Publications by authors named "Alexander Rosenkranz"

136 Publications

Blockade of tumor necrosis factor superfamily members CD30 and OX40 abrogates disease activity in murine immune-mediated glomerulonephritis.

Kidney Int 2021 Mar 27. Epub 2021 Mar 27.

Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Co-stimulation is a prerequisite for pathogenic activity in T cell-mediated diseases and has been demonstrated to achieve tolerance in organ-specific autoimmunity as a therapeutic target. Here, we evaluated the involvement of the tumor necrosis factor family members CD30 and OX40 in immune-complex mediated kidney disease. In vitro stimulation and proliferation studies were performed with CD4 cells from wild type and CD30/OX40 double knock-out (CD30OX40) mice. In vivo studies were performed by induction of nephrotoxic serum nephritis in wild type, CD30OX40 , CD30, OX40, reconstituted Rag1 and C57Bl/6J mice treated with αCD30L αOX40L antibodies. CD30, OX40 and their ligands were upregulated on various leukocytes in nephrotoxic serum nephritis. CD30OX40 mice, but not CD30 or OX40 mice were protected from nephrotoxic serum nephritis. Similar protection was found in Rag1 mice injected with CD4 T cells from CD30OX40 mice compared to Rag1 mice injected with CD4 T cells from wild type mice. Furthermore, CD4 T cells deficient in CD30OX40 displayed decreased expression of CCR6 in vivo. CD30OX40 cells were fully capable of differentiating into disease mediating T helper cell subsets, but showed significantly decreased levels of proliferation in vivo and in vitro compared to wild type cells. Blocking antibodies against CD30L and OX40L ameliorated nephrotoxic serum nephritis without affecting pan-effector or memory T cell populations. Thus, our results indicate disease promotion via CD30 and OX40 signaling due to facilitation of exaggerated T cell proliferation and migration of T helper 17 cells in nephrotoxic serum nephritis. Hence, co-stimulation blockade targeting the CD30 and OX40 signaling pathways may provide a novel therapeutic strategy in autoimmune kidney disease.
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http://dx.doi.org/10.1016/j.kint.2021.02.039DOI Listing
March 2021

Efficacy and Safety of a Novel Nicotinamide Modified-Release Formulation in the Treatment of Refractory Hyperphosphatemia in Patients Receiving Hemodialysis-A Randomized Clinical Trial.

Kidney Int Rep 2021 Mar 19;6(3):594-604. Epub 2020 Dec 19.

Medical Department, MEDICE Arzneimittel Pütter GmbH & Co KG, Iserlohn, Germany.

Introduction: Despite widespread use of phosphate binders (PBs), phosphate control is insufficient in many hemodialysis patients. Preliminary clinical observations suggest that nicotinamide may act synergistically with PBs to improve phosphate control.

Methods: This multinational, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of nicotinamide modified release (NAMR) in combination with oral PB in a large cohort of hemodialysis patients with abnormal serum phosphate concentration (>4.5 mg/dl) despite treatment with PB. Patients entered a proof-of-efficacy phase (12 weeks [W12]) in which adjustments of relevant comedication were not permitted, followed by a safety extension phase for up to 52 weeks. Here, we report the results of the first phase.

Results: The intention-to-treat (ITT) population consisted of 539 patients in the NAMR and 183 patients in the placebo group. NAMR and placebo were orally administered once daily (250-1500 mg/d). Mean age of patients was 61.8 years, and 63.0% were men. In the confirmatory analysis that estimated the difference in serum phosphate concentration after 12 weeks, NAMR proved superior over placebo with a significant difference of -0.51 mg/dl (95% confidence interval [CI] -0.72, -0.29;  < 0.0001). This effect was associated with significantly lower intact parathyroid hormone (iPTH) values (NAMR: 292.4±300.4 pg/ml vs. placebo: 337.0±302.7 pg/ml;  = 0.04) and an improved calcification propensity (T50 time; NAMR: 23.8±97.1 minutes vs. placebo: 2.3±100.7 minutes;  = 0.02). Diarrhea and pruritus were more frequent in the NAMR group.

Conclusion: NAMR combined with oral PB significantly improved phosphate control in hemodialysis patients.
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http://dx.doi.org/10.1016/j.ekir.2020.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938065PMC
March 2021

Agonism of Prostaglandin E2 Receptor 4 Ameliorates Tubulointerstitial Injury in Nephrotoxic Serum Nephritis in Mice.

J Clin Med 2021 Feb 18;10(4). Epub 2021 Feb 18.

Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.

Selectively targeting the E-type prostanoid receptor 4 (EP4) might be a new therapeutic option in the treatment of glomerulonephritis (GN), since the EP4 receptor is expressed on different immune cells, resident kidney cells, and endothelial cells, which are all involved in the pathogenesis of immune-complex GN. This study aimed to evaluate the therapeutic potential and to understand the mode of action of EP4 agonist in immune-complex GN using the murine model of nephrotoxic serum nephritis (NTS). In vivo, NTS mice were treated two times daily with two different doses of an EP4 agonist ONO AE1-329 or vehicle for 14 days total. The effect of PGE2 and EP4 agonism and antagonism was tested on murine distal convoluted tubular epithelial cells (DCT) in vitro. In vivo, the higher dose of the EP4 agonist led to an improved NTS phenotype, including a reduced tubular injury score and reduced neutrophil gelatinase-associated lipocalin (NGAL) and blood urea nitrogen (BUN) levels. EP4 agonist treatment caused decreased CD4 T cell infiltration into the kidney and increased proliferative capacity of tubular cells. Injection of the EP4 agonist resulted in dose-dependent vasodilation and hypotensive episodes. The low-dose EP4 agonist treatment resulted in less pronounced episodes of hypotension. In vitro, EP4 agonism resulted in cAMP production and increased distal convoluted tubular (DCT) proliferation. Taken together, EP4 agonism improved the NTS phenotype by various mechanisms, including reduced blood pressure, decreased CD4 T cell infiltration, and a direct effect on tubular cells leading to increased proliferation probably by increasing cAMP levels.
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http://dx.doi.org/10.3390/jcm10040832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922874PMC
February 2021

Effect of short-interval rituximab and high-dose corticosteroids on kidney function in systemic sclerosis: Long-term experience of a single centre.

Int J Clin Pract 2021 Feb 4:e14069. Epub 2021 Feb 4.

Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Introduction: Scleroderma renal crisis (SRC) is a rare but one of the most recognised complications of systemic sclerosis (SSc). Corticosteroid (CS) use has been considered as a major risk factor for SRC. Several studies reported the efficacy of rituximab (RTX) with an acceptable safety profile in SSc. However, data on the long-term effect of high-dose CS concomitant to RTX on kidney function are lacking.

Methods: We retrospectively analysed SSc patients (n = 35) treated with a lower dosage and short-interval RTX and concomitant high-dose CS at the Department of Internal Medicine at the Medical University of Graz between 2010 and 2019. The kidney function was assessed using the estimated glomerular filtration rate (eGFR) at every RTX admission. The annual decline of kidney function was evaluated by linear mixed model analysis.

Results: At the RTX initiation, one patient had a decreased kidney function indicated by eGFR < 60 mL/min/1.73 m (median: 96 mL/min/1.73 m ; interquartile range (IQR): 43-136). Patients received RTX and complementary high-dose CS for a median follow-up time of 3.4 years (range 0.6-9.5). A linear mixed model analysis with the patient as random effect and time from first RTX as fixed effect estimated an annual decline of 1.98 mL/min/1.73 m of the eGFR (95% confidence interval: [-2.24, -1.72]; P <.001). During the follow-up period, no patient experienced SRC or a significant drop in kidney function.

Conclusions: A regular, high-dose CS given contemporary to RTX seems to be a safe option for kidney function in patients with SSc. Our findings provide additional knowledge in risk evaluation and planning of individualised therapies or designing clinical studies using RTX.
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http://dx.doi.org/10.1111/ijcp.14069DOI Listing
February 2021

Acute and Chronic Kidney Dysfunction and Outcome After Stroke Thrombectomy.

Transl Stroke Res 2021 Jan 4. Epub 2021 Jan 4.

Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria.

Data on the impact of kidney dysfunction on outcome in patients with stroke due to large vessel occlusion are scarce. The few available studies are limited by only considering single kidney parameters measured at one time point. We thus investigated the influence of both chronic kidney disease (CKD) and acute kidney injury (AKI) on outcome after mechanical thrombectomy. We included consecutive patients with anterior circulation large vessel occlusion stroke receiving mechanical thrombectomy at our center over an 8-year period. We extracted clinical data from a prospective registry and investigated kidney serum parameters at admission, the following day and throughout hospital stay. CKD and AKI were defined according to established nephrological criteria. Unfavorable outcome was defined as scores of 3-6 on the modified Rankin Scale 3 months post-stroke. Among 465 patients, 31.8% had an impaired estimated glomerular filtration rate (eGFR) at admission (< 60 ml/min/1.73 m). Impaired admission eGFR was related to unfavorable outcome in univariable analysis (p = 0.003), but not after multivariable adjustment (p = 0.96). Patients frequently met AKI criteria at admission (24.5%), which was associated with unfavorable outcome in a multivariable model (OR 3.03, 95% CI 1.73-5.30, p < 0.001). Moreover, patients who developed AKI during hospital stay also had a worse outcome (p = 0.002 in multivariable analysis). While CKD was not associated with 3-month outcome, we identified AKI either at admission or throughout the hospital stay as an independent predictor of unfavorable prognosis in this study cohort. This finding warrants further investigation of kidney-brain crosstalk in the setting of acute stroke.
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http://dx.doi.org/10.1007/s12975-020-00881-2DOI Listing
January 2021

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Authors:
Mathias Gorski Bettina Jung Yong Li Pamela R Matias-Garcia Matthias Wuttke Stefan Coassin Chris H L Thio Marcus E Kleber Thomas W Winkler Veronika Wanner Jin-Fang Chai Audrey Y Chu Massimiliano Cocca Mary F Feitosa Sahar Ghasemi Anselm Hoppmann Katrin Horn Man Li Teresa Nutile Markus Scholz Karsten B Sieber Alexander Teumer Adrienne Tin Judy Wang Bamidele O Tayo Tarunveer S Ahluwalia Peter Almgren Stephan J L Bakker Bernhard Banas Nisha Bansal Mary L Biggs Eric Boerwinkle Erwin P Bottinger Hermann Brenner Robert J Carroll John Chalmers Miao-Li Chee Miao-Ling Chee Ching-Yu Cheng Josef Coresh Martin H de Borst Frauke Degenhardt Kai-Uwe Eckardt Karlhans Endlich Andre Franke Sandra Freitag-Wolf Piyush Gampawar Ron T Gansevoort Mohsen Ghanbari Christian Gieger Pavel Hamet Kevin Ho Edith Hofer Bernd Holleczek Valencia Hui Xian Foo Nina Hutri-Kähönen Shih-Jen Hwang M Arfan Ikram Navya Shilpa Josyula Mika Kähönen Chiea-Chuen Khor Wolfgang Koenig Holly Kramer Bernhard K Krämer Brigitte Kühnel Leslie A Lange Terho Lehtimäki Wolfgang Lieb Ruth J F Loos Mary Ann Lukas Leo-Pekka Lyytikäinen Christa Meisinger Thomas Meitinger Olle Melander Yuri Milaneschi Pashupati P Mishra Nina Mononen Josyf C Mychaleckyj Girish N Nadkarni Matthias Nauck Kjell Nikus Boting Ning Ilja M Nolte Michelle L O'Donoghue Marju Orho-Melander Sarah A Pendergrass Brenda W J H Penninx Michael H Preuss Bruce M Psaty Laura M Raffield Olli T Raitakari Rainer Rettig Myriam Rheinberger Kenneth M Rice Alexander R Rosenkranz Peter Rossing Jerome I Rotter Charumathi Sabanayagam Helena Schmidt Reinhold Schmidt Ben Schöttker Christina-Alexandra Schulz Sanaz Sedaghat Christian M Shaffer Konstantin Strauch Silke Szymczak Kent D Taylor Johanne Tremblay Layal Chaker Pim van der Harst Peter J van der Most Niek Verweij Uwe Völker Melanie Waldenberger Lars Wallentin Dawn M Waterworth Harvey D White James G Wilson Tien-Yin Wong Mark Woodward Qiong Yang Masayuki Yasuda Laura M Yerges-Armstrong Yan Zhang Harold Snieder Christoph Wanner Carsten A Böger Anna Köttgen Florian Kronenberg Cristian Pattaro Iris M Heid

Kidney Int 2021 04 31;99(4):926-939. Epub 2020 Oct 31.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany. Electronic address:

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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http://dx.doi.org/10.1016/j.kint.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010357PMC
April 2021

Impact of Timely Public Health Measures on Kidney Transplantation in Austria during the SARS-CoV-2 Outbreak-A Nationwide Analysis.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, 6020 Innsbruck, Austria.

SARS-CoV-2 led to considerable morbidity/mortality worldwide and tremendously impacted on daily life. Strict lockdown measures were implemented early to contain the viral outbreak in Austria. Massive changes in organizational structures of healthcare facilities followed with unclear implications on the care of non-COVID-19-affected patients. We studied the nationwide impact of COVID-19 on kidney transplantation in Austria during the first six months of 2020. Concurrent with general lockdown measures, all kidney transplant activity was suspended from 13 March to 9 April. Nevertheless, between January and June, total transplant ( = 0.48) and procured donor organ numbers ( = 0.6) did not differ significantly from earlier years. Ten (0.18%) of 5512 prevalent Austrian kidney transplant recipients were diagnosed with SARS-CoV-2. The case fatality rate (one death; 10%) in renal transplant patients was less than in other countries but higher than in Austria's general population (2.4%). We conclude that early and strict general lockdown measures imposed by the government allowed an early, however cautious, re-opening of Austrian transplant programs and played a crucial role for the favorable outcomes of SARS-CoV-2 in Austrian kidney transplant patients. Even though it may be uncertain whether similar results may be obtainable in other countries, the findings may support early intervention strategies during similar episodes in the future.
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http://dx.doi.org/10.3390/jcm9113465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693584PMC
October 2020

Individual uromodulin serum concentration is independent of glomerular filtration rate in healthy kidney donors.

Clin Chem Lab Med 2021 Feb 13;59(3):563-570. Epub 2020 Oct 13.

Department of Internal Medicine, Division of Nephrology, Medical University of Graz, Graz, Austria.

Objectives: The mucoprotein uromodulin is considered to correlate with glomerular filtration rates (GFR) in patients with chronic kidney disease (CKD). Here we investigated how serum uromodulin is associated with measured GFR using inulin-clearance and GFR estimated by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation in healthy subjects.

Methods: We assessed possible correlations between uromodulin serum concentrations, inulin-GFR and CKD-EPI-GFR in a well characterized study cohort of 112 healthy living kidney donors with two kidneys before and 64 with one kidney after kidney donation. A subgroup of 32 individuals, which presented data before and after nephrectomy, was assessed separately.

Results: All 112 healthy living kidney donors with two kidneys revealed individual serum uromodulin concentrations between 60.1 and 450.5 µg/L. Sixty-four healthy kidney donors after nephrectomy had significantly lower median (interquartile range) serum uromodulin concentrations (124 [101-166] vs. 185 [152-238] µg/L), inulin-GFR (67.3 [60.6-74.6] vs. 93.5 [82.1-104.4] mL/min/1.73 m), and CKD-EPI-GFR (61.2 [53.1-69.7] vs. 88.6 [80.0-97.1] mL/min/1.73 m) as compared to the 112 donors before donation (p<0.001). The subgroup of 32 subjects, which presented data before and after nephrectomy, showed almost the same pattern of kidney function. No statistically relevant associations were found between serum uromodulin and inulin-GFR or CKD-EPI-GFR regarding this healthy population.

Conclusions: These novel findings indicate that - in contrast to patients with CKD - serum uromodulin concentrations are not correlated with measured and estimated GFR in healthy individuals.
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http://dx.doi.org/10.1515/cclm-2020-0894DOI Listing
February 2021

Impact of cardiovascular risk stratification strategies in kidney transplantation over time.

Nephrol Dial Transplant 2020 10;35(10):1810-1818

Department of Internal Medicine, Division of Nephrology, Medical University of Graz, Graz, Austria.

Background: Kidney transplant recipients exhibit a dramatically increased cardiovascular (CV) risk. In 2007, Austrian centres implemented a consensus of comprehensive CV screening programme prior to kidney transplantation (KT). The consensus placed a particular emphasis on screening for coronary artery disease (CAD) with cardiac computed tomography (CT) or coronary angiography (CAG) in patients with diabetes mellitus, known CAD or those having multiple conventional CV risk factors. Here, we investigate if this affected risk stratification and post-transplant CV outcomes.

Methods: In a retrospective chart review, we evaluated 551 KTs performed from 2003 to 2015 in our centre. Patients were categorized into three groups: KT before (2003-07), directly after (2008-11) and 5 years after (2012-15) implementation of the consensus. We analysed clinical characteristics, the rate of cardiac CTs and CAGs prior to KT as well as major adverse cardiac events (MACEs) during a 2-year follow-up after KT.

Results: The three study groups showed a homogeneous distribution of comorbidities and age. Significantly more cardiac CTs (13.6% versus 10.2% versus 44.8%; P = 0.002) and CAGs (39.6% versus 43.9% versus 56.2%; P = 0.003) were performed after the consensus. Coronary interventions were performed during 42 out of 260 CAGs (16.2%), the cumulative 2-year MACE incidence was 8.7%. Regarding MACE occurrence, no significant difference between the three groups was found.

Conclusion: CV risk stratification has become more rigorous and invasive after the implementation of the consensus; however, this was not associated with an improvement in CV outcome.
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http://dx.doi.org/10.1093/ndt/gfaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538198PMC
October 2020

The Case | Glomerulonephritis in a patient with rheumatoid arthritis.

Kidney Int 2020 10;98(4):1057-1058

Divison of Nephrology, Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.05.010DOI Listing
October 2020

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA), Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI), Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI), Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI), Österreichische Gesellschaft für Pneumologie (ÖGP) in co-operation with the German, Austrian, and Swiss ARIA groups, and the European Academy of Allergy and Clinical Immunology (EAACI).

Authors:
Ludger Klimek Oliver Pfaar Margitta Worm Thomas Eiwegger Jan Hagemann Markus Ollert Eva Untersmayr Karin Hoffmann-Sommergruber Alessandra Vultaggio Ioana Agache Sevim Bavbek Apostolos Bossios Ingrid Casper Susan Chan Alexia Chatzipetrou Christian Vogelberg Davide Firinu Paula Kauppi Antonios Kolios Akash Kothari Andrea Matucci Oscar Palomares Zsolt Szépfalusi Wolfgang Pohl Wolfram Hötzenecker Alexander R Rosenkranz Karl-Christian Bergmann Thomas Bieber Roland Buhl Jeroen Buters Ulf Darsow Thomas Keil Jörg Kleine-Tebbe Susanne Lau Marcus Maurer Hans Merk Ralph Mösges Joachim Saloga Petra Staubach Uta Jappe Klaus F Rabe Uta Rabe Claus Vogelmeier Tilo Biedermann Kirsten Jung Wolfgang Schlenter Johannes Ring Adam Chaker Wolfgang Wehrmann Sven Becker Laura Freudelsperger Norbert Mülleneisen Katja Nemat Wolfgang Czech Holger Wrede Randolf Brehler Thomas Fuchs Peter-Valentin Tomazic Werner Aberer Antje-Henriette Fink-Wagner Fritz Horak Stefan Wöhrl Verena Niederberger-Leppin Isabella Pali-Schöll Wolfgang Pohl Regina Roller-Wirnsberger Otto Spranger Rudolf Valenta Mübecell Akdis Paolo M Matricardi François Spertini Nicolai Khaltaev Jean-Pierre Michel Larent Nicod Peter Schmid-Grendelmeier Marco Idzko Eckard Hamelmann Thilo Jakob Thomas Werfel Martin Wagenmann Christian Taube Erika Jensen-Jarolim Stephanie Korn Francois Hentges Jürgen Schwarze Liam O Mahony Edward F Knol Stefano Del Giacco Tomás Chivato Pérez Jean Bousquet Anna Bedbrook Torsten Zuberbier Cezmi Akdis Marek Jutel

Allergol Select 2020 7;4:53-68. Epub 2020 Sep 7.

European Academy of Allergy and Clinical Immunology (EAACI).

Background: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2.

Materials And Methods: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic.

Results: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future.

Conclusion: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.
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http://dx.doi.org/10.5414/ALX02166EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480069PMC
September 2020

Estimation versus measurement of the glomerular filtration rate for kidney function assessment in patients with cancer undergoing cisplatin-based chemotherapy.

Sci Rep 2020 07 8;10(1):11219. Epub 2020 Jul 8.

Division of Oncology, Department of Internal Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Glomerular filtration rate (GFR) assessment is indicated before every administration of cisplatin. The optimal modality for this purpose [GFR measurement by urinary Creatinine Clearance (uCrCl) versus GFR estimation (eGFR) by the CKD-EPI formula versus both] is unclear. We investigated whether eGFR only is safe in this setting. Paired uCrCl and eGFR determinations from 470 cisplatin cycles from 121 patients were analyzed [median age: 55 years; most frequent tumor site: genitourinary (45%); palliative treatment: n = 41 (34%)]. Primary endpoint was the proportion of cycles with uCrCl < 50 ml/min/1.73m and eGFR ≥ 50 ml/min/1.73m (i.e. a "false negative" result when only determining eGFR). The primary endpoint occurred in 8 of 470 cisplatin cycles (1.7%, 95%CI 0.5-2.9). In all 8 events, uCrCl was lower than eGFR (mean uCrCl vs. eGFR: 43 versus 112 ml/min/1.73m). The uCrCl was re-measured in all patients, and showed normal results in all but 1 patient. None of these events precluded the administration of cisplatin at the planned date, and no subsequent cases of acute nephrotoxicity occurred. Overall agreement between uCrCl and eGFR was low, with qualitative analysis suggesting frequent incompliance with 24-h urine collection. We conclude that an eGFR is sufficient for assessing kidney function in patients with cancer undergoing cisplatin therapy.
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http://dx.doi.org/10.1038/s41598-020-68010-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343883PMC
July 2020

Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemie: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H.

Allergo J 2020 24;29(4):14-27. Epub 2020 Jun 24.

Zentrum für Rhinologie & Allergologie, An den Quellen 10, 65183 Wiesbaden, Germany.

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http://dx.doi.org/10.1007/s15007-020-2553-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289636PMC
June 2020

Employment Status and Associations with Workability, Quality of Life and Mental Health after Kidney Transplantation in Austria.

Int J Environ Res Public Health 2020 02 15;17(4). Epub 2020 Feb 15.

Department of Physical Medicine, Rehabilitation and Occupational Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Kidney transplantation (KTx) in end-stage renal disease is associated with a significant increase in quality of life (QoL) and self-perceived health, optimally leading to the maintenance of employment or return to work (RTW) in working-age patients. The aim of this study was to assess individual factors including the QoL and mental health of kidney transplant recipients (KTRs) associated with employment after transplantation. A cross-sectional study including working-age patients with a history of KTx after 2012 was conducted at two Austrian study centers (Vienna and Graz). Brief Symptom Inventory (BSI-18), World Health Organization Quality of Life (WHOQOL-Bref) and Workability Index (WAI) were assessed along with detailed questionnaires on employment status. Out of = 139 KTRs (43.2 ± 9.07 years; 57.6% male), 72 (51.8%) were employed. Employed patients were more frequently in a partnership ( = 0.018) and had higher education levels ( = 0.01) and QoL scores (<0.001). Unemployed KTRs reported fatigue and mental health issues more often ( < 0.001), and had significantly higher anxiety, depression and somatization scores (BSI-18). In unadjusted logistical regression, workability score (WAS; odds ratio (OR) = 3.39; 95% confidence interval (CI) = 1.97-5.82; < 0.001), partnership (OR = 5.47; 95% CI 1.43-20.91; = 0.013) and no psychological counseling after KTx (OR = 0.06; 95% CI = 0.003-0.969; = 0.048) were independently associated with employment. Self-assessed mental health, workability and QoL were significantly associated with employment status after KTx. Thus, in order to facilitate RTW after KTx in Austria, vocational rehabilitation and RTW programs addressing KTRs should focus on increasing social support and care for their mental health.
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http://dx.doi.org/10.3390/ijerph17041254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068411PMC
February 2020

Supine equilibration of extracellular fluid in peritoneal dialysis varies with intra-abdominal pressure.

Perit Dial Int 2020 09 13;40(5):477-486. Epub 2020 Jan 13.

Division of Nephrology, Department of Internal Medicine, 31475Medical University of Graz, Graz, Austria.

Background: Increased intra-abdominal pressure (PIA) leads to venous congestion in splanchnic and adjoining circulations. The aim is to examine whether PIA in peritoneal dialysis (PD) affects the mobilization of extracellular fluid from the lower body in supine body position.

Methods: Patients were studied during a regular peritoneal equilibration test (PET) in supine body position using multifrequency bioimpedance analysis to determine extracellular resistance and absolute volume overload (AVO) in wrist-to-ankle (W2A) as well as in ankle-to-ankle (A2A) configurations. Measurements were taken at baseline (T0) after draining the peritoneal cavity, at T1 shortly after filling with 2 L of standard dialysate, and at T2 before taking the 2 h PET samples. PIA was measured from the column height in the PD catheter. Extracellular resistance in the lower extremities (RL) was taken as half of the A2A resistance.

Results: Eighteen patients (56 ± 15 years, 76 ± 21 kg, body mass index (BMI) 26.4 ± 7 kg/m, 13 men) were studied. After having assumed a supine body position for the duration of 17, 77, and 155 min, AVO continuously decreased from 1.6 ± 1.3 (T0) to 1.2 ± 1.5 (T1) and 1.0 ± 1.4 L (T2). RL significantly increased from 238 ± 57 (T0) to 254 ± 62 (T1) and 264 ± 67 Ohm (T2). This increase was negatively correlated to BMI and PIA measured at any time point, but not to net ultrafiltration volume.

Conclusions: Orthostatic fluid shifts from the lower limbs may take up to 2 h in supine PD patients, especially with high BMI and PIA because of venous congestion in splanchnic and adjoining circulations.
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http://dx.doi.org/10.1177/0896860819895176DOI Listing
September 2020

Repeated kidney re-transplantation-the Eurotransplant experience: a retrospective multicenter outcome analysis.

Transpl Int 2020 Jun 30;33(6):617-631. Epub 2020 Jan 30.

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

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.
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http://dx.doi.org/10.1111/tri.13569DOI Listing
June 2020

Glucagon-Like Peptide-1 Receptor Agonism Improves Nephrotoxic Serum Nephritis by Inhibiting T-Cell Proliferation.

Am J Pathol 2020 02 22;190(2):400-411. Epub 2019 Nov 22.

Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell-dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy.
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http://dx.doi.org/10.1016/j.ajpath.2019.10.008DOI Listing
February 2020

Contrast Induced Acute Kidney Injury and its Impact on Mid-Term Kidney Function, Cardiovascular Events and Mortality.

Sci Rep 2019 11 15;9(1):16896. Epub 2019 Nov 15.

Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.

The existence and clinical relevance of contrast induced acute kidney injury (CI-AKI) is still heavily debated and angiographic procedures are often withheld in fear of CI-AKI, especially in CKD-patients. We investigated the incidence of CI-AKI in cardiovascular high risk patients undergoing intra-arterial angiography and its impact on mid-term kidney function, cardiovascular events and mortality. We conducted a prospective observational trial on patients undergoing planned intra-arterial angiographic procedures. All subjects received standardized intravenous hydration prior to contrast application. CI-AKI was defined according to a ≥25% increase of creatinine from baseline to either 24hrs or 48hrs after angiography. Plasma creatinine and eGFR were recorded from the institutional medical record system one and three months after hospital discharge. Patients were followed up for two years to investigate the long term effects of CI-AKI on cardiovascular events and mortality. We studied 706 (317 female) patients with a mean eGFR of 52.0 ± 15 ml·min·1.73 m. The incidence of CI-AKI was 10.2% (72 patients). In 94 (13.3%) patients serum creatinine decreased ≥25% either 24 or 48 hours after angiography. Patients with CI-AKI had a lower creatinine and a higher eGFR at baseline, but no other independent predictors of CI-AKI could be identified. Kidney function was not different between both groups one and three months after discharge. After a two year follow up the overall incidence of cardiovascular events was 56.5% in the CI-AKI group and 58.8% in the Non CI-AKI group (p = 0.8), the incidence of myocardial infarctions, however, was higher in CI-AKI-patients. Overall survival was also not different between patients with CI-AKI (88.6%) and without CI-AKI (84.7%, p = 0.48). The occurrence of CI-AKI did not have any negative impact on mid-term kidney function, the incidence of cardiovascular events and mortality. Considerable fluctuations of serum creatinine interfere with the presumed diagnosis of CI-AKI. Necessary angiographic procedures should not be withheld in fear of CI-AKI.
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http://dx.doi.org/10.1038/s41598-019-53040-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858434PMC
November 2019

Early renal dysfunction and fibroblast growth factor-23 in patients with small vessel disease-related stroke.

Sci Rep 2019 10 28;9(1):15410. Epub 2019 Oct 28.

Department of Neurology, Medical University of Graz, Graz, Austria.

Interactions between cerebral small vessel disease (CSVD) and renal dysfunction (RD) have been reported, but previous studies were mostly retrospective and limited to measurements of estimated glomerular filtration rate (eGFR). In this prospective, longitudinal study of patients with CSVD-related recent small subcortical infarcts (RSSI), we aimed at a comprehensive exploration of markers of early RD and their association with microvascular brain damage. We investigated 101 stroke patients (mean age: 60.2 ± 10.7 years) with an MRI-confirmed RSSI who underwent follow-up brain MRI 15 months post-stroke. Besides serum creatinine and eGFR, we assessed urinary Albumin-Creatinine Ratio and fibroblast growth factor-23 (FGF-23). RD was classified according to recent Kidney Disease: Improving Global Outcomes criteria. We identified 24 patients with RD, only six patients revealed an eGFR <60 mL/min/1.73 m². RSSI patients with RD more often had severe white matter hyperintensities (WMH, 58% vs. 36%, p = 0.04). CSVD progression was not dependent on RD. However, patients in the highest FGF-23 quartile more frequently had new microangiopathic lesions on follow-up MRI (50% vs. 21%, p = 0.03). Early RD was found in a quarter of RSSI patients and associated with WMH severity, but not CSVD progression. High FGF-23 indicates an increased risk for ongoing microvascular brain damage, warranting further studies.
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http://dx.doi.org/10.1038/s41598-019-51965-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817845PMC
October 2019

Cholemic Nephropathy Reloaded.

Semin Liver Dis 2020 02 18;40(1):91-100. Epub 2019 Oct 18.

Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Acute kidney injury (AKI) is a dreaded complication in patients with liver disease and jaundice, since it is associated with significant morbidity and mortality. Cholemic nephropathy (CN) is thought to represent a widely underestimated important cause of AKI in advanced liver diseases with jaundice. The umbrella term CN describes impaired renal function along with histomorphological changes consisting of intratubular cast formation and tubular epithelial cell injury directed primarily toward distal nephron segments. In cholestasis, biliary constituents may be excreted via the kidney and bilirubin or bile acids may trigger tubular injury and cast formation, but as we begin to understand the underlying pathophysiologic mechanisms, we become increasingly aware of the urgent need for clearly defined diagnostic criteria. In the following, we aim to summarize current knowledge of clinical and morphological characteristics of CN, discuss potential pathomechanisms, and raise key questions to stimulate evolution of a research strategy for CN.
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http://dx.doi.org/10.1055/s-0039-1698826DOI Listing
February 2020

Author Correction: Structural and functional differences in gut microbiome composition in patients undergoing haemodialysis or peritoneal dialysis.

Sci Rep 2019 Jun 6;9(1):8522. Epub 2019 Jun 6.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-43263-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551338PMC
June 2019

[Diabetic kidney disease (Update 2019) : Position paper of the Austrian Diabetes Association and the Austrian Society for Nephrology].

Wien Klin Wochenschr 2019 May;131(Suppl 1):151-163

Klinische Abteilung für Nephrologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Graz, Österreich.

Recent epidemiological investigations have shown that approximately 2-3% of all Austrians suffer from diabetes with renal involvement, i. e. 250,000 people in Austria are affected. The risk of occurrence and progression of this disease can be ameliorated by life style interventions as well as optimization of blood pressure, blood glucose levels and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society for Nephrology for the diagnostics and treatment strategies of diabetic kidney disease.
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http://dx.doi.org/10.1007/s00508-018-1425-xDOI Listing
May 2019

MicroRNA-142-3p improves vascular relaxation in uremia.

Atherosclerosis 2019 01 10;280:28-36. Epub 2018 Nov 10.

Department of Internal Medicine, Clinical Division of Nephrology, Medical University of Graz, Graz, Austria.

Background And Aims: Chronic kidney disease (CKD) is strongly associated with a high burden of cardiovascular morbidity and mortality. Therefore, we aimed to characterize the putative role of microRNAs (miR)s in uremic vascular remodelling and endothelial dysfunction.

Methods: We investigated the expression pattern of miRs in two independent end-stage renal disease (ESRD) cohorts and in the animal model of uremic DBA/2 mice via quantitative RT-PCR. Moreover, DBA/2 mice were treated with intravenous injections of synthetic miR-142-3p mimic and were analysed for functional and morphological vascular changes by mass spectrometry and wire myography.

Results: The expression pattern of miRs was regulated in ESRD patients and was reversible after kidney transplantation. Out of tested miRs, only blood miR-142-3p was negatively associated with carotid-femoral pulse-wave velocity in CKD 5D patients. We validated these findings in a murine uremic model and found similar suppression of miR-142-3p as well as decreased acetylcholine-mediated vascular relaxation of the aorta. Therefore, we designed experiments to restore bioavailability of aortic miR-142-3p in vivo via intravenous injection of synthetic miR-142-3p mimic. This intervention restored acetylcholine-mediated vascular relaxation.

Conclusions: Taken together, we provide compelling evidence, both in humans and in mice, that miR-142-3p constitutes a potential pharmacological agent to prevent endothelial dysfunction and increased arterial stiffness in ESRD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591123PMC
January 2019

A randomized controlled trial of alanyl-glutamine supplementation in peritoneal dialysis fluid to assess impact on biomarkers of peritoneal health.

Kidney Int 2018 12 22;94(6):1227-1237. Epub 2018 Oct 22.

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Medical University of Vienna, Vienna, Austria.

In early clinical testing, acute addition of alanyl-glutamine (AlaGln) to glucose-based peritoneal dialysis (PD) fluids restored peritoneal cellular stress responses and leukocyte function. This study was designed to test the effect of extended treatment with AlaGln-supplemented PD fluid on biomarkers of peritoneal health. In a double-blinded, randomized crossover design, stable PD patients were treated with AlaGln (8 mM) or placebo added to PD fluid for eight weeks. As primary outcome measures, dialysate cancer-antigen 125 (CA-125) appearance rate and ex vivo stimulated interleukin-6 (IL-6) release were assessed in peritoneal equilibration tests. In 8 Austrian centers, 54 patients were screened, 50 randomized, and 41 included in the full analysis set. AlaGln supplementation significantly increased CA-125 appearance rate and ex vivo stimulated IL-6 release. AlaGln supplementation also reduced peritoneal protein loss, increased ex vivo stimulated tumor necrosis factor (TNF)-α release, and reduced systemic IL-8 levels. No adverse safety signals were observed. All 4 peritonitis episodes occurred during standard PD fluid treatment. A novel AlaGln-supplemented PD fluid improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation compared to unsupplemented PD fluid with neutral pH and low-glucose degradation. A phase 3 trial is needed to determine the impact of AlaGln supplementation on hard clinical outcomes.
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http://dx.doi.org/10.1016/j.kint.2018.08.031DOI Listing
December 2018

Blockade of prostaglandin E receptor 4 ameliorates nephrotoxic serum nephritis.

Am J Physiol Renal Physiol 2018 12 17;315(6):F1869-F1880. Epub 2018 Oct 17.

Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Prostaglandin E (PGE) signaling is known to modulate inflammation and vascular resistance. Receptors of PGE [E-type prostanoid receptors (EP)] might be an attractive pharmacological target in immune-mediated diseases such as glomerulonephritis. We hypothesized that selective EP4 antagonism improves nephrotoxic serum nephritis (NTS) by its anti-inflammatory properties. Mice were subjected to NTS and treated with the EP4 antagonist ONO AE3-208 (10 mg·kg body wt·day] or vehicle starting from disease initiation. In one set of experiments, treatment was started 4 days after NTS induction. Tubular epithelial cells were evaluated in vitro under starving conditions. EP4 antagonist treatment significantly improved the NTS phenotype without affecting blood pressure levels. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. EP4 antagonism decreased tubular chemokine (C-X-C motif) ligand ( Cxcl) 1 and Cxcl-5 expression and thereby subsequently reduced interstitial neutrophil infiltration into the kidney. In vitro, tubular epithelial cells increasingly expressed Cxcl-5 mRNA and Cxcl-5 protein when treated with PGE or an EP4 agonist under starving conditions, which was blunted by EP4 antagonist treatment. Together, EP4 antagonism improves the NTS phenotype, probably by decreasing mainly Cxcl-5 production in tubular cells, thereby reducing renal neutrophil infiltration.
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http://dx.doi.org/10.1152/ajprenal.00113.2018DOI Listing
December 2018

Intradialytic kinetics of middle molecules during hemodialysis and hemodiafiltration.

Nephrol Dial Transplant 2019 05;34(5):870-877

Gambro Dialysatoren, Hechingen, Germany.

Background: The kinetics of β2-microglobulin during hemodialysis and hemodiafiltration is well described by a two-compartment model where clearance by the dialyzer is from a central compartment volume that approximates plasma volume and a total distribution volume that approximates extracellular fluid volume. The kinetics of middle molecules with molecular weights larger than β2-microglobulin have not been extensively studied.

Methods: Intradialytic plasma concentrations and overall dialyzer clearances of β2-microglobulin (11.8 kD), myoglobin (16.7 kD) and complement factor D (24.4 kD) were used to estimate three kinetic parameters from a two-compartment model, namely intercompartmental clearance, central compartment volume and total distribution volume, in hemodialysis patients; these data were collected during two clinical trials of medium cut-off dialyzers (with extended middle molecule removal) during hemodialysis and high-flux dialyzers during hemodialysis and hemodiafiltration. In the current exploratory analyses, the kinetic parameters from all dialyzers were combined. Overall dialyzer clearance was evaluated by total mass removed in the dialysate.

Results: In total, 345 sets of kinetic parameters from 35 patients were determined. Intercompartmental clearance and central compartment volume for myoglobin and complement factor D were smaller (P < 0.001) than those for β2-microglobulin. Independent of middle molecule, intercompartmental clearance and central compartment volume were associated with overall dialyzer clearance (P < 0.001), but total distribution volume was not (P = 0.083).

Conclusions: A two-compartment kinetic model can only describe intradialytic kinetics of middle molecules with molecular weights larger than β2-microglobulin if the central compartment is small and dependent on overall dialyzer clearance.
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http://dx.doi.org/10.1093/ndt/gfy304DOI Listing
May 2019

Autophagy Protects From Uremic Vascular Media Calcification.

Front Immunol 2018 14;9:1866. Epub 2018 Aug 14.

Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored by culturing MOVAS under calcifying conditions. Both, and , autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic , but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. , rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification and . Rapamycin reduced transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.
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http://dx.doi.org/10.3389/fimmu.2018.01866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102358PMC
September 2019

Atypical chemokine receptors-"chemokine PACMANs" as new therapeutic targets in glomerulonephritis.

Kidney Int 2018 04;93(4):774-775

Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Inflammatory cells are recruited to sites of inflammation by chemokines. Atypical chemokine receptors regulate chemokine gradients, thereby limiting inflammation. In this issue of Kidney International, atypical chemokine receptor 2 knockouts were described to be increasingly susceptible to immune complex-mediated glomerulonephritis. By degrading CCL2, atypical chemokine receptor 2 limited the recruitment of immune cells and myofibroblasts to the renal interstitial compartment. Therefore, not only inflammation, but also fibrosis, was effectively inhibited, making atypical chemokine receptor 2 an attractive therapeutic target in glomerulonephritis.
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http://dx.doi.org/10.1016/j.kint.2017.12.021DOI Listing
April 2018

A New Murine Model of Chronic Kidney Disease-Mineral and Bone Disorder.

Int J Endocrinol 2017 14;2017:1659071. Epub 2017 Dec 14.

Clinical Division of Nephrology, Medical University of Graz, Graz, Austria.

Chronic kidney disease (CKD) is associated with mineral and bone disorder (MBD), which is the main cause of the extensively increased cardiovascular mortality in the CKD population. We now aimed to establish a new murine experimental CKD-MBD model. Dilute brown non-Agouti (DBA/2) mice were fed with high-phosphate diet for 4 (HPD4) or 7 (HPD7) days, then with standard chow diet (SCD) and subsequently followed until day 84. They were compared to DBA/2 mice maintained on SCD during the whole study period. Both 4 and 7 days HPD-fed mice developed phosphate nephropathy with tubular atrophy, interstitial fibrosis, decreased glomerular filtration rate, and increased serum urea levels. The abdominal aorta of HPD-treated mice showed signs of media calcification. Histomorphometric analysis of HPD-treated mice showed decreased bone volume/tissue volume, low mineral apposition rate, and low bone formation rate as compared to SCD-fed mice, despite increased parathyroid hormone levels. Overall, the observed phenotype was more pronounced in the HPD7 group. In summary, we established a new, noninvasive, and therefore easy to perform reproducible CKD-MBD model, which showed media calcification, secondary hyperparathyroidism, and low-turnover bone disease.
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http://dx.doi.org/10.1155/2017/1659071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745741PMC
December 2017