Publications by authors named "Christoph Schmaderer"

84 Publications

[COVID-19 pandemic: preferences and barriers for dissemination of evidence syntheses : Survey of intensive care personnel in Germany].

Anaesthesist 2021 Sep 21. Epub 2021 Sep 21.

Klinik und Poliklinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie, Universitätsklinikum Würzburg, Würzburg, Deutschland.

Background: In the context of COVID-19, the German CEOsys project (COVID-19 Evidenz Ökosystem, www.covid-evidenz.de ) identifies, evaluates and summarizes the results of scientific studies to obtain evidence on this disease. The evidence syntheses are used to derive specific recommendations for clinical practice and to contribute to national guidelines. Besides the necessity of conducting good quality evidence syntheses during a pandemic, just as important is that the dissemination of evidence needs to be quick and efficient, especially in a health crisis. The CEOsys project has set itself this challenge.

Objective: Preparing the most suitable distribution of evidence syntheses as part of the CEOsys project tasks.

Methods: Intensive care unit (ICU) personnel in Germany were surveyed via categorical and free text questions. The survey focused on the following topics: evidence syntheses, channels and strategies of distribution, possibility of feedback, structure and barriers of dissemination and trustworthiness of various organizations. Profession, qualification, setting and size of the facility were recorded. Questionnaires were pretested throughout the queried professions (physician, nurse, others). The survey was anonymously carried out online through SosciSurvey® and an e‑mail was sent directly to 940 addresses. The survey was launched on 3 December, a reminder was sent after 14 days and it ended on 31 December. The survey was also announced via e‑mail through DIVI.

Results: Of 317 respondents 200 completed the questionnaire. All information was analyzed including the responses from incomplete questionnaires. The most stated barriers were lack of time and access. Especially residents and nurses without specialization in intensive care mentioned uncertainty or insufficient experience in dealing with evidence syntheses as a barrier. Active distribution of evidence syntheses was clearly preferred. More than half of the participants chose websites of public institutions, medical journals, professional societies and e‑mail newsletters for drawing attention to new evidence syntheses. Short versions, algorithms and webinars were the most preferred strategies for dissemination. Trust in organizations supplying information on the COVID-19 pandemic was given to professional societies and the Robert Koch Institute (RKI) as the German governmental institute for infections and public health. The respondents' prioritized topics are long-term consequences of the disease, protection of medical personnel against infection and possibilities of ventilation treatment.

Conclusion: Even though universally valid, evidence syntheses should be actively brought to the target audience, especially during a health crisis such as the COVID-19 pandemic with its exceptional challenges including lack of time and uncertainties in patient care. The contents should be clear, short (short versions, algorithms) and with free access. E‑mail newsletters, websites or medical journals should continuously report on new evidence syntheses. Professional societies and the governmental institute for infections and public health should be involved in dissemination due to their obvious trustworthiness.
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http://dx.doi.org/10.1007/s00101-021-01037-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454015PMC
September 2021

SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19.

Cochrane Database Syst Rev 2021 09 2;9:CD013825. Epub 2021 Sep 2.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19).

Objectives: To assess the effectiveness and safety of SARS-CoV-2-neutralising mAbs for treating patients with COVID-19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS-CoV-2-targeting mAbs from first tests in humans onwards.  SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane COVID-19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)-only search on 30 July 2021.

Selection Criteria: We included studies that evaluated SARS-CoV-2-neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID-19. We excluded studies on prophylactic use of SARS-CoV-2-neutralising mAbs.

Data Collection And Analysis: Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all-cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE.

Main Results: We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non-hospitalised participants, and 61 years in two studies of hospitalised participants. Non-hospitalised individuals with COVID-19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision).  Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3-4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3-4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16).  Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3-4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs.  Hospitalised individuals with COVID-19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included.   Bamlanivimab compared to placebo  We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3-4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported.  AUTHORS' CONCLUSIONS: The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs. Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences.
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http://dx.doi.org/10.1002/14651858.CD013825.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411904PMC
September 2021

COVID-19 Vaccination Acceptance and Hesitancy among Healthcare Workers in Germany.

Vaccines (Basel) 2021 Jul 12;9(7). Epub 2021 Jul 12.

Department of Nephrology, School of Medicine, Technical University of Munich, Klinikum Rechts der Isar, 81675 Munich, Germany.

Vaccination hesitancy is a threat to herd immunity. Healthcare workers (HCWs) play a key role in promoting Coronavirus disease 2019 (COVID-19) vaccination in the general population. We therefore aimed to provide data on COVID-19 vaccination acceptance/hesitancy among German HCWs. For this exploratory, cross-sectional study, an online survey was conducted in February 2021. The survey included 54 items on demographics; previous vaccination behavior; trust in vaccines, physicians, the pharmaceutical industry and health politics; fear of adverse effects; assumptions regarding the consequences of COVID-19; knowledge about vaccines; and information seeking behavior. Odds ratios with 95% confidence intervals were calculated and chi-square tests were performed. Four thousand five hundred surveys were analyzed. The overall vaccination acceptance was 91.7%. The age group ≤20 years showed the lowest vaccination acceptance. Factors associated with vaccination hesitancy were lack of trust in authorities and pharmaceutical companies. Attitudes among acquaintances were associated with vaccination hesitancy too. Participants with vaccination hesitancy more often obtained information about COVID-19 vaccines via messenger services or online video platforms and underperformed in the knowledge test. We found high acceptance amongst German HCWs. Several factors associated with vaccination hesitancy were identified which could be targeted in HCW vaccination campaigns.
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http://dx.doi.org/10.3390/vaccines9070777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310090PMC
July 2021

Metabolic profiling links cardiovascular risk and vascular end organ damage.

Atherosclerosis 2021 08 13;331:45-53. Epub 2021 Jul 13.

Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Basel, Switzerland.

Background And Aims: An untargeted metabolomics approach allows for a better understanding and identification of new candidate metabolites involved in the etiology of vascular disease. We aimed to investigate the associations of cardiovascular (CV) risk factors with the metabolic fingerprint and macro- and microvascular health in an untargeted metabolomic approach in predefined CV risk groups of aged individuals.

Methods: The metabolic fingerprint and the macro- and microvascular health from 155 well-characterized aged (50-80 years) individuals, based on the EXAMIN AGE study, were analysed. Nuclear magnetic resonance spectroscopy was used to analyse the metabolic fingerprint. Carotid-femoral pulse wave velocity and retinal vessel diameters were assessed to quantify macro- and microvascular health.

Results: The metabolic fingerprint became more heterogeneous with an increasing number of risk factors. There was strong evidence for higher levels of glutamine [estimate (95% CI): -14.54 (-17.81 to -11.27), p < 0.001], glycine [-5.84 (-7.88 to -3.79), p < 0.001], histidine [-0.73 (-0.96 to -0.50), p < 0.001], and acetate [-1.68 (-2.91 to -0.46), p = 0.007] to be associated with a lower CV risk profile. Tryptophan, however, was positively associated with higher CV risk [0.31 (0.06-0.56), p = 0.015]. The combination of a priori defined CV risk factors explained up to 45.4% of the metabolic variation. The metabolic fingerprint explained 20% of macro- and 23% of microvascular variation.

Conclusions: Metabolic profiling has the potential to improve CV risk stratification by identifying new underlying metabolic pathways associated with atherosclerotic disease development, from cardiovascular risk to metabolites, to vascular end organ damage.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.07.005DOI Listing
August 2021

Development and validation of a simplified risk score for the prediction of critical COVID-19 illness in newly diagnosed patients.

J Med Virol 2021 Jul 31. Epub 2021 Jul 31.

Department of Nephrology, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.

Scores to identify patients at high risk of progression of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may become instrumental for clinical decision-making and patient management. We used patient data from the multicentre Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) and applied variable selection to develop a simplified scoring system to identify patients at increased risk of critical illness or death. A total of 1946 patients who tested positive for SARS-CoV-2 were included in the initial analysis and assigned to derivation and validation cohorts (n = 1297 and n = 649, respectively). Stability selection from over 100 baseline predictors for the combined endpoint of progression to the critical phase or COVID-19-related death enabled the development of a simplified score consisting of five predictors: C-reactive protein (CRP), age, clinical disease phase (uncomplicated vs. complicated), serum urea, and D-dimer (abbreviated as CAPS-D score). This score yielded an area under the curve (AUC) of 0.81 (95% confidence interval [CI]: 0.77-0.85) in the validation cohort for predicting the combined endpoint within 7 days of diagnosis and 0.81 (95% CI: 0.77-0.85) during full follow-up. We used an additional prospective cohort of 682 patients, diagnosed largely after the "first wave" of the pandemic to validate the predictive accuracy of the score and observed similar results (AUC for the event within 7 days: 0.83 [95% CI: 0.78-0.87]; for full follow-up: 0.82 [95% CI: 0.78-0.86]). An easily applicable score to calculate the risk of COVID-19 progression to critical illness or death was thus established and validated.
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http://dx.doi.org/10.1002/jmv.27252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426905PMC
July 2021

Pretransplant Serum Uromodulin and Its Association with Delayed Graft Function Following Kidney Transplantation-A Prospective Cohort Study.

J Clin Med 2021 Jun 11;10(12). Epub 2021 Jun 11.

Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.

Delayed graft function (DGF) following kidney transplantation is associated with increased risk of graft failure, but biomarkers to predict DGF are scarce. We evaluated serum uromodulin (sUMOD), a potential marker for tubular integrity with immunomodulatory capacities, in kidney transplant recipients and its association with DGF. We included 239 kidney transplant recipients and measured sUMOD pretransplant and on postoperative Day 1 (POD1) as independent variables. The primary outcome was DGF, defined as need for dialysis within one week after transplantation. In total, 64 patients (27%) experienced DGF. In multivariable logistic regression analysis adjusting for recipient, donor and transplant associated risk factors each 10 ng/mL higher pretransplant sUMOD was associated with 47% lower odds for DGF (odds ratio (OR) 0.53, 95% confidence interval (95%-CI) 0.30-0.82). When categorizing pretransplant sUMOD into quartiles, the quartile with the lowest values had 4.4-fold higher odds for DGF compared to the highest quartile (OR 4.41, 95%-CI 1.54-13.93). Adding pretransplant sUMOD to a model containing established risk factors for DGF in multivariable receiver-operating-characteristics (ROC) curve analysis, the area-under-the-curve improved from 0.786 [95%-CI 0.723-0.848] to 0.813 [95%-CI 0.755-0.871, = 0.05]. SUMOD on POD1 was not associated with DGF. In conclusion, higher pretransplant sUMOD was independently associated with lower odds for DGF, potentially serving as a non-invasive marker to stratify patients according to their risk for developing DGF early in the setting of kidney transplantation.
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http://dx.doi.org/10.3390/jcm10122586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230896PMC
June 2021

Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing.

Front Genet 2021 26;12:642849. Epub 2021 May 26.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA. A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES). 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x , 1x , 2x , 1x ) could be identified. This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation.
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http://dx.doi.org/10.3389/fgene.2021.642849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188481PMC
May 2021

Electrocardiographic parameters of left ventricular hypertrophy and prediction of mortality in hemodialysis patients.

J Nephrol 2021 May 20. Epub 2021 May 20.

Department of Nephrology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

Background: In hemodialysis patients, left ventricular hypertrophy (LVH) contributes to high cardiovascular mortality. We examined cardiovascular mortality prediction by the recently proposed Peguero-Lo Presti voltage since it identifies more patients with electrocardiographic (ECG) LVH than Cornell or Sokolow-Lyon voltages.

Methods: A total of 308 patients on hemodialysis underwent 24 h ECG recordings. LVH parameters were measured before and after dialysis. The primary endpoint of cardiovascular mortality was recorded during a median 3-year follow up. Risk prediction was assessed by Cox regression, both unadjusted and adjusted for the Charlson Comorbidity Index and the Cardiovascular Mortality Risk Score.

Results: The Peguero-Lo Presti voltage identified with 21% the most patients with positive LVH criteria. All voltages significantly increased during dialysis. Factors such as ultrafiltration rate, Kt/V, body mass index, sex, and phosphate were the most relevant for these changes. During follow-up, 26 cardiovascular deaths occurred. Post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages were independently associated with cardiovascular mortality in unadjusted and adjusted analysis. The Sokolow-Lyon voltage was not significantly associated with mortality. An optimal cut-off for the prediction of cardiovascular mortality was estimated at 1.38 mV for the Peguero-Lo Presti.

Conclusions: The post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages allowed independent risk prediction of cardiovascular mortality in hemodialysis patients. Measuring the ECG LVH parameters after dialysis might allow a standardized interpretation as dialysis-specific factors influence the voltages.
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http://dx.doi.org/10.1007/s40620-021-01068-0DOI Listing
May 2021

Fabry disease: what the cardiologist should consider in non-cardiac screening, diagnosis, and management-narrative review.

Cardiovasc Diagn Ther 2021 Apr;11(2):661-671

Department of Nephrology, Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Munich, Germany.

Fabry disease (FD) is a rare X chromosomally transmitted lysosomal storage disorders with an absence or deficiency of the enzyme alpha-galactosidase. The deposition of globotriaosylceramide (Gb3) may cause damage to all organs, particularly brain, heart and kidney. While acroparaesthesia, hypo- or anhydrosis and diarrhoea are the main symptoms in childhood, cardiac involvement with left ventricular hypertrophy (LVH), renal insufficiency, diffuse pain attacks and apoplexy are the main symptoms in adulthood. Regular examinations are necessary to record organ involvement and its progression. A major challenge is therefore to make a diagnosis at an early disease stage. This is the only way that treatment can be started if there is an indication. If FD is suspected, alpha-galactosidase should be tested in male patients and genetic testing should be performed in females to confirm the diagnosis. Since 2001, enzyme replacement therapy (ERT) has been available as a causal therapy. In 2016, chaperone therapy with the drug Migalastat was approved in the European Union, which leads to stabilisation of the defective alpha-galactosidase. Studies on gene therapy to cure FD in phase I/II. This review summarizes which patient should be screened, how to confirm the diagnosis and which examinations should be performed in FD patients during the course of the disease.
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http://dx.doi.org/10.21037/cdt-20-845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102250PMC
April 2021

Application of regularized regression to identify novel predictors of mortality in a cohort of hemodialysis patients.

Sci Rep 2021 04 29;11(1):9287. Epub 2021 Apr 29.

Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Cohort studies often provide a large array of data on study participants. The techniques of statistical learning can allow an efficient way to analyze large datasets in order to uncover previously unknown, clinically relevant predictors of morbidity or mortality. We applied a combination of elastic net penalized Cox regression and stability selection with the aim of identifying novel predictors of mortality in a cohort of prevalent hemodialysis patients. In our analysis we included 475 patients from the "rISk strAtification in end-stage Renal disease" (ISAR) study, who we split into derivation and confirmation cohorts. A wide array of examinations was available for study participants, resulting in over a hundred potential predictors. In the selection approach many of the well established predictors were retrieved in the derivation cohort. Additionally, the serum levels of IL-12p70 and AST were selected as mortality predictors and confirmed in the withheld subgroup. High IL-12p70 levels were specifically prognostic of infection-related mortality. In summary, we demonstrate an approach how statistical learning can be applied to a cohort study to derive novel hypotheses in a data-driven way. Our results suggest a novel role of IL-12p70 in infection-related mortality, while AST is a promising additional biomarker in patients undergoing hemodialysis.
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http://dx.doi.org/10.1038/s41598-021-88655-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085040PMC
April 2021

Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.

Dis Model Mech 2021 Mar 18;14(3). Epub 2021 Mar 18.

Department of Microbiology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Krakow 30-387, Poland

Myeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes ( C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as , , and , affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.
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http://dx.doi.org/10.1242/dmm.047589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988765PMC
March 2021

Identification of cardiovascular high risk groups from dynamic retinal vessel signals using untargeted machine learning.

Cardiovasc Res 2021 Feb 10. Epub 2021 Feb 10.

Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

Aims: Dynamic retinal vessel analysis (DVA) provides a noninvasive way to asses microvascular function in patients and potentially to improve predictions of individual cardiovascular (CV) risk. The aim of our study was to use untargeted machine learning on DVA in order to improve CV mortality prediction and to identify corresponding response alterations.

Methods And Results: We adopted a workflow consisting of noise reduction and extraction of independent components within DVA signals. Predictor performance was assessed in survival random forest models. Applying our technique to the prediction of all-cause mortality in a cohort of 214 hemodialysis patients resulted in the selection of a component which was highly correlated to maximal venous dilation following flicker stimulation (vMax), a previously identified predictor, confirming the validity of our approach. When fitting for CV mortality as the outcome of interest, a combination of three components derived from the arterial signal resulted in a marked improvement in predictive performance. Clustering analysis suggested that these independent components identified groups of patients with substantially higher CV mortality.

Conclusions: Our results provide a machine learning workflow to improve the predictive performance of DVA and identify groups of hemodialysis patients at high risk of CV mortality. Our approach may also prove to be promising for DVA signal analysis in other CV disease states.

Translational Perspective: DVA is a noninvasive technique which can help to assess microvascular dysfunction, one of the driving factors of CV disease. This study demonstrates a machine learning method which improves DVA interpretation for the estimation of CV risk in hemodialysis patients. Similar techniques can help doctors to identify high risk patients for timely therapeutic interventions and to monitor the effects of these interventions.
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http://dx.doi.org/10.1093/cvr/cvab040DOI Listing
February 2021

Kidney transplantation after rescue allocation-meticulous selection yields the chance for excellent outcome.

Nephrol Dial Transplant 2021 02;36(3):551-560

TransplanTUM, Munich Transplant Center, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

Background: The small number of organ donors forces transplant centres to consider potentially suboptimal kidneys for transplantation. Eurotransplant established an algorithm for rescue allocation (RA) of kidneys repeatedly declined or not allocated within 5 h after procurement. Data on the outcomes and benefits of RA are scarce to date.

Methods: We conducted a retrospective 8-year analysis of transplant outcomes of RA offers based on our in-house criteria catalogue for acceptance and decline of organs and potential recipients.

Results: RA donors and recipients were both older compared with standard allocation (SA). RA donors more frequently had a history of hypertension, diabetes or fulfilled expanded criteria donor key parameters. RA recipients had poorer human leucocyte antigen (HLA) matches and longer cold ischaemia times (CITs). However, waiting time was shorter and delayed graft function, primary non-function and biopsy-proven rejections were comparable to SA. Five-year graft and patient survival after RA were similar to SA. In multivariate models accounting for confounding factors, graft survival and mortality after RA and SA were comparable as well.

Conclusions: Facing relevant comorbidities and rapid deterioration with the risk of being removed from the waiting list, kidney transplantation after RA was identified to allow for earlier transplantation with excellent outcome. Data from this survey propose not to reject categorically organs from multimorbid donors with older age and a history of hypertension or diabetes to aim for the best possible HLA matching and to carefully calculate overall expected CIT.
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http://dx.doi.org/10.1093/ndt/gfaa286DOI Listing
February 2021

Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients.

Sci Rep 2020 10 26;10(1):18277. Epub 2020 Oct 26.

School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.
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http://dx.doi.org/10.1038/s41598-020-75260-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589537PMC
October 2020

Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice.

Int J Mol Sci 2020 Sep 23;21(19). Epub 2020 Sep 23.

LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität Munich, 80336 München, Germany.

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.
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http://dx.doi.org/10.3390/ijms21196978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583818PMC
September 2020

Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS.

Eur J Hum Genet 2021 02 4;29(2):262-270. Epub 2020 Sep 4.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was <18 years. In 7/24 index patients with adult disease onset, a disease-causing variant could be identified by ES leading to a diagnostic yield of 29%. Eight different variants were identified in six known genes associated with monogenic kidney diseases. Six of these variants had been described before as disease-causing. In patients with a disease-causing variant, the median age at disease onset and end-stage renal disease was 26 and 38 years, respectively. The overall median time to a definite genetic diagnosis was 9 years. In 29% of patients with adult disease onset and suspected hereditary FSGS, a monogenic cause could be identified. The long delay up to the definite genetic diagnosis highlights the importance of obtaining an early genetic diagnosis to allow for personalized treatment options including weaning of immunosuppressive treatment, avoidance of repeated renal biopsy, and provision of accurate genetic counseling.
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http://dx.doi.org/10.1038/s41431-020-00719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868362PMC
February 2021

Heart Failure and Atrial Fibrillation Modify the Associations of Nocturnal Blood Pressure Dipping Pattern With Mortality in Hemodialysis Patients.

Hypertension 2020 10 31;76(4):1231-1239. Epub 2020 Aug 31.

Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece (C.L., M.T., A.B., A.P., P.A.S.).

Heart failure (HF), hypertension, and abnormal nocturnal blood pressure dipping are highly prevalent in hemodialysis patients. Atrial fibrillation (AF) and HF might be important mediators for the association of abnormal dipping patterns with worse prognosis. Thus, the aim of this study is to investigate the association of dipping with mortality in hemodialysis patients and to assess the influence of AF and HF. In total, 525 hemodialysis patients underwent 24-hour ambulatory blood pressure monitoring. All-cause and cardiovascular mortality served as end points. Patients were categorized according to their systolic dipping pattern (dipper, nondipper, and reverse dipper). Cox regression analysis was performed to determine the association between dipping pattern and study end points with dipping as reference. Subgroup analysis was performed for patients with and without AF or HF. In total, 185 patients with AF or HF and 340 patients without AF or HF were included. During a median follow-up of 37.8 months, 177 patients died; 81 from cardiovascular causes. Nondipping and reverse dipping were significantly associated with all-cause mortality in the whole cohort (nondipper: hazard ratio, 1.95 [1.22-3.14]; =0.006; reverse dipper: hazard ratio, 2.31 [1.42-3.76]; <0.001) and in patients without AF or HF (nondipper: hazard ratio, 2.78 [1.16-6.66]; =0.02; reverse dipper: hazard ratio, 4.48 [1.87-10.71]; <0.001) but not in patients with AF or HF. For cardiovascular mortality, associations were again significant in patients without AF or HF and in the whole cohort. The observed associations remained significant after adjustment for possible confounders. This study provides well-powered evidence for the association between abnormal dipping patterns and mortality in hemodialysis patients and suggests that HF or AF modifies this association.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15420DOI Listing
October 2020

In Vitro Closure Times (PFA-100) Are Different Between Peritoneal Dialysis and Hemodialysis.

Hamostaseologie 2020 Dec 27;40(5):671-678. Epub 2020 Jul 27.

Department of Nephrology, Ege University, İzmir, Turkey.

Introduction:  Platelet dysfunction is not uncommon in patients with end-stage renal disease (ESRD). Type of renal replacement therapy may have an effect on platelet functions, which has not been well investigated. We evaluated in vitro closure time (CT) differences between peritoneal dialysis (PD) and hemodialysis (HD) patients using platelet function analyzer (PFA-100)and observed a significant difference between these renal replacement therapies.

Methods:  Patients with ESRD undergoing PD ( = 24) or HD ( = 23) for more than 6 months were included. Blood samples for collagen/epinephrine (Col/EPI) and collagen/adenosine diphosphate (Col/ADP) measurements were obtained before HD at a mid-week session for HD patients and at an outpatient control time for PD patients.

Results:  Three of 24 (12.5%) PD patients and 16 of 23 (69.5%) HD patients had prolonged PFA-100 Col/EPI, < 0.001. Likewise, 4.2% of PD patients and 87.0% of HD patients had prolonged PFA-100 Col/ADP, < 0.001. Moreover, the median times of PFA-Col/EPI and PFA-100 Col/ADP were significantly lower in PD patients compared with those of HD patients (< 0.001). Multivariate analysis showed that the type of renal replacement was a risk factor for both elevated PFA-100 Col/ADP and PFA-100 Col/EPI after adjusted for platelets, hematocrit, and urea (< 0.001).

Conclusions:  The type of renal replacement therapy may have an effect on in vitro CTs; therefore, studies including more patients with long-term follow-up are needed to investigate if the difference has any impact on clinical outcomes.
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http://dx.doi.org/10.1055/a-1171-0499DOI Listing
December 2020

Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies.

Am J Kidney Dis 2020 10 28;76(4):460-470. Epub 2020 Apr 28.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address:

Rationale & Objective: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders.

Study Design: Cross-sectional cohort study.

Setting & Participants: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other."

Results: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases.

Limitations: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease).

Conclusions: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
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http://dx.doi.org/10.1053/j.ajkd.2019.12.008DOI Listing
October 2020

Cardiovascular Mortality Can Be Predicted by Heart Rate Turbulence in Hemodialysis Patients.

Front Physiol 2020 11;11:77. Epub 2020 Feb 11.

Abteilung für Nephrologie, Klinikum Rechts der Isar, Fakultät für Medizin, Technische Universität München, Munich, Germany.

Background: Excess mortality in hemodialysis patients is mostly of cardiovascular origin. We examined the association of heart rate turbulence (HRT), a marker of baroreflex sensitivity, with cardiovascular mortality in hemodialysis patients.

Methods: A population of 290 prevalent hemodialysis patients was followed up for a median of 3 years. HRT categories 0 (both turbulence onset [TO] and slope [TS] normal), 1 (TO or TS abnormal), and 2 (both TO and TS abnormal) were obtained from 24 h Holter recordings. The primary end-point was cardiovascular mortality. Associations of HRT categories with the endpoints were analyzed by multivariable Cox regression models including HRT, age, albumin, and the improved Charlson Comorbidity Index for hemodialysis patients. Multivariable linear regression analysis identified factors associated with TO and TS.

Results: During the follow-up period, 20 patients died from cardiovascular causes. In patients with HRT categories 0, 1 and 2, cardiovascular mortality was 1, 10, and 22%, respectively. HRT category 2 showed the strongest independent association with cardiovascular mortality with a hazard ratio of 19.3 (95% confidence interval: 3.69-92.03; < 0.001). Age, calcium phosphate product, and smoking status were associated with TO and TS. Diabetes mellitus and diastolic blood pressure were only associated with TS.

Conclusion: Independent of known risk factors, HRT assessment allows identification of hemodialysis patients with low, intermediate, and high risk of cardiovascular mortality. Future prospective studies are needed to translate risk prediction into risk reduction in hemodialysis patients.
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http://dx.doi.org/10.3389/fphys.2020.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027389PMC
February 2020

Decreased Vascular Pulsatility in Alzheimer's Disease Dementia Measured by Transcranial Color-Coded Duplex Sonography.

Neuropsychiatr Dis Treat 2019 20;15:3487-3499. Epub 2019 Dec 20.

Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, Department of Psychiatry and Psychotherapy, Munich, Germany.

Purpose: Impaired paravascular drainage of β-Amyloid (Aβ) has been proposed as a contributing cause for sporadic Alzheimer's disease (AD), as decreased cerebral blood vessel pulsatility and subsequently reduced propulsion in this pathway could lead to the accumulation and deposition of Aβ in the brain. Therefore, we hypothesized that there is an increased impairment in pulsatility across AD spectrum.

Patients And Methods: Using transcranial color-coded duplex sonography (TCCS) the resistance and pulsatility index (RI; PI) of the middle cerebral artery (MCA) in healthy controls (HC, n=14) and patients with AD dementia (ADD, n=12) were measured. In a second step, we extended the sample by adding patients with mild cognitive impairment (MCI) stratified by the presence (MCI-AD, n=8) or absence of biomarkers (MCI-nonAD, n=8) indicative for underlying AD pathology, and compared RI and PI across the groups. To control for atherosclerosis as a confounder, we measured the arteriolar-venular-ratio of retinal vessels.

Results: Left and right RI (p=0.020; p=0.027) and left PI (p=0.034) differed between HC and ADD controlled for atherosclerosis with AUCs of 0.776, 0.763, and 0.718, respectively. The RI and PI of MCI-AD tended towards ADD, of MCI-nonAD towards HC, respectively. RIs and PIs were associated with disease severity (p=0.010, p=0.023).

Conclusion: Our results strengthen the hypothesis that impaired pulsatility could cause impaired amyloid clearance from the brain and thereby might contribute to the development of AD. However, further studies considering other factors possibly influencing amyloid clearance as well as larger sample sizes are needed.
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http://dx.doi.org/10.2147/NDT.S225754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929935PMC
December 2019

IFN Regulatory Factor 4 Controls Post-ischemic Inflammation and Prevents Chronic Kidney Disease.

Front Immunol 2019 1;10:2162. Epub 2019 Oct 1.

Department of Nephrology, Klinikum der Ludwig-Maximilians-Universität München, Medizinische Klinik und Poliklinik IV, Munich, Germany.

Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)-mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury , a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies.
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http://dx.doi.org/10.3389/fimmu.2019.02162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781770PMC
October 2020

Weak within-individual association of blood pressure and pulse wave velocity in hemodialysis is related to adverse outcomes.

J Hypertens 2019 11;37(11):2200-2208

Hospital and FCRIN INI-CRCTC, Manhes, France.

Objectives: Hemodialysis patients have premature arterial stiffness, and the relationship between pulse wave velocity (PWV) and blood pressure (BP) may be different than in other hypertensives. Previous studies in such patients showed that when BP decrease is accompanied by PWV decrease the survival is improved. This study examines the prognostic role of the mean BP (MBP)-PWV association for cardiovascular outcomes and all-cause mortality in hemodialysis.

Methods: A total of 242 hemodialysis patients underwent 48-h ambulatory BP monitoring with Mobil-O-Graph-NG and were followed for 33.17 ± 19.68 months. The within-individual MBP-PWV association (MBP, dependent and PWV independent variable) was evaluated using the β-coefficient value from simple linear regression analysis for each patient. The primary end-point was first occurrence of all-cause death, nonfatal myocardial infarction or nonfatal stroke. Secondary end-points were all-cause mortality, cardiovascular mortality and a combination of cardiovascular events.

Results: Higher quartiles of β-coefficients (indicating strong within-individual association of MBP with PWV) were related to greater cumulative freedom from the primary end-point (50.8, 60.0, 70.0 and 80.3% for quartiles 1-4, respectively; log-rank P = 0.001), better overall survival (60.7, 61.7, 73.3, 86.9%; log-rank P = 0.002) and better cardiovascular survival (78.7, 75.0, 81.7, 91.8% for quartiles 1-4; log-rank P = 0.044). The future risks of the primary end-point, all-cause and cardiovascular mortality and the combined outcome were progressively increasing with lower quartiles of β-coefficients, indicating patients with weak MBP-PWV association (hazard ratios for all-cause mortality 3.395; 95% confidence interval: 1.524-7.563, P = 0.003 for quartile 1 vs. quartile 4).

Conclusion: Weaker within-individual MBP-PWV association, based on ABPM recordings, is associated with higher risk of death and cardiovascular events in hemodialysis. These findings support that arterial stiffness insensitive to BP changes is the underlying factor for adverse outcomes in these individuals.
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http://dx.doi.org/10.1097/HJH.0000000000002153DOI Listing
November 2019

Retinal endothelial function in cardiovascular risk patients: A randomized controlled exercise trial.

Scand J Med Sci Sports 2020 Feb 28;30(2):272-280. Epub 2019 Oct 28.

Department of Sport, Exercise and Health, Medical Faculty, University of Basel, Basel, Switzerland.

The aim of this study was to investigate, for the first time, the effects of high-intensity interval training (HIIT) on retinal microvascular endothelial function in cardiovascular (CV) risk patients. In the randomized controlled trial, middle-aged and previously sedentary patients with increased CV risk (aged 58 ± 6 years) with ≥ two CV risk factors were randomized into a 12-week HIIT (n = 33) or control group (CG, n = 36) with standard physical activity recommendations. A blinded examiner measured retinal endothelial function by flicker light-induced maximal arteriolar (ADmax) and venular (VDmax) dilatation as well as the area under the arteriolar (AFarea) and venular (VFarea) flicker curve using a retinal vessel analyzer. Standardized assessments of CV risk factors, cardiorespiratory fitness, and retinal endothelial function were performed before and after HIIT. HIIT reduced body mass index, fat mass, and low-density lipoprotein and increased muscle mass and peak oxygen uptake (VO2peak). Both ADmax (pre: 2.7 ± 2.1%, post: 3.0 ± 2.2%, P = .018) and AFarea (pre: 32.6 ± 28.4%*s, post: 37.7 ± 30.6%*s, P = .016) increased after HIIT compared with CG (ADmax, pre: 3.2 ± 1.8%, post: 2.9 ± 1.8%, P = .254; AFarea, pre: 41.6 ± 28.5%*s, post: 37.8 ± 27.0%*s, P = .186). Venular function remained unchanged after HIIT. There was a significant association between ∆-change VO2peak and ∆-changes ADmax and AFarea (P = .026, R  = 0.073; P = .019, R  = 0.081, respectively). 12-weeks of HIIT improved retinal endothelial function in middle-aged patients with increased CV risk independent of the reduction in classical CV risk factors. Exercise has the potential to reverse or at least postpone progression of small vessel disease in older adults with increased CV risk under standard medication. Dynamic retinal vessel analysis seems to be a sensitive tool to detect treatment effects of exercise interventions on retinal microvascular endothelial function in middle-aged individuals with increased CV risk.
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http://dx.doi.org/10.1111/sms.13560DOI Listing
February 2020

Plasma C-terminal agrin fragment and rapid kidney function decline in chronic kidney disease patients.

Medicine (Baltimore) 2019 May;98(19):e15597

Technische Universität München, Fakultät für Medizin, Klinikum rechts der Isar, Abteilung für Nephrologie, Munich, Germany.

C-terminal agrin fragment (tCAF) is a promising biomarker for glomerular filtration. Data regarding biomarkers that have the ability to predict rapid progression of chronic kidney disease (CKD) are sparse but necessary in order to identify patients at high risk for rapid progression. This study addresses the value of tCAF as a predictor of rapid kidney function decline in CKD patients.We measured plasma tCAF in a retrospective observational cohort study of 277 prevalent CKD patients stage I-V. Using multivariable Cox proportional hazards regression analysis, we evaluated the association of tCAF with end-stage-renal-disease (ESRD), ≥30%-decline of estimated glomerular filtration rate (eGFR) and the composite endpoint of both, adjusting for eGFR, age, systolic blood pressure, proteinuria and diabetes.The median age was 58 [interquartile range 47, 71] years, 36% were female. Median tCAF level was 822 [594, 1232] pM, eGFR was 32 [19, 48] ml/min/1.73 m. tCAF was correlated to eGFR and proteinuria (r = -0.76 and r = 0.49, P < .001 resp.). During a follow-up of 57.1 [42.9, 71.9] weeks, 36 (13%) patients developed ESRD and 13 (5%) had an eGFR decline of ≥30% (composite endpoint: 49 (18%)). In multivariable analysis, each 100 pM higher tCAF was independently associated with ESRD (hazard ratio (HR) 1.05 (95%-CI 1.02-1.08)), ≥30% eGFR decline (HR 1.10 (1.03-1.18)) and the composite endpoint (HR 1.07 (1.04-1.1)).Plasma tCAF may identify CKD patients at risk for rapid kidney function decline independent of eGFR and other risk factors for eGFR loss such as proteinuria.
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http://dx.doi.org/10.1097/MD.0000000000015597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531159PMC
May 2019

A complex pattern of autonomic dysfunction in familial Mediterranean fever. Results from a controlled cross-sectional study.

Clin Exp Rheumatol 2019 Nov-Dec;37 Suppl 121(6):35-42. Epub 2019 Mar 18.

Division of Rheumatology and Clinical Immunology, Med. Klinik und Poliklinik IV, University of Munich, Germany.

Objectives: Autonomic dysfunction (AD) has been described in various chronic inflammatory diseases. Studies of AD in patients with familial Mediterranean fever (FMF) are inconclusive. We aimed to assess AD in a cohort of FMF patients.

Methods: Signs and symptoms of AD were investigated in patients with FMF and compared to age and gender matched healthy controls. Symptoms of AD were assessed by COMPASS-31, a validated questionnaire to evaluate orthostatic, vasomotor, secretomotor, gastrointestinal, pupillomotor and bladder function domains. Assessment of objective AD comprised heart rate variability during deep breathing, skin conductance changes during mental arithmetic, blood pressure response to pain and dynamic infrared pupillometry.

Results: 25 patients and 25 healthy controls were included and evaluated by COMPASS-31 and objective testing of AD. FMF patients had higher median COMPASS-31 total scores than controls (23.7 vs. 1.6, p=0.024). Significant differences were also found in the secretomotor and gastrointestinal sub-domains (4.2 vs. 0.0; p<0.001 and 8.0 vs. 0.0; p=0.004, respectively). Symptoms of autonomic dysfunction were correlated with patient reported global disease activity (r=0.71; p<0.001) and pain level (r=0.68; p<0.001). There were no differences in heart rate variability (HRV), skin conductance, blood pressure response to pain or sympathetic pupillomotor function between patients and controls. FMF patients revealed impaired parasympathetic pupillomotor function that was not associated with clinical parameters. However, patients that were on IL-1-blocking therapy had better parasympathetic pupillary function than patients on conventional treatment.

Conclusions: FMF patients have AD in terms of symptoms and parasympathetic pupillomotor function. Dynamic pupillometry can provide additional information on autonomic regulation in patients with FMF.
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January 2020

Impaired Retinal Vessel Dilation Predicts Mortality in End-Stage Renal Disease.

Circ Res 2019 Apr 1. Epub 2019 Apr 1.

Nephrology, Technical University of Munich.

Rationale: Patients with end-stage renal disease (ESRD) are characterized by increased cardiovascular (CV) and all-cause mortality due to advanced remodeling of the macro- and microvascular beds.

Objective: The aim of this study was to determine whether retinal microvascular function can predict all-cause and CV mortality in patients with ESRD.

Methods And Results: In the multicenter prospective observational ISAR (Risk Stratification in End-Stage Renal Disease) study, data on dynamic retinal vessel analysis (DVA) was available in a sub-cohort of 214 dialysis patients (mean age 62.6{plus minus}15.0; 32% female). Microvascular dysfunction was quantified by measuring maximum arteriolar (aMax) and venular dilation (vMax) of retinal vessels in response to flicker light stimulation. During a mean follow-up of 44 months, 55 patients died, including 25 CV and 30 non-CV fatal events. vMax emerged as a strong independent predictor for all-cause mortality. In the Kaplan-Meier analysis, individuals within the lowest tertile of vMax showed significantly shorter three-year survival rates than those within the highest tertile (66.9{plus minus}5.8% vs 92.4{plus minus}3.3%). Uni- and multivariate hazard ratios for all-cause mortality per SD increase of vMax were 0.62 [0.47;0.82] and 0.65[0.47;0.91], respectively. aMax and vMax were able to significantly predict nonfatal and fatal CV events (HR 0.74[0.57;0.97] and 0.78[0.61;0.99], respectively).

Conclusions: Our results provide the first evidence that impaired retinal venular dilation is a strong and independent predictor of all-cause mortality in hemodialyzed ESRD patients. DVA provides added value for prediction of all-cause mortality and may be a novel diagnostic tool to optimize CV risk stratification in ESRD and other high-risk CV cohorts.

Clinical Trial Registration: NCT01152892.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.314318DOI Listing
April 2019

Comparison of 24-hour and Office Pulse Wave Velocity for Prediction of Mortality in Hemodialysis Patients.

Am J Nephrol 2019 27;49(4):317-327. Epub 2019 Mar 27.

Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Background: Mortality in hemodialysis patients still remains unacceptably high. Enhanced arterial stiffness is a known cardiovascular risk factor, and pulse wave velocity (PWV) has proven to be a valid parameter to quantify risk. Recent studies showed controversial results regarding the prognostic significance of PWV for mortality in hemodialysis patients, which may be due to methodological issues, such as assessment of PWV in the office setting (Office-PWV).

Method: This study cohort contains patients from the "Risk stratification in end-stage renal disease - the ISAR study," a multicenter prospective longitudinal observatory cohort study. We examined and compared the predictive value of ambulatory 24-hour PWV (24 h-PWV) and Office-PWV on mortality in a total of 344 hemodialysis patients. The endpoints of the study were all-cause and cardiovascular mortality. Survival analysis included Kaplan-Meier estimates and Cox regression analysis.

Results: During a follow-up of 36 months, a total of 89 patients died, 35 patients due to cardiovascular cause. Kaplan-Meier estimates for tertiles of 24 h-PWV and Office-PWV were similarly associated with mortality. In univariate Cox regression analysis, 24 h-PWV and Office-PWV were equivalent predictors for all-cause and cardiovascular mortality. After adjustment for common risk factors, only 24 h-PWV remained solely predictive for all-cause mortality (hazard ratio 2.51 [95% CI 1.31-4.81]; p = 0.004).

Conclusions: Comparing both measurements, 24 h-PWV is an independent predictor for all-cause-mortality in hemodialysis patients beyond Office-PWV.
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http://dx.doi.org/10.1159/000499532DOI Listing
May 2020

Cognitive Impairment is Associated with Mortality in Hemodialysis Patients.

J Alzheimers Dis 2018 ;66(4):1529-1537

Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Background: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality.

Objective: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients.

Methods: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA).Cognitive impairment was defined as a MoCA test score ≤24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality.

Results: A MoCA test score ≤24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683-4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007-3.038; p = 0.047).

Conclusion: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population.
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http://dx.doi.org/10.3233/JAD-180767DOI Listing
November 2019
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