Publications by authors named "Thorsten Wiech"

86 Publications

ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage.

J Am Soc Nephrol 2021 Mar 30. Epub 2021 Mar 30.

Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: Podocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which could be mediated by shedding of cell-adhesion molecules through the regulated activity of cell surface-expressed proteases. A Disintegrin and Metalloproteinase 10 (ADAM10) is such a protease known to mediate ectodomain shedding of adhesion molecules, among others. Here we evaluate the involvement of ADAM10 in the process of antibody-induced podocyte injury.

Methods: Membrane proteomics, immunoblotting, high-resolution microscopy, and immunogold electron microscopy were used to analyze human and murine podocyte ADAM10 expression in health and kidney injury. The functionality of ADAM10 ectodomain shedding for podocyte development and injury was analyzed, and , in the anti-podocyte nephritis (APN) model in podocyte-specific, ADAM10-deficient mice.

Results: ADAM10 is selectively localized at foot processes of murine podocytes and its expression is dispensable for podocyte development. Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner.

Conclusions: ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020081213DOI Listing
March 2021

Deep learning-based molecular morphometrics for kidney biopsies.

JCI Insight 2021 Apr 8;6(7). Epub 2021 Apr 8.

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Morphologic examination of tissue biopsies is essential for histopathological diagnosis. However, accurate and scalable cellular quantification in human samples remains challenging. Here, we present a deep learning-based approach for antigen-specific cellular morphometrics in human kidney biopsies, which combines indirect immunofluorescence imaging with U-Net-based architectures for image-to-image translation and dual segmentation tasks, achieving human-level accuracy. In the kidney, podocyte loss represents a hallmark of glomerular injury and can be estimated in diagnostic biopsies. Thus, we profiled over 27,000 podocytes from 110 human samples, including patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), an immune-mediated disease with aggressive glomerular damage and irreversible loss of kidney function. We identified previously unknown morphometric signatures of podocyte depletion in patients with ANCA-GN, which allowed patient classification and, in combination with routine clinical tools, showed potential for risk stratification. Our approach enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.144779DOI Listing
April 2021

[Creatinine rise, fever and hemoptysis].

Nephrologe 2021 Mar 5:1-4. Epub 2021 Mar 5.

Sektion für Translationale Immunologie, III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11560-021-00495-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934114PMC
March 2021

Rituximab Induces Complete Remission of Proteinuria in a Patient With Minimal Change Disease and No Detectable B Cells.

Front Immunol 2020 8;11:586012. Epub 2021 Feb 8.

III. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Minimal change disease (MCD) is a common cause of nephrotic syndrome. Treatment with steroids is usually effective, but frequent relapses are therapeutic challenges. The anti-CD20 antibody rituximab has shown promising results for treatment of steroid-sensitive nephrotic syndrome. Since predictive biomarkers for treatment efficacy and the accurate rituximab dosage for effective induction of remission are unknown, measurement of CD19 B cells in blood is often used as marker of successful B cell depletion and treatment efficacy. A male patient with relapsing MCD was successfully treated with rituximab, but developed relapse of proteinuria 1 year later, although no B cells were detectable in his blood. B and T cell populations in the patient's blood were analyzed before and after treatment with rituximab using FACS analysis. Rituximab binding to B and T cells were measured using Alexa Fluor 647 conjugated rituximab. We identified a population of CD20 CD19 cells in the patient's blood, which consisted mostly of CD20 CD3 T cells. Despite the absence of B cells in the blood, the patient was again treated with rituximab. He developed complete remission of proteinuria and depletion of CD20 T cells. In a control patient with relapsing MCD initial treatment with rituximab led to depletion of both CD20 B and T cells. Rituximab induces remission of proteinuria in patients with MCD even if circulating B cells are absent. CD20 T cells may play a role in the pathogenesis of MCD and might be a promising treatment target in patients with MCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.586012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897659PMC
February 2021

The authors reply.

Kidney Int 2021 02;99(2):489-490

Institut für Pathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.11.005DOI Listing
February 2021

Upregulation of HLA-F expression by BK polyomavirus infection induces immune recognition by KIR3DS1-positive natural killer cells.

Kidney Int 2020 Dec 23. Epub 2020 Dec 23.

German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany; Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. Electronic address:

BK polyomavirus-associated nephropathy is a common complication after kidney transplantation leading to reduced graft function or loss. The molecular pathogenesis of BK polyomavirus-induced nephropathy is not well understood. A recent study had described a protective effect of the activating natural killer cell receptor KIR3DS1 in BK polyomavirus-associated nephropathy, suggesting a role of NK cells in modulating disease progression. Using an in vitro cell culture model of human BK polyomavirus infection and kidney biopsy samples from patients with BK polyomavirus-associated nephropathy, we observed significantly increased surface expression of the ligand for KIR3DS1, HLA-F, on BK polyomavirus-infected kidney tubular cells. Upregulation of HLA-F expression resulted in significantly increased binding of KIR3DS1 to BK polyomavirus-infected cells and activation of primary KIR3DS-positive natural killer cells. Thus, our data provide a mechanism by which KIR3DS-positive natural killer cells can control BK polyomavirus infection of the kidney, and rationale for exploring HLA-F/KIR3DS1 interactions for immunotherapeutic approaches in BK polyomavirus-associated nephropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.12.014DOI Listing
December 2020

Renal disease associated with myeloproliferative neoplasms and myelodysplastic syndrome/myeloproliferative neoplasms.

Histopathology 2021 Apr 14;78(5):738-748. Epub 2020 Dec 14.

Institute of Pathology, University Medical Centre of the Johannes Guttenberg University Mainz, Mainz, Germany.

Aims: Renal changes in patients with myeloproliferative neoplasms (MPNs) or myelodysplastic syndrome (MDS)/MPNs have been addressed by few, respectively no, reports. The aim of this study was to focus on a systematic evaluation of renal biopsies in patients with MPNs or MDS/MPNs.

Methods And Results: The cohort comprised 29 patients (23 men) aged 67 ± 11 years (mean ± standard deviation), diagnosed with chronic myeloid leukaemia (n = 5), polycythaemia vera (n = 9), primary myelofibrosis (n = 5), essential thrombocythaemia (n = 2), or chronic myelomonocytic leukaemia (n = 4), as well as MPNs or MDS/MPNs not otherwise specified (n = 4). Patients manifested with proteinuria (93%), partially in the nephrotic range (46%), haematuria (72%), and impaired kidney function (93%). The most prominent histological findings included double-contoured glomerular basement membranes (71%), acute endothelial damage (68%), intracapillary platelet aggregation (62%), mesangiolysis (21%), thrombotic microangiopathy (24%), segmental glomerulosclerosis (66%), mesangial hypercellularity and sclerosis, extramedullary haematopoiesis (17%), and also IgA nephropathy (21%) and glomerulonephritis (GN) with features of infection-related GN (21%). MPN and MDS/MPN patients showed significantly more chronic changes than age-matched and sex-matched controls, including global and segmental glomerulosclerosis, mesangial sclerosis, and hypercellularity, whereas the extent of arteriosclerosis was comparable.

Conclusions: MPN and MDS/MPN patients show glomerular scarring that exceeds age-related phenomena. Ongoing endothelial damage, growth factors released by platelets and deposition of immune complexes are probably the causative mechanisms. Early recognition of renal failure heralded by proteinuria and haematuria, and consequent control of risk factors for kidney failure, should be recommended for MPN and MDS/MPN patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.14282DOI Listing
April 2021

Pathogen-induced tissue-resident memory T17 (T17) cells amplify autoimmune kidney disease.

Sci Immunol 2020 08;5(50)

Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (T) cells persist in peripheral organs and provide immune protection against reinfection. However, whether T cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4 T cells with a T17 signature (termed T17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal T17 cells were induced by pathogens infecting the kidney, such as , , and uropathogenic , and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney T17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced T17 cells have a previously unrecognized function in aggravating autoimmune disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.aba4163DOI Listing
August 2020

Visualization of C3/C5 Convertases to Differentiate Complement Activation.

Kidney Int Rep 2020 Jun 21;5(6):927-930. Epub 2020 Apr 21.

Nephropathology Section, Institute of Pathology, University Hospital Hamburg Eppendorf, Hamburg, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271008PMC
June 2020

Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy.

Kidney Int 2020 09 21;98(3):615-629. Epub 2020 May 21.

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

A wide spectrum of immunological functions has been attributed to Interleukin 9 (IL-9), including effects on the survival and proliferation of immune and parenchymal cells. In recent years, emerging evidence suggests that IL-9 expression can promote tissue repair in inflammatory conditions. However, data about the involvement of IL-9 in kidney tissue protection is very limited. Here, we investigated the role of IL-9 in Adriamycin-induced nephropathy (AN), a mouse model for proteinuric chronic kidney disease. Compared to wild type mice, IL-9 knockout (Il9) mice with AN displayed accelerated development of proteinuria, aggravated glomerulosclerosis and deterioration of kidney function. At an early stage of disease, the Il9 mice already displayed a higher extent of glomerular podocyte injury and loss of podocyte number compared to wild type mice. In the kidney, T cells and innate lymphoid cells produced IL-9. However, selective deficiency of IL-9 in the innate immune system in Il9Rag2 mice that lack T and B cells did not alter the outcome of AN, indicating that IL-9 derived from the adaptive immune system was the major driver of tissue protection in this model. Mechanistically, we could show that podocytes expressed the IL-9 receptor in vivo and that IL-9 signaling protects podocytes from Adriamycin-induced apoptosis in vitro. Finally, in vivo treatment with IL-9 effectively protected wild type mice from glomerulosclerosis and kidney failure in the AN model. The detection of increased serum IL-9 levels in patients with primary focal and segmental glomerulosclerosis further suggests that IL-9 production is induced by glomerular injury in humans. Thus, IL-9 confers protection against experimental glomerulosclerosis, identifying the IL-9 pathway as a potential therapeutic target in proteinuric chronic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.04.036DOI Listing
September 2020

Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

J Am Soc Nephrol 2020 04 21;31(4):799-816. Epub 2020 Feb 21.

Institute of Pathology,

Background: Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.

Methods: Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.

Results: Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term . In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of , , or had no effect on the manifestations of 2,8-DHA nephropathy.

Conclusions: Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019080827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191925PMC
April 2020

A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients.

Kidney Int 2020 05 9;97(5):913-919. Epub 2019 Nov 9.

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The phospholipase A2 receptor 1 (PLA2R1) is the major autoantigen in patients suffering from membranous nephropathy. To date, the lack of endogenous glomerular expression of PLA2R1 in mice and rats has impeded the establishment of PLA2R1-dependent animal models of this disease. Here, we generated a transgenic mouse line expressing murine full-length PLA2R1 in podocytes. Furthermore, expression of murine PLA2R1 did not result in any morphological disturbance as high-resolution confocal microscopy demonstrated an intact nephrin distribution with normal foot processes. Transfer of rabbit anti-mPLA2R1 antibodies to these mice induced nephrotic range proteinuria, hypercholesterolemia, and histomorphological signs of membranous nephropathy. Immunohistochemical and immunofluorescence analyses revealed enhanced staining for murine PLA2R1 in the presence of unaffected staining for murine thrombospondin type-1 domain-containing 7A in the diseased mice, resembling what is classically found in patients with PLA2R1-associated membranous nephropathy Thus, our mouse model of membranous nephropathy will allow investigation of PLA2R1-specific pathomechanisms and may help to develop and assess antigen-specific treatments in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2019.10.022DOI Listing
May 2020

Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy.

J Am Soc Nephrol 2020 02 24;31(2):241-256. Epub 2020 Jan 24.

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.

Sequence and copy number variations in the human gene cluster comprising the complement genes , , , , , and are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant genes, as well as hybrid genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: , , and gene alterations combined with intact , , and genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five genes in the context of an intact gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019050515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003313PMC
February 2020

Complement Inhibitors in Clinical Trials for Glomerular Diseases.

Front Immunol 2019 27;10:2166. Epub 2019 Sep 27.

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.

Defective complement action is a cause of several human glomerular diseases including atypical hemolytic uremic syndrome (aHUS), anti-neutrophil cytoplasmic antibody mediated vasculitis (ANCA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, ischemic reperfusion injury, lupus nephritis, membranous nephropathy, and chronic transplant mediated glomerulopathy. Here we summarize ongoing clinical trials of complement inhibitors in nine glomerular diseases and show which inhibitors are used in trials for these renal disorders (http://clinicaltrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776600PMC
October 2020

Severe Acute Kidney Injury Due to Nivolumab/Ipilimumab-induced Granulomatosis and Fibrinoid Vascular Necrosis.

J Immunother 2020 01;43(1):29-31

Institute of Pathology and Nephropathology Section, University Hospital Hamburg Eppendorf.

Immune-checkpoint inhibitors have revolutionized the treatment of cancers in recent years. Four drugs have obtained FDA approval in a variety of cancer types. Immune-related adverse events are common and occur in up to 60% of treated patients. Common manifestations of immune-related adverse events include rash, colitis, hepatitis, and hypophysitis. Most cases are mild to moderate in grade; however, severe manifestations with lethal outcomes have been described. Acute kidney injury is reported as a rare complication. In this case report, we present a patient with metastatic melanoma undergoing combined immune-checkpoint inhibitor therapy and displaying multiple immune-related adverse events. Despite receiving systemic steroid therapy for extrarenal immune-related adverse events, the patient developed acute progressive kidney injury requiring renal replacement therapy. Findings on renal biopsy included granulomatous interstitial nephritis, vasculitis, and thrombotic microangiopathy-like lesions. This case indicates that, although severe acute kidney injury is a rare complication of immune-checkpoint inhibitors, fulminant cases do occur and can be resistant to therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CJI.0000000000000296DOI Listing
January 2020

The authors reply.

Kidney Int 2019 10;96(4):1037-1038

Institut für Pathologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2019.07.008DOI Listing
October 2019

mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans.

JCI Insight 2019 09 19;4(18). Epub 2019 Sep 19.

Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.

The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.99271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795295PMC
September 2019

Role of phospholipase A2 receptor 1 antibody level at diagnosis for long-term renal outcome in membranous nephropathy.

PLoS One 2019 9;14(9):e0221293. Epub 2019 Sep 9.

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Membranous nephropathy (MN) is an autoimmune disease induced by circulating antibodies against the podocyte protein phospholipase A2 receptor 1 (PLA2R1-ab) in 80% of patients and represents the leading cause of nephrotic syndrome in adults. PLA2R1-ab levels correlate with disease activity and treatment response. However, their predictive role for long-term renal outcome is not clear.

Methods: The aim of this prospective observational multicenter study was to investigate the predictive role of PLA2R1-ab levels at the time of diagnosis for long-term outcome in a cohort of 243 patients with newly diagnosed biopsy-proven PLA2R1-associated MN. Statistical analyses included Cox proportional hazard models. The primary study endpoint was defined prior to data collection as doubling of serum creatinine or development of end-stage renal disease.

Results: During the median follow-up time of 48 months, 36 (15%) patients reached the study endpoint. Independent predictors for reaching the study endpoint were baseline PLA2R1-ab levels (HR = 1.36, 95%CI 1.11-1.66, p = 0.01), percentage of tubular atrophy and interstitial fibrosis (HR = 1.32, 95%CI 1.03-1.68, p = 0.03), PLA2R1-ab relapse during follow-up (HR = 3.22, 95%CI 1.36-7.60, p = 0.01), and relapse of proteinuria (HR = 2.60, 95%CI 1.17-5.79, p = 0.02). Fifty-four (22%) patients received no immunosuppressive treatment during the study, in 41 (76%) of them PLA2R1-ab spontaneously disappeared during follow-up, 29 (54%) patients had a complete remission of proteinuria, and 19 (35%) had a partial remission. Patients not treated with immunosuppression were more often females and had lower PLA2R1-ab levels, proteinuria, and serum creatinine at baseline compared to patients receiving immunosuppression. However, no conclusion on the efficacy of immunosuppressive therapies can be made, since this was not a randomized controlled study and treatment decisions were not made per-protocol.

Conclusions: PLA2R1-ab levels are, in addition to pre-existing renal damage, predictive factors for long-term outcome and should therefore be considered when deciding the treatment of patients with MN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221293PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733455PMC
March 2020

Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies.

Nat Commun 2019 07 4;10(1):2961. Epub 2019 Jul 4.

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany.

Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10766-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609651PMC
July 2019

The authors reply.

Kidney Int 2019 07;96(1):245-246

Institut für Pathologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2019.01.048DOI Listing
July 2019

[Renal cortical necrosis after application of tranexamic acid in peripartal hemorrhage].

Dtsch Med Wochenschr 2019 05 13;144(10):678-682. Epub 2019 May 13.

Klinik für Nephrologie, Medizinische Fakultät, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland.

History: A 28-years old patient delivers a daughter by primary caesarian section (41. WOP) in breech presentation after a complication-free pregnancy except increased blood pressure readings at the morning of caesarian section. During the caesarian section a major bleeding of the atonic uterus with hemorrhagic shock appears. Haemostasis is achieved by mechanical tamponade, the application of red blood cell concentrates and the substitution of clotting factors, also tranexamic acid. Because of an anuric renal failure due to the shock hemodialysis is initiated.

Examinations/findings: Clinical examination and blood tests show the constellation of a thrombotic microangiopathy. There are no hints for a thrombotic thrombocytopenic purpura (TTP) or a hemolytic-uremic syndrome (HUS). In addition, a genetic testing gives no hints for an atypical HUS. After 4 weeks of dialysis duty a renal biopsy is performed. The renal biopsy shows a partly reversible tubular damage with an older ischemic cortical necrosis.

Diagnosis/therapy: In the further course the resumption of the diuresis can be observed. The dialysis treatment has to be continued because of an insufficient excretory renal function. Fortunately a living-donor kidney transplantation (mother) can be carry out successfully already one year after the hemorrhagic shock.

Conclusion: The combination of peripartal bleeding with hemorrhagic shock, possibly aggravated by (pre-)eclampsia or HELLP-syndrome, and the application of tranexamic acid with its prothrombotic effect seems to be responsible for the major renal cortical necrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0857-8606DOI Listing
May 2019

Renal proximal tubular epithelial cells exert immunomodulatory function by driving inflammatory CD4 T cell responses.

Am J Physiol Renal Physiol 2019 07 24;317(1):F77-F89. Epub 2019 Apr 24.

Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany.

In immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN), inflammatory CD4 T cells accumulate within the tubulointerstitial compartment in close contact to proximal and distal tubular epithelial cells and drive renal inflammation and tissue damage. However, whether renal epithelial cell populations play a role in the pathogenesis of cGN by modulating CD4 T cell responses is less clear. In the present study, we aimed to investigate the potential of renal epithelial cells to function as antigen-presenting cells, thereby stimulating CD4 T cell responses. Using a FACS-based protocol that allowed comparative analysis of cortical epithelial cell populations, we showed that particularly proximal tubular epithelial cells (PTECs) express molecules linked with antigen-presenting cell function, including major histocompatibility complex class II (MHCII), CD74, CD80, and CD86 in homeostasis and nephrotoxic nephritis, a murine model of cGN. Protein expression was visualized at the PTEC single cell level by imaging flow cytometry. Interestingly, we found inflammation-dependent regulation of epithelium-expressed CD74, CD80, and CD86, whereas MHCII expression was not altered. Antigen-specific stimulation of CD4 T cells by PTECs in vitro supported CD4 T cell survival and induced CD4 T cell activation, proliferation, and inflammatory cytokine production. In patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis, MHCII and CD74 were expressed by both proximal and distal tubules, whereas CD86 was predominantly expressed by proximal tubules. Thus, particularly PTECs have the potential to induce an inflammatory phenotype in CD4 T cells in vitro, which might also play a role in the pathology of immune-mediated kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00427.2018DOI Listing
July 2019

Diagnostic role of renal biopsy in PLAR1-antibody-positive patients with nephrotic syndrome.

Mod Pathol 2019 09 8;32(9):1320-1328. Epub 2019 Apr 8.

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Renal biopsy is the gold standard for diagnosis of membranous nephropathy. Circulating PLAR1 antibody found in 75% of patients with membranous nephropathy is very specific for the diagnosis of this disease. Therefore, the question arises whether PLAR1-antibody-positive patients still need a diagnostic renal biopsy. In this study we investigated whether additional relevant information is obtained by performing renal biopsy in nephrotic patients, who are PLAR1-antibody positive. A detailed analysis of renal biopsies, including immunohistochemistry and electron microscopy, was performed in 263 patients with biopsy-proven membranous nephropathy, of whom 194 patients were PLAR1-antibody positive, to detect diagnostic features additional to membranous nephropathy. Twelve (6%) of the 194 PLAR1-antibody-positive patients had a second relevant diagnosis in addition to membranous nephropathy: five (3%) patients had interstitial nephritis, in five (3%) other patients a diabetic nephropathy was diagnosed and two (1%) patients had IgA nephropathy. Patients with a second diagnosis in addition to membranous nephropathy had a significantly higher serum creatinine (p < 0.01) and lower eGFR (p = 0.04) compared to patients in whom only the diagnosis of membranous nephropathy was made. In 7 (10%) of 69 PLAR1-antibody-negative patients, renal biopsies showed an additional diagnosis to membranous nephropathy: one (1%) case of IgA nephropathy, cholesterol emboli, IgG4-related disease, necrotising glomerulonephritis, thrombotic microangiopathy, interstitial nephritis and diabetic nephropathy each. The advantage of detecting an additional diagnosis to membranous nephropathy in 6% of PLAR1-antibody-positive patients by renal biopsy has to be balanced to the potential risks and costs of the biopsy procedure. Renal biopsy is particularly relevant in patients presenting with impaired renal function and abnormalities in urinalysis going beyond proteinuria. Immunohistochemical staining for PLAR1 was the only histomorphologic analysis allowing a reliable differentiation of PLAR1-antibody-positive from PLAR1-antibody-negative membranous nephropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0267-zDOI Listing
September 2019

Reply to Tison and Saraux.

Clin Infect Dis 2019 08;69(5):905

Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciz095DOI Listing
August 2019

Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts.

Hepatology 2019 05 14;69(5):2107-2119. Epub 2019 Mar 14.

Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.

Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in patients with cirrhosis (HRS-AKI, type 1). Causes of non-HRS-AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN are obtained primarily from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 and 2016 at the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent European Association for the Study of the Liver criteria, 45 of 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD). Renal biopsy revealed the diagnosis of CN in 8 of 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase, and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin, and the diagnosis of CN revealed loss of aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy-related complications requiring medical intervention occurred in 4 of 79 patients (5.1%). Conclusion: CN is a common finding in patients with liver disease, AKI, and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and in part be responsible for the impairment of renal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30499DOI Listing
May 2019

Bevacizumab-associated glomerular microangiopathy.

Mod Pathol 2019 05 14;32(5):684-700. Epub 2018 Dec 14.

Institute of Pathology and Nephropathology Section, University Hospital Hamburg Eppendorf, Hamburg, Germany.

Bevacizumab is a humanized monoclonal IgG1 antibody, which neutralizes vascular endothelial growth factor and is used for treating multiple cancer types. As a known and frequent adverse event, this therapy can lead to renal damage including proteinuria and nephrotic syndrome. In a retrospective approach, we analyzed 17 renal biopsies from patients receiving bevacizumab treatment. We observed a distinctive histopathological pseudothrombotic pattern different from the previously reported thrombotic microangiopathy. Since this pattern includes some features similar to acute and chronic thrombotic microangiopathy, focal segmental glomerulosclerosis and cryoglobulinemic membranoproliferative glomerulonephritis, biopsies with these diagnoses were included for comparison. Clinical, laboratory, light microscopic, immunohistochemical (including a proximity ligation assay), proteomic and electron microscopic features were assessed. Nephrotic syndrome was present in 15 of the 17 bevacizumab-treated patients. All 17 displayed a patchy pattern of variably PAS-positive hyaline pseudothrombi occluding markedly dilated glomerular capillaries in their biopsies. Mass spectrometry-based proteome analysis revealed a special protein pattern demonstrating some features of thrombotic microangiopathy and some of cryoglobulinemic glomerulonephritis, including a strong accumulation of IgG in the pseudothrombi. Proximity ligation assay did not show interaction of IgG with C1q, arguing for accumulation without classic pathway complement activation. In contrast to thrombi in thrombotic microangiopathy cases, the hyaline pseudothrombi did not contain clusters of CD61-positive platelets. Electron microscopy of bevacizumab cases did not show fibrin polymers or extensive loss of podocyte foot processes. Even though cases of bevacizumab-associated microangiopathy share some features with thrombotic microangiopathy, its overall histopathological pattern is quite different from acute or chronic thrombotic microangiopathy cases. We conclude that bevacizumab therapy can lead to a unique hyaline occlusive glomerular microangiopathy, likely arising from endothelial leakage followed by subendothelial accumulation of serum proteins. It can be diagnosed by light microscopy and is an important differential diagnosis in cancer patients with nephrotic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-018-0186-4DOI Listing
May 2019

Development and validation of a renal risk score in ANCA-associated glomerulonephritis.

Kidney Int 2018 12 29;94(6):1177-1188. Epub 2018 Oct 29.

Institut für Pathologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.

Predicting renal outcome in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) remains a major challenge. We aimed to identify reliable predictors of end-stage renal disease (ESRD) and to develop and validate a clinicopathologic score to predict renal outcome in ANCA-associated GN. In a prospective training cohort of 115 patients, the percentage of normal glomeruli (without scarring, crescents, or necrosis within the tuft) was the strongest independent predictor of death-censored ESRD. Regression tree analysis identified predictive cutoff values for three parameters: percentage normal glomeruli (N0 >25%, N1 10 to 25%, N2 <10%), percentage tubular atrophy and interstitial fibrosis (T0 ≤25%, T1 >25%), and estimated glomerular filtration rate at the time of diagnosis (G0 >15 ml/min/1.73 m, G1 ≤15 ml/min/1.73 m). Cox regression analysis was used to assign points to each parameter (N1 = 4, N2 = 6, T1 = 2, G1 = 3 points), and the resulting risk score was used to classify predicted ESRD risk as low (0), intermediate (2 to 7), or high (8 to 11 points). The risk score accurately predicted ESRD at 36 months in the training cohort (0%, 26%, and 68%, respectively) and in an independent validation cohort of 90 patients (0%, 27%, and 78%, respectively). Here, we propose a clinically applicable renal risk score for ANCA-associated GN that highlights the importance of unaffected glomeruli as a predictor of renal outcome and allows early risk prediction of ESRD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2018.07.020DOI Listing
December 2018

Potential Role for Urine Polymerase Chain Reaction in the Diagnosis of Whipple's Disease.

Clin Infect Dis 2019 03;68(7):1089-1097

Institute of Pathology, Nephropathology Section, University Hospital Hamburg-Eppendorf.

Background: Whipple's disease (WD) is a rare infection with Tropheryma whipplei that is fatal if untreated. Diagnosis is challenging and currently based on invasive sampling. In a case of WD diagnosed from a kidney biopsy, we observed morphologically-intact bacteria within the glomerular capsular space and tubular lumens. This raised the questions of whether renal filtration of bacteria is common in WD and whether polymerase chain reaction (PCR) testing of urine might serve as a diagnostic test for WD.

Methods: We prospectively investigated urine samples of 12 newly-diagnosed and 31 treated WD patients by PCR. As controls, we investigated samples from 110 healthy volunteers and patients with excluded WD or acute gastroenteritis.

Results: Out of 12 urine samples from independent, therapy-naive WD patients, 9 were positive for T. whipplei PCR. In 3 patients, fluorescence in situ hybridization visualized T. whipplei in urine. All control samples were negative, including those of 11 healthy carriers with T. whipplei-positive stool samples. In our study, the detection of T. whipplei in the urine of untreated patients correlated in all cases with WD.

Conclusions: T. whipplei is detectable by PCR in the urine of the majority of therapy-naive WD patients. With a low prevalence but far-reaching consequences upon diagnosis, invasive sampling for WD is mandatory and must be based on a strong suspicion. Urine testing could prevent patients from being undiagnosed for years. Urine may serve as a novel, easy-to-obtain specimen for guiding the initial diagnosis of WD, in particular in patients with extra-intestinal WD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciy664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424077PMC
March 2019

The chemokine receptor CXCR1 reduces renal injury in mice with angiotensin II-induced hypertension.

Am J Physiol Renal Physiol 2018 12 12;315(6):F1526-F1535. Epub 2018 Sep 12.

III. Department of Medicine, University Hospital Hamburg-Eppendorf , Hamburg , Germany.

The role of CXCR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CXCR1 in hypertensive renal and cardiac injury. Expression of CXCR1 was determined using CXCR1 mice that express a green fluorescent protein (GFP) reporter in CXCR1 cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45 cells expressed CXCR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CXCR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g·min) and a high-salt diet in wild-type ( n = 15) and CXCR1-deficient mice ( n = 18). CXCR1 deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80 macrophages and CD11b/Ly6G neutrophils in ANG II-infused mice. Surprisingly, CXCR1-deficient mice exhibited increased albuminuria, glomerular injury, and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis, and expression of fetal genes, and matrix components were not different between both genotypes. Our findings suggest that CXCR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CXCR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00149.2018DOI Listing
December 2018