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BACKGROUND: Rigid age limits in the current allocation system for post-mortem donor kidneys in Germany may have problematic effects. The new German national transplantion registry enables data analysis with respect to this question. METHODS: Using anonymized data from the German national transplantion registry, we extracted and evaluated information on the recipients and postmortem donors of kidneys that were allocated in Germany through Eurotransplant over the period 2006-2020. RESULTS: Data on 19 664 kidney transplantations in Germany from 2006 to 2020 were analyzed. The median waiting time for kidney transplantation was 5.8 years. Persons under age 18 waited a median of 1.7 years; persons aged 18 to 64, 7.0 years; and persons aged 65 and older, 3.8 years. Over the period of observation, post-mortem kidneys were transplanted into 401 people of age 64 (2.0% of all organ recipients) and 1,393 people of age 65 (7.1% of all organ recipients). The difference in waiting times between allocation programs for persons under age 65 (ETKAS, "Eurotransplant Kidney Allocation System") and those aged 65 and older (ESP, "Eurotransplant Senior Program") increased over the period of observation, from 2.6 years in 2006-2010 to 4.1 years in 2017-2020. CONCLUSION: The rigid age limits in the current allocation rules for post-mortem kidney donations in Germany are prolonging the waiting times for transplants among patients aged 18 to 64. We think these rules need to be fundamentally reassessed.
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Background: Motor mapping allows for determining the macroscopic organization of motor circuits and corresponding motor movement representations on the cortex. Techniques such as intracortical microstimulation (ICMS) are robust, but can be time consuming and invasive, making them non-ideal for cortex-wide mapping or longitudinal studies. In contrast, optogenetic motor mapping offers a rapid and minimally invasive technique, enabling mapping with high spatiotemporal resolution. However, motor mapping has seen limited use in tracking 3-dimensonal, multi-limb movements in awake animals. This gap has left open questions regarding the underlying organizational principles of motor control of coordinated, ethologically relevant movements involving multiple limbs. Objective: Our first objective was to develop Multi-limb Optogenetic Motor Mapping (MOMM) to concurrently map motor movement representations of multiple limbs with high fidelity in awake mice. Having established MOMM, our next objective was determine whether maps of coordinated and ethologically relevant motor output were topographically organized on the cortex. Methods: We combine optogenetic stimulation with a deep learning driven pose-estimation toolbox, DeepLabCut (DLC), and 3-dimentional triangulation to concurrently map motor movements of multiple limbs in awake mice. Results: MOMM consistently revealed cortical topographies for all mapped features within and across mice. Many motor maps overlapped and were topographically similar. Several motor movement representations extended beyond cytoarchitecturally defined somatomotor cortex. Finer articulations of the forepaw resided within gross motor movement representations of the forelimb. Moreover, many cortical sites exhibited concurrent limb coactivation when photostimulated, prompting the identification of several cortical regions harboring coordinated and ethologically relevant movements. Conclusions: The cortex appears to be topographically organized by motor programs, which are responsible for coordinated, multi-limbed, and behavioral-like movements.
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There are various dialysis methods available to treat patients with chronic kidney failure. Generally, a distinction is made between peritoneal dialysis and hemodialysis, as well as between home dialysis methods and center-based dialysis methods. To be able to advise patients optimally, it is important to understand the opportunities and limitations of the different method variants. This article provides an overview of the therapy options and describes their strengths and weaknesses.
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Hemodiálise no Domicílio , Falência Renal Crônica , Diálise Peritoneal , Diálise Renal , Humanos , Hemodiálise no Domicílio/métodos , Falência Renal Crônica/terapia , Diálise Renal/métodos , Diálise Peritoneal/métodosRESUMO
One possible pathway toward reducing the cost of III-V solar cells is to remove them from their growth substrate by spalling fracture, and then reuse the substrate for the growth of multiple cells. Here we consider the growth of III-V cells on spalled GaAs(100) substrates, which typically have faceted surfaces after spalling. To facilitate the growth of high-quality cells, these faceted surfaces should be smoothed prior to cell growth. In this study, we show that these surfaces can be smoothed during organometallic vapor-phase epitaxy growth, but the choice of epilayer material and modification of the various surfaces by impurities/dopants greatly impacts whether or not the surface becomes smooth, and how rapidly the smoothing occurs. Representative examples are presented along with a discussion of the underlying growth processes. Although this work was motivated by solar cell growth, the methods are generally applicable to the growth of any III-V device on a nonplanar substrate.
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Doença Antimembrana Basal Glomerular , Técnicas de Imunoadsorção , Troca Plasmática , Humanos , Doença Antimembrana Basal Glomerular/terapia , Doença Antimembrana Basal Glomerular/imunologia , Troca Plasmática/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Alemanha , Idoso , Resultado do TratamentoRESUMO
BACKGROUND: Peritoneal dialysis (PD) remains underutilised in Germany, prompting the initiation of the Sustainable Intensification of Peritoneal Dialysis in Schleswig-Holstein (SKIP-SH) project. The SKIP-SH cohort study aims to demonstrate the presumed benefits of PD, including enhanced quality of life and reduced healthcare personnel requirements, and to generate data to strengthen the use of PD. METHODS: The prospective SKIP-SH cohort study recruits patients with advanced chronic kidney disease (CKD) and their caregivers. Comprehensive data, including demographic information, medical history, clinical course, laboratory data, and quality-of-life assessments, are collected. Additionally, biomaterials will be obtained. Primary study objectives are documenting the clinical course and complications, time on therapy for new dialysis patients, reasons influencing treatment modality choices, circumstances at the initiation of dialysis, and quality of life for patients with CKD and their caregivers. The collected biomaterials will serve as a basis for further translational research. Secondary objectives include identifying factors impacting disease-related quality of life, clinical complications, and therapy dropout, estimating ecological footprints, and evaluating healthcare costs and labour time for initiating and sustaining PD treatment. DISCUSSION: PD is notably underutilised in Germany. The current therapy approach for advanced CKD often lacks emphasis on patient-focused care and quality-of-life considerations. Furthermore, adequate explorative research programs to improve our knowledge of mechanisms leading to disease progression and therapy failure in PD patients are scarce. The overarching goal of the SKIP-SH cohort study is to address the notably low PD prevalence in Germany whilst advocating for a shift towards patient-focused care, quality-of-life considerations, and robust translational research. TRIAL REGISTRATION: This study was registered with the German trial registry (Deutsches Register klinischer Studien) on November 7, 2023, under trial number DRKS00032983.
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Falência Renal Crônica , Diálise Peritoneal , Insuficiência Renal Crônica , Humanos , Diálise Renal/efeitos adversos , Falência Renal Crônica/epidemiologia , Estudos de Coortes , Qualidade de Vida , Estudos Prospectivos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Progressão da Doença , Materiais BiocompatíveisRESUMO
Chlorine gas (Cl2) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. Modeling the human etiology of Cl2-induced acute lung injury (ALI), forensic biomarkers, and targeted countermeasures development have been hampered by inadequate large animal models. The objective of this study was to develop a translational model of Cl2-induced ALI in swine to understand toxico-pathophysiology and evaluate whether it is suitable for screening potential medical countermeasures and to identify biomarkers useful for forensic analysis. Specific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl2 (≤240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. Exposure to Cl2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Cl2 exposure resulted in increased total leucocyte and neutrophil counts in bronchoalveolar lavage fluid, vascular leakage, and pulmonary edema compared with the air-exposed group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-l-tyrosine and 3,5-dichloro-l-tyrosine) were detected in plasma and lung tissue after Cl2 exposure. In this study, we developed a translational swine model that recapitulates key features of human Cl2 inhalation injury and is suitable for testing medical countermeasures, and validated chlorinated fatty acids and protein adducts as biomarkers of Cl2 inhalation.NEW & NOTEWORTHY We established a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute lung injury and is suitable for screening potential medical countermeasures. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers of chlorine inhalation.
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Lesão Pulmonar Aguda , Cloro , Humanos , Animais , Suínos , Cloro/toxicidade , Cloro/metabolismo , Pulmão/metabolismo , Líquido da Lavagem Broncoalveolar , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Biomarcadores/metabolismo , Ácidos Graxos/metabolismoRESUMO
BACKGROUND: Kidney graft rejections are classified based on the Banff classification. The RejectClass algorithm, initially derived from a cohort comprising mostly protocol biopsies, identifies data-driven phenotypes of acute rejection and chronic pathology using Banff lesion scores. It also provides composite scores for inflammation activity and chronicity. This study independently evaluates the performance of RejectClass in a cohort consisting entirely of indication biopsies. METHODS: We retrospectively applied RejectClass to 441 patients from the German TRABIO (TRAnsplant BIOpsies) cohort who had received indication biopsies. The primary endpoint was death-censored graft failure during 2 y of follow-up. RESULTS: The application of RejectClass to our cohort demonstrated moderately comparable phenotypic features with the derivation cohort, and most clusters indicated an elevated risk of graft loss. However, the reproduction of all phenotypes and the associated risks of graft failure, as depicted in the original studies, was not fully accomplished. In contrast, adjusted Cox proportional hazards analyses substantiated that both the inflammation score and the chronicity score are independently associated with graft loss, exhibiting hazard ratios of 1.7 (95% confidence interval, 1.2-2.3; P = 0.002) and 2.2 (95% confidence interval, 1.8-2.6; P < 0.001), respectively, per 0.25-point increment (scale: 0.0-1.0). CONCLUSIONS: The composite inflammation and chronicity scores may already have direct utility in quantitatively assessing the disease stage. Further refinement and validation of RejectClass clusters are necessary to achieve more reliable and accurate phenotyping of rejection.
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Rejeição de Enxerto , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Biópsia , Sobrevivência de Enxerto , Algoritmos , Fatores de Risco , Fenótipo , Modelos de Riscos Proporcionais , Doença Aguda , Rim/fisiopatologia , Rim/patologia , Reprodutibilidade dos Testes , Alemanha/epidemiologia , Medição de Risco , Idoso , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
We couple halide vapor phase epitaxy (HVPE) growth of III-V materials with liftoff from an ultrathin carbon release layer to address two significant cost components in III-V device - epitaxial growth and substrate reusability. We investigate nucleation and growth of GaAs layers by HVPE on a thin amorphous carbon layer that can be mechanically exfoliated, leaving the substrate available for reuse. We study nucleation as a function of carbon layer thickness and growth rate and find island-like nucleation. We then study various GaAs growth conditions, including V/III ratio, growth temperature, and growth rate in an effort to minimize film roughness. High growth rates and thicker films lead to drastically smoother surfaces with reduced threading dislocation density. Finally, we grow an initial photovoltaic device on a carbon release layer that has an efficiency of 7.2%. The findings of this work show that HVPE growth is compatible with a carbon release layer and presents a path toward lowering the cost of photovoltaics with high throughput growth and substrate reuse.
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BACKGROUND: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries. METHODS: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods. RESULTS: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y. CONCLUSIONS: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.
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Introduction: The time from dialysis onset to enrollment on the kidney waiting list (listing time) is a crucial step on the path to receiving a kidney allograft; however, this process has received very little research attention in the Eurotransplant (ET) area. Methods: We retrospectively analyzed data from the German transplantation registry, including patients who were on the waiting list for a first kidney transplant in Germany between 2006 and 2016. Listing time was evaluated using a mixed linear model. The outcomes on the kidney waiting list were assessed using competing risk analyses. Results: We assessed a total of 43,955 patients. Listing occurred at a higher pace in patients receiving living donor transplantations (median 0.4 years from dialysis onset) than in deceased donor transplantations (Eurotransplant Kidney Allocation System [ETKAS] 1.1 years, European Senior Program [ESP] 1.4 years, Acceptable Mismatch program 1.3 years), with 28.5% of living donor transplantations performed preemptively. There was only modest variation in listing time between the transplant centers. Patients with a history of viral infection, high immunization; hemodialysis patients; and patients with a higher body mass index (BMI) had a delayed listing process. Two of 3 patients listed in the ETKAS, excluding those with potential bonus points (pediatric, other organ transplantations), were eventually transplanted. Older patients, male patients, patients with blood type O, and patients with diabetic nephropathy as the underlying renal disease had the highest risk not to proceed to transplantation. Conclusion: Although long waiting times remain the biggest hurdle for transplantation in Germany, there is ample room for improvement of the listing process.
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BACKGROUND: Outcome data regarding clinically relevant endpoints after starting dialysis for end-stage renal disease (ESRD) are sparse, and early events after starting dialysis are particularly underestimated. The aim of this study was to describe patient-focused outcomes in ESRD patients starting from first dialysis. METHODS: The data basis for this retrospective observational study were anonymized healthcare data from Germany's largest statutory health insurer. We identified ESRD patients who initiated dialysis in 2017. Deaths, hospitalizations and occurrence of functional impairment within 4 years after starting dialysis were recorded starting from first treatment. Hazard ratios in dialysis patients compared with an age- and sex-matched reference population without dialysis were generated, stratified by age. RESULTS: The dialysis cohort included 10 328 ESRD patients who started dialysis in 2017. First dialysis was performed in-hospital for 7324 patients (70.9%), and 865 of these died during the same hospitalization. One-year mortality for ESRD patients initiating dialysis was 33.8%. Functional impairment occurred in 27.1% of patients, while 82.8% of patients required hospitalization within 1 year. Hazard ratios of dialysis patients compared with the reference population for mortality, functional impairment and hospitalization at 1-year were 8.6, 4.3 and 6.2. Dialysis patients <50 years were disproportionately affected, with >40-fold increased risk of adverse events compared with their peers. CONCLUSIONS: The emergence of morbidity and mortality after starting dialysis for ESRD is significant, especially in younger patients. Patients have a right to be informed about the prognosis associated with their condition.
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Falência Renal Crônica , Diálise Renal , Humanos , Diálise Renal/efeitos adversos , Falência Renal Crônica/complicações , Hospitalização , Estudos Retrospectivos , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Early-on post kidney transplantation, there is a high risk of graft rejection and opportunistic viral infections. A low tacrolimus concentration/dose (C/D) ratio as a surrogate marker of fast tacrolimus metabolism has been established for risk stratification 3 months post-transplantation (M3). However, many adverse events occurring earlier might be missed, and stratification at 1 month post-transplantation (M1) has not been investigated. We retrospectively analyzed case data from 589 patients who had undergone kidney transplantation between 2011 and 2021 at three German transplant centers. Tacrolimus metabolism was estimated by use of the C/D ratio at M1, M3, M6, and M12. C/D ratios increased substantially during the year, particularly between M1 and M3. Many viral infections and most graft rejections occurred before M3. Neither at M1 nor at M3 was a low C/D ratio associated with susceptibility to BKV viremia or BKV nephritis. A low C/D ratio at M1 could not predict acute graft rejections or impaired kidney function, whereas at M3 it was significantly associated with subsequent rejections and impairment of kidney function. In summary, most rejections occur before M3, but a low C/D ratio at M1 does not identify patients at risk, limiting the predictive utility of this stratification approach.
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Transplante de Rim , Tacrolimo , Humanos , Tacrolimo/efeitos adversos , Transplante de Rim/efeitos adversos , Imunossupressores/efeitos adversos , Estudos Retrospectivos , Rejeição de EnxertoRESUMO
Introduction: Macrophages and monocytes are main players in innate immunity. The relevance of mononuclear phagocyte infiltrates on clinical outcomes remains to be determined in native kidney diseases. Methods: Our cross-sectional study included 324 patients with diagnostic renal biopsies comprising 17 disease entities and normal renal tissues for comparison. All samples were stained for CD68+ macrophages. Selected groups were further subtyped for CD14+ monocytes and CD163+ alternatively activated macrophages. Using precise pixel-based digital measurements, we quantified cell densities as positively stained areas in renal cortex and medulla as well as whole renal tissue. Laboratory and clinical data of all cases at the time of biopsy and additional follow-up data in 158 cases were accessible. Results: Biopsies with renal disease consistently revealed higher CD68+-macrophage densities and CD163+-macrophage densities in cortex and medulla compared to controls. High macrophage densities correlated with impaired renal function at biopsy and at follow-up in all diseases and in diseases analyzed separately. High cortical CD68+-macrophage densities preceded shorter renal survival, defined as requirement of permanent dialysis. CD14+ monocyte densities showed no difference compared to controls and did not correlate with renal function. Conclusion: Precise quantification of macrophage densities in renal biopsies may contribute to risk stratification to identify patients with high risk for end-stage renal disease (ESRD) and might be a promising therapeutic target in renal disease.
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BACKGROUND: The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety. OBJECTIVES: This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting. METHODS: We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls). RESULTS: Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%. CONCLUSION: Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www. CLINICALTRIALS: gov as #NCT04985318.
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Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Anticorpos de Domínio Único , Trombose , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Proteína ADAMTS13RESUMO
We retrospectively analysed all German inpatient cases of haemophagocytic lymphohistiocytosis (HLH) from 2014 to 2020 to describe the epidemiology, clinical course, and underlying diseases of 4065 HLH patients. The age-standardized incidence rate of HLH in Germany was 0.52/100 000 people in 2014 and steadily increased by 10% per year to 0.97/100 000 in 2020 (mean 0.70/100 000). Inpatient deaths related to HLH increased from 0.84/1 000 000 people in 2014 to 2.32/1 000 000 people in 2020, caused by rising numbers of older HLH patients. Overall, HLH is more frequent than previously expected and incidence as well as HLH-related deaths increased significantly.
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Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Estudos Retrospectivos , Alemanha/epidemiologiaRESUMO
Background: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infectious disease of immunocompromised patients. Its incidence has decreased worldwide in the past, but data concerning its recent epidemiology are lacking. Methods: We retrospectively analyzed all German inpatient cases from January 1, 2014 to December 31, 2019, to describe the recent epidemiology, incidence, clinical course, mortality and underlying diseases of PCP. Simultaneously, we conducted a retrospective multi-center study at two German university hospitals, and analyzed PCP cases treated there to gain deeper insights on the basis of primary patient data. Findings: The incidence of PCP significantly increased from 2·3 to 2·6 per 100,000 population from 2014 to 2019 (1,857 to 2,172 cases, +17·0%, p < 0·0001), as well as PCP-related deaths (516 to 615 cases, +19·2%, p = 0·011). The spectrum of underlying diseases changed: Risk groups with established chemoprophylaxis for PCP based on international guidelines (HIV, hematologic malignancies, and transplantation) showed a significant decrease in PCP cases and deaths. Others, especially those with solid malignancies, and autoimmune and pulmonary diseases showed a significant increase in case numbers and deaths. Data from the retrospective multi-center study added information regarding prophylaxis and diagnostics of PCP. Interpretation: The incidence of PCP has reversed its trend, showing a significant increase in mortality on population level. Patients who were not previously considered in prophylactic measures are increasingly affected by PCP. This development deserves further investigation, and additional comprehensive guidelines for the use of chemoprophylaxis in new risk groups are needed. Funding: Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Kiel.
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INTRODUCTION: Despite continued efforts, long-term outcomes of kidney transplantation remain unsatisfactory. Kidney graft rejections are independent risk factors for graft failure. At the participating centres of the TRAnsplant BIOpsies study group, a common therapeutic standard has previously been defined for the treatment of graft rejections. The outcomes of this strategy will be assessed in a prospective, observational cohort study. METHODS AND ANALYSIS: A total of 800 kidney transplantation patients will be enrolled who undergo a graft biopsy because of deteriorating kidney function. Patients will be stratified according to the Banff classification, and the influence of the treatment strategy on end points will be assessed using regression analysis. Primary end points will be all-cause mortality and graft survival. Secondary end points will be worsening of kidney function (≥30% decline of estimated Glomerular Filtration Rate [eGFR] or new-onset large proteinuria), recurrence of graft rejection and treatment response. Baseline data and detailed histopathology data will be entered into an electronic database on enrolment. During a first follow-up period (within 14 days) and subsequent yearly follow-ups (for 5 years), treatment strategies and clinical course will be recorded. Recruitment at the four participating centres started in September 2016. As of August 2020, 495 patients have been included. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the ethics committee of Kiel (AZ B 278/16) and was confirmed by the committees of Munich, Mainz and Stuttgart. The results will be reported in a peer-reviewed journal, according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria. TRIAL REGISTRATION NUMBER: ISRCTN78772632; Pre-results.