Publications by authors named "Björn Tampe"

47 Publications

Correspondence on 'Second COVID-19 infection in a patient with granulomatosis with polyangiitis on rituximab'.

Ann Rheum Dis 2021 May 12. Epub 2021 May 12.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany

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http://dx.doi.org/10.1136/annrheumdis-2021-220382DOI Listing
May 2021

Proteinuria Indicates Decreased Normal Glomeruli in ANCA-Associated Glomerulonephritis Independent of Systemic Disease Activity.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Background: Renal involvement is a common and severe complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), potentially resulting in a pauci-immune necrotizing and crescentic ANCA glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. There is recent evidence that the degree of proteinuria at diagnosis is associated with long-term renal outcome in ANCA GN. Therefore, we here aimed to systematically describe the association between proteinuria and clinicopathological characteristics in 53 renal biopsies with ANCA GN and corresponding urinary samples at admission.

Methods: A total number of 53 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included from 2015 to 2021 in a single-center study.

Results: Proteinuria correlated with myeloperoxidase (MPO) subtype, diagnosis of microscopic polyangiitis (MPA) and severe deterioration of kidney function. Proteinuria was most prominent in sclerotic class ANCA GN and ANCA renal risk score (ARRS) high risk attributed to nonselective proteinuria, including both glomerular and tubular proteinuria. Finally, there was no association between proteinuria and systemic disease activity, suggesting that proteinuria reflected specific renal involvement in AAV rather that systemic disease activity.

Conclusions: In conclusion, proteinuria correlated with distinct clinicopathological characteristics in ANCA GN, mostly attributed to a reduced fraction of normal glomeruli. Furthermore, proteinuria in ANCA GN reflected specific renal involvement in AAV rather than systemic disease activity. Therefore, urinary findings could further improve our understanding of mechanisms promoting kidney injury and progression of ANCA GN.
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http://dx.doi.org/10.3390/jcm10071538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038827PMC
April 2021

Bowman's capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis.

Clin Exp Rheumatol 2021 Apr 7. Epub 2021 Apr 7.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Germany.

Objectives: We have recently described the frequency of Bowman's capsule (BC) rupture in a considerable subset of patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). Interestingly, recent reports established a better performance of glomerulocentric ANCA scoring systems after adding BC rupture to these classification systems, suggesting that characteristics of this lesion are independent from glomerular lesions. Since BC rupture may link glomerular damage to tubulointerstitial lesions via direct interaction with the surrounding interstitium, we here aimed to expand our current knowledge of this distinct lesion by a systematic description of tubulointerstitial lesions analogous to the Banff classification in association with the presence of BC rupture in ANCA GN.

Methods: A total number of 44 kidney biopsies with confirmed renal involvement of ANCA GN were retrospectively included between 2015 till 2020 in a single-centre observational study.

Results: We here show that presence of BC rupture was associated with severe deterioration of kidney function at disease onset, similar to previous findings regarding long-term renal survival. Furthermore, BC rupture in ANCA GN was associated with tubulointerstitial inflammation and ultrastructural analysis revealed direct cellular exchange between Bowman's space and the interstitium, potentially contributing to the observed deterioration of kidney function and worse renal outcome in ANCA GN.

Conclusions: BC rupture is associated with renal outcome in ANCA GN, therefore underscoring the need for further studies with regard to the glomerular-tubulointerstitial interaction in this disease.
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April 2021

Systematic Histological Scoring Reveals More Prominent Interstitial Inflammation in Myeloperoxidase-ANCA Compared to Proteinase 3-ANCA Glomerulonephritis.

J Clin Med 2021 Mar 16;10(6). Epub 2021 Mar 16.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Kidney involvement is a common and severe complication of ANCA AAV which is observed in a considerable subset of patients, mainly affecting glomeruli. However, tubulointerstitial lesions have also been described in ANCA glomerulonephritis (GN). Therefore, we aim to describe active and chronic tubulointerstitial lesions in ANCA GN subtypes by systematic scoring analogous to the Banff scoring system while also utilizing clinical and laboratory findings.

Methods: A total of 49 kidney biopsies with ANCA GN were retrospectively included in a single-center cohort study between 2015-2020.

Results: We report that MPO-ANCA GN is associated with more severe deterioration of kidney function independent of systemic markers of AAV disease activity, and is also associated with increased proteinuria in MPO-ANCA GN and a decreased fraction of normal glomeruli. Finally, MPO-ANCA GN showed distinct, active, and chronic tubulointerstitial lesions.

Conclusion: New insights into the pathophysiology of both entities, as well as differences in the clinical presentation of MPO- versus PR3-ANCA GN, could potentially pave the way for more precise treatment regimens. Therefore, it is important to understand the differences in histopathological presentation, especially in yet underestimated active tubulointerstitial lesions of ANCA GN subtypes. This research could further improve our understanding of distinct pathophysiological mechanisms.
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http://dx.doi.org/10.3390/jcm10061231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061772PMC
March 2021

Histopathological Findings Predict Renal Recovery in Severe ANCA-Associated Vasculitis Requiring Intensive Care Treatment.

Front Med (Lausanne) 2020 9;7:622028. Epub 2021 Feb 9.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Renal involvement is a common and severe complication of AAV as it can cause ESRD. Histopathological subgrouping and ARRS are helpful to predict long-term ESRD in patients with AAV. Because a subgroup of critically ill patients with severe AAV present with deterioration of kidney function requiring RRT at admission, we here aimed to evaluate histopathological findings and predictive value of Berden's histopathological subgrouping and ARRS for severity of AKI and requirement of RRT during the short-term clinical course in critically ill patients requiring intensive care treatment and predictors for short-term renal recovery in patients requiring RRT. A subgroup of 15/46 (32. 6%) AAV patients with biopsy-proven AAV required RRT during the short-term course of disease, associated with requirement of critical care treatment. While histopathological subgrouping and ARRS were associated with requirement of acute RRT, presence of global glomerular scarring was the strongest predictor of failure to recover from RRT after initiation of remission induction therapy. This new aspect requires further investigation in a prospective controlled setting for therapeutic decision making especially in this subgroup.
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http://dx.doi.org/10.3389/fmed.2020.622028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900153PMC
February 2021

Editorial: Interstitial Lung Disease in the Context of Systemic Disease: Pathophysiology, Treatment and Outcomes.

Front Med (Lausanne) 2020 20;7:644075. Epub 2021 Jan 20.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of Miami Miller School of Medicine, Miami, FL, United States.

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http://dx.doi.org/10.3389/fmed.2020.644075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874049PMC
January 2021

Variable Expression of Programmed Cell Death Protein 1-Ligand 1 in Kidneys Independent of Immune Checkpoint Inhibition.

Front Immunol 2020 21;11:624547. Epub 2021 Jan 21.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Context: Due to recent advantages in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death protein 1-ligand 1 (PD-L1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) in the kidney observed in patients receiving ICIs and the most common biopsy-proven diagnosis in patients who develop acute kidney injury (AKI). Based on previous reports, AIN in patients receiving ICIs is associated with tubular positivity for PD-L1, implicating that PD-L1 positivity reflects susceptibility to develop renal complications with these agents. It remains unclear if PD-L1 positivity is acquired specifically during ICI therapy or expressed independently in the kidney.

Methods: PD-L1 was analyzed in experimental mouse models of ischemia-reperfusion injury (IRI), folic acid-induced nephropathy (FAN), unilateral ureteral obstruction (UUO), and nephrotoxic serum nephritis (NTN) by immunostaining, SDS-PAGE, and subsequent immunoblotting. In addition, we included a total number of 87 human kidney samples (six renal biopsies with AIN related to ICI therapy, 13 nephrectomy control kidneys, and 68 ICI-naïve renal biopsies with various underlying kidney diseases to describe PD-L1 expression.

Results: We here report distinct PD-L1 expression in renal compartments in multiple murine models of kidney injury and human cases with various underlying kidney diseases, including ICI-related AIN and renal pathologies independent of ICI therapy. PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. In addition, we provide evidence that tubular PD-L1 positivity in the kidney is associated with detection of urinary PD-L1 tubular epithelial cells.

Conclusion: Our study implicates that PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. Because non-invasive detection of PD-L1 cells in corresponding urine samples correlates with intrarenal PD-L1 positivity, it is attractive to speculate that further non-invasive detection of PD-L1 cells may identify patients at risk for ICI-related AIN.
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http://dx.doi.org/10.3389/fimmu.2020.624547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858644PMC
January 2021

Correspondence on 'Bowman's capsule rupture on renal biopsy improves the outcome prediction of ANCA-associated glomerulonephritis classifications'.

Ann Rheum Dis 2021 Feb 5. Epub 2021 Feb 5.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany

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http://dx.doi.org/10.1136/annrheumdis-2021-219970DOI Listing
February 2021

Correspondence on 'Preliminary predictive criteria for COVID-19 cytokine storm'.

Ann Rheum Dis 2021 Jan 7. Epub 2021 Jan 7.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany

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http://dx.doi.org/10.1136/annrheumdis-2020-219709DOI Listing
January 2021

Correspondence on 'What comes after the lockdown? Clustering of ANCA-associated vasculitis: single-centre observation of a spatiotemporal pattern'.

Ann Rheum Dis 2021 Jan 6. Epub 2021 Jan 6.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Gottingen, Germany

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http://dx.doi.org/10.1136/annrheumdis-2020-219687DOI Listing
January 2021

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.

Nat Neurosci 2021 02 30;24(2):168-175. Epub 2020 Nov 30.

Department of Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.
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http://dx.doi.org/10.1038/s41593-020-00758-5DOI Listing
February 2021

Constitutive Atg5 overexpression in mouse bone marrow endothelial progenitor cells improves experimental acute kidney injury.

BMC Nephrol 2020 11 23;21(1):503. Epub 2020 Nov 23.

Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Göttingen, Germany.

Background: Endothelial Progenitor Cells have been shown as effective tool in experimental AKI. Several pharmacological strategies for improving EPC-mediated AKI protection were identified in recent years. Aim of the current study was to analyze consequences of constitutive Atg5 activation in murine EPCs, utilized for AKI therapy.

Methods: Ischemic AKI was induced in male C57/Bl6N mice. Cultured murine EPCs were systemically injected post-ischemia, either natively or after Atg5 transfection (Adenovirus-based approach). Mice were analyzed 48 h and 6 weeks later.

Results: Both, native and transfected EPCs (EPCs) improved persisting kidney dysfunction at week 6, such effects were more pronounced after injecting EPCs. While matrix deposition and mesenchymal transdifferentiation of endothelial cells remained unaffected by cell therapy, EPCs, particularly EPCs completely prevented the post-ischemic loss of peritubular capillaries. The cells finally augmented the augophagocytic flux in endothelial cells.

Conclusions: Constitutive Atg5 activation augments AKI-protective effects of murine EPCs. The exact clinical consequences need to be determined.
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http://dx.doi.org/10.1186/s12882-020-02149-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684746PMC
November 2020

Camostat Mesylate May Reduce Severity of Coronavirus Disease 2019 Sepsis: A First Observation.

Crit Care Explor 2020 Nov 16;2(11):e0284. Epub 2020 Nov 16.

Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Germany.

Severe acute respiratory syndrome coronavirus 2 cell entry depends on angiotensin-converting enzyme 2 and transmembrane serine protease 2 and is blocked in cell culture by camostat mesylate, a clinically proven protease inhibitor. Whether camostat mesylate is able to lower disease burden in coronavirus disease 2019 sepsis is currently unknown.

Design: Retrospective observational case series.

Setting: Patient treated in ICU of University hospital Göttingen, Germany.

Patients: Eleven critical ill coronavirus disease 2019 patients with organ failure were treated in ICU.

Interventions: Compassionate use of camostat mesylate (six patients, camostat group) or hydroxychloroquine (five patients, hydroxychloroquine group).

Measurements And Main Results: Clinical courses were assessed by Sepsis-related Organ Failure Assessment score at days 1, 3, and 8. Further, viral load, oxygenation, and inflammatory markers were determined. Sepsis-related Organ Failure Assessment score was comparable between camostat and hydroxychloroquine groups upon ICU admission. During observation, the Sepsis-related Organ Failure Assessment score decreased in the camostat group but remained elevated in the hydroxychloroquine group. The decline in disease severity in camostat mesylate treated patients was paralleled by a decline in inflammatory markers and improvement of oxygenation.

Conclusions: The severity of coronavirus disease 2019 decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed in patients receiving hydroxychloroquine. Camostat mesylate thus warrants further evaluation within randomized clinical trials.
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http://dx.doi.org/10.1097/CCE.0000000000000284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671878PMC
November 2020

Therapeutic Implications of Renal Biopsies to Detect Proliferative Lupus Nephritis in Patients With Low-Grade Proteinuria.

Kidney Int Rep 2020 Nov 28;5(11):2120-2121. Epub 2020 Aug 28.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1016/j.ekir.2020.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609901PMC
November 2020

Correspondence on 'Interleukin-6 receptor blockade with subcutaneous tocilizumab in severe COVID-19 pneumonia and hyperinflammation: case-control study'.

Ann Rheum Dis 2020 Sep 21. Epub 2020 Sep 21.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany

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http://dx.doi.org/10.1136/annrheumdis-2020-218836DOI Listing
September 2020

There is no intraocular affection on a SARS-CoV-2 - Infected ocular surface.

Am J Ophthalmol Case Rep 2020 Dec 20;20:100884. Epub 2020 Aug 20.

University Medical Center Goettingen, Institute for Pathology, Germany.

Purpose: The presence of SARS-CoV-2 RNA in anterior chamber fluid and/or the vitreous in patients with SARS-CoV-2 RNA on the ocular surface is unclear. Knowledge about the infectious state of intraocular structures could influence the daily work of ophthalmic surgeons.

Observations: We analyzed ocular samples from a patient who had succumbed to COVID-19 pneumonia for the prevalence of SARS-CoV-2 RNA. We detected viral RNA in the ocular-surface samples on one swab and in one excidate from the conjunctiva. Samples from the anterior chamber and vitreous revealed no SARS-CoV-2 RNA.

Conclusions: SARS-CoV-2 can effectively be inactivated with standard disinfection agents. The now proven absence of SARS-CoV-2 in intraocular fluids could influence how ophthalmic surgeons work. Without having to account for the risk of a contagion via the anterior chamber and/or vitreous body, the surgical staff would require no additional, more elaborate protection.
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http://dx.doi.org/10.1016/j.ajoc.2020.100884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439011PMC
December 2020

The Secretome Analysis of Activated Human Renal Fibroblasts Revealed Beneficial Effect of the Modulation of the Secreted Peptidyl-Prolyl Cis-Trans Isomerase A in Kidney Fibrosis.

Cells 2020 07 18;9(7). Epub 2020 Jul 18.

Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.

The secretome is an important mediator in the permanent process of reciprocity between cells and their environment. Components of secretome are involved in a large number of physiological mechanisms including differentiation, migration, and extracellular matrix modulation. Alteration in secretome composition may therefore trigger cell transformation, inflammation, and diseases. In the kidney, aberrant protein secretion plays a central role in cell activation and transition and in promoting renal fibrosis onset and progression. Using comparative proteomic analyses, we investigated in the present study the impact of cell transition on renal fibroblast cells secretome. Human renal cell lines were stimulated with profibrotic hormones and cytokines, and alterations in secretome were investigated using proteomic approaches. We identified protein signatures specific for the fibrotic phenotype and investigated the impact of modeling secretome proteins on extra cellular matrix accumulation. The secretion of peptidyl-prolyl cis-trans isomerase A (PPIA) was demonstrated to be associated with fibrosis phenotype. We showed that the in-vitro inhibition of PPIA with ciclosporin A (CsA) resulted in downregulation of PPIA and fibronectin (FN1) expression and significantly reduced their secretion. Knockdown studies of PPIA in a three-dimensional (3D) cell culture model significantly impaired the secretion and accumulation of the extracellular matrix (ECM), suggesting a positive therapeutic effect on renal fibrosis progression.
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http://dx.doi.org/10.3390/cells9071724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407823PMC
July 2020

Severely destructive unilateral wrist arthritis as a rare variant of rheumatoid arthritis: analysis of clinical and imaging features.

Clin Exp Rheumatol 2021 Mar-Apr;39(2):372-377. Epub 2020 Jun 23.

Department of Nephrology and Rheumatology, University Medical Centre Göttingen, Germany.

Objectives: Rheumatoid arthritis (RA) is a common autoimmune disease typically affecting joints symmetrically. A small number of patients develop unilateral and severely destructive wrist arthritis (DWA). The objective of our study was to characterise patients with this type of affection.

Methods: This was a retrospective cohort study of RA patients with positive RF/anti-CCP antibodies. Clinical characteristics, including, age, gender, disease duration, dexterity, occupational history, smoking status, and the number of prescribed DMARDs were recorded. Conventional radiographs were evaluated using the modified Sharp/van der Heijde scoring (mSS) method.

Results: We analysed our laboratory database of 1247 patients and identified 559 patients with a clinical diagnosis of RA. For 395 of the patients, radiographs of the hands were available for evaluation. 25 patients had extensive unilateral DWA, corresponding to a prevalence of 6.3% (25 of 395 patients). 11 patients were excluded due to incomplete data. Of the remaining 14 patients, 13 were female with a median age of 61 (33-83) years, and median disease duration of 18 (1-33) years. 8 of 11 (72.7%) patients were smokers; in three, smoking status was not known. 80% with known dexterity developed unilateral DWA in the dominant hand. Total mSS was significantly higher on the affected side (39, interquartile range 35.25-46.25) versus non-affected (13, IQR 3-23). MSS were not different if the carpal bones were excluded from scoring. Side of involvement (left vs. right), or dominant versus non-dominant hand, did not result in a different mSS.

Conclusions: Unilateral DWA is a rare variant of RA which predominantly affects women who smoke.
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April 2021

Clinical Efficacy of Routinely Administered Belimumab on Proteinuria and Neuropsychiatric Lupus.

Front Med (Lausanne) 2020 27;7:222. Epub 2020 May 27.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Belimumab (BEL) is a monoclonal antibody approved for the treatment of active systemic lupus erythematosus (SLE) but not for lupus nephritis (LN) and neuropsychiatric systemic lupus erythematosus (NPSLE). We aimed to assess BEL's effects on these severe, potentially life-threatening manifestations. Retrospective observational cohort study using routine clinical data in a case series of patients with SLE receiving BEL. Sixteen patients received BEL therapy for active SLE. Nine were excluded because they had no LN or NPSLE. Six suffered from LN, and one patient had NPSLE. All LN patients received BEL in addition to standard therapy including glucocorticoids, hydroxychloroquine, and mycophenolate mofetil in five cases, and tacrolimus in one case. Three patients with proteinuria >1,000 mg/g creatinine responded well (one complete, two partial renal responses); all other patients had decreasing proteinuria and a reduction in anti-dsDNA levels. The patient with NPSLE who had failed previous therapies had persistent clinical improvement of cutaneous and neuropsychiatric manifestations. There was one mild allergic reaction and one lower respiratory tract infection, but no other adverse events. One patient discontinued therapy due to a lack of improvement in clinical symptoms, another because of clinical remission. In our series, BEL led to a decrease of proteinuria in patients with proteinuria of more than 1,000 mg/g creatinine despite standard of care treatment, and led to a marked clinical improvement in one patient with NPSLE. No adverse events were observed. Routinely administered BEL shows clinical efficacy on non-approved manifestations, but careful patient selection is warranted.
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http://dx.doi.org/10.3389/fmed.2020.00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267006PMC
May 2020

Rheopheresis for Digital Ulcers and Raynaud's Phenomenon in Systemic Sclerosis Refractory to Conventional Treatments.

Front Med (Lausanne) 2019 18;6:208. Epub 2019 Sep 18.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Raynaud's phenomenon (RP) is almost universally present in patients with Systemic Sclerosis (SSc). RP represents a generalized vasculopathy and potentially lead to digital ulcers (DU), which may be complicated by superinfection, tissue necrosis, and limb loss. We report the analysis of an extracorporeal procedure in a 36-year-old female patient with diffuse SSc with refractory RP and DU despite treatment with diltiazem, candesartan, sildenafil, and intravenous iloprost. We performed rheopheresis (RheoP), a variant of double-filtration plasmapheresis, as a potential new treatment option for refractory patients despite optimal medical therapy. We performed two RheoP per week every 4 weeks for a total of 3 months. Clinical improvement in DU healing occurred with no adverse events directly related to the treatment. While there was no reduction in the number of Raynaud attacks with RheoP, a significant reduction of the duration of attacks from a median of 15 (5-45, 95% CI 10-15) to 7 (3-30, 95% CI 6-10) minutes with an improvement of the Raynaud Condition Score (RCS) improved from 4 to 2. In conclusion, RheoP is a feasible and potentially beneficial treatment modality in patients with refractory RP and DU. We propose that RheoP should be investigated in a larger number of patients in a clinical trial setting.
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http://dx.doi.org/10.3389/fmed.2019.00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759692PMC
September 2019

[A 82-Year-Old Female Patient with Rheumatoid Arthritis and Neck Pain].

Dtsch Med Wochenschr 2019 03 5;144(5):305-306. Epub 2019 Mar 5.

Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen.

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http://dx.doi.org/10.1055/a-0818-9623DOI Listing
March 2019

Modulation of NCAM/FGFR1 signaling suppresses EMT program in human proximal tubular epithelial cells.

PLoS One 2018 1;13(11):e0206786. Epub 2018 Nov 1.

Institute of Pathology, University of Belgrade-Faculty of Medicine, Belgrade, Serbia.

Neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor 1 (FGFR1) cross-talk have been involved in epithelial-to-mesenchymal transition (EMT) process during carcinogenesis. Since EMT also contributes to maladaptive repair and parenchymal damage during renal fibrosis, we became encouraged to explore the role of NCAM/FGFR1 signaling as initiating or driving forces of EMT program in cultured human proximal tubular epithelial cells (TECs). TECs stimulated with TGF-β1 (10ng/mL) was used as an established in vitro EMT model. TGF-β1 downstream effectors were detected in vitro, as well as in 50 biopsies of different human kidney diseases to explore their in vivo correlation. NCAM/FGFR1 signaling and its modulation by FGFR1 inhibitor PD173074 (100nM) were analyzed by light microscopy, immunolabeling, qRT-PCR and scratch assays. Morphological changes associated with EMT appeared 48h after TGF-ß1 treatment and was clearly apparent after 72 hours, followed by loss of CDH1 (encoding E-Cadherin) and transcriptional induction of SNAI1 (SNAIL), SNAI2 (SLUG), TWIST1, MMP2, MMP9, CDH2 (N-Cadherin), ITGA5 (integrin-α5), ITGB1 (integrin-β1), ACTA2 (α-SMA) and S100A4 (FSP1). Moreover, at the early stage of EMT program (24 hours upon TGF-β1 exposure), transcriptional induction of several NCAM isoforms along with FGFR1 was observed, implicating a mechanistic link between NCAM/FGFR1 signaling and induction of EMT. These assumptions were further supported by the inhibition of the EMT program after specific blocking of FGFR1 signaling by PD173074. Finally, there was evidence for an in vivo TGF-β1 pathway activation in diseased human kidneys and correlation with impaired renal excretory functions. Collectively, NCAM/FGFR1 signaling appears to be involved in the initial phase of TGF-ß1 initiated EMT which can be effectively suppressed by application of FGFR inhibitor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211750PMC
April 2019

High-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis.

Nat Commun 2018 08 29;9(1):3509. Epub 2018 Aug 29.

German Center for Cardiovascular Research (DZHK) Partner Site, Göttingen, Germany.

While suppression of specific genes through aberrant promoter methylation contributes to different diseases including organ fibrosis, gene-specific reactivation technology is not yet available for therapy. TET enzymes catalyze hydroxymethylation of methylated DNA, reactivating gene expression. We here report generation of a high-fidelity CRISPR/Cas9-based gene-specific dioxygenase by fusing an endonuclease deactivated high-fidelity Cas9 (dHFCas9) to TET3 catalytic domain (TET3CD), targeted to specific genes by guiding RNAs (sgRNA). We demonstrate use of this technology in four different anti-fibrotic genes in different cell types in vitro, among them RASAL1 and Klotho, both hypermethylated in kidney fibrosis. Furthermore, in vivo lentiviral delivery of the Rasal1-targeted fusion protein to interstitial cells and of the Klotho-targeted fusion protein to tubular epithelial cells each results in specific gene reactivation and attenuation of fibrosis, providing gene-specific demethylating technology in a disease model.
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http://dx.doi.org/10.1038/s41467-018-05766-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115451PMC
August 2018

Hemodiafiltration Treatment for Severe Valproic Acid Intoxication: Case Report and Updated Systematic Literature Review.

Front Med (Lausanne) 2018 10;5:224. Epub 2018 Aug 10.

Department of Nephrology and Rheumatology, University Medical Center, Göttingen, Germany.

Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum disorders. With increasing administration, reports of intoxications are more frequently reported. The most common findings of VPA intoxication are central nervous system depression, respiratory depression, hypotension, metabolic acidosis, and elevated lactate, among others. We describe a case report of VPA intoxication with hemodiafiltration (HDF) as extracorporeal treatment (ECTR) for removal of VPA. This treatment modality has only rarely been reported in the current literature. In addition, we performed an updated systematic literature review (SLR) of additional cases on the topic ranging from December 1st, 2014 to April 20th, 2018. We searched MEDLINE and Web of Science for relevant references. In the presented case, VPA intoxication occurred in a 46-year-old female patient after oral ingestion of 56 g of VPA. In addition to vasopressors and endotracheal intubation, we administered L-Carnitine (L-Car) and performed hemodiafiltration treatment. After intravenous therapy with L-Car and simultaneous HDF sessions, we observed full recovery without neurological sequelae. The SLR identified 8 additional articles reporting favorable outcomes with extracorporeal treatments in most cases. HDF and other extracorporeal procedures are safe and effective therapeutic options in patients with VPA intoxication. The choice of ECTR modality mainly depends on local experience and the setting. In the present case, ingestion of 56 g was successfully treated with HDF. These findings are in line with several other case reports describing positive outcomes. Extracorporeal treatment, including HDF, should be considered early in the management of VPA intoxication. Supporting evidence is emerging, but it is of limited quality.
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http://dx.doi.org/10.3389/fmed.2018.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095960PMC
August 2018

The "rapid atrial swirl sign" for assessing central venous catheters: Performance by medical residents after limited training.

PLoS One 2018 16;13(7):e0199345. Epub 2018 Jul 16.

Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany.

Rationale: Central venous catheter (CVC) placement is a standard procedure in critical care. Ultrasound guidance during placement is recommended by current guidelines, but there is no consensus on the best method for evaluating the correct CVC tip position. Recently, the "rapid atrial swirl sign" (RASS) has been investigated in a limited number of studies.

Objectives: We performed a prospective diagnostic accuracy study of focused echocardiography for the evaluation of CVC tip position in our medical ICU and IMC units.

Methods: We performed a prospective diagnostic accuracy study in 100 patients admitted to the Intensive Care Unit and Intermediate Care Unit at our center. The first 10 subjects were assessed by one staff physician investigator (reference cohort), the remaining 90 patients by different residents (test cohort). All patients received a post-procedural chest radiograph (CXR) as gold standard. CVC placement was assessed with focused echocardiography performed by residents after a short training session. A rapid opacification of the right atrium (RASS) after injection of 10 mL of normal saline was regarded as "positive", flush after more than two seconds was defined as "delayed", no flush was a "negative" test result.

Measurements And Main Results: Overall sensitivity of the RASS was 100% (95% CI 73.54-100%), specificity was 94.32% (CI 87.24-98.13%). Positive and negative predictive values were 70.59% (CI 44.04-89.09%) and 100% (CI 95.65-100%), respectively. Median time for echocardiographic testing was 5 minutes (1-28) in the whole cohort, CXRs were available after 49.5 minutes (13-254). Interrater agreement of the RASS was 0.77 (Cohen's kappa), Measurement of CVC tip position was not different between two observers. Test characteristics were similar among differently experienced residents.

Conclusions: Presence of the RASS by focused echocardiography showed excellent sensitivity and specificity and was equally performed by residents after minimal training. In patients with a positive RASS, routine CXR can be safely omitted, reducing time, costs and radiation exposure. A negative RASS should lead to a search for misplaced catheters.

Clinical Trial Registration: The study was registered with www.clinicaltrials.gov (NCT02661607).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047781PMC
January 2019

Sarcoidosis and autoimmune diseases: differences, similarities and overlaps.

Curr Opin Pulm Med 2018 09;24(5):504-512

Academic Rheumatology Department, King's College London.

Purpose Of Review: Sarcoidosis is a rare, multisystem granulomatous disease of incompletely understood pathogenesis. Clinically, it shares common features with several systemic and organ-specific autoimmune diseases, although known autoantibodies or useful serologic markers for diagnosis and monitoring of disease activity are lacking. Sarcoidosis can both coexist with or mimic connective tissue diseases or vasculitis. Here, we review possible common etiologic factors between sarcoidosis and autoimmune disease, comparing clinical, laboratory and imaging features.

Recent Findings: Autoimmune diseases may precede or follow the diagnosis of sarcoidosis. Overall, the prevalence of both co-existing is unknown because of limited evidence. The presence of autoantibodies in sarcoidosis should raise suspicion of an underlying autoimmune disease that mimics or co-occurs with sarcoidosis. Silica dust exposure has been associated with an increased prevalence of both sarcoidosis and rheumatoid arthritis. In another study, autoimmune thyroid disease, Sjogren's syndrome and ankylosing spondylitis have been reported to be more frequent in sarcoidosis compared with healthy controls.

Summary: A systematic diagnostic work-up is necessary to detect overlapping disease features in patients with sarcoidosis. Immune-modulating therapies need to be taken into account as these can induce paradoxical reactions.
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http://dx.doi.org/10.1097/MCP.0000000000000500DOI Listing
September 2018

Pharmacological induction of hypoxia-inducible transcription factor ARNT attenuates chronic kidney failure.

J Clin Invest 2018 07 11;128(7):3053-3070. Epub 2018 Jun 11.

Department of Nephrology and Rheumatology.

Progression of chronic kidney disease associated with progressive fibrosis and impaired tubular epithelial regeneration is still an unmet biomedical challenge because, once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. Prompted by various studies across multiple organs demonstrating that preconditioning regimens to induce endogenous regenerative mechanisms protect various organs from later incurring acute injuries, we here aimed to gain insights into the molecular mechanisms underlying successful protection and to explore whether such pathways could be utilized to inhibit progression of chronic organ injury. We identified a protective mechanism controlled by the transcription factor ARNT that effectively inhibits progression of chronic kidney injury by transcriptional induction of ALK3, the principal mediator of antifibrotic and proregenerative bone morphogenetic protein-signaling (BMP-signaling) responses. We further report that ARNT expression itself is controlled by the FKBP12/YY1 transcriptional repressor complex and that disruption of such FKBP12/YY1 complexes by picomolar FK506 at subimmunosuppressive doses increases ARNT expression, subsequently leading to homodimeric ARNT-induced ALK3 transcription. Direct targeting of FKBP12/YY1 with in vivo morpholino approaches or small molecule inhibitors, including GPI-1046, was equally effective for inducing ARNT expression, with subsequent activation of ALK3-dependent canonical BMP-signaling responses and attenuated chronic organ failure in models of chronic kidney disease, and also cardiac and liver injuries. In summary, we report an organ-protective mechanism that can be pharmacologically modulated by immunophilin ligands FK506 and GPI-1046 or therapeutically targeted by in vivo morpholino approaches.
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http://dx.doi.org/10.1172/JCI89632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025987PMC
July 2018

Chromatin dynamics at the core of kidney fibrosis.

Matrix Biol 2018 08 21;68-69:194-229. Epub 2018 Feb 21.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Georg August University, Göttingen, Germany. Electronic address:

Progression of chronic kidney disease is a principal challenge in Nephrology, as effective therapies to halt or even reverse established lesion are not available yet. While numerous growth factors and environmental stimuli that drive progression of chronic kidney disease are present within the fibrotic microenvironment, the effector cells' genetic information needs to be accessible in order to enable the pro-fibrotic response. As more than 2 m of DNA encoding the genetic information is crammed as protein-DNA complex called chromatin within the nucleus of each cell, an accessible chromatin state is a prerequisite in the hierarchical order of events to enable production of fibrotic proteins and fibrotic cellular responses. Here, we review contribution and underlying mechanisms of chromatin organization, histone modifications and DNA methylation to progression of chronic kidney disease, provide recent evidence for cell type-specific cell fate decisions and discuss possible diagnostic and therapeutic applications.
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http://dx.doi.org/10.1016/j.matbio.2018.02.015DOI Listing
August 2018

Cognitive, emotional and social phenotyping of mice in an observer-independent setting.

Neurobiol Learn Mem 2018 04 21;150:136-150. Epub 2018 Feb 21.

Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address:

Based on the intellicage paradigm, we have developed a novel cognitive, emotional and social phenotyping battery that permits comprehensive standardized behavioral characterization of mice in an experimenter-independent social setting. Evaluation of this battery in a large number of male and female C57BL/6 wildtype mice, tested in >20 independent cohorts, revealed high reproducibility of the behavioral readouts and may serve as future reference tool. We noticed robust sex-specific differences in general activity, cognitive and emotional behavior, but not regarding preference for social pheromones. Specifically, female mice revealed higher activity, decreased sucrose preference, impaired reversal and place-time-reward learning. Furthermore, female mice reacted more sensitively than males to reward-withdrawal showing a negative emotional contrast/Crespi-effect. In a series of validation experiments, we tested mice with different pathologies, including neuroligin-3 deficient mice (male Nlgn3 and female Nlgn3) for autistic behavior, oligodendrocyte-specific erythropoietin receptor knockout (oEpoR) mice for cognitive impairment, as well as mouse models of renal failure (unilateral ureteral obstruction and 5/6 nephrectomy) and of type 2 diabetes (ApoE) - for delineating potentially confounding effects of motivational factors (thirst, glucose-craving) on learning and memory assessments. As prominent features, we saw in Nlgn3 mutants reduced preference for social pheromones, whereas oEpoR mice showed learning deficits in place or reversal learning tasks. Renal failure led to increased water intake, and diabetic metabolism to enhanced glucose preference, limiting interpretation of hereon based learning and memory performance in these mice. The phenotyping battery presented here may be well-suited as high-throughput multifaceted diagnostic instrument for translational neuropsychiatry and behavioral genetics.
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http://dx.doi.org/10.1016/j.nlm.2018.02.023DOI Listing
April 2018