Sichere Shuntchirurgie - aus der Sicht des Nephrologen

Hintergrund: Aufgrund des zunehmenden Alters und der Komorbiditäten der Dialysepatienten haben sich die Voraussetzungen für Dialysezugänge und für eine sichere Shuntchirurgie verändert. Fragestellung: Welchen Beitrag leistet der Nephrologe zur Sicherheit der Versorgung von Patienten mit chronischer Niereninsuffizienz mit Dialysezugängen? Material und Methodik: Erfahrungsbericht und Literaturübersicht von Nephrologen, eingebettet in ein interdisziplinäres Team für Gefäßzugänge. Ergebnisse: Eine wesentliche Komponente für eine sichere Shuntchirurgie ist die zeitgerechte Planung und Anlage des optimalen Gefäßzugangs. Der Patient steht hier im Zentrum und entscheidet die Art der Dialyse. Dem interdisziplinären Team an behandelnden Ärzten (Hausarzt, Nephrologe, Angiologe, interventioneller Radiologe, Gefäßchirurg) kommt die Aufgabe einer zeitgerechten Planung und Durchführung des Eingriffs zu. Schließlich muss die Reifung des Shunts postoperativ überwacht werden. Schlussfolgerung: Für die Sicherheit des Patienten ist sowohl die Entscheidung für den richtigen Zugang als auch der richtige Zeitpunkt von Bedeutung. Um den Trend der häufigen Nutzung von Kathetern entgegen zu wirken, ist zukünftig eine noch frühere Planung notwendig. Background: The population of patients in need of renal replacement therapy has changed with an increase in age and a rising number of comorbidities. Therefore, the prerequisites for a vascular access for hemodialysis have become less favorable and the risk for the patient has increased. Objective: What is the role of the nephrologist for a safe access placement in patients with chronic renal insufficiency? Material and methods: A literature search was carried out and descriptions of experiences of nephrologists working in an interdisciplinary vascular access team were included. Results: Nephrologists play a pivotal role in the timely patient education and planning of an optimal vascular access. The decision of the patient defines the type of dialysis to be used. The nephrologist together with the interdisciplinary vascular access team (general practitioner, angiologist, interventional radiologist and vascular surgeon) decides on the best access, depending on the clinical needs, clinical examination and duplex sonography mapping. Timely planning of access creation and surveillance after surgery are important tasks for the nephrologist. Conclusion: For the safety of the patient the decision for the best access and correct timing are of pivotal importance. To reduce the number of catheters it will probably be necessary to start with the planning of a vascular access earlier in the future

HLA antibodies are associated with deterioration of kidney allograft function irrespective of donor specificity

BACKGROUND Donor-specific antibodies are associated with high immunological risk and poor allograft outcome. Risk and clinical relevance of non-donor-specific HLA antibodies is less clear. METHODS A retrospective single-center study was conducted in all patients receiving a first kidney transplant at the University hospital of Zürich between 01/2006 and 02/2015. Patients were stratified into 3 groups having either no HLA antibodies at all (NoAB), HLA antibodies with donor specificity (DSA) and HLA antibodies without donor specificity (NonDSA). Allograft outcome was assessed using the slope of the estimated glomerular filtration rate (eGFR slope) starting at 12 months after transplantation. RESULTS During a median follow-up of 1808 days HLA antibodies were detected in 106 of 238 eligible patients (44%). Out of these, 73 patients (69%) had DSA and 33 patients (31%) had NonDSA only. Medium-term allograft function, as determined by eGFR slope over three years, improved in patients with NoAB (months 12-48: +0.7 ml/min/1.73 m$^{2}$) but deteriorated significantly in patients with both DSA (months 12-48: -1.5 ml/min per1.73 m$^{2}$/year, p = 0.015) and NonDSA (months 12-48: -1.8 ml/min per1.73 m$^{2}$/year, p = 0.03) as compared to the group with NoAB. CONCLUSION Both, donor-specific and non-donor-specific HLA antibodies are associated with medium-term kidney allograft dysfunction as compared to patients with no HLA antibodies

Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

Survival of lymphocytes and melanocyte stem cells critically depends on B cell lymphoma 2 (Bcl-2). In T lymphocytes, a basal calcineurin activity maintains Bcl-2 expression in naïve cells, and the activation of the calcineurin pathway orchestrates the regulation of the intrinsic apoptosis pathway after antigen recognition. Therefore, calcineurin inhibitors might potentiate the pro-apoptotic effect of pharmacological Bcl-2 inhibitors on lymphatic cells. In vitro, a reduced Bcl-2 expression in lymphocytes exposed to calcineurin inhibitors increased their sensitivity to the small molecule Bcl-2 inhibitor ABT-737. This correlated with an augmented pro-apoptotic activity of ABT-737 on lymphocytes in combination with cyclosporine A in naïve mice in vivo. Interestingly, similar processes were observed in melanocytes. ABT-737 induced a fur depigmentation at the site of injection, and this effect was expanded to a generalized depigmentation in combination with cyclosporine A. Thus, inhibiting calcineurin increases the pro-apoptotic potency of ABT-737 in cells depending on Bcl-2 for survival. The increased efficacy of Bcl-2 inhibitors in combination with cyclosporine A might be relevant to exploit their anti-neoplastic and immuno-modulatory propertie

Ambient temperature and kidney function in primary care patients

Introduction Exposure to high ambient temperatures is associated with a risk of acute kidney injury. However, evidence comes from emergency departments or extreme weather exposures. It is unclear whether temperature-related adverse kidney outcomes can also be detected at a community level in a temperate climate zone. Methods In a 9.5-year retrospective cohort study we correlated estimated glomerular filtration rate (eGFR) values of Swiss adult primary care patients from the FIRE cohort (Family medicine Research using Electronic medical records) with same-day maximum local ambient temperature data. We investigated 5 temperature groups (< 15 °C, 15–19 °C, 20–24 °C, 25–29 °C and  ≥ 30 °C) as well as possible interactions for patients with increased kidney vulnerability (chronic heart failure, diabetes, chronic kidney disease, therapy with renin–angiotensin–aldosterone-system (RAAS) inhibitors, diuretics or non-steroidal anti-inflammatory drugs). Results We included 18,000 primary care patients who altogether provided 132,176 creatinine measurements. In the unadjusted analysis, higher ambient temperatures were associated with lower eGFR across all age and vulnerability groups. In the adjusted models, we did not find a consistent association.The highest ambient temperature differences (> 25 or > 30 versus < 15 °C) were associated with marginally reduced kidney function only in patients with ≥ 3 risk factors for kidney vulnerability, with a maximum estimated glomerular filtration rate reduction of −2.9 ml/min/1.73m$^{2}$ (SE 1.0), P 0.003. Discussion In a large primary care cohort from a temperate climate zone, we did not find an association between ambient temperatures and kidney function. A marginal inverse association in highly vulnerable patients is of unclear clinical relevance

Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846). Keywords: COVID - 19; chimerism; hematopoietic stem cell transplantation (HSCT); immunocompetence; kidney transplantation; toleranc

Immune monitoring-guided vs fixed duration of antiviral prophylaxis against cytomegalovirus in solid-organ transplant recipients. A Multicenter, Randomized Clinical Trial

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T-cell-mediated immunity may individualize the duration of antiviral prophylaxis in transplant recipients. METHODS: In this open-label randomized trial, adult kidney and liver transplant recipients from six centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving anti-thymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune-monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV-specific interferon gamma release assay (T-Track® CMV); prophylaxis in the intervention group was stopped if the assay was positive. The primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring and 101 in the control group) of which 185 had evaluation of the primary endpoint (87 and 98 patients, respectively). Clinically significant CMV infection occurred in 26/87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32/98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference -0.1, 95%CI -13.0%, 12.7%; p = 0.064). The duration of antiviral prophylaxis was shorter in the immune-monitoring group (adjusted difference -26.0 days, 95%-CI -41.1 to -10.8 days, p < 0.001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary endpoint of CMV infection

Immune monitoring-guided vs fixed duration of antiviral prophylaxis against cytomegalovirus in solid-organ transplant recipients. A Multicenter, Randomized Clinical Trial.

BACKGROUND The use of assays detecting cytomegalovirus (CMV)-specific T-cell-mediated immunity may individualize the duration of antiviral prophylaxis in transplant recipients. METHODS In this open-label randomized trial, adult kidney and liver transplant recipients from six centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving anti-thymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune-monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV-specific interferon gamma release assay (T-Track® CMV); prophylaxis in the intervention group was stopped if the assay was positive. The primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS Overall, 193 patients were randomized (92 in the immune-monitoring and 101 in the control group) of which 185 had evaluation of the primary endpoint (87 and 98 patients, respectively). Clinically significant CMV infection occurred in 26/87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32/98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference -0.1, 95%CI -13.0%, 12.7%; p = 0.064). The duration of antiviral prophylaxis was shorter in the immune-monitoring group (adjusted difference -26.0 days, 95%-CI -41.1 to -10.8 days, p < 0.001). CONCLUSIONS Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary endpoint of CMV infection