMR) and allograft loss. Follicular regulatory T (TFR) cells counteract TFH cell activity. Here, we investigated the implications of TFH and TFR cells on dnDSA formation after renal transplantation (RTX). Considering TFH cells to be CXCR5+ and IL-21+, we found by flow cytometry that patients with dnDSA produced IL-21 more abundantly compared to healthy volunteers. In in vitro alloreactivity assays, patients with dnDSA featured an enhanced alloreactive TH cell pool in response to donor-specific HLA antigens. Besides, longitudinal investigations suggested enhanced alloreactivity shortly after transplantation increasing the risk of dnDSA development. Taken together, in spite of continuous immunosuppression we report a strong IL-21 response in TFH cells and an expanded reservoir of donor-specific memory TH cells in patients with dnDSA. This warrants further investigations if aberrant TFH cell activation may precede the formation of dnDSA promoting AMR.

Patients receiving dialysis are at high risk of contracting SARS-CoV-2 and developing severe COVID-19. Established SARS-CoV-2 vaccination schemes might lack efficacy in these patients and a personalized approach is therefore necessary. Importantly, given the enhanced infection risks associated with dialysis, current vaccines do not replace non-pharmacological measures to prevent infection.

The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.

Allograft-specific regulatory T cells (Trₑg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Trₑg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Trₑg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Trₑg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3⁺ T cell infiltrated, higher Trₑg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Trₑg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Trₑg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment. CA extern

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities

Background Peritoneal dialysis (PD)-related peritonitis is a rare but serious complication and is associated with increased morbidity and mortality rates. It is most commonly caused by Staphylococcus aureus or Staphylococcus epidermidis, but infection with Listeria monocytogenes may also occur. Recommendations for antibiotic treatment of a Listeria infection are currently based on a small number of case reports and suggest the administration of ampicillin. But unlike vancomycin or gentamicin, for ampicillin the route of application, the dosage, and the duration of treatment have not yet been established. We report a case in which PD-associated peritonitis due to Listeria infection was treated with ampicillin administered intravenously and intraperitoneally, separately and in combination. Case presentation A 72-year-old man with chronic kidney disease stage 5 dialysis (CKDG5D) secondary to hypertension and diabetes was hospitalised in April 2020 because of PD-related peritonitis caused by a Listeria infection. In accordance with the results of resistance tests, the patient was treated with intravenous ampicillin at a dosage of 6 g twice daily. After initial treatment the leukocyte count in the PD effluent had decreased substantially, but it was permanently reduced only with the addition of intraperitoneal ampicillin (4 g daily). Efficient serum concentrations of ampicillin were determined for both routes of administration, intravenous and intraperitoneal. Conclusion This is the first case report demonstrating that PD-related peritonitis due to Listeria monocytogenes infection can be treated with intraperitoneal ampicillin and monitored by the determination of peripheral serum concentrations of ampicillin.

Background and Aims Anti-neutrophil-cytoplasmic-antibody (ANCA)-associated-vasculitis (AAV) is an autoimmune small-vessel-vasculitis. T-cells play a pivotal role in pathogenesis as drivers of autoantibody formation and vasculitic damage. However, the involvement of T-cells in renal vasculitis is understood poorly. IL-17C is secreted by epithelial parenchymal cells enhancing the pathogenicity of Th17 cells. Furthermore, IL-17C is a chemotactic factor for Th17 cells. The aim of this study was to assess the role of Th17 cells and IL-17C in the pathogenesis of ANCA-vasculitis in an animal model of AAV. Method Wistar-Kyoto-rats were immunized with myeloperoxidase (MPO) in Freunds Adjuvant to induce AAV. Control rats were immunized with Freunds Adjuvant only. Albuminuria was determined weekly and rats were culled after two, four and six weeks. At the time of harvest, renal T-cells were isolated and characterized by flow cytometry. Antigen-specificity was determined by ELiSPOT. Petechial bleedings on the lung surface reflecting pulmonary vasculitis were quantified after harvest. Gene expression in spleen, kidneys and lungs was studied by PCR and is expressed as fold change over controls. IL-17C levels were measured in sera by ELISA. Results MPO-rats developed detectable titres of anti-MPO by week two. By week six, all MPO-animals developed renal vasculitis with significant albuminuria and pulmonary vasculitis. Accordingly, MPO animals showed significant crescent formation as compared to the controls (% of affected glomeruli: 11.4 ±10.5% vs. 0.4 ±0.7%, p Conclusion Th17 and Th22 cells are drivers of renal inflammation in ANCA-vasculitis. The role of IL-17C in this cascade needs to be determined.

Background and Aims B cell activating factor (BAFF) is a cytokine which drives B cell survival and maturation. Several studies have shown that elevated BAFF levels in renal transplant patients are associated with increased risk for the development of donor specific antibodies and antibody mediated rejection. It was the aim of this study to investigate neutrophils as cellular source of BAFF in renal transplant patients. Method Neutrophils (NT) were freshly isolated from whole blood of healthy controls (HC) and renal transplant patients (RTX). After isolation, purity of neutrophils was usually above 98%. Neutrophils were stimulated with LPS or TNFα in presence of Granulocyte-colony stimulating factor (GCSF) or Granulocyte macrophage colony-stimulating factor (GMCSF). In selected conditions, FK506 or rapamycin was added. Supernatants were harvested after 20 hours of culture and BAFF levels were determined by ELISA. Results GCSF/TNFα and GCSF/LPS were the most potent stimuli leading to BAFF secretion of NT in HC (403 ±64 pg/ml and 421 ±69 pg/ml). NT derived RTX showed similar capacity to secrete BAFF as compared to HC (GCSF/TNFα: 515 ±31 pg/ml and GCSF/LPS: 539.4 ±36 pg/ml). Treatment of cultures with rapamycin reduced BAFF levels (515 ±100 pg/ml vs. 348 ±27 pg/ml, p Conclusion NT may enhance of B cell maturation and survival via BAFF. BAFF-secretion by NT can be suppressed with mTOR inhibitors. In renal transplantation, NT might promote formation of allo-antibodies and drive antibody mediated rejection.

Background and Aims Extracorporeal cytokine adsorption is a new option in septic shock as an additional measure to prevent severe cytokinaemia. The purpose of this study was to investigate the effects of extracorporeal cytokine adsorption on hemodynamics in patients with acute kidney injury (AKI) and septic shock after cardiac surgery. Method In this retrospective study 64 patients with AKI and septic shock after cardiac surgery were investigated for the effect of extracorporeal cytokine adsorption by CytoSorb® columns on hemodynamics. In all patients CytoSorb®-treatment was applied in addition to continuous renal replacement therapy (CRRT) with citrate anticoagulation. A paired t-test has been performed to determine statistical significance. Results Before treatment, the mean noradrenalin dose to reach a mean arterial pressure (MAP) > 65 mmHg was 0.49 µg/kg bw/min, the mean adrenalin dose was 0.1 µg/kg bw/min. 24 h after treatment, significantly reduced catecholamine doses were necessary to maintain a MAP > 65 mmHg (0.23 µg/kg bw/min noradrenalin; p***< 0.0002 and 0.06 µg/kg bw/min adrenalin; p* < 0.02). The mean SOFA-score for these patients with AKI and septic shock 24 h before CytoSorb®- treatment was 16.6 points. The mean predicted in-hospital mortality rate based on this SOFA-score of 16.6 points was 77 % while the all-cause mortality rate of the patients in this study was 59.4 %. Conclusion In patients with AKI and septic shock after cardiac surgery, 24 h after extracorporeal cytokine adsorption by CytoSorb® the catecholamine dose required to maintain a MAP > 65 mmHg was halved. Additionally, observed in-hospital mortality was lower than SOFA-score predicted mortality.

Although infant organ donors remain a rare source of organs for transplantation, technical challenges have resulted in increased rates of complications and inferior graft function. The aim of the present study was to investigate the outcomes of kidneys procured from juvenile and infant donors.We evaluated all kidney transplants from deceased donors 16 years of age performed at our center between 01/2008 and 08/2019. We defined three groups based on quartiles of donor body weight:13 kg (infant donors), 13-40 kg (juvenile donors), and 40 kg (standard criteria donors). Clinical characteristics and outcomes were compared between groups.Ninety-two transplants were included in this study. Out of 92 recipients, there were 32 (34.8%) adult and 60 (65.2%) pediatric patients. All groups demonstrated excellent graft function and survival on both short and long-term follow-up. 1-year, 3-year, and 5-year graft survival rates for the standard criteria donor group were 100%, 95.2%, and 88.4%, respectively, compared with 95.8% for infant and 95% for juvenile donors at all times (P = .79). eGFR at 5 years was 98.9 ± 5.5, 74.1 ± 6.2, and 81.6 ± 6.9 mL/min/1.73 mInfant donor allografts can be transplanted with excellent long-term outcomes in both pediatric and adult recipients. Implanting them as single allografts onto pediatric candidates allows for the transplantation of two patients. As such, pediatric recipients should be prioritized for these donor organs.

Background 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 Twenty-three SLE-patients and eight healthy controls were enrolled. Nineteen 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. The BTLA-4 expression was significantly decreased on CD154+CD3+ T-cells in CMV IgG negative patients as compared to CMV IgG positive. Conclusion SLE-patients show a significant decreased expression of BTLA on CMV-specific T-cells. The co-inhibitors PD-1 and BTLA usually promote T-cell suppression. Thus a decrease may prone to severe symptomatic infections.

BACKGROUND: In patients with acute kidney injury (AKI), specialized treatment—initiated in response to an early-warning system—may be beneficial compared with routine treatment. METHOD: To explore effect estimators in a pilot trial (DRKS00010530), patients with AKI on regular wards of a university hospital were treated either in the usual way (control group) or more intensively (intervention group). The subjects were allotted randomly to the two treatment groups. The more intensive treatment consisted of an early warning system for a rise in the serum creatinine concentration, immediate consultation of a specialist, and the issuance of a patient kidney passport. The primary endpoint was recovery of renal function after AKI during the index hospitalization. Renal complications and process indicators were the secondary endpoints. RESULTS: The proportion of patients whose renal function returned to baseline after AKI was 50% in the intervention group (N = 26) and 42% in the control group (N = 26) (odds ratio 1.4, 95% confidence interval [0.5; 4.0], p = 0.58). The calculated glomerular filtration rate went down, from hospital admission to discharge, by 3 mL/min/1.73 m(2) (1st–3rd quartile: [6; –20]) in the intervention group and by 13 mL/min/1.73 m(2) in the control group (1st–3rd quartile: [0; –25]; p = 0.09). Complications of AKI such as hyperkalemia, pulmonary edema, and renal acidosis were rarer in the intervention group (15% versus 39%; p = 0.03). In the intervention group, compared with the control group, the cause of AKI was identified more frequently (27% versus 4%; p = 0.05); drugs with relevance to the kidney were discontinued more frequently (65% versus 31%; p = 0.01); and the diagnosis of AKI was more frequently documented in the patient’s chart (58% versus 37%; p = 0.03). CONCLUSION: Specialized consultations supported by an early warning system for AKI seem to be beneficial for patients. The findings of this pilot trial should be verified in larger-scale randomized controlled trials.

The immunosuppressive non-classical human leukocyte antigen-G (HLA-G) promotes transplant tolerance as well as viral immune escape. HLA-G expression is associated with regulatory elements targeting certain single nucleotide polymorphisms (SNPs) in the HLA-G 3′ untranslated region (UTR). Thus, we evaluated the impact of HLA-G 3′UTR polymorphisms as surrogate markers for BK polyomavirus (BKPyV) replication or nephropathy (PyVAN) and acute cellular and antibody mediated rejection (ACR/AMR) in 251 living-donor kidney-transplant recipient pairs. After sequencing of the HLA-G 3′UTR, fourteen SNPs between +2960 and +3227 and the 14 bp insertion/deletion polymorphism, which arrange as UTR haplotypes, were identified. The UTR-4 haplotype in donors and recipients was associated with occurrence of BKPyV/PyVAN compared to the other UTR haplotypes. While the UTR-4 recipient haplotype provided protection against AMR, the UTR-2 donor haplotype was deleteriously associated with ACR/AMR. Deduction of the UTR-2/4 haplotypes to specific SNPs revealed that the +3003C variant (unique for UTR-4) in donors as well as in recipients is responsible for BKPyV/PyVAN and also provides protection against AMR; whereas the +3196G variant (unique for UTR-2) promotes allograft rejection. Thus, HLA-G 3′UTR variants are promising genetic predisposition markers both in donors and recipients that may help to predict susceptibility to either viral infectious complication of BKPyV or allograft rejection.

Cold preservation sensitizes organ grafts to exacerbation of tissue injury upon reperfusion. This reperfusion injury is not fully explained by the mere re-introduction of oxygen but rather is pertinent to the immediate rise in metabolic turnover associated with the abrupt restoration of normothermia. Here we report the first clinical case of gradual resumption of graft temperature upon ex vivo machine perfusion from hypothermia up to normothermic conditions using cell-free buffer as a perfusate. A kidney graft from an extended criteria donor was put on the machine after 12.5 hours of cold storage. During ex vivo perfusion, perfusion pressure and temperature were gradually elevated from 30 mm Hg and 8°C to 75 mm Hg and 35°C, respectively. Perfusate consisted of diluted Steen solution, oxygenated with 100% oxygen. Final flow rates at 35°C were 850 mL/min. The kidney was transplanted without complications and showed good immediate function. Serum creatinine fell from preoperative 720 µmol/L to 506 µmol/L during the first 24 hours after transplantation. Clearance after 1 week was 43.1 mL/min. Controlled oxygenated rewarming prior to transplantation can be performed up to normothermia without blood components or artificial oxygen carriers and may represent a promising tool to mitigate cold-induced reperfusion injury or to evaluate graft performance.