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2.
Kidney Int ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33607177

RESUMO

Data reproducibility and single-center bias are concerns in preclinical research and compromise translation from animal to human. Multicenter preclinical randomized controlled trials (pRCT) may reduce the gap between experimental studies and RCT and improve the predictability of results, for example Jak1/2 inhibition in lupus nephritis. To evaluate this, we conducted the first pRCT in the kidney domain at two Spanish and two German academic sites. Eligible MRL/MpJ-Faslpr mice (female, age13-14 weeks, stress scores of less than two and no visible tumor or signs of infection) were equally randomized to either oral treatment with the Jak1/2 inhibitor baricitinib or vehicle for four weeks. Central blinded histology analysis was performed at an independent fifth site. The primary endpoint was the urinary protein/creatinine ratio. Baricitinib treatment did not significantly affect proteinuria, histological markers of activity and chronicity, or the glomerular filtration rate but significantly improved plasma autoantibody levels and lymphadenopathy. Data heterogeneity was noted across the different centers referring in part to phenotype differences between MRL/MpJ-Faslpr mice bred at different sites, mimicking well patient phenotype diversity in lupus trials. Multicenter pRCT can overcome single-center bias at the cost of increasing variability and reducing effect size. Thus, our pRCT predicts a low effect size of baricitinib treatment on human lupus nephritis in heterogeneous study populations.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33527142

RESUMO

Acute Kidney Injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology Public Policy Committee (NPPC) of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) is to promote several key aspects of European nephrology. One of the targets proposed by NPPC was to advance European nephrology involvement in AKI. We undertook literature analyses to define the current position of European nephrology in the field of AKI compared to other regions, and about how different European countries compare to each other. It appeared that vis-à-vis countries with a comparable socio-economic status (the US, Australia, New Zealand, Canada), the European contribution was almost 50% lower. Within Europe, Central/Eastern Europe and countries with a lower gross domestic product (GDP) showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend for a change over the last decade. It is concluded that there is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe, the creation of a pan-European nephrology network of interested units is proposed, to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology, and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33313878

RESUMO

In 2020, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial first demonstrated that inhibition of the sodium-glucose transporter-2 (SGLT2) with dapagliflozin attenuates the progression of chronic kidney disease (CKD) with proteinuria in patients with or without diabetes at an unprecedented effect size. These results have far-reaching implications for a series of traditional concepts in Nephrology. It now became obvious that CKD with and without diabetes involves a predominant SGLT2-driven pathophysiology compared with the other pathogenic pathways currently under consideration. As SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, treating CKD rather than 'diabetic nephropathy' becomes the central paradigm. Indeed, in older adults with type 2 diabetes, CKD is rather of multifactorial origin. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard. The same applies for patients with podocytopathy-related focal segmental glomerulosclerosis lesions. From now on, IgAN and podocytopathy trials without SGLT2 inhibition as background therapy and without glomerular filtration rate decline as primary outcome criterion will be of limited value. These and other potential implications will trigger broad discussions and secondary research activities with conclusions difficult to predict today. However, one is for sure: Nephrology after the DAPA-CKD trial will be not the same as it was before. Finally!

7.
Artigo em Inglês | MEDLINE | ID: mdl-33186226

RESUMO

PURPOSE OF REVIEW: Despite ground-breaking innovations for most autoimmune diseases, the treatment of lupus nephritis has remained largely the same for decades because none of the tested drugs demonstrated superiority over standard-of-care in randomized controlled clinical trials. RECENT FINDINGS: Recently, the Belimumab in Subjects with Systemic Lupus Erythematosus - Lupus Nephritis trial tested belimumab, an inhibitor of B-cell activating factor, as an add-on therapy to steroids and either mycophenolate mofetil (MMF) or cyclophosphamide when given IV monthly over a period of 104 weeks at an effect size of 11% for a Primary Efficacy Renal Response. The NOBILITY trial reported positive results for the B-cell-depleting agent obinutuzumab as an add-on therapy to steroids and MMF when given IV every 6 months over a period of 76 weeks at an effect size of 22% for a complete renal response (CRR). The AURORA trial reported positive results for the calcineurin inhibitor voclosporin as an oral add-on therapy to low dose steroids and MMF when given twice daily over a period of 52 weeks at an effect size of 18.5% for a CRR. SUMMARY: These studies will change the treatment landscape of lupus nephritis. In which way is discussed in this article.

8.
Life Sci ; : 118644, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33141039

RESUMO

Klotho is a novel renoprotective anti-aging protein available in membrane-bound or soluble form. Klotho is expressed in brain, pancreas, and other solid organs but shows highest expression levels in the kidney. Klotho sustains normal kidney physiology but Klotho regulation also contributes to the progression of kidney disease. Systemic and intrarenal levels of Klotho fall drastically during acute kidney injury, kidney fibrosis, diabetic nephropathy, and other forms of chronic kidney disease, etc. Moreover, exogenous supplementation or overexpression of endogenous Klotho attenuates kidney disease. The regulation of endogenous Klotho expression involves epigenetic as well as non-epigenetic mechanisms. The epigenetic modifications such as DNA methylation, post-translational histone modifications, miRNAs regulate the change in Klotho expression in kidney disease. Non-epigenetic mechanisms such as ER stress, Wnt signaling, activation of the renin angiotensin system (RAS), excessive reactive oxygen species and cytokine generation, albumin overload, and PPAR-γ signaling also contribute to Klotho regulation. Evolving evidence highlight the capacity of natural products to regulate Klotho expression in kidney disease. All these preclinical data suggest that Klotho could be a novel biomarker as well as therapeutic target. Here we review the different mechanisms of Klotho regulation in the context of Klotho as a biomarker and potential therapeutic agent.

9.
Cells ; 9(11)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33203124

RESUMO

Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. We hypothesized that crystals of ion-exchange resins like sevelamer, polystyrene sulfonate, and cholestyramine can trigger the formation of neutrophil and monocyte extracellular traps by contributing to intestinal barrier dysfunction. Light and fluorescence microscopy of the colonic resection specimen from a patient with chronic kidney disease revealed severe intestinal necrosis, ulceration, sevelamer crystals, and inflammation upon oral intake of sevelamer, as well as the formation of neutrophil extracellular traps in proximity to small sevelamer crystals. Indeed, drug crystals reduced metabolic activity and induced barrier dysfunction and cell death in human intestinal epithelial cells in vitro. In addition, drug crystals triggered the release of neutrophil and monocyte extracellular traps. Taken together, these data raise the possibility that besides other factors including chronic kidney disease, diabetes mellitus, and hypertension, drug crystals may further amplify a pre-existing barrier dysfunction and necroinflammation in a crescendo of local intestinal necrosis and systemic inflammation/infection, as occasionally observed in patients on ion-exchange resin therapy.

10.
Front Immunol ; 11: 568513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117353

RESUMO

Clotting and inflammation are effective danger response patterns positively selected by evolution to limit fatal bleeding and pathogen invasion upon traumatic injuries. As a trade-off, thrombotic, and thromboembolic events complicate severe forms of infectious and non-infectious states of acute and chronic inflammation, i.e., immunothrombosis. Factors linked to thrombosis and inflammation include mediators released by platelet granules, complement, and lipid mediators and certain integrins. Extracellular deoxyribonucleic acid (DNA) was a previously unrecognized cellular component in the blood, which elicits profound proinflammatory and prothrombotic effects. Pathogens trigger the release of extracellular DNA together with other pathogen-associated molecular patterns. Dying cells in the inflamed or infected tissue release extracellular DNA together with other danger associated molecular pattern (DAMPs). Neutrophils release DNA by forming neutrophil extracellular traps (NETs) during infection, trauma or other forms of vascular injury. Fluorescence tissue imaging localized extracellular DNA to sites of injury and to intravascular thrombi. Functional studies using deoxyribonuclease (DNase)-deficient mouse strains or recombinant DNase show that extracellular DNA contributes to the process of immunothrombosis. Here, we review rodent models of immunothrombosis and the evolving evidence for extracellular DNA as a driver of immunothrombosis and discuss challenges and prospects for extracellular DNA as a potential therapeutic target.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32888017

RESUMO

Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now embedded into the missions of most scientific societies. To promote kidney research funding in Europe, the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), rather than acting as an individual society advocating for the fight against kidney disease, has actively helped to create an alliance of national associations centred on kidney diseases, the European Kidney Health Alliance (EKHA), and joined the Biomedical Alliance (BMA). The ERA-EDTA is fully committed to supporting its working groups (WGs) and consortia of its members to allow them to produce valuable kidney research. The framing and formalization of projects, and the regulatory issues related to submission to the European Commission, are complex. To help WGs to gain expert advice from agencies with specific know-how, the ERA-EDTA has adopted a competitive approach. The best research projects proposed by WGs and consortia of other European investigators will receive seed funding to cover the costs of consultancy by expert agencies. Via its broader platforms, the EKHA and the BMA, the ERA-EDTA will strive towards broader recognition of kidney disease and related clusters of non-communicable diseases, by European and national agencies, as major threats to the qualities of life of their populations and their economies.

12.
Cells ; 9(9)2020 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-32962213

RESUMO

Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...].

13.
Int J Mol Sci ; 21(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977372

RESUMO

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-ß (TGF-ß) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.

14.
J Am Soc Nephrol ; 31(12): 2773-2792, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32938648

RESUMO

BACKGROUND: The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression. METHODS: MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD. RESULTS: Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective. CONCLUSIONS: Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.

15.
Nat Rev Dis Primers ; 6(1): 71, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855422

RESUMO

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients.

16.
Nat Rev Dis Primers ; 6(1): 68, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792490

RESUMO

Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

17.
Cells ; 9(6)2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32498376

RESUMO

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Animais , Betacoronavirus/fisiologia , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Complicações do Diabetes/virologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Necrose/imunologia , Necrose/patologia , Neutrófilos/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico
18.
J Am Soc Nephrol ; 31(8): 1729-1745, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32576600

RESUMO

BACKGROUND: Progression of CKD in type 2 diabetes, despite dual inhibition of sodium-glucose transporter-2 and the renin-angiotensin system, remains a concern. Bromoindirubin-3'-oxime (BIO), previously reported to promote podocyte survival and regeneration, is a candidate additional drug to elicit renoprotective effects beyond therapy with metformin, ramipril, and empagliflozin (MRE). Evaluating a drug with standard therapeutics more closely mimics the clinical setting than evaluating the drug alone. METHODS: Uninephrectomized BKS-Lepr-/- (db/db) mice treated with or without MRE served as a model of progressive CKD in type 2 diabetes. Mice on or off MRE were randomized to only 4 weeks of add-on BIO or vehicle. The primary end point was slope of GFR (ΔGFR). RESULTS: Four weeks of MRE treatment alone did not affect ΔGFR, but significantly attenuated hyperglycemia, albuminuria, and glomerulosclerosis and increased podocyte filtration slit density, as assessed by STED super-resolution microscopy upon tissue clearing. BIO alone improved albuminuria, podocyte density in superficial and juxtamedullary nephrons, and podocyte filtration slit density. MRE+BIO combination therapy had additive protective effects on ΔGFR, glomerulosclerosis, podocyte density in juxtamedullary nephrons, and filtration slit density. CONCLUSIONS: Add-on treatment with BIO for only 4 weeks attenuates progression of CKD beyond MRE therapy in mice with type 2 diabetes. Additional drug combinations may help to further delay ESKD in type 2 diabetes.

19.
Front Cell Dev Biol ; 8: 398, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582696

RESUMO

Alloantigen presentation is an essential process in acute allorejection. In this context, we speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to promote antigenic peptide loading into MHC class II and to activate protease-activated receptor (PAR)-2 on intrarenal microvascular endothelial and tubular epithelial cells. Single-cell RNA sequencing and immunostaining of human kidney allografts confirmed Cat-S expression in intrarenal mononuclear phagocytes. In vitro, Cat-S inhibition suppressed CD4 + T cell lymphocyte activation in a mixed lymphocyte assay. In vivo, we employed a mouse model of kidney transplantation that showed preemptive Cat-S inhibition significantly protected allografts from tubulitis and intimal arteritis. To determine the contribution of PAR-2 activation, first, Balb/c donor kidneys were transplanted into Balb/c recipient mice without signs of rejection at day 10. In contrast, kidneys from C57BL/6J donor mice revealed severe intimal arteritis, tubulitis, interstitial inflammation, and glomerulitis. Kidneys from Par2-deficient C57BL/6J mice revealed partial protection from tubulitis and lower intrarenal expression levels for Fasl, Tnfa, Ccl5, and Ccr5. Together, we conclude that Cat-S and PAR-2 contribute to immune dysregulation and kidney allograft rejection, possibly involving Cat-S-mediated activation of PAR-2 on recipient parenchymal cells in the allograft.

20.
J Immunol ; 205(3): 789-800, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32561569

RESUMO

Although monosodium urate (MSU) crystals are known to trigger inflammation, published data on soluble uric acid (sUA) in this context are discrepant. We hypothesized that diverse sUA preparation methods account for this discrepancy and that an animal model with clinically relevant levels of asymptomatic hyperuricemia and gouty arthritis can ultimately clarify this issue. To test this, we cultured human monocytes with different sUA preparation solutions and found that solubilizing uric acid (UA) by prewarming created erroneous results because of UA microcrystal contaminants triggering IL-1ß release. Solubilizing UA with NaOH avoided this artifact, and this microcrystal-free preparation suppressed LPS- or MSU crystal-induced monocyte activation, a process depending on the intracellular uptake of sUA via the urate transporter SLC2A9/GLUT9. CD14+ monocytes isolated from hyperuricemic patients were less responsive to inflammatory stimuli compared with monocytes from healthy individuals. Treatment with plasma from hyperuricemic patients impaired the inflammatory function of CD14+ monocytes, an effect fully reversible by removing sUA from hyperuricemic plasma. Moreover, Alb-creERT2;Glut9 lox/lox mice with hyperuricemia (serum UA of 9-11 mg/dl) showed a suppressed inflammatory response to MSU crystals compared with Glut9 lox/lox controls without hyperuricemia. Taken together, we unravel a technical explanation for discrepancies in the published literature on immune effects of sUA and identify hyperuricemia as an intrinsic suppressor of innate immunity, in which sUA modulates the capacity of monocytes to respond to danger signals. Thus, sUA is not only a substrate for the formation of MSU crystals but also an intrinsic inhibitor of MSU crystal-induced tissue inflammation.

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