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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 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.

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.

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.

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 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.

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.

Objectives A separate subset of Granzyme B (GrB) producing B-cells regulating T-cell mediated immunity has been identified. In the present study, we investigated the role of GrB + B-cells in renal transplant patients (RTX). Methods 12 healthy controls (HC) and 26 RTX patients were enrolled. In addition, 19 healthy volunteers treated with cyclosporine A (CsA) were enrolled. GrB + B-cells were determined via flow cytometry. Results RTX Patients showed a diminished fraction of GrB + B-cells as compared to HC. CsA treatment of healthy volunteers had no impact on the development of GrB + B-cells. RTX patients with a history of allograft rejection showed an increased frequency of GrB + B-cells. RTX patients with at least one episode of CMV viremia tended to have lower GrB + B-cells as compared to patients without viremic episodes. Conclusion We demonstrate that treatment with CsA does not impair the development of GrB + B-cells. GrB + B-cells may have a dual role in renal transplantation as regulatory cells to maintain allospecific tolerance and as effector cells enhancing viral control.

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 Ischemia and reperfusion (I/R) is one of the major causes of acute kidney injury (AKI). Citrate reduces hypoxia-induced mitochondrial energetic deficits in isolated proximal tubules. Moreover, citrate anticoagulation is now frequently used in renal replacement therapy. In the present study a rat model of I/R-induced AKI was utilized to examine renal protection by citrate in vivo. Methods AKI was induced by bilateral renal clamping (40 min) followed by reperfusion (3 h). Citrate was infused at three different concentrations (0.3 mmol/kg/h; 0.6 mmol/kg/h and 1.0 mmol/kg/h) continuously for 60 min before and 45 min after ischemia. Plasma calcium concentrations were kept stable by infusion of calcium gluconate. The effect of citrate was evaluated by biomonitoring, blood and plasma parameters, histopathology and tissue ATP content. Results In comparison to the normoxic control group bilateral renal ischemia led to an increase of creatinine and lactate dehydrogenase activity and a decrease in tissue ATP content and was accompanied by a drop in mean arterial blood pressure. Infusion of 1.0 mmol/kg/h citrate led to lower creatinine and reduced LDH activity compared to the I/R control group and a tendency for higher tissue ATP content. Pre-ischemic infusion of 1.0 mmol/kg/h citrate stabilized blood pressure during ischemia. Conclusions Citrate has a protective effect during I/R-induced AKI, possibly by limiting the mitochondrial deficit as well as by beneficial cardiovascular effects. This strengthens the rationale of using citrate in continuous renal replacement therapy and encourages consideration of citrate infusion as a therapeutic treatment for AKI in humans. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0546-1) contains supplementary material, which is available to authorized users.

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.

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 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.

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.

Journal of molecular medicine 97(10), 1451-1463 (2019). doi:10.1007/s00109-019-01823-8, Published by Springer, New York, NY

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.

Objectives Cytomegalovirus infection (CMVi) occurs frequently in transplant patients. Co-inhibitory molecules on CMV-specific T-cells (TCMV) in patients after lung transplantation were investigated. Methods 59 lung transplant patients were stratified according to anti-CMV serostatus at time of transplantation. The co-inhibitors Programmed-Death-Receptor-1 (PD1) and B-and-T-Lymphocyte-Attenuator (BTLA) were detected on TCMV by flow cytometry (FACS). Results TCMV were detectable in CMV sero-positive patients (R+) and in CMV sero-negative patients with a lung graft of a CMV sero-positive donor (D+/R−); in both cases, the frequency of TCMV was higher than in healthy controls (HC). PD-1 on TCMV was increased in D+/R+ and D+/R− patients as compared to HC. BTLA was significantly enhanced on TCMV of D+/R− patients vs. HC. R+ patients with CMV reactivation in the past had an increased fraction of BTLA+ TCMV. Conclusion In conclusion, the expression pattern of co-inhibitory molecules on TCMV is altered in patients after lung transplantation.

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.

Acute kidney injury (AKI) occurs frequently in hospitals worldwide, but the therapeutic options are limited. Diabetes mellitus (DM) affects more and more people around the globe. The disease worsens the prognosis of AKI even further. In recent years, cell-based therapies have increasingly been applied in experimental AKI. The aim of the study was to utilize two established autophagy inducers for pharmacological preconditioning of so-called proangiogenic cells (PACs) in PAC treatment of diabetic AKI. Insulin-dependent DM was induced in male C57/Bl6N mice by intraperitoneal injections of streptozotocine. Six weeks later, animals underwent bilateral renal ischemia for 45 min, followed by intravenous injections of either native or zVAD (benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone)- or Z-Leu-Leu-Leu-al (MG132)-pretreated syngeneic murine PACs. Mice were analyzed 48 h (short term) and 6 wk (long term) later, respectively. DM worsened postischemic AKI, and PAC preconditioning with zVAD and MG132 resulted in a further decline of excretory kidney function. Injection of native PACs reduced fibrosis in nondiabetic mice, but cell preconditioning promoted interstitial matrix accumulation significantly. Both substances aggravated endothelial-to-mesenchymal transition (EndoMT) under diabetic conditions; these effects occurred either exclusively in the short (zVAD) or in the short and long term (MG132). Preconditioned cells stimulated the autophagocytic flux in intrarenal endothelial cells, and all experimental groups displayed increased endothelial abundances of senescence-associated β-galactosidase, a marker of premature cell senescence. Pharmacological autophagy activation may not serve as an effective strategy for improving PAC competence in diabetic AKI in general. On the contrary, several outcome parameters (excretory function, fibrosis, EndoMT) may even be worsened.

Objective: Sepsis is one of the leading causes of the deaths in hospitals. During sepsis, patients are exposed to endotoxemia, which may contribute to the dysregulation of the immune system frequently observed in sepsis. This dysregulation leads to impaired pro-inflammatory responses and may increase the risk for secondary infections in sepsis. The experimental human endotoxemia model is widely used as a model system to study the acute effects of endotoxemia. Under physiological circumstances, the immune system is tightly regulated. Effector T-cells exert pro-inflammatory function and are restrained by regulatory T-cells (Tregs), which modulate pro-inflammatory effector responses. Endotoxemia may induce inadequate Treg activity or render effector T-cells dysfunctional. It was the aim of the study to investigate effector T-cell and Treg responses in an experimental human endotoxemia model. Methods: In a cross-over designed placebo-controlled study, 20 healthy male volunteers received an intravenous injection of either lipopolysaccharide (LPS) (0.8 ng/kg body weight) or a placebo (saline 0.9%). CD3⁺ T-cells, CD4⁺ T-cells, CD8⁺ T-cells, and intracellular cytokine profiles were measured with flow cytometry at baseline and at repeated points after LPS/placebo injection. Complete blood cell counts were obtained with an automated hematology analyzer and cytokines were quantified by ELISA. Results: Circulating neutrophils were significantly increased 2 h after LPS injection (p < 0.001) while absolute number of CD3⁺ T-cells, CD4⁺ T-cells, and CD8⁺ T-cells decreased (p < 0.001). Effector T-helper-cells (THs) showed a significant-but transient-decrease of pro-inflammatory IFNγ, interleukin (IL)-2, TNFα, and IL-17A production after LPS injection (p < 0.001). In contrast, the frequency of Treg and the capacity to produce IL-10 were unchanged (p = 0.21). Conclusion: Effector THs fail to produce pro-inflammatory Th1-/Th17-associated cytokines after LPS challenge. In contrast, IL-10 production by Treg is not affected. Thus, endotoxemia-induced suppression of pro-inflammatory THs might be considered as a contributing factor to immunoparalysis in sepsis. CA Witzke

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.

Die potenziellen Nebenwirkungen kontrastmittelverstarkter Bildgebung stellen Nephrologen und Radiologen im klinischen Alltag immer wieder vor schwierige Entscheidungen. Bewertung der unmittelbar mit der Nierenfunktion in Zusammenhang stehenden Krankheitsbilder kontrastmittelinduziertes akutes Nierenversagen (KM-induziertes ANV) und nephrogene systemische Sklerose (NSF). Literaturrecherche in PubMed und Medline uber „Nierenfunktion“ und „Kontrastmittel“, erganzt durch eigene Erfahrungen. Fur das KM-induzierte ANV erfolgt derzeit eine klinische Neubewertung, die NSF tritt unter bestimmten praventiven Masnahmen und enger Indikationsstellung aktuell nicht mehr auf. Nach aktueller Studienlage wurde das klinische Risiko eines KM-induzierten ANV lange Zeit uberschatzt und sollte keinesfalls eine KM-Gabe verhindern, wenn es keine gleichwertigen diagnostischen Alternativen gibt. Die wirksamste Prophylaxe bleibt die Vermeidung uberflussiger KM-Gaben.

Methods Levels of serum BAFF, IgG anti-BAFF and BAFF-IgG complexes were quantified by enzyme-linked immunosorbent assay. IgG anti-BAFF and BAFF-IgG complexes were further characterized using serum fractions obtained by fast protein liquid chromatography. To study the association of serum BAFF, IgG anti-BAFF and BAFF-IgG complex levels with SLE manifestations, 373 visits from 178 patients prospectively included in the Swiss SLE Cohort Study were analysed. Results While IgG anti-BAFF levels were not associated with clinical manifestations of SLE, serum BAFF levels correlated with disease activity and were higher in patients with renal involvement. Interestingly, we could also demonstrate the occurrence of BAFF-IgG complexes of different sizes in the sera of SLE patients, which were not due to treatment with belimumab and differed from complexes constructed in vitro. Most strikingly, the levels of these BAFF-IgG complexes were found to strongly correlate with overall disease activity, low complement levels and a history of lupus nephritis. Conclusion BAFF-IgG complexes strongly correlate with disease activity in SLE patients, suggesting a pathogenic role in SLE.

Transcatheter aortic valve implantation (TAVI) has evolved to a treatment of choice in high-risk patients and is therefore ideal for patients with advanced chronic kidney disease, as patients with end-stage renal disease and kidney transplant recipients. Especially, outcome of this special patient group is very important. 22 patients with chronic kidney disease stage 5 undergoing intermittent hemodialysis treatment (CKD 5D) and 8 kidney transplant recipients (KT) with severe aortic valve stenosis underwent transfemoral TAVI. TAVI was successfully performed in all patients. Postinterventional acute kidney injury (AKI) occurred in four kidney transplant recipients (KDIGO grade 1: n = 3, grade 3: n = 1) but creatinine/eGFR returned to baseline values in all patients. Short-term (30-day) mortality was 3% (1 patient in CKD 5D group). KT had a higher 2-year mortality than CKD5D patients (31% vs. 53%; p = 0.309), and cause of death was non-cardiac because of sepsis in all cases. The amount of contrast medium during TAVI was not associated with the development of acute kidney injury. TAVI is feasible in patients with CKD5D and in KT. Postinterventional AKI in these patients is often mild and does not impact renal function at day 30, while infection/ sepsis is the leading cause of mid-term mortality.

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.

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.

Background Permanent renal function decline, and development and deterioration of chronic kidney disease (CKD) are associated with serious complications. How frequent is renal function decline after infrarenal abdominal aortic aneurysm (iAAA) repair according to current definitions and what are its risk factors, especially potentially modifiable ones? Methods Retrospective observational study including all patients with elective or urgent iAAA repair from 2007 to 2011. The primary outcome was renal function decline in the first year after iAAA repair, defined as permanent reduction of estimated glomerular filtration rate (eGFR) ≥20% from baseline and/or end-stage renal disease (ESRD), all in the first year after iAAA repair. According to current Kidney Disease Improving Global Outcomes guidelines, CKD and periprocedural AKI were defined and classified. Multivariate Cox proportional hazards model was used to assess associations of the primary end point with potential risk factors. Results Two hundred sixty-eight patients with iAAA repair were studied, 61 patients (22.7%) developed declining eGFR ≥20% and/or ESRD. The primary end point was independently associated with preexisting CKD (hazard ratio [HR] 3.14 [1.61–6.09]), renal artery stenosis (RAS) ≥70% (HR 4.34 [1.49–12.67]), open aortic aneurysm repair (OAR) (HR 1.69 [1.14–2.68]), and periprocedural AKI (HR 15.25 [7.49–31.05]). When comparing the subsets of patients with and without OAR and periprocedural AKI, these 2 modifiable risk factors had an additive impact. Declining eGFR ≥20% and/or ESRD was most frequent in patients receiving OAR who developed AKI. Conclusions A permanent decline of renal function 1 year after iAAA repair is frequent. Preexisting CKD, RAS ≥70%, OAR, and periprocedural AKI are independent risk factors, the latter 2 with additive effect.

Experimental endotoxemia is a translational model to study inflammatory mechanisms involved in the pathophysiology of mood disorders including depression. Disturbed affective cognition constitutes a core aspect in depression, but has never been studied in the context of inflammation. We combined experimental endotoxemia with an established experimental mood induction procedure to assess the interaction between acute inflammation and sad mood and their effects on affective cognition. In this randomized cross-over study, N = 15 healthy males received endotoxin (0.8 ng/kg lipopolysaccharide iv) on one study day and placebo an otherwise identical study day. The affective Go/Nogo task was conducted after experimental induction of neutral and sad mood. Inflammatory markers were assessed hourly. Endotoxin application induced a transient systemic inflammation, characterized by increased leukocyte counts, TNF-alpha and interleukin-6 plasma concentrations (all p p p p

Cognitive impairment is a frequent finding in patients with chronic kidney disease (CKD). We examined cognitive performance in a prospective study of 119 patients with CKD stages 3–5 (including dialysis) and 54 control patients of the same age without CKD but with similar vascular risk profiles. Analysis included a comprehensive test battery evaluating memory, information processing speed, executive function, language, and visuoconstructive function, in addition to depression and anxiety. Thirty percent of patients with CKD had cognitive deficits (one or more s.d. below control patient performance). Cognitive deficits ( T -value related to published norm values) were mild but significantly decreased to 48.8 in patients with stage 3–5 CKD not requiring hemodialysis and 47.2 in patients with stage 5D disease requiring hemodialysis, compared with 51.5 in control patients. Linear regressions among patients with CKD (forced entry strategy) showed that age ( β =-0.50 per s.d.), HbA1c ( β =-0.18 per s.d.), and fibrinogen ( β= -0.18 per s.d.) predicted cognitive performance. Interestingly, HbA1c discriminated cognition in all age groups, while fibrinogen differentiated cognition particularly in patients over 70 years of age. Thus, our cross-sectional study suggests the severity of cognitive impairment in CKD is mild. As such, longitudinal studies are required to further characterize the role of cognitive deficits in CKD.

Background Hepatitis E virus (HEV) genotype 3 infection frequently progresses to chronic disease with persisting HEV viremia in immunocompromised patients. Here, we evaluated the prevalence of HEV infection in renal allograft recipients and investigated the efficacy and tolerability of ribavirin monotherapy. Methods A total of 947 recipients on average 8.7 years post transplant were screened for anti-HEV IgG, IgM and HEV-RNA. Sixteen HEV-viremic renal allograft recipients were treated with ribavirin for 12 weeks. HEV-RNA concentration, laboratory and clinical parameters were assessed at baseline, during therapy and 12 weeks after treatment cessation. HEV-genotyping was performed in all HEV-viremic patients. Results Past HEV infection was detected serologically in 18% of the renal allograft recipients. Ongoing HEV replication was found in 16 recipients (all genotype 3). Unanimously, distinct HEV sequences were revealed in all HEV-viremic patients. At the start of ribavirin treatment, median HEV-RNA viral load was 4.3 × 106 (8000-5.0 × 106 ) IU/mL. Ninety-four percentage of HEV-infected allograft recipients showed a sustained virological response 12 weeks after treatment cessation. Ribavirin treatment was associated with rapid decrease in liver enzymes and rare occurrence of anemia. Conclusions Prevalence of active HEV infection is important in renal transplant patients without signs of nosocomial infection. Ribavirin treatment was safe and effective.

Background Treatment of chronic hepatitis C virus (HCV) infection after renal allograft transplantation has been an obstacle because of contraindications associated with IFN-based therapies. Direct-acting antiviral agents are highly efficient treatment options that do not require IFN and may not require ribavirin. Therefore, we assessed the efficacy and safety of sofosbuvir and ledipasvir in renal transplant patients with chronic HCV infection. Methods Fifteen renal allograft recipients with therapy-naive HCV genotype (GT) 1a, 1b, or 4 were treated with the combination of sofosbuvir and ledipasvir without ribavirin for 8 or 12 weeks. Clinical data were retrospectively analyzed for viral kinetics and for renal and liver function parameters. Patients were closely monitored for trough levels of immunosuppressive agents, laboratory values, and potential adverse effects. Results Ten patients (66%) exhibited a rapid virologic response within 4 weeks (HCV GT1a, n = 4; HCV GT1b, n = 6). The other 5 patients exhibited a virologic response within 8 (HCV GT 1b, n = 4) or 12 weeks (HCV GT4, n = 1). One hundred percent of patients exhibited sustained virologic response at week 12 after the end of treatment. Clinical measures of liver function improved substantially for all patients. Adverse events were scarce; renal transplant function and proteinuria remained stable. Importantly, dose adjustments for tacrolimus were necessary for maintaining sufficient trough levels. Conclusions The described regimen appears to be safe and effective for patients after renal transplant and is a promising treatment regimen for eradicating HCV in this patient population.

Decreased β-amyloid (Aβ) clearance from the brain has been suggested to contribute to cerebral Aβ accumulation in Alzheimer’s disease. Based on the idea of a dynamic Aβ equilibrium in different body compartments, plasma Aβ levels have been investigated as biomarker candidates for preclinical Alzheimer’s pathology, yet with inconsistent results. Since the kidneys are involved in Aβ elimination from the blood, we evaluated how chronic kidney disease (CKD) affects the association between plasma Aβ and cognitive deficits and cognitive decline. In 28 CKD patients, stages 3–5D, and 26 control subjects with comparable vascular risk profile from the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, plasma total Aβ was determined with a highly sensitive electrochemiluminescence immunoassay. Cognition was evaluated using a comprehensive battery of ten neuropsychological tests at baseline and 2-year follow-up. Subjects with high plasma Aβ level (above median) demonstrated a significantly worse baseline cognitive performance than subjects exhibiting low Aβ level (summary score of global cognitive performance at baseline z = −0.46 ± 0.76 vs z = −0.08 ± 0.57, p = 0.045). Cognitive performance moderately decreased over the 2-year follow-up in subjects with high plasma Aβ level (Δz = −0.13 ± 0.51), but increased in subjects with low plasma Aβ level (Δz = 0.16 ± 0.41, p = 0.023). In linear regression analyses, baseline plasma Aβ was significantly associated with cognitive decline both in unadjusted analyses (β = −0.28, 95% CI = −0.55 to −0.01) and analyses adjusted for age (β = −0.27, 95% CI = −0.54 to −0.01). Our results suggest the utility of plasma Aβ level in predicting cognitive decline in patients suffering from CKD.

CA Becker Abstract: Skin changes are common in patients on dialysis. This study focused on putative associations of specific skin findings with comorbidities and mortality. We performed a retrospective analysis of data from 508 patients on maintenance hemodialysis therapy in 7 centers in the German State of North Rhine Westphalia. Data had been collected by interview, from patient files, and from targeted physical examination in an earlier prospective study screening hemodialysis patients for the presence of nephrogenic systemic fibrosis. While on dialysis, patients’ extremities had been examined for any of the following: edematous skin at the lower extremities, hyperpigmentation, induration, and xerosis cutis. Our present data analyses focused on associated mortality and comorbidities. Five hundred eight patients (median age 71 years, range 20.0–95.9; n = 292 men) had agreed to participate in the initial study: 48% (n = 243) were diabetics and 46% (n = 232) had been diagnosed with coronary heart disease. On examination, 86% of patients (n = 439) presented with at least 1 of the prespecified skin changes. Skin edema (n = 89; 18%), hyperpigmentation (n = 74; 15%), and induration (n = 9; 2%) were independently associated with increased mortality over 24 months (P < 0.002, P < 0.030, and P < 0.020, respectively). In our study, prespecified skin changes indicated an increased mortality risk in patients on chronic hemodialysis. Routinely assessing the skin of dialysis patients represents a simple, reliable, and cost effective means of identifying those at greatest risk.

Item does not contain fulltext BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.

Disturbed brain-to-blood elimination of β-amyloid (Aβ) promotes cerebral Aβ accumulation in Alzheimer’s disease. Considering that the kidneys are involved in Aβ elimination from the blood, we evaluated how chronic kidney disease (CKD) affects plasma Aβ. In 106 CKD patients stages 3–5 (including 19 patients on hemodialysis and 15 kidney recipients), 53 control subjects with comparable vascular risk profile and 10 kidney donors, plasma Aβ was determined using electrochemiluminescence immunoassay and gel electrophoresis followed by Western blotting. Plasma Aβ increased with CKD stage (control = 182.98 ± 76.73 pg/ml; CKD3A = 248.34 ± 103.77 pg/ml; CKD3B = 259.25 ± 97.74 pg/ml; CKD4 = 489.16 ± 154.16 pg/ml; CKD5 = 721.19 ± 291.69 pg/ml) and was not influenced by hemodialysis (CKD5D = 697.97 ± 265.91 pg/ml). Renal transplantation reduced plasma Aβ (332.57 ± 162.82 pg/ml), whereas kidney donation increased it (251.51 ± 34.34 pg/ml). Gel electrophoresis confirmed stage-dependent elevation namely of Aβ1-40, the most abundant Aβ peptide. In a multivariable regression including age, sex, estimated glomerular filtration rate (eGFR), potassium, hemoglobin, urine urea, and urine total protein, the factors eGFR (β = −0.42, p

Background As kidney and brain functions decline with aging, chronic kidney disease (CKD) and dementia are becoming increasing health burdens worldwide. Among the risk factors for cognitive impairment, CKD is increasingly recognized. The precise impact of CKD on the development of cognitive impairment is poorly understood. Methods In the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, which was recruited in a dedicated nephrology department, we examined the 2-year course of cognitive performance in 120 patients (73 patients with CKD stages 3–5D, 47 control patients without CKD with similar vascular risk profile) using a comprehensive battery of 10 neuropsychological tests. Results Kidney function, vascular risk factors and cognitive performance were highly stable both in CKD and control patients. The summary score of cognitive performance in CKD patients was very similar at baseline (z = -0.63±0.76) and follow-up (z = -0.54±0.79, p = 0.113), as was cognitive performance in control patients (z = -0.01±0.59 and 0.01±0.70, p = 0.862, at baseline and follow-up, respectively). Total serum cholesterol (199.6±36.0 and 186.0±32.9, p = 0.005 in controls; 194.4±46.1 and 181.2±41.2, p = 0.008 in CKD) and common carotid intima-media thickness (0.87±0.18 and 0.84±0.17, p = 0.351 in controls; 0.88±0.21 and 0.82±0.16, p = 0.002 in CKD) moderately but significantly decreased during the follow-up. In multivariable regression analyses, high age (β = -0.28, 95%CI = -0.48 to 0.08, p = 0.007) predicted decrease in cognitive performance. Conclusions In this well-defined cohort receiving state-of-the-art therapy, cognitive performance did not decrease over 2 years. Our data emphasize the aspect of risk factor control, suggesting that dedicated medical care might prevent cognitive decline in CKD patients.