Publications by authors named "Sandrine Florquin"

305 Publications

Renal amyloidosis: validation of a proposed histological scoring system in an independent cohort.

Clin Kidney J 2021 Mar 24;14(3):855-862. Epub 2020 Mar 24.

Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: In systemic amyloidosis, the kidney is frequently affected and renal involvement has a major impact on survival. Renal involvement is clinically characterized by decreased estimated glomerular filtration rate (eGFR) and proteinuria. The two most common renal amyloidosis types are light chain-related amyloidosis (AL) and serum amyloid A (AA) amyloidosis. Standardized histopathological scoring of amyloid deposits is crucial to assess disease progression. Therefore, we aimed to validate the proposed scoring system from Rubinstein . (Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis. Amyloid 2017; 24: 205-211) in an independent patient cohort.

Methods: We attempt to reproduce the scoring system, consisting of an amyloid score (AS) and a composite scarring injury score (CSIS), in a multicentre AL and AA case series. Additionally, we analysed all renal amyloidosis kidney biopsies performed in the Netherlands between 1993 and 2012.

Results: Similar to the original study, AS and CSIS correlated to eGFR ( = -0.45, P = 0.0061 and = -0.60, P < 0.0001, respectively) but not to proteinuria at diagnosis. Furthermore, AS, but not CSIS, was associated with renal outcome. The scoring system was not reproducible in AA patients. The median incidence rate for renal amyloidosis in the Netherlands was 2.3 per million population per year, and increased during the study period.

Conclusions: In our AL case series and the original study, AS and CSIS were correlated to eGFR but not to proteinuria, and AS correlated with renal outcome. Overall, we regard this scoring system as competent for standardized histopathological assessment of amyloid deposits burden and thereby disease advancement in renal biopsies.
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http://dx.doi.org/10.1093/ckj/sfaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986350PMC
March 2021

Bisphosphonate nephropathy: A case series and review of the literature.

Br J Clin Pharmacol 2021 Feb 17. Epub 2021 Feb 17.

Department of Internal Medicine, Spaarne Gasthuis, Haarlem/Hoofddorp, the Netherlands.

From rat studies, human case reports and cohort studies, bisphosphonates seem to impair renal function. However, when critically reviewing the literature, zoledronate and pamidronate are more frequently involved in renal deterioration than other bisphosphonates. When bisphosphonate nephropathy occurs, zoledronate more frequently induces tubular toxicity whereas pamidronate typically induces focal segmental glomerulosclerosis. Thus, although bisphosphonates are highly effective in preventing complications for patients with osseous metastases and are highly effective in preventing fractures for patients with osteoporosis, renal function should be monitored closely after initiation of these drugs.
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http://dx.doi.org/10.1111/bcp.14780DOI Listing
February 2021

The dysregulation of metabolic pathways and induction of the pentose phosphate pathway in renal ischaemia-reperfusion injury.

J Pathol 2021 Apr 31;253(4):404-414. Epub 2021 Jan 31.

Department of Pathology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center (Location AMC), Amsterdam, The Netherlands.

Lipid accumulation is associated with various forms of acute renal injury; however, the causative factors and pathways underpinning this lipid accumulation have not been thoroughly investigated. In this study, we performed lipidomic profiling of renal tissue following ischaemia-reperfusion injury (IRI). We identified a significant accumulation of cholesterol and specific phospholipids and sphingolipids in kidneys 24 h after IRI. In light of these findings, we hypothesised that pathways involved in lipid metabolism may also be altered. Through the analysis of published microarray data, generated from sham and ischaemic kidneys, we identified nephron-specific metabolic pathways affected by IRI and validated these findings in ischaemic renal tissue. In silico analysis revealed the downregulation of several energy and lipid metabolism pathways, including mitochondrial fatty acid beta-oxidation (FAO), peroxisomal lipid metabolism, fatty acid (FA) metabolism, and glycolysis. The pentose phosphate pathway (PPP), which is fuelled by glycolysis, was the only metabolic pathway that was upregulated 24 h following IRI. In this study, we describe the effect of renal IRI on metabolic pathways and how this contributes to lipid accumulation. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986929PMC
April 2021

Interleukin-33 improves local immunity during Gram-negative pneumonia by a combined effect on neutrophils and inflammatory monocytes.

J Pathol 2021 Apr 19;253(4):374-383. Epub 2021 Jan 19.

Center of Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Pneumonia represents a major health care burden and Gram-negative bacteria provide an increasing therapeutic challenge at least in part through the emergence of multidrug-resistant strains. IL-33 is a multifunctional cytokine belonging to the IL-1 family that can affect many different cell types. We sought here to determine the effect of recombinant IL-33 on the host response during murine pneumonia caused by the common Gram-negative pathogen Klebsiella pneumoniae. IL-33 pretreatment prolonged survival for more than 1 day during lethal airway infection and decreased bacterial loads at the primary site of infection and distant organs. Postponed treatment with IL-33 (3 h) also reduced bacterial growth and dissemination. IL-33-mediated protection was not observed in mice deficient for the IL-33 receptor component IL-1 receptor-like 1. IL-33 induced a brisk type 2 response, characterized by recruitment of type 2 innate lymphoid cells to the lungs and enhanced release of IL-5 and IL-13. However, neither absence of innate lymphoid cells or IL-13, nor blocking of IL-5 impacted on IL-33 effects in mice infected with Klebsiella. Likewise, IL-33 remained effective in reducing bacterial loads in mice lacking B, T, and natural killer T cells. Experiments using antibody-mediated cell depletion indicated that neutrophils and inflammatory monocytes were of importance for antibacterial defense. The capacity of IL-33 to restrict bacterial growth in the lungs was strongly reduced in mice depleted of both neutrophils and inflammatory monocytes, but not in mice selectively depleted of either one of these cell types. These results suggest that IL-33 boosts host defense during bacterial pneumonia by a combined effect on neutrophils and inflammatory monocytes. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986604PMC
April 2021

Biopsy-Controlled Non-Invasive Quantification of Collagen Type VI in Kidney Transplant Recipients: A Post-Hoc Analysis of the MECANO Trial.

J Clin Med 2020 Oct 7;9(10). Epub 2020 Oct 7.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands.

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) ( < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.
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http://dx.doi.org/10.3390/jcm9103216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600059PMC
October 2020

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.

Lancet Microbe 2020 Nov 25;1(7):e290-e299. Epub 2020 Sep 25.

Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy.

Methods: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course.

Findings: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78). Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets..

Interpretation: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19.

Funding: Amsterdam UMC Corona Research Fund.
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http://dx.doi.org/10.1016/S2666-5247(20)30144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518879PMC
November 2020

Platelet inhibition by ticagrelor is protective against diabetic nephropathy in mice.

FASEB J 2020 Oct 27;34(10):13750-13761. Epub 2020 Aug 27.

Department of Pathology, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands.

Diabetic nephropathy (DN) is a major complication of diabetes and is associated with high risk for cardiovascular mortality, which is partially related to elevated platelet activity. Platelets are also active players in inflammation and fibrosis. In this study, we examine the effect of ticagrelor-induced platelet inhibition on the development of DN. DN was induced by unilateral nephrectomy followed by streptozotocin injections for 5 days. Mice received ticagrelor (300 mg/kg) or vehicle every other day, for 16 weeks. Experimental groups: non-diabetic control, diabetic control, non-diabetic ticagrelor, and diabetic ticagrelor. Ticagrelor treatment in diabetic mice lowered urinary albumin excretion, it prevented diabetes-induced mesangial matrix expansion, podocyte effacement, and glomerular endothelial cell injury, which includes loss of endothelial fenestrations, ICAM-1 expression, and PECAM expression. In addition, ticagrelor treatment prevented collagen IV deposition and macrophage infiltration in the tubulointerstitium and these diabetic mice showed lower systemic and tubular inflammation and tubular apoptosis. This tubular protection is likely to be a result of protection to the glomerular endothelium by ticagrelor, which reduces albuminuria and albumin toxicity to the tubules and reduced tubular and interstitial inflammation and fibrosis. In conclusion, ticagrelor-induced platelet inhibition protects against renal injury in diabetic mice, likely by protecting the glomerular endothelial cells.
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http://dx.doi.org/10.1096/fj.202000897RDOI Listing
October 2020

Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration.

Front Immunol 2020 7;11:1346. Epub 2020 Jul 7.

Department of Pathology, Amsterdam UMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, Netherlands.

Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells (TECs). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and TEC repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra- and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that TEC-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides TECs with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within TECs, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in TECs: from programmed cell death (PCD) and mitochondrial dysfunction-mediated metabolic rewiring of TECs to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in TECs and their therapeutic potential in both experimental and clinical research.
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http://dx.doi.org/10.3389/fimmu.2020.01346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358591PMC
April 2021

Clinical consequences of primary CMV infection after renal transplantation: a case-control study.

Transpl Int 2020 Sep 4;33(9):1116-1127. Epub 2020 Jul 4.

Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.

The impact of primary cytomegalovirus infection (pCMV) on renal allograft function and histology is controversial. We evaluated the influence on incidence of acute rejection, allograft loss, allograft function and interstitial fibrosis/tubular atrophy (IF/TA). Retrospective case-control study, recipients transplanted between 2000 and 2014. Risk of acute rejection and allograft loss for those who experienced pCMV infection compared with those who did not, within an exposure period of two months after transplantation. Besides, its influence on allograft function and histology at one to three years after transplantation. Of 113 recipients experienced pCMV infection, 306 remained CMV seronegative. pCMV infection in the exposure period could not be proven as increasing the risk for acute rejection [HR = 2.18 (95% CI 0.80-5.97) P = 0.13] or allograft loss [HR = 1.11 (95%CI 0.33-3.72) P = 0.87]. Combination of pCMV infection and acute rejection posed higher hazard for allograft loss than acute rejection alone [HR = 3.69 (95% CI 1.21-11.29) P = 0.02]. eGFR(MDRD) values did not significantly differ at years one [46 vs. 50], two [46 vs. 51] and three [46 vs. 52]. No association between pCMV infection and IF/TA could be demonstrated [OR = 2.15 (95%CI 0.73-6.29) P = 0.16]. pCMV infection was not proven to increase the risk for acute rejection or allograft loss. However, it increased the risk for rejection-associated allograft loss. In remaining functioning allografts, it was not significantly associated with decline in function nor with presence of IF/TA.
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http://dx.doi.org/10.1111/tri.13667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540315PMC
September 2020

Caspase-11 contributes to pulmonary host defense against and local activation of coagulation.

Am J Physiol Lung Cell Mol Physiol 2020 07 13;319(1):L105-L114. Epub 2020 May 13.

Center of Experimental and Molecular Medicine, Amsterdam, The Netherlands.

is a common cause of gram-negative pneumonia and sepsis. Caspase-11 is an intracellular receptor for lipopolysaccharide and regulates pyroptosis, a specific form of inflammatory cell death, which aids in host defense against intracellular gram-negative bacteria. Recently, caspase-11 has also been implicated in blood coagulation. Previously, we found that local fibrin formation contributes to protective immunity against infection of the lung. The aim of the present study was to determine the role of caspase-11 in host defense during -evoked pneumonia and sepsis. Therefore, we infected wild-type and caspase-11-deficient () mice with a low-dose via the airways to induce a gradually evolving pneumosepsis. mice displayed increased bacterial numbers in the lung 12 h and 48 h after inoculation. Analysis of pulmonary IL-1α, IL-1β, and TNF levels showed reduced IL-1α levels in bronchoalveolar lavage fluid and increased TNF levels in the lung of mice at 48 h after inoculation. Lung γH2AX staining (marker for cell death), lung pathology and neutrophil influx in the lung, as well as bacterial dissemination and organ damage, however, were not altered in mice after infection. Strikingly, analysis of cross-linked fibrin and D-dimer (markers for coagulation) revealed significantly less fibrin formation in the lungs of mice at either time point after infection. These data reveal that caspase-11 contributes to protective immunity against possibly by activation of blood coagulation in the lung.
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http://dx.doi.org/10.1152/ajplung.00422.2019DOI Listing
July 2020

Authors' Response to Letter to the Editor on "Unidentified Variables May Account for Variability in Multiplexing Results".

J Histochem Cytochem 2020 05;68(5):355-356

Department of Dermatology, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1369/0022155420925082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226621PMC
May 2020

Comparison of Two Different Immunohistochemical Quadruple Staining Approaches to Identify Innate Lymphoid Cells in Formalin-fixed Paraffin-embedded Human Tissue.

J Histochem Cytochem 2020 02 27;68(2):127-138. Epub 2019 Dec 27.

Department of Dermatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Lack of specific markers for innate lymphoid cells (ILCs) limit our knowledge on their spatial organization in situ. We compared two quadruple-color staining protocols for detection of the three principal human ILC subsets in formalin-fixed paraffin-embedded specimens. ILC subset-associated archetypical transcription factors (TFs) T-bet, GATA3, and RORγt were used as positive identifiers in combination with lymphoid lineage markers to exclude non-ILCs. One method ("virtual quadruple staining") comprised of iterative single stainings on the same section performing digital scanning and subsequent immunoglobulin and chromogen stripping after each staining round. The second technique ("true-color quadruple staining") comprised sequential double stainings with permanent colors. Both protocols appeared suitable for accurate detection of each ILC subset, and as added result, concomitant visualization of their T cell subset counterpart. Only true-color quadruple staining enabled simultaneous detection of all three ILC subsets within one section. Furthermore, we found that type 3 and type 1 ILCs (ILC1s) represent the major subsets in colon and that part of the ILC1s typically colocalizes with blood vessels. Our data highlight the utility of TFs combined with lineage markers for the identification of ILC subsets and proposed workflow opens the way to gain deeper insight of their anatomical distribution.
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http://dx.doi.org/10.1369/0022155419897257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003497PMC
February 2020

β-Cyclodextrin counteracts obesity in Western diet-fed mice but elicits a nephrotoxic effect.

Sci Rep 2019 11 27;9(1):17633. Epub 2019 Nov 27.

Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, North Holland, The Netherlands.

Obesity has become a worldwide health crisis and is associated with a plethora of comorbidities. The multi-organ effects of obesity have been linked to ectopic lipid accumulation. Thus, there is an urgent need to tackle the obesity crisis by developing effective lipid-lowering therapies. 2-hydroxypropyl-β-Cyclodextrin (2HP-β-CD) has been previously shown to reduce lysosomal cholesterol accumulation in a murine model of Niemann Pick Type C (NPC) disease. Using a murine model of Western diet-induced obesity (DIO), we report the effects of 2HP-β-CD in counteracting weight gain, expansion of adipose tissue mass and ectopic lipid accumulation. Interestingly, DIO caused intracellular storage of neutral lipids in hepatic tissues and of phospholipids in kidneys, both of which were prevented by 2HP-β-CD. Importantly, this report brings attention to the nephrotoxic effects of 2HP-β-CD: renal tubular damage, inflammation and fibrosis. These effects may be overlooked, as they are best appreciated upon assessment of renal histology.
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http://dx.doi.org/10.1038/s41598-019-53890-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881402PMC
November 2019

Complement activation and long-term graft function in ABO-incompatible kidney transplantation.

World J Nephrol 2019 Oct;8(6):95-108

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen NL-9700 RB, Netherlands.

Background: ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.

Aim: To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.

Methods: We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.

Results: Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 69 mL/min, = 0.02, Modification of Diet in Renal Disease 46 52 mL/min/1.73 m, = 0.08), due to a high rate of early rejection (33% 15%, = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.

Conclusion: Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.
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http://dx.doi.org/10.5527/wjn.v8.i6.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817790PMC
October 2019

Cellular origin and microRNA profiles of circulating extracellular vesicles in different stages of diabetic nephropathy.

Clin Kidney J 2021 Jan 23;14(1):358-365. Epub 2019 Oct 23.

Department of Pathology, Amsterdam Infection & Immunity Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Diabetic nephropathy (DN) is a major complication of diabetes and the main cause of end-stage renal disease. Extracellular vesicles (EVs) are small cell-derived vesicles that can alter disease progression by microRNA (miRNA) transfer.

Methods: In this study, we aimed to characterize the cellular origin and miRNA content of EVs in plasma samples of type 2 diabetes patients at various stages of DN. Type 2 diabetes patients were classified in three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. The concentration and cellular origin of plasma EVs were measured by flow cytometry. A total of 752 EV miRNAs were profiled in 18 subjects and differentially expressed miRNAs were validated.

Results: Diabetic patients with microalbuminuria and/or macroalbuminuria showed elevated concentrations of total EVs and EVs from endothelial cells, platelets, leucocytes and erythrocytes compared with diabetic controls. miR-99a-5p was upregulated in macroalbuminuric patients compared with normoalbuminuric and microalbuminuric patients. Transfection of miR-99a-5p in cultured human podocytes downregulated mammalian target of rapamycin (mTOR) protein expression and downregulated the podocyte injury marker vimentin.

Conclusions: Type 2 diabetes patients with microalbuminuria and macroalbuminuria display differential EV profiles. miR-99a-5p expression is elevated in EVs from macroalbuminuria and mTOR is its validated mRNA target.
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http://dx.doi.org/10.1093/ckj/sfz145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857783PMC
January 2021

Role of tissue factor in the procoagulant and antibacterial effects of human adipose-derived mesenchymal stem cells during pneumosepsis in mice.

Stem Cell Res Ther 2019 09 23;10(1):286. Epub 2019 Sep 23.

Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Adult mesenchymal stem cells (MSCs) improve the host response during experimental sepsis in animals. MSCs from various sources express a procoagulant activity that has been linked to the expression of tissue factor. This study sought to determine the role of tissue factor associated with adipose-derived MSCs (ASCs) in their procoagulant and antibacterial effects during pneumonia-derived sepsis.

Methods: Mice were infused intravenously with ASCs or vehicle after infection with the common human pathogen Klebsiella pneumoniae via the airways.

Results: Infusion of freshly cultured or cryopreserved ASCs induced the expression of many genes associated with tissue factor signaling and coagulation activation in the lungs. Freshly cultured and cryopreserved ASCs, as well as ASC lysates, exerted procoagulant activity in vitro as determined by a fibrin generation assay, which was almost completely inhibited by an anti-tissue factor antibody. Infusion of cryopreserved ASCs was associated with a rise in plasma thrombin-antithrombin complexes (indicative of coagulation activation) and formation of multiple thrombi in the lungs 4 h post-infusion. Preincubation of ASCs with anti-tissue factor antibody prior to infusion prevented the rise in plasma thrombin-antithrombin complex concentrations but did not influence thrombus formation in the lungs. ASCs reduced bacterial loads in the lungs and liver at 48 h after infection, which was not influenced by preincubation with anti-tissue factor antibody. At this late time point, microthrombi in the lungs were not detected anymore.

Conclusion: These data indicate that ASC-associated tissue factor is responsible for systemic activation of coagulation after infusion of ASCs but not for the formation of microthrombi in the lungs or antibacterial effects.
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http://dx.doi.org/10.1186/s13287-019-1391-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757441PMC
September 2019

Deep Learning-Based Histopathologic Assessment of Kidney Tissue.

J Am Soc Nephrol 2019 10 5;30(10):1968-1979. Epub 2019 Sep 5.

Departments of Pathology and

Background: The development of deep neural networks is facilitating more advanced digital analysis of histopathologic images. We trained a convolutional neural network for multiclass segmentation of digitized kidney tissue sections stained with periodic acid-Schiff (PAS).

Methods: We trained the network using multiclass annotations from 40 whole-slide images of stained kidney transplant biopsies and applied it to four independent data sets. We assessed multiclass segmentation performance by calculating Dice coefficients for ten tissue classes on ten transplant biopsies from the Radboud University Medical Center in Nijmegen, The Netherlands, and on ten transplant biopsies from an external center for validation. We also fully segmented 15 nephrectomy samples and calculated the network's glomerular detection rates and compared network-based measures with visually scored histologic components (Banff classification) in 82 kidney transplant biopsies.

Results: The weighted mean Dice coefficients of all classes were 0.80 and 0.84 in ten kidney transplant biopsies from the Radboud center and the external center, respectively. The best segmented class was "glomeruli" in both data sets (Dice coefficients, 0.95 and 0.94, respectively), followed by "tubuli combined" and "interstitium." The network detected 92.7% of all glomeruli in nephrectomy samples, with 10.4% false positives. In whole transplant biopsies, the mean intraclass correlation coefficient for glomerular counting performed by pathologists versus the network was 0.94. We found significant correlations between visually scored histologic components and network-based measures.

Conclusions: This study presents the first convolutional neural network for multiclass segmentation of PAS-stained nephrectomy samples and transplant biopsies. Our network may have utility for quantitative studies involving kidney histopathology across centers and provide opportunities for deep learning applications in routine diagnostics.
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http://dx.doi.org/10.1681/ASN.2019020144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779356PMC
October 2019

Prevention of relapses with levamisole as adjuvant therapy in children with a first episode of idiopathic nephrotic syndrome: study protocol for a double blind, randomised placebo-controlled trial (the LEARNS study).

BMJ Open 2019 08 1;9(8):e027011. Epub 2019 Aug 1.

Paediatric Nephrology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Idiopathic nephrotic syndrome (INS) is characterised by a high relapse rate up to 80% after initial response to standard therapy with corticosteroids. Steroid toxicity is common and causes a great burden of disease that negatively influences the health-related quality of life (HRQoL). Recently, studies have shown that levamisole, an anthelminthic drug, significantly improves relapse-free survival in children with frequent relapses or steroid dependency. Compared with other steroid-sparing drugs, levamisole has relatively few side effects. We hypothesise that adding levamisole to standard therapy with corticosteroids in children with a first episode of INS will prevent relapses, decrease cumulative dosage of steroids used and improve HRQoL. This paper presents the study protocol for the LEARNS study (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome).

Methods And Analysis: An international, double-blind, placebo-controlled randomised trial will be conducted in 20 participating hospitals in the Netherlands and Belgium. Participants (n=92) with a first episode of INS, aged 2-16 years, who achieve remission after 4 weeks of oral prednisolone will be randomly assigned (1:1) to receive either levamisole 2.5 mg/kg alternate day or placebo added to prednisolone (18-week tapering schedule) for a total of 24 weeks. Follow-up will be until 2 years after first presentation. Additionally, parents and/or children will fill out five HRQoL questionnaires. Primary outcome of the LEARNS study is occurrence of relapses within 12 months after first presentation. Secondary outcomes include time to first relapse, cumulative steroid dose after 2 years, safety parameters and quality of life scores.

Ethics And Dissemination: The trial was approved by the Medical Ethical Committee. Results of the study will be published in a peer-reviewed journal.

Trial Registration Number: NL6826, 2017-001025-41.
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http://dx.doi.org/10.1136/bmjopen-2018-027011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688689PMC
August 2019

Experimental thrombocytopenia does not affect acute kidney injury 24 hours after renal ischemia reperfusion in mice.

Platelets 2020 31;31(3):383-391. Epub 2019 Jul 31.

Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

The pathophysiology of renal ischemia/reperfusion (I/R) injury is characterized by excessive activation of inflammation and coagulation processes followed by abnormal renal tissue repair, resulting in renal injury and function loss. Platelets are important actors in these processes, however to what extent platelets contribute to the pathophysiology of renal I/R injury still needs to be elucidated. In the current study, we treated wild-type mice with a platelet depleting antibody, which caused thrombocytopenia. We then investigated the role of platelets during the pathophysiology of renal I/R by subjecting control wild-type mice with normal platelet counts and thrombocytopenic wild-type mice to renal I/R injury. Our results showed that in the early phase of renal I/R injury, thrombocytopenia 24 hours after ischemia reperfusion does not influence renal injury, neutrophil infiltration and accumulation of inflammatory chemokines (e.g. keratinocyte chemoattractant, monocyte chemoattractant protein 1, tumor necrosis factor alpha). In the recovery and regeneration phase of I/R injury, respectively 5 and 10 days post-ischemia, thrombocytopenia did also not affect the accumulation of intra-renal neutrophils and macrophages, renal injury, and renal fibrosis. Together, these results imply that lowering platelet counts do not impact the pathogenesis of I/R injury in mice.
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http://dx.doi.org/10.1080/09537104.2019.1646899DOI Listing
September 2020

TREM1/3 Deficiency Impairs Tissue Repair After Acute Kidney Injury and Mitochondrial Metabolic Flexibility in Tubular Epithelial Cells.

Front Immunol 2019 9;10:1469. Epub 2019 Jul 9.

Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Long-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be mediated by aberrant innate immune activation, mitochondrial pathology, and accumulation of senescent tubular epithelial cells (TECs). Herein, we show that the innate immune receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) links mitochondrial metabolism to tubular epithelial senescence. TREM-1 is expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Hence, we subjected WT and TREM1/3 KO mice to different models of renal IR. TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis, and TEC senescence. , we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO primary TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, resulting in decreased wound healing capacity. Treatment with a mitochondria anti-oxidant partly prevented the senescent phenotype, suggesting a role for mitochondria herein. In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility.
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http://dx.doi.org/10.3389/fimmu.2019.01469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629955PMC
October 2020

Pharmacological PAR-1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy.

FASEB J 2019 10 9;33(10):10966-10972. Epub 2019 Jul 9.

Center for Experimental and Molecular Medicine, Amsterdam University Medical Center (UMC), Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, The Netherlands.

Vorapaxar-dependent protease-activated receptor (PAR)-1 inhibition diminishes diabetic nephropathy in experimental type 1 diabetes. As most patients with diabetic nephropathy suffer from type 2 diabetes, the aim of this study was to investigate whether PAR-1 inhibition also limits diabetic nephropathy in experimental type 2 diabetes. Consequently, leptin-deficient black and tan brachyuric (BTBR) mice were randomly assigned to vorapaxar (1.75 mg/kg; twice weekly oral gavage) or vehicle treatment, whereas matched wild-type (WT) BTBR (BTBR) mice served as nondiabetic controls. Weight and (nonfasting) blood glucose levels were monitored for up to 18 wk, after which kidney function and histologic damage was evaluated postmortem. We show that blood glucose levels and body weight increased in diabetic BTBR mice compared with nondiabetic BTBR controls. Vorapaxar-dependent PAR-1 inhibition reduced but did not normalize blood glucose levels in BTBR mice, whereas it potentiated the increase in body weight. Vorapaxar did not, however, preserve kidney function, whereas it only minimally reduced histopathological signs of kidney injury. Overall, we thus show that PAR-1 inhibition reduces blood glucose levels during the progression of diabetic nephropathy in experimental type 2 diabetes but does not improve renal function. This is in contrast to the therapeutic potential of vorapaxar in type 1 diabetes-induced nephropathy, highlighting the importance of disease-dependent treatment modalities.-Waasdorp, M., Florquin, S., Duitman, J., Spek, C. A. Pharmacological PAR-1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy.
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http://dx.doi.org/10.1096/fj.201900516RDOI Listing
October 2019

NLRX1 does not play a role in diabetes nor the development of diabetic nephropathy induced by multiple low doses of streptozotocin.

PLoS One 2019 25;14(3):e0214437. Epub 2019 Mar 25.

Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, North Holland, The Netherlands.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus that results in both tubular and glomerular injury. Low-grade inflammation and oxidative stress are two mechanisms known to drive the progression of DN. Nucleotide-binding leucine-rich repeat containing family member X1 (NLRX1) is an innate immune receptor, uniquely located in mitochondria, that has been found to regulate inflammatory responses and to dampen renal oxidative stress by regulating oxidative phosphorylation. For this reason, we investigated the role of NLRX1 in the development of DN in a Type 1 Diabetes mouse model. We analyzed the effect of NLRX1 deficiency on diabetes development and the accompanied renal damage, inflammation, and fibrosis. We found that multiple low doses of streptozotocin induced body weight loss, polydipsia, hyperglycemia, glycosuria, and a mild DN phenotype in wildtype and NLRX1-deficient mice, without significant differences between these mouse strains. Despite increased NLRX1 expression in diabetic wildtype mice, NLRX1 deficiency did not affect the diabetic phenotype induced by streptozotocin treatment, as reflected by similar levels of polyuria, microalbuminuria, and increased renal markers of oxidative stress and inflammation in wildtype and NLRX1-deficient mice. The present findings show that NLRX1 does not mediate the development of streptozotocin-induced diabetes and diabetic-induced nephropathy in mice after multiple low doses of streptozotocin. This data implies that, while NLRX1 can be triggered by cellular stress, its regulatory and functional effects may be dependent on the specific physiological conditions. In the case of DN, NLRX1 may be neither helpful nor harmful, but rather a marker of metabolic stress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214437PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433286PMC
December 2019

A Multicenter Application of the 2018 Banff Classification for BK Polyomavirus-associated Nephropathy in Renal Transplantation.

Transplantation 2019 12;103(12):2692-2700

Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam Infection & Immunity Institute (AI&II), Amsterdam Cardiovascular Sciences (ACS), Meibergdreef 9, Amsterdam, The Netherlands.

Background: With current immunosuppressive regimens, BK polyomavirus-associated nephropathy (BKPyVAN) is still a matter of concern. Stratification of patients at risk for allograft loss is of uttermost importance to guide treatment choice and assess prognosis. In 2018, the Banff working group proposed a classification scheme for the prognosis of BKPyVAN, but external application on independent cohorts is yet to be performed. We investigated how the 2018 Banff classification would perform in a multicenter cohort comprising 50 cases of biopsy-proven BKPyVAN compared to previously published classification systems.

Methods: We analyzed consecutive BKPyVAN cases from two Dutch university hospitals between 2002 and 2013, retrieved clinical data, and scored all biopsies according to the Banff 2018 classification, and as a comparison, 4 previously proposed BKPyVAN classification systems. We used estimated glomerular filtration rate trajectories and death-censored graft survival as primary endpoints.

Results: The 2018 Banff classification did not associate with estimated glomerular filtration rate decline or graft failure and performed only slightly better than the 4 previously proposed classifiers. Anti-human leukocyte antigen donor-specific antibodies (DSAs), especially in combination with ongoing biopsy-proven BKPyVAN on follow-up, did correlate with graft function and survival. Patients who were DSA+/BKPyVAN+ on follow-up had more inflammation at the baseline biopsy, which by itself was not associated with graft outcomes.

Conclusions: Neither the 2018 Banff BKPyVAN classification nor previously published stratification systems could be applied to our multicenter patient cohort. Our data suggest that there might be a prognostic value for follow-up biopsies and DSA measurements to improve risk stratification after BKPyVAN, although prospective multicenter efforts with protocol measurements are needed to confirm this.
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http://dx.doi.org/10.1097/TP.0000000000002712DOI Listing
December 2019

Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis.

Thromb Haemost 2019 Jun 14;119(6):930-940. Epub 2019 Mar 14.

Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Platelet Bruton's tyrosine kinase (Btk) is an essential signalling protein for the collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type-lectin-like receptor-2, which are platelet receptors implicated in the maintenance of vascular integrity during inflammation. Moreover, platelets, platelet GPVI and Btk are important for host defence during murine bacterial pneumosepsis. The aim of this study was to determine the role of platelet Btk in vascular integrity and host defence during murine pneumosepsis caused by the common human pathogens and . Using the Cre-loxP system, male platelet-specific Btk-deficient mice (PF4creBtk/Y) were created. Similar to platelets from total Btk-deficient mice, platelets from PF4creBtk/Y mice showed abrogated aggregation and P-selectin expression when stimulated with the GPVI ligand cross-linked collagen-related peptide. Upon infection with , PF4creBtk/Y mice showed increased lung bleeding, but unimpaired anti-bacterial defence. During pneumosepsis evoked by , platelet Btk deficiency was not associated with lung bleeding and did not impact on host defence, even when platelet function was further compromised by blocking secondary platelet activation by the P2Y receptor antagonist clopidogrel. Together, these data indicate that, while platelet Btk is not important for anti-bacterial defence in pneumosepsis, its role in maintaining vascular integrity in the lung depends on the causative pathogen.
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http://dx.doi.org/10.1055/s-0039-1681046DOI Listing
June 2019

Histological characteristics of Acute Tubular Injury during Delayed Graft Function predict renal function after renal transplantation.

Physiol Rep 2019 03;7(5):e14000

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Acute Tubular Injury (ATI) is the leading cause of Delayed Graft Function (DGF) after renal transplantation (RTX). Biopsies taken 1 week after RTX often show extensive tubular damage, which in most cases resolves due to the high regenerative capacity of the kidney. Not much is known about the relation between histological parameters of renal damage and regeneration immediately after RTX and renal outcome in patients with DGF. We retrospectively evaluated 94 patients with DGF due to ATI only. Biopsies were scored for morphological characteristics of renal damage (edema, casts, vacuolization, and dilatation) by three independent blinded observers. The regenerative potential was quantified by tubular cells expressing markers of proliferation (Ki67) and dedifferentiation (CD133). Parameters were related to renal function after recovery (CKD-EPI 3, 6, and 12 months posttransplantation). Quantification of morphological characteristics was reproducible among observers (Kendall's W ≥ 0.56). In a linear mixed model, edema and casts significantly associated with eGFR within the first year independently of clinical characteristics. Combined with donor age, edema and casts outperformed the Nyberg score, a well-validated clinical score to predict eGFR within the first year after transplantation (R  = 0.29 vs. R  = 0.14). Although the number of Ki67+ cells correlated to the extent of acute damage, neither CD133 nor Ki67 correlated with renal functional recovery. In conclusion, the morphological characteristics of ATI immediately after RTX correlate with graft function after DGF. Despite the crucial role of regeneration in recovery after ATI, we did not find a correlation between dedifferentiation marker CD133 or proliferation marker Ki67 and renal recovery after DGF.
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http://dx.doi.org/10.14814/phy2.14000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395310PMC
March 2019

Author Correction: Combining streptozotocin and unilateral nephrectomy is an effective method for inducing experimental diabetic nephropathy in the 'resistant' C57Bl/6J mouse strain.

Sci Rep 2019 Feb 27;9(1):3425. Epub 2019 Feb 27.

Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-38075-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391405PMC
February 2019

Challenges and opportunities for nephrology in Western Europe.

Kidney Int 2019 05 16;95(5):1037-1040. Epub 2019 Feb 16.

Oxford Kidney Unit and Transplant Centre, Churchill Hospital, Oxford, UK.

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http://dx.doi.org/10.1016/j.kint.2018.09.028DOI Listing
May 2019

Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia.

Mol Med 2019 01 15;25(1). Epub 2019 Jan 15.

Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-132, 1105, AZ, Amsterdam, the Netherlands.

Background: Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key signaling protein controlling the activation of various immune cells, including macrophages and neutrophils. The aim of this study was to determine whether ibrutinib treatment ameliorates acute lung inflammation during pneumococcal pneumonia.

Methods: Mice were treated orally with ibrutinib and the effect on acute pulmonary inflammation elicited by the gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during ceftriaxone-treated pneumococcal pneumonia was assessed.

Results: Treatment with ibrutinib prior to and after intranasal LTA instillation reduced alveolar macrophage activation, neutrophil influx, cytokine release and plasma leakage into the lung. Postponed treatment with ibrutinib supplementing antibiotic therapy during ongoing pneumococcal pneumonia did not impair bacterial killing in lung, blood and spleen. In this setting, ibrutinib reduced alveolar macrophage and systemic neutrophil activation and substantially diminished further monocyte and neutrophil influx in the lung. In vitro, ibrutinib inhibited macrophage TNF secretion and neutrophil activation upon LTA and pneumococcal stimulation.

Conclusions: Taken together, these data indicate that the Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses during acute pulmonary inflammation evoked by LTA and antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting.
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http://dx.doi.org/10.1186/s10020-018-0069-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332549PMC
January 2019

Calcineurin inhibitor Tacrolimus impairs host immune response against urinary tract infection.

Sci Rep 2019 01 14;9(1):106. Epub 2019 Jan 14.

Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Calcineurin inhibitor Tacrolimus, is a potent immunosuppressive drug widely used in order to prevent acute graft rejection. Urinary tract infection (UTI) is the most frequent infectious complication in renal transplant patients and long-term use of Tacrolimus might be involved in higher susceptibility to bacterial infections. It remains largely unknown how Tacrolimus affects the host innate immune response against lower and upper UTI. To address this issue, we used experimental UTI model by intravesical inoculation of uropathogenic E.coli in female wild-type mice pre-treated with Tacrolimus or solvent (CTR). We found that Tacrolimus pre-treated mice displayed higher bacterial loads (cystitis, pyelonephritis and bacteremia) than CTR mice. Granulocytes from Tacrolimus pre-treated mice phagocytized less E. coli, released less MPO and expressed decreased levels of CXCR2 receptor upon infection. Moreover, Tacrolimus reduced TLR5 expression in bladder macrophages during UTI. This immunosuppressive state can be explained by the upregulation of TLR-signaling negative regulators (A20, ATF3, IRAK-M and SOCS1) and parallel downregulation of TLR5 as observed in Tacrolimus treated granulocytes and macrophages. We conclude that Tacrolimus impairs host innate immune responses against UTI.
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http://dx.doi.org/10.1038/s41598-018-37482-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331640PMC
January 2019

Evaluation of the current post-transplantation Human Leukocyte Antigen antibody screening in pediatric renal transplant recipients.

Pediatr Transplant 2019 03 11;23(2):e13338. Epub 2019 Jan 11.

Pediatric Nephrology Department, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands.

The necessity of post-transplant monitoring for donor-specific antibodies (DSAs) is unclear. This study evaluates the clinical relevance of post-transplantation donor-specific HLA antibodies in pediatric renal transplant recipients, aiming at better stratification of patients at risk of graft dysfunction and better recommendations for post-transplant monitoring. A cohort of 68 pediatric kidney recipients, involving 76 transplantations between 2004 and 2014, was studied retrospectively. All patients were screened for HLA antibodies at 1, 3, 6, and 12 months after transplantation and yearly thereafter. Samples testing positive were further analyzed to detect DSA. A biopsy was performed on clinical indication. We studied the baseline characteristics of the patients with biopsy, with DSA, and with rejection. We assessed the effect of post-transplant DSA on clinical outcome, including antibody-mediated acute rejection and GFR decrease. In our cohort, the prevalence of DSA was 19% (13/68 transplantations). Most patients with HLA antibodies after transplantation were DSA-positive (76%; 13/17). A clear association between DSA and subsequent rejection was found. At the end of the study period, a significantly lower GFR was found in patients with biopsy, DSA, or rejection. Based on our observations, we recommend routine post-transplantation screening for HLA and DSA. The presence of DSA justifies a renal biopsy even in the absence of clinical signs of rejection.
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http://dx.doi.org/10.1111/petr.13338DOI Listing
March 2019