Publications by authors named "Jan U Becker"

59 Publications

Differential expression of microRNA miR-150-5p in IgA nephropathy as a potential mediator and marker of disease progression.

Kidney Int 2021 Jan 5. Epub 2021 Jan 5.

The Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Understanding why certain patients with IgA nephropathy progress to kidney failure while others maintain normal kidney function remains a major unanswered question. To help answer this, we performed miRnome profiling by next generation sequencing of kidney biopsies in order to identify microRNAs specifically associated with the risk of IgA nephropathy progression. Following sequencing and validation in independent cohorts, four microRNAs (-150-5p, -155-5p, -146b-5p, -135a-5p) were found to be differentially expressed in IgA nephropathy progressors compared to non-progressors, and patients with thin membrane nephropathy, lupus nephritis and membranous nephropathy, and correlated with estimated glomerular filtration rate, proteinuria, and the Oxford MEST-C scores (five histological features that are independent predictors of clinical outcome). Each individual microRNA increased the discrimination score of the International IgAN Prediction Tool, although due to the small number of samples the results did not reach statistical significance. miR-150-5p exhibited the largest amplitude of expression between cohorts and displayed the best discrimination between IgA nephropathy progressors and non-progressors by receiver operating curve analysis (AUC: 0.8). However, expression was similarly upregulated in kidneys with established fibrosis and low estimated glomerular filtration rates at the time of biopsy. Consistent with a more generic role in kidney fibrosis, in situ hybridization revealed that miR-150-5p was found in lymphoid infiltrates, and areas of proliferation and fibrosis consistent with the known drivers of progression. Thus, miR-150-5p may be a potential functional mediator of kidney fibrosis that may add value in predicting risk of progression in IgA nephropathy and other kidney diseases.
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http://dx.doi.org/10.1016/j.kint.2020.12.028DOI Listing
January 2021

Artificial intelligence and machine learning in nephropathology.

Kidney Int 2020 07 1;98(1):65-75. Epub 2020 Apr 1.

Department of Electrical and Computer Engineering, University of Houston, Houston, Texas, USA.

Artificial intelligence (AI) for the purpose of this review is an umbrella term for technologies emulating a nephropathologist's ability to extract information on diagnosis, prognosis, and therapy responsiveness from native or transplant kidney biopsies. Although AI can be used to analyze a wide variety of biopsy-related data, this review focuses on whole slide images traditionally used in nephropathology. AI applications in nephropathology have recently become available through several advancing technologies, including (i) widespread introduction of glass slide scanners, (ii) data servers in pathology departments worldwide, and (iii) through greatly improved computer hardware to enable AI training. In this review, we explain how AI can enhance the reproducibility of nephropathology results for certain parameters in the context of precision medicine using advanced architectures, such as convolutional neural networks, that are currently the state of the art in machine learning software for this task. Because AI applications in nephropathology are still in their infancy, we show the power and potential of AI applications mostly in the example of oncopathology. Moreover, we discuss the technological obstacles as well as the current stakeholder and regulatory concerns about developing AI applications in nephropathology from the perspective of nephropathologists and the wider nephrology community. We expect the gradual introduction of these technologies into routine diagnostics and research for selective tasks, suggesting that this technology will enhance the performance of nephropathologists rather than making them redundant.
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http://dx.doi.org/10.1016/j.kint.2020.02.027DOI Listing
July 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Molecular Analysis of Renal Allograft Biopsies: Where Do We Stand and Where Are We Going?

Transplantation 2020 12;104(12):2478-2486

Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

A renal core biopsy for histological evaluation is the gold standard for diagnosing renal transplant pathology. However, renal biopsy interpretation is subjective and can render insufficient precision, making it difficult to apply a targeted therapeutic regimen for the individual patient. This warrants a need for additional methods assessing disease state in the renal transplant. Significant research activity has been focused on the role of molecular analysis in the diagnosis of renal allograft rejection. The identification of specific molecular expression patterns in allograft biopsies related to different types of allograft injury could provide valuable information about the processes underlying renal transplant dysfunction and can be used for the development of molecular classifier scores, which could improve our diagnostic and prognostic ability and could guide treatment. Molecular profiling has the potential to be more precise and objective than histological evaluation and may identify injury even before it becomes visible on histology, making it possible to start treatment at the earliest time possible. Combining conventional diagnostics (histology, serology, and clinical data) and molecular evaluation will most likely offer the best diagnostic approach. We believe that the use of state-of-the-art molecular analysis will have a significant impact in diagnostics after renal transplantation. In this review, we elaborate on the molecular phenotype of both acute and chronic T cell-mediated rejection and antibody-mediated rejection and discuss the additive value of molecular profiling in the setting of diagnosing renal allograft rejection and how this will improve transplant patient care.
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http://dx.doi.org/10.1097/TP.0000000000003220DOI Listing
December 2020

Utility of immunohistochemistry with C3d in C3 glomerulopathy.

Mod Pathol 2020 03 2;33(3):431-439. Epub 2019 Sep 2.

Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

C3-dominance by immunofluorescence is a defining feature in the diagnosis of C3 glomerulopathy. Most pathologists stain for C3c, which has been reported as a trace/negative even in otherwise clear-cut cases of dense deposit disease. We investigated the usefulness of C3d immunohistochemistry in biopsies with C3 glomerulopathy as an ancillary diagnostic tool. All biopsies from patients diagnosed with C3 glomerulopathy in the period January 2005 to June 2017 in the Erasmus MC, Rotterdam were included (n = 14; 10 C3 glomerulonephritis, 4 dense deposit disease). The staining pattern of C3d and C4d by immunohistochemistry was analyzed. As controls, biopsies from patients with immune complex membranoproliferative glomerulonephritis (n = 2), infection-associated glomerulonephritis (n = 6), pauci-immune crescentic glomerulonephritis (n = 7), tubulointerstitial nephritis (n = 7) and chronic-active antibody-mediated rejection (n = 9) were included. All 14 biopsies with C3 glomerulopathy showed a C3d score of ≥2, including two clear-cut biopsies with C3 glomerulopathy originally showing a trace/negative staining for C3c. In the control group, a C3d score ≥2 was observed in 11 biopsies (35%; 2 with immune complex membranoproliferative glomerulonephritis (100%), 6 with infection-associated glomerulonephritis (100%), 1 with pauci-immune crescentic glomerulonephritis (14%), 1 with tubulointerstitial nephritis (14%) and 1 with chronic-active antibody-mediated rejection (11%)). C4d was positive in 71% of the biopsies with C3 glomerulopathy (10/14). In conclusion, C3d immunohistochemistry is a valuable tool in the diagnosis of C3 glomerulopathy, especially in cases in which C3c immunofluorescence shows a trace/negative. We recommend the use of C3d in addition to C3c in cases suspicious for C3 glomerulopathy.
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http://dx.doi.org/10.1038/s41379-019-0348-zDOI Listing
March 2020

Case report: a peculiar glomerulopathy in a patient suffering from nephrotic syndrome.

BMC Nephrol 2019 08 22;20(1):326. Epub 2019 Aug 22.

Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Background: Podocyte infolding glomerulopathy (PIG) is a rare histopathologic finding with global infolding of the podocytes into the glomerular basement membrane (GBM), accompanied by microstructures underneath. Described in 2002 for the first time, PIG was proposed as a new pathological entity in 2008 based on the largest case series so far. Yet all of the described cases derive from Asian countries. We report a case from Germany fulfilling the diagnostic criteria of PIG. Considering the scarcity of data on this entity especially in Western countries, collecting cases like ours and multicentric meta-analyses will be crucial to obtain a better understanding of PIG, its causes, clinical course and potential treatment options.

Case Presentation: A 56-year-old Caucasian woman with a history of rheumatoid arthritis (RA), no other comorbidities and no known renal disease was admitted to the hospital with acute kidney injury (AKI) and nephrotic syndrome. Physical examination was unremarkable except for anasarca. Renal ultrasound revealed no abnormalities. Laboratory and urine analyses were consistent with the nephrotic syndrome and renal failure. Serological studies regarding ANA, ANCA, anti-PLA2R autoantibodies, complement, virus infections, immunofixation and quantitative light chain analysis were unremarkable. A renal biopsy was performed. Light microscopic examination showed flattened tubular epithelium consistent with acute tubular damage, no infiltrates and unremarkable glomeruli except diffuse and global holes in the GBM (Fig. 1a) and negative staining for immunoglobulin heavy-chains, light-chains and complement split products. Electron microscopy revealed a rare correlate for these holes: global peculiar infolding of podocyte cytoplasm into the GBM. Most of these infoldings were accompanied by condensation of the GBM underneath. No such condensation or electron dense deposits were found without these infoldings or outside the GBM.

Conclusion: Here we report the first case of PIG outside of Asia. Since there are only few reports about this specific finding, we feel there is a need to share information in an attempt to accumulate knowledge about this possible new entity and potential treatment options.
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http://dx.doi.org/10.1186/s12882-019-1478-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704495PMC
August 2019

Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI.

J Am Soc Nephrol 2019 10 11;30(10):1857-1869. Epub 2019 Jul 11.

Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany;

Background: Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function.

Methods: To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted studies in mouse and human kidney cells and studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl.

Results: Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of and or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI.

Conclusions: Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
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http://dx.doi.org/10.1681/ASN.2018121218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779355PMC
October 2019

The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury.

Kidney Int 2019 02 3;95(2):333-349. Epub 2018 Dec 3.

Department II of Internal Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany. Electronic address:

Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions-caloric restriction and hypoxic preconditioning-in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data.
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http://dx.doi.org/10.1016/j.kint.2018.08.037DOI Listing
February 2019

A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.

Transplantation 2018 11;102(11):1795-1814

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward.
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http://dx.doi.org/10.1097/TP.0000000000002366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597974PMC
November 2018

Pathological manifestations of Farber disease in a new mouse model.

Biol Chem 2018 09;399(10):1183-1202

Department of Molecular Biology, University of Duisburg-Essen, Hufelandstraße 55, D-45147 Essen, Germany.

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.
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http://dx.doi.org/10.1515/hsz-2018-0170DOI Listing
September 2018

Author Correction: Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.

Sci Rep 2018 Apr 12;8(1):6003. Epub 2018 Apr 12.

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-23760-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897403PMC
April 2018

Mycophenolate mofetil following glucocorticoid treatment in Henoch-Schönlein purpura nephritis: the role of early initiation and therapeutic drug monitoring.

Pediatr Nephrol 2018 04 25;33(4):619-629. Epub 2017 Nov 25.

Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Kerpener Street 62, 50937, Cologne, Germany.

Background: Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial.

Methods: This retrospective, single-center study involved 18 patients presenting with HSPN and nephrotic-range proteinuria. We aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) and identify a cut-off level for estimated mycophenolic acid area under the curve (eMPA-AUC) values, which can predict complete remission with high sensitivity.

Results: Despite prior insufficient therapeutic response to corticosteroids, 89% of patients showed a significant decrease in proteinuria after 1 month of MMF treatment. None of them relapsed during treatment; however, two children relapsed after discontinuation. Based on results of a receiver operating characteristic (ROC) analysis, an eMPA-AUC >56.4 mg*h/l was a predictor for complete remission within 3 months (80% sensitivity, 83.3% specificity, p = 0.035). During MMF administration, we encountered no adverse event requiring discontinuation of treatment.

Conclusion: Our study demonstrates that MMF is a safe and potentially effective secondary treatment option for children with HSPN to achieve and maintain long-term remission without serious side effects. To achieve complete remission within 3 months, resolve severe inflammatory glomerular lesions, and avoid progression to chronic kidney disease, we propose timely diagnosis and early initiation of MMF with an eMPA-AUC value of 56.4 mg*h/l.
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http://dx.doi.org/10.1007/s00467-017-3846-6DOI Listing
April 2018

Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.

Sci Rep 2017 11 6;7(1):14554. Epub 2017 Nov 6.

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Changes in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes. A better understanding could lead to novel diagnostic tools and reveal novel therapeutic targets. We explored deregulated miRNAs in an glomeruloendothelial in vitro model of ABMR due to class I human leukocyte antigen (HLA) with and without complement activation. We studied a set of 16 promising candidate miRNAs in microdissected glomeruli a confirmation set of 20 human transplant biopsies (DSA+) compared to 10 matched controls without evidence for ABMR. Twelve out of these 16 glomerulocapillary miRNAs could successfully be confirmed as dysregulated in vivo with 10 upregulated (let-7c-5p, miR-28-3p, miR-30d-5p, miR-99b-5p, miR-125a-5p, miR-195-5p, miR-374b-3p, miR-484, miR-501-3p, miR-520e) and 2 downregulated (miR29b-3p, miR-885-5p) in DSA+ vs.

Controls: A random forest analysis based on glomerular miRNAs identified 18/20 DSA+ and 8/10 controls correctly. This glomerulocapillary miRNA signature associated with HLA class I-DSA could improve our understanding of ABMR and be useful for diagnostic or therapeutic purposes.
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http://dx.doi.org/10.1038/s41598-017-14674-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673998PMC
November 2017

Regulation of Arthritis Severity by the Acid Sphingomyelinase.

Cell Physiol Biochem 2017 16;43(4):1460-1471. Epub 2017 Oct 16.

Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.

Background/aims: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities.

Methods: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline.

Results: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint.

Conclusion: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.
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http://dx.doi.org/10.1159/000481968DOI Listing
December 2017

Regardless of etiology, progressive renal disease causes ultrastructural and functional alterations of peritubular capillaries.

Kidney Int 2017 01 24;91(1):70-85. Epub 2016 Sep 24.

Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Division of Nephrology, RWTH University of Aachen, Aachen, Germany. Electronic address:

Progressive renal diseases are associated with rarefaction of peritubular capillaries, but the ultrastructural and functional alterations of the microvasculature are not well described. To study this, we analyzed different time points during progressive kidney damage and fibrosis in 3 murine models of different disease etiologies. These models were unilateral ureteral obstruction, unilateral ischemia-reperfusion injury, and Col4a3-deficient mice, we analyzed ultrastructural alterations in patient biopsy specimens. Compared with kidneys of healthy mice, we found a significant and progressive reduction of peritubular capillaries in all models analyzed. Ultrastructurally, compared with the kidneys of control mice, focal widening of the subendothelial space and higher numbers of endothelial vacuoles and caveolae were found in fibrotic kidneys. Quantitative analysis showed that peritubular capillary endothelial cells in fibrotic kidneys had significantly and progressively reduced numbers of fenestrations and increased thickness of the cell soma and lamina densa of the capillary basement membrane. Similar ultrastructural changes were also observed in patient's kidney biopsy specimens. Compared with healthy murine kidneys, fibrotic kidneys had significantly increased extravasation of Evans blue dye in all 3 models. The extravasation could be visualized using 2-photon microscopy in real time in living animals and was mainly localized to capillary branching points. Finally, fibrotic kidneys in all models exhibited a significantly greater degree of interstitial deposition of fibrinogen. Thus, peritubular capillaries undergo significant ultrastructural and functional alterations during experimental progressive renal diseases, independent of the underlying injury. Analyses of these alterations could provide read-outs for the evaluation of therapeutic approaches targeting the renal microvasculature.
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http://dx.doi.org/10.1016/j.kint.2016.07.038DOI Listing
January 2017

A Multicenter Study of the Predictive Value of Crescents in IgA Nephropathy.

J Am Soc Nephrol 2017 02 9;28(2):691-701. Epub 2016 Sep 9.

Kidney Unit, National Fukuoka Higashi Medical Center, Fukuoka, Japan.

The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in one fourth or more of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.
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http://dx.doi.org/10.1681/ASN.2016040433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5280027PMC
February 2017

Comparison of different normalization strategies for the analysis of glomerular microRNAs in IgA nephropathy.

Sci Rep 2016 08 24;6:31992. Epub 2016 Aug 24.

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Small nucleolar RNAs (snoRNAs) have been used for normalization in glomerular microRNA (miRNA) quantification without confirmation of validity. Our aim was to identify glomerular reference miRNAs in IgA nephropathy. We compared miRNAs in human paraffin-embedded renal biopsies from patients with cellular-crescentic IgA-GN (n = 5; crescentic IgA-GN) and non-crescentic IgA-GN (n = 5; IgA-GN) to mild interstitial nephritis without glomerular abnormalities (controls, n = 5). Laser-microdissected glomeruli were used for expression profiling of 762 miRNAs by low-density TaqMan arrays (cards A and B). The comparison of different normalization methods (GeNormPlus, NormFinder, global mean and snoRNAs) in crescentic IgA-GN, IgA-GN and controls yielded similar results. However, levels of significance and the range of relative expression differed. In median, two normalization methods demonstrated similar results. GeNormPlus and NormFinder gave different top ranked reference miRNAs. Stability ranking for snoRNAs varied between cards A and B. In conclusion, we suggest the geometric mean of the most stable reference miRNAs found in GeNormPlus (miR-26b-5p), NormFinder (miR-28-5p) and snoRNAs (RNU44) as reference. It should be considered that significant differences could be missed using one particular normalization method. As a starting point for glomerular miRNA studies in IgA nephropathy we provide a library of miRNAs.
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http://dx.doi.org/10.1038/srep31992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995590PMC
August 2016

Live or Let Die: Is There any Cell Death in Podocytes?

Semin Nephrol 2016 05;36(3):208-19

Department II of Internal Medicine, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany. Electronic address:

Ultimately, the common final pathway of any glomerular disease is podocyte effacement, podocyte loss, and, eventually, glomerular scarring. There has been a long-standing debate on the underlying mechanisms for podocyte depletion, ranging from necrosis and apoptosis to detachment of viable cells from the glomerular basement membrane. However, this debate still continues because additional pathways of programmed cell death have been reported in recent years. Interestingly, viable podocytes can be isolated out of the urine of proteinuric patients easily, emphasizing the importance of podocyte detachment in glomerular diseases. In contrast, detection of apoptosis and other pathways of programmed cell death in podocytes is technically challenging. In fact, we still are lacking direct evidence showing, for example, the presence of apoptotic bodies in podocytes, leaving the question unanswered as to whether podocytes undergo mechanisms of programmed cell death. However, understanding the mechanisms leading to podocyte depletion is of particular interest because future therapeutic strategies might interfere with these to prevent glomerular scarring. In this review, we summarize our current knowledge on podocyte cell death, the different molecular pathways and experimental approaches to study these, and, finally, focus on the mechanisms that prevent the onset of programmed cell death.
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http://dx.doi.org/10.1016/j.semnephrol.2016.03.008DOI Listing
May 2016

Current status of pediatric renal transplant pathology.

Authors:
Jan U Becker

Pediatr Nephrol 2017 03 24;32(3):425-437. Epub 2016 May 24.

Institute of Pathology, University Hospital of Cologne, Kerpener Straße 62, 50937, Cologne, Germany.

Histopathology is still an indispensable tool for the diagnosis of kidney transplant dysfunction in adult and pediatric patients. This review presents consolidated knowledge, recent developments and future prospects on the biopsy procedure, the diagnostic work-up, classification schemes, the histopathology of rejection, including antibody-mediated forms, ABO-incompatible transplants, protocol biopsies, recurrent and de novo disease, post-transplant lymphoproliferative disorder, infectious complications and drug-induced toxicity. It is acknowledged that frequently the correct diagnosis can only be reached in consensus with clinical, serological, immunogenetical, bacteriological and virological findings. This review shall enhance the understanding of the pediatric nephrologist for the thought processes of nephropathologists with the aim to facilitate teamwork between these specialist groups for the benefit of the patient.
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http://dx.doi.org/10.1007/s00467-016-3381-xDOI Listing
March 2017

Do programmed death 1 (PD-1) and its ligand (PD-L1) play a role in patients with non-clear cell renal cell carcinoma?

Med Oncol 2016 Jun 10;33(6):59. Epub 2016 May 10.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Street 1, 30625, Hannover, Germany.

Clinical trials targeting programmed death 1 (PD-1) and its ligand PD-L1 (PD-L1) for metastatic renal cell cancer (RCC) are ongoing. The aim of this study is to validate their roles as prognostic markers in non-clear cell (non-cc) RCC. Sixty-four non-cc RCC tissue specimens were collected from patients undergoing renal tumor surgery. Expressions of biomarkers were assessed using immunohistochemistry and compared with clinical characteristics. Survival analyses were performed with a median follow-up of 77.5 (range: 0-176) months. No significant correlations were found for PD-1(+) tumor-infiltrating mononuclear cells (TIMC) or PD-L1(+) expression and clinical attributes in patients with non-cc RCC. Kaplan-Meier analysis revealed no differences in 5- and 10-year cancer-specific survival (CSS) for PD-1(-) TIMC compared to PD-1(+) TIMC (71.4 and 63 % versus 72.2 and 61.9 %; p = 0.88). Intratumoral expression of PD-L1 did not appear to influence the 5- and 10-year CSS significantly, even though a trend was identified (68 and 53.6 % versus 80.1 and 75.7 %; p = 0.08). In multivariate analysis, neither PD-1(+) TIMC nor intratumoral PD-L1(+) expression proved to be independent predictors of CSS (p = 0.99 and p = 0.68, respectively). Our study demonstrates that PD-1(+) TIMC and intratumoral PD-L1(+) expression did not significantly impact tumor aggressiveness or clinical outcome in non-ccRCC specimens. Due to rare incidence of non-cc RCC in particular according to PD-L1 expression, further analyzes are warranted.
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http://dx.doi.org/10.1007/s12032-016-0770-8DOI Listing
June 2016

German recommendations for pretransplantation donor kidney biopsies.

Langenbecks Arch Surg 2016 Mar 19;401(2):133-40. Epub 2016 Mar 19.

Institute of Pathology, University Hospital of Cologne, Kerpener Straße 62, 50937, Cologne, Germany.

Purpose: This manuscript reviews the data about the histopathologic and develops recommendations to standardise and improve the biopsy procedure, the biopsy handling, the histopathological evaluation, the communication of results and the collection of data from pretransplantation kidney biopsies of deceased donors in Germany.

Methods: The recommendations are based on this literature review, on discussions at two workshops held by the German Society of Pathology and the German Organ Transplantation Foundation and on personal experiences of the authors.

Results: These German recommendations advocate the use of punch biopsies, paraffin embedding and detailed descriptive reporting of histopathological findings.

Conclusions: These recommendations constitute only a starting point. Periodical revisions will help to simplify and optimise the recommendations with the ultimate goal to prospectively gather data for the elaboration of a computer-based algorithm that allows the exact prediction of transplantation outcome for a given match of donor and recipient.
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http://dx.doi.org/10.1007/s00423-016-1384-5DOI Listing
March 2016

TRPC6 G757D Loss-of-Function Mutation Associates with FSGS.

J Am Soc Nephrol 2016 09 18;27(9):2771-83. Epub 2016 Feb 18.

Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, Tübingen, Germany;

FSGS is a CKD with heavy proteinuria that eventually progresses to ESRD. Hereditary forms of FSGS have been linked to mutations in the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene encoding a nonselective cation channel. Most of these TRPC6 mutations cause a gain-of-function phenotype, leading to calcium-triggered podocyte cell death, but the underlying molecular mechanisms are unclear. We studied the molecular effect of disease-related mutations using tridimensional in silico modeling of tetrameric TRPC6. Our results indicated that G757 is localized in a domain forming a TRPC6-TRPC6 interface and predicted that the amino acid exchange G757D causes local steric hindrance and disruption of the channel complex. Notably, functional characterization of model interface domain mutants suggested a loss-of-function phenotype. We then characterized 19 human FSGS-related TRPC6 mutations, the majority of which caused gain-of-function mutations. However, five mutations (N125S, L395A, G757D, L780P, and R895L) caused a loss-of-function phenotype. Coexpression of wild-type TRPC6 and TRPC6 G757D, mimicking heterozygosity observed in patients, revealed a dominant negative effect of TRPC6 G757D. Our comprehensive analysis of human disease-causing TRPC6 mutations reveals loss of TRPC6 function as an additional concept of hereditary FSGS and provides molecular insights into the mechanism responsible for the loss-of-function phenotype of TRPC6 G757D in humans.
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http://dx.doi.org/10.1681/ASN.2015030318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004639PMC
September 2016

Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease.

Nephrol Dial Transplant 2016 07 17;31(7):1088-99. Epub 2015 Dec 17.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Background: In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously.

Methods: We conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sex-matched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescence microscopy, qRT-PCR and western blotting.

Results: The majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant.

Conclusions: Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.
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http://dx.doi.org/10.1093/ndt/gfv421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388939PMC
July 2016

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

J Am Soc Nephrol 2015 Nov 18;26(11):2860-70. Epub 2015 Mar 18.

Department of Nephrology and Hypertension, Center for Internal Medicine and

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.
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http://dx.doi.org/10.1681/ASN.2014050477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625662PMC
November 2015

A rolling circle amplification screen for polyomaviruses other than BKPyV in renal transplant recipients confirms high prevalence of urinary JCPyV shedding.

Intervirology 2015 13;58(2):88-94. Epub 2015 Feb 13.

Institute of Virology, Hannover Medical School, Hannover, Germany.

Objectives: Multiple novel human polyomaviruses (HPyVs) have been discovered in the last few years. These or other, unknown, nephrotropic HPyVs may potentially be shed in urine.

Methods: To search for known and unknown HPyVs we investigated BKPyV-negative urine samples from 105 renal transplant recipients (RTR) by rolling circle amplification (RCA) analysis and quantitative JCPyV PCR. Clinical data was analysed to identify risk factors for urinary polyomavirus shedding.

Results: In 10% (11/105) of the urine samples RCA with subsequent sequencing revealed JCPyV, but no other HPyV sequences. Using quantitative JCPyV PCR, 24% (25/105) of the samples tested positive. Overall sensitivities of RCA of 44% (11/25) in detecting JCPyV in JCPyV DNA-positive urine and 67% (10/15) for samples with JCPyV loads >10,000 copies/ml can be assumed. Despite frequent detectable urinary shedding of JCPyV in our cohort, this could not be correlated with clinical risk factors.

Conclusion: Routine urinary JCPyV monitoring in BKPyV-negative RTR without suspected polyomavirus-associated nephropathy might be of limited diagnostic value. As RCA works in a sequence-independent manner, detection of novel and known polyomaviruses shed in sufficient quantities is feasible. High-level shedding of HPyVs other than BKPyV or JCPyV in the urine of RTR is unlikely to occur.
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http://dx.doi.org/10.1159/000369210DOI Listing
January 2016

Acute and chronic antibody-mediated rejection in pediatric kidney transplantation.

Pediatr Nephrol 2015 Mar 28;30(3):417-24. Epub 2014 May 28.

Department of Pediatric Nephrology, Hannover Medical School, Carl-Neuberg-Straße 1, 30655, Hannover, Germany,

Acute antibody-mediated rejection is a diagnostic challenge in renal transplantation medicine. However, it is an important diagnosis to make, since chronic antibody-mediated rejection (CAMR) is the main cause of long-term graft loss. Antibody-mediated rejection is diagnosed by detecting donor-specific antibodies (DSAs) in the blood in combination with observing typical histomorphological signs in kidney biopsy, as described in the Banff classification. Therapy is based on the removal of DSAs by administering intravenous immunoglobulins (IVIGs), plasmapheresis, or immunoadsorption. Reoccurrence of antibodies is diminished by the use of rituximab, increased immunosuppression, and in some cases additional experimental substances. A combination of these techniques has been shown to be successful in the majority of cases of acute and chronic antibody-mediated rejection. Routine DSA monitoring is warranted for early detection of antibody-mediated rejection.
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http://dx.doi.org/10.1007/s00467-014-2851-2DOI Listing
March 2015

Primary mucinous adenocarcinoma of the renal pelvis with carcinoma in situ in the ureter.

J Egypt Natl Canc Inst 2014 Mar 9;26(1):51-4. Epub 2014 Jan 9.

Departments of Pathology, Hanover Medical School, Hanover, Germany.

Primary epithelial tumor of the renal pelvis is rare and only 100 cases are reported in the literature [1]. Histological examination of the tumor showed glands, cysts, and papillae lined by pseudostratified columnar epithelium with hyperchromatic nuclei. Scattered signet ring-type cells were also seen floating in large pools of extracellular mucin. Sections from the ureter showed a component of adenocarcinoma in situ. No invasive tumor was identified in ureteric tissue. One case was reported with carcinoma in situ of the ureter (2). Immunohistochemically: The tumor showed positivity for CK7, CK20, CK8/18, GATA-3, MSH-2, MSH-6, MLH-1, Ber-EP4, and S-100-P with focal positivity for CDX-2, weak positivity for PMS-2 and negativity in TTF-1 and Her-2. Molecular pathological analysis revealed microsatellite stability and without mutation in K-ras-gene. Thus, a diagnosis of mucinous adenocarcinoma of the renal pelvis with in situ adenocarcinoma of the ureter was made.
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http://dx.doi.org/10.1016/j.jnci.2013.11.002DOI Listing
March 2014

Renal phospholipidosis possibly induced by ranolazine.

Clin Kidney J 2014 Feb 10;7(1):62-4. Epub 2013 Dec 10.

Medizinische Abteilung , St. Franziskus-Hospital , Münster , Germany.

A 76-year-old male Caucasian patient was treated in our hospital for acutely decompensated heart failure due to restrictive cardiomyopathy. Acute-on-chronic kidney failure developed with serum creatinine rising from 160 to 345 μmol/L (1.8-3.9 mg/dL); therefore, a kidney biopsy was performed. Besides secondary focal-segmental glomerulosclerosis and minimal amyloidosis, histological analysis showed zebra bodies in the cytoplasm of some podocytes, suggesting renal phospholipidosis (PL). Possible causes for this storage disorder encompass Fabry's disease, in rare cases silicosis, and an iatrogenic drug-induced aetiology. The main suspects are cationic amphiphilic drugs, such as amiodarone and chloroquine. The only cationic amphiphilic drug our patient had taken was the anti-anginal ranolazine, a compound not yet associated with PL. The patient had taken ranolazine for diastolic dysfunction over a period of 9 months until 6 weeks before renal biopsy. In the absence of a hereditary disorder, silicosis and well-known pharmaceutical triggers, a causative role of ranolazine seems likely, and this drug should be considered in the differential diagnosis of drug-induced PL.
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http://dx.doi.org/10.1093/ckj/sft141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389157PMC
February 2014

Beyond C4d: the ultrastructural appearances of endothelium in ABO-incompatible renal allografts.

Nephrol Dial Transplant 2013 Dec 29;28(12):3101-9. Epub 2013 Sep 29.

Institute for Pathology, Hannover Medical School, Hannover, Germany.

Background: ABO incompatibility is no longer a barrier in kidney transplantation. C4d is frequently positive in ABO-incompatible (iABO) biopsies without further signs of microcirculation injury. This phenomenon is assumed to represent graft accommodation. However, ultrastructural examination of glomerular and peritubular capillary endothelium might reveal subtle endothelial damage.

Methods: We studied the ultrastructural appearance of the endothelium in 67 biopsies from 21 patients with iABO allografts and compared it with 20 patients (29 biopsies) with ABO-compatible (cABO) grafts with C4d positivity and 25 ABO-compatible control patients (25 biopsies) without serological or histological evidence of humoral rejection (C4d negative). Ten ultrastructural parameters indicative of chronic and acute glomerular and peritubular capillary damage in transmission electron microscopy (TEM) were semi-quantitatively graded and expressed in a sum score. Clinico-pathological data were compared as well as graft function at the time of biopsy and follow-up.

Results: Ultrastructural parameters did not significantly differ between iABO and controls. In contrast, C4d-positive cABO had the highest TEM sum score (P = 0.001 versus iABO, P = 0.002 versus controls). The sum score did not differ between C4d-positive and C4d-negative iABO but did differ between patients with and without anti-HLA donor-specific antibodies (DSA). Graft function in iABO at the time of biopsy and at follow-up was similar to controls.

Conclusions: Our ultrastructural observations support the concept of endothelial accommodation in iABO renal transplants. C4d positivity in the ABO-incompatible situation does not indicate injurious activation of the complement cascade and does not seem to impact on the graft function, in contrast to C4d deposition in cABO with antibody-mediated rejection.
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http://dx.doi.org/10.1093/ndt/gft373DOI Listing
December 2013

Hypoxia Induces Mesenchymal Gene Expression in Renal Tubular Epithelial Cells: An in vitro Model of Kidney Transplant Fibrosis.

Nephron Extra 2013 Jan 6;3(1):50-8. Epub 2013 Jun 6.

Institute of Pathology, Hannover Medical School, Hannover, Germany ; Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.

Background: The development of interstitial fibrosis and tubular atrophy is a common complication after kidney transplantation and is associated with reduced long-term outcome. The hallmark of tubulointerstitial fibrosis is an increase in extracellular matrix resulting from exaggerated activation of fibroblasts/myofibroblasts, and tubular atrophy is characterized by a decrease in tubular diameter and loss of function. Atrophic epithelial cells may undergo epithelial-to-mesenchymal transition (EMT) with potential differentiation into interstitial fibroblasts. One potential driver of EMT in developing interstitial fibrosis and tubular atrophy is chronic hypoxia.

Methods: The expression of 46 EMT-related genes was analyzed in an in vitro hypoxia model in renal proximal tubular epithelial cells (RPTEC). Furthermore, the expression of 342 microRNAs (miR) was evaluated in hypoxic culture conditions.

Results: Hypoxic RPTEC expressed markers of a more mesenchymal phenotype and showed an increased expression of matrix metalloproteinase-2 (MMP2). MMP2 expression in RPTEC correlated inversely with a decreased expression of miR-124, which was found to have a putative binding site for the MMP2 transcript. Overexpression of miR-124 inhibited MMP2 protein translation. Hypoxia was associated with increased migration/proliferation of RPTEC which was reversed by miR-124.

Conclusions: These results indicate that hypoxia promotes a mesenchymal and migratory phenotype in renal epithelial cells, which is associated with increased MMP2 expression. Hypoxia-dependent MMP2 expression is regulated via a reduced transcription of miR-124. Overexpression of miR-124 antagonizes hypoxia-induced cell migration. Further research is needed to elucidate the functional role of miR-124 and MMP2 in the development of fibrosis in renal transplant degeneration.
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http://dx.doi.org/10.1159/000351046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711002PMC
January 2013