Publications by authors named "Jürgen Floege"

429 Publications

Cardiovascular disease in patients with chronic kidney disease.

Herz 2021 Jun 10;46(3):205. Epub 2021 Jun 10.

Division of Nephrology and Clinical Immunology, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.

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http://dx.doi.org/10.1007/s00059-021-05029-yDOI Listing
June 2021

[Coronavirus disease 2019 pandemic from a nephrological perspective].

Internist (Berl) 2021 Jun 9. Epub 2021 Jun 9.

Klinik für Nephrologie, Klinikum Lüdenscheid, Lüdenscheid, Deutschland.

Background: The coronavirus disease 2019 (COVID-19) pandemic has also resulted in substantial challenges for nephrology worldwide. Patients with chronic kidney diseases are a particularly vulnerable patient group in this context and in severe courses of COVID-19 the kidneys are most frequently affected by organ failure after the lungs.

Material And Methods: In order to reliably evaluate the prevalence and mortality of dialysis patients in Germany with respect to COVID-19, during the first wave in spring 2020 the German Society of Nephrology implemented a registry for dialysis patients. Weekly data on the number and course of dialysis patients affected by COVID-19 were recorded and analyzed.

Results: The prevalence of COVID-19 in dialysis patients in Germany developed in two waves, similar to the course of the pandemic in the general population. In spring the prevalence in dialysis patients reached 1.4% and considerably declined during the summer. In December during the second wave of the pandemic the prevalence again rose to 1.9%, despite comprehensively implemented hygiene measures in dialysis centers. Similar to other industrial nations, dialysis patients in Germany also showed a very high lethality of COVID-19 of up to 20%.

Conclusion: Immediate consequences for hygiene measures in dialysis institutions as well as vaccination strategies and vaccination prioritization for this patient group and the personnel treating them can be derived from the high mortality in dialysis patients. A consequence of the frequent involvement of the kidneys during infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients who had not previously suffered from advanced kidney disease should be the consistent nephrological aftercare.
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http://dx.doi.org/10.1007/s00108-021-01078-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188747PMC
June 2021

Development of an international Delphi survey to establish core outcome domains for trials in adults with glomerular disease.

Kidney Int 2021 May 5. Epub 2021 May 5.

Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.

Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making.
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http://dx.doi.org/10.1016/j.kint.2021.04.027DOI Listing
May 2021

Parathyroid hormone oxidation in chronic kidney disease: clinical relevance?

Kidney Int 2021 05;99(5):1070-1072

Department of Nephrology and Clinical Immunology, University Hospital, Rheinisch Westfälische Technische Hochschule Aachen, Aachen, Germany.

In chronic kidney disease, parathyroid hormone (PTH), like all proteins, can undergo post-translational modifications, including oxidation. This can lead to structural and functional changes of the hormone. It has been hypothesized that currently used PTH measurement methods do not adequately reflect PTH-related bone and cardiovascular abnormalities in chronic kidney disease owing to the presence of oxidized, biologically inactive PTH in the circulation. Ursem et al. now report a strong correlation between serum non-oxidized and total PTH, and comparable associations with histomorphometric and circulating bone turnover markers, pleading against this hypothesis.
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http://dx.doi.org/10.1016/j.kint.2021.01.019DOI Listing
May 2021

Key metalloproteinase-mediated pathways in the kidney.

Nat Rev Nephrol 2021 Apr 20. Epub 2021 Apr 20.

Institute of Molecular Pharmacology, RWTH Aachen University, Aachen, Germany.

Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs) belong to the metzincin family of zinc-containing multidomain molecules, and can act as soluble or membrane-bound proteases. These enzymes inactivate or activate other soluble or membrane-expressed mediator molecules, which enables them to control developmental processes, tissue remodelling, inflammatory responses and proliferative signalling pathways. The dysregulation of MMPs and ADAMs has long been recognized in acute kidney injury and in chronic kidney disease, and genetic targeting of selected MMPs and ADAMs in different mouse models of kidney disease showed that they can have detrimental and protective roles. In particular, MMP-2, MMP-7, MMP-9, ADAM10 and ADAM17 have been shown to have a mainly profibrotic effect and might therefore represent therapeutic targets. Each of these proteases has been associated with a different profibrotic pathway that involves tissue remodelling, Wnt-β-catenin signalling, stem cell factor-c-kit signalling, IL-6 trans-signalling or epidermal growth factor receptor (EGFR) signalling. Broad-spectrum metalloproteinase inhibitors have been used to treat fibrotic kidney diseases experimentally but more targeted approaches have since been developed, including inhibitory antibodies, to avoid the toxic side effects initially observed with broad-spectrum inhibitors. These advances not only provide a solid foundation for additional preclinical studies but also encourage further translation into clinical research.
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http://dx.doi.org/10.1038/s41581-021-00415-5DOI Listing
April 2021

SGLT-2 inhibition in IgA nephropathy: the new standard of care?

Kidney Int 2021 Apr 17. Epub 2021 Apr 17.

Division of Nephrology and Immunology, Rheinisch Westfälische Technische Hochschule (RWTH) University of Aachen, Aachen, Germany. Electronic address:

Despite supportive measures that slow the rate of progression of chronic kidney disease in IgA nephropathy, many patients still progress to end-stage kidney disease. Currently employed immunosuppressive strategies lack conclusive efficacy data, while there is evidence for treatment-emergent toxicity. A subanalysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease Trial, which encompassed 270 patients with a diagnosis of IgA nephropathy, now provides early evidence that dapagliflozin may be a safe and effective addition to current standard of care in IgA nephropathy.
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http://dx.doi.org/10.1016/j.kint.2021.04.002DOI Listing
April 2021

Effects of Perfusion Pressures on Podocyte Loss in the Isolated Perfused Mouse Kidney.

Cell Physiol Biochem 2021 Apr;55(S4):1-12

Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany,

Background/aims: Podocytes are lost in most glomerular diseases, leading to glomerulosclerosis and progressive kidney disease. It is generally assumed, that podocytes are exposed to the filtration flow and thus to significant shear forces driving their detachment from the glomerular basement membrane (GBM). In this context, foot process effacement has been proposed as potential adaptive response to increase adhesion of podocytes to the GBM.

Methods: We have tested these hypotheses using optical clearing and high-resolution 3-dimensional morphometric analysis in the isolated perfused murine kidney. We investigated the dynamics of podocyte detachment at different perfusion pressures (50, 300 and more than 450 mmHg) in healthy young or old mice (20 vs. 71 weeks of age), or mice injected with anti-GBM serum to induce global foot process effacement.

Results: Results show that healthy podocytes in young mice are tightly attached onto the GBM and even supramaximal pressures did not cause significant detachment. Compared to young mice, in aged mice and mice with anti-GBM nephritis and foot process effacement, gradual progressive loss of podocytes had occurred already before perfusion. High perfusion pressures resulted in a relatively minor additional loss of podocytes in aged mice. In mice with anti-GBM nephritis significant additional podocyte loss occurred at this early time point when increasing perfusion pressures to 300 mmHg or higher.

Conclusion: This work provides the first experimental evidence that podocytes are extraordinarily resistant to acutely increased perfusion pressures in an ex vivo isolated kidney perfusion model. Only in glomerular disease, significant numbers of injured podocytes detached following acute increases in perfusion pressure.
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http://dx.doi.org/10.33594/000000355DOI Listing
April 2021

Dapagliflozin, advanced chronic kidney disease, and mortality: new insights from the DAPA-CKD trial.

Eur Heart J 2021 03;42(13):1228-1230

Division of Nephrology and Clinical Immunology, University Hospital, RWTH Aachen University, Aachen, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014504PMC
March 2021

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

Am J Kidney Dis 2021 Mar 26. Epub 2021 Mar 26.

Departments of Population Health Sciences and Internal Medicine, University of Utah, Salt Lake City, UT.

Rationale & Objective: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope.

Study Design: Individual patient-level meta-analysis.

Setting & Study Populations: Individual data of 1,037 patients from 12 randomized trials.

Selection Criteria For Studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome.

Analytical Approach: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria.

Results: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years.

Limitations: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions.

Conclusions: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.
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http://dx.doi.org/10.1053/j.ajkd.2021.03.007DOI Listing
March 2021

The STARMEN trial: rethinking calcineurin inhibitor therapy in membranous nephropathy.

Kidney Int 2021 04;99(4):811-813

Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA. Electronic address:

The STARMEN trial postulated that in primary membranous nephropathy (pMN) treatment with tacrolimus plus rituximab would be superior to a traditional Ponticelli regimen of alternating cyclophosphamide and glucocorticoids. This was not the case. Significantly more remissions were achieved in cyclophosphamide-treated patients, and more of these were complete remissions. Considering these results with those of the Mentor trial, which compared rituximab with cyclosporine in pMN, we offer an evidence-based perspective on the role of calcineurin inhibition for pMN treatment.
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http://dx.doi.org/10.1016/j.kint.2020.11.019DOI Listing
April 2021

Time on previous renal replacement therapy is associated with worse outcomes of COVID-19 in a regional cohort of kidney transplant and dialysis patients.

Medicine (Baltimore) 2021 Mar;100(10):e24893

Department of Nephrology and Rheumatology.

Abstract: Chronic renal replacement therapy by either a kidney transplant (KTX) or hemodialysis (HD) predisposes patients to an increased risk for adverse outcomes of COVID-19. However, details on this interaction remain incomplete. To provide further characterization, we undertook a retrospective observational cohort analysis of the majority of the hemodialysis and renal transplant population affected by the first regional outbreak of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) in Germany. In a region of 250,000 inhabitants we identified a total of 21 cases with SARS-CoV-2 among 100 KTX and 260 HD patients, that is, 7 KTX with COVID-19, 14 HD with COVID-19, and 3 HD with asymptomatic carrier status. As a first observation, KTX recipients exhibited trends for a higher mortality (43 vs 18%) and a higher proportion of acute respiratory distress syndrome (ARDS) (57 vs 27%) when compared to their HD counterparts. As a novel finding, development of ARDS was significantly associated with the time spent on previous renal replacement therapy (RRT), defined as the composite of dialysis time and time on the transplant (non-ARDS 4.3 vs ARDS 10.6 years, P = .016). Multivariate logistic regression analysis showed an OR of 1.7 per year of RRT. The association remained robust when analysis was confined to KTX patients (5.1 vs 13.2 years, P = .002) or when correlating the time spent on a renal transplant alone (P = .038). Similarly, longer RRT correlated with death vs survival (P = .0002). In conclusion our data suggest renal replacement vintage as a novel risk factor for COVID-19-associated ARDS and death. The findings should be validated by larger cohorts.
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http://dx.doi.org/10.1097/MD.0000000000024893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969209PMC
March 2021

Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options.

Circulation 2021 Mar 15;143(11):1157-1172. Epub 2021 Mar 15.

Department of Internal Medicine I (Cardiology) (N.M.), University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Aachen, Germany.

Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events is already significantly higher in patients with early CKD stages (CKD stages 1-3) compared with the general population, patients with advanced CKD stages (CKD stages 4-5) exhibit a markedly elevated risk. Cardiovascular rather than end-stage kidney disease (CKD stage 5) is the leading cause of death in this high-risk population. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves. In this respect, CKD mimics an accelerated aging of the cardiovascular system. This overview article summarizes the current understanding and clinical consequences of cardiovascular disease in CKD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969169PMC
March 2021

Recommendations for the use of COVID-19 vaccines in patients with immune-mediated kidney diseases.

Nephrol Dial Transplant 2021 Mar 9. Epub 2021 Mar 9.

Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Coronavirus Disease 19 (COVID-19) vaccine platforms are becoming available and are the most promising strategy to curb the spread of SARS-CoV-2 infections. However, numerous uncertainties exist regarding the pros and cons of vaccination, especially in patients with (immune-mediated) kidney diseases on immunosuppressive drugs. Here, members of the Immunonephrology Working Group (IWG) of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) discuss thirteen frequently-asked questions regarding safety and efficacy of the most promising vaccine candidates. Post-marketing surveillance should be performed to estimate the rate of vaccine response (humoral and cellular) of different vaccine platforms, and surveillance of disease activity following administration of COVID-19 vaccines. Some of the candidates induce signaling pathways which also promote autoimmune kidney diseases, e.g. type I interferons in systemic lupus erythematosus. Efficacy estimates would thus far favor the use of selected COVID-19 vaccines, such as BNT162b2, mRNA-1273 or Gam-COVID-Vac. Humoral immune response after vaccination should be monitored using appropriate assays. Even in the absence of neutralizing antibodies patients might be protected by a sufficient cellular immune response capable to reduce severity of COVID-19. A reduced vaccine response after the use of CD20-depleting agents is anticipated, and it is particularly important to discuss strategies to improve vaccine response with these patients. Distancing and shielding measures remain important as not all vaccines fully protect from coronavirus infection. In-depth information about the most pressing vaccine questions is essential to reduce vaccine hesitancy of patients.
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http://dx.doi.org/10.1093/ndt/gfab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989374PMC
March 2021

Survival on four compared with three times per week haemodialysis in high ultrafiltration patients: an observational study.

Clin Kidney J 2021 Feb 28;14(2):665-672. Epub 2020 Dec 28.

Department of Renal Medicine, University College London, UK.

Background: The harm caused by the long interdialytic interval in three-times-per-week haemodialysis regimens (3×WHD) may relate to fluid accumulation and associated high ultrafiltration rate (UFR). Four-times-per-week haemodialysis (4×WHD) may offer a solution, but its impact on mortality, hospitalization and vascular access complications is unknown.

Methods: From the AROii cohort of incident in-centre haemodialysis patients, 3×WHD patients with a UFR >10 mL/kg/h were identified. The hazard for the outcomes of mortality, hospitalization and vascular access complications in those who switched to 4×WHD compared with staying on 3×WHD was estimated using a marginal structural Cox proportional hazards model. Adjustment included baseline patient and treatment characteristics with inverse probability weighting used to adjust for time-varying UFR and cardiovascular comorbidities.

Results: From 10 637 European 3×WHD patients, 3842 (36%) exceeded a UFR >10 mL/kg/h. Of these, 288 (7.5%) started 4×WHD and at baseline were more comorbid. Event rates while receiving 4×WHD compared with 3×WHD were 12.6 compared with 10.8 per 100 patient years for mortality, 0.96 compared with 0.65 per year for hospitalization and 14.7 compared with 8.0 per 100 patient years for vascular access complications. Compared with 3×WHD, the unadjusted hazard ratio (HR) for mortality on 4×WHD was 1.05 [95% confidence interval (CI) 0.78-1.42]. Following adjustment for baseline demographics, time-varying treatment probability and censoring risks, this HR was 0.73 (95% CI 0.50-1.05; P = 0.095). Despite these adjustments on 4×WHD, the HR for hospitalization remained elevated and vascular access complications were similar to 3×WHD.

Conclusions: This observational study was not able to demonstrate a mortality benefit in patients switched to 4×WHD. To demonstrate the true benefits of 4×WHD requires a large, well-designed clinical trial. Our data may help in the design of such a study.
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http://dx.doi.org/10.1093/ckj/sfaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886573PMC
February 2021

Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation.

Eur J Clin Nutr 2021 Feb 2. Epub 2021 Feb 2.

Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany.

Background/objectives: A diet following chronic kidney disease (CKD)-specific recommendations is considered essential for optimal management of patients with CKD. However, data on the adherence to these recommendations and its implications for health-relevant biomarkers are lacking. The objectives were to estimate adherence to CKD-specific dietary recommendations, to identify characteristics and lifestyle variables associated with poor adherence, and to investigate the relationship of adherence with biomarkers.

Methods: In this cross-sectional analysis, average dietary intake was estimated in 3193 participants with moderately severe CKD enrolled into the observational multicenter German CKD study using a food frequency questionnaire. A CKD diet score was developed to assess adherence to CKD-specific dietary recommendations based on intake of sodium, potassium, fiber, protein, sugar, and cholesterol. The associations of dietary adherence with characteristics, lifestyle variables, and biomarker levels were determined.

Results: Logistic regression analysis revealed younger age, higher body mass index, male gender, lower educational attainment, various lifestyle variables (cigarette smoking, infrequent alcohol consumption, low physical activity), and lower estimated glomerular filtrate rate associated with lower adherence to dietary recommendations. Low adherence to dietary recommendations was further associated with dyslipidemia, higher uric acid, and C-reactive protein levels. Associations between low dietary adherence and biomarkers were mostly driven by low intake of fiber and potassium, and high intake of sugar and cholesterol.

Conclusions: This study revealed differential characteristics and biomarkers associated with lower adherence to CKD-specific dietary recommendations. Promotion of CKD-specific dietary recommendations may help to mitigate the adverse prognosis in CKD patients.
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http://dx.doi.org/10.1038/s41430-020-00849-3DOI Listing
February 2021

[COVID-19].

Nephrologe 2021 21;16(1):1-2. Epub 2021 Jan 21.

Klinik für Nephrologie und Klinische Immunologie, Medizinische Klinik II, Universitätsklinikum Aachen, Pauwelsstraße 30, 52057 Aachen, Deutschland.

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http://dx.doi.org/10.1007/s11560-020-00477-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818132PMC
January 2021

Hyperuricemia and progression of chronic kidney disease: to treat or not to treat?

Kidney Int 2021 01;99(1):14-16

Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

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http://dx.doi.org/10.1016/j.kint.2020.10.022DOI Listing
January 2021

Decoding myofibroblast origins in human kidney fibrosis.

Nature 2021 01 11;589(7841):281-286. Epub 2020 Nov 11.

Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.

Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.
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http://dx.doi.org/10.1038/s41586-020-2941-1DOI Listing
January 2021

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review.

Cells 2020 11 6;9(11). Epub 2020 Nov 6.

Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, University Hospital Aachen, 52074 Aachen, Germany.

Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.
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http://dx.doi.org/10.3390/cells9112428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694747PMC
November 2020

Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP-2 Inhibitor for the Treatment of IgA Nephropathy.

Kidney Int Rep 2020 Nov 13;5(11):2032-2041. Epub 2020 Aug 13.

Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.

Introduction: Narsoplimab is a human monoclonal antibody against mannan-associated lectin-binding serine protease-2 (MASP-2). Now in a phase 3 study, narsoplimab was evaluated in a staged phase 2 study assessing safety and effectiveness in high-risk patients with IgA nephropathy (IgAN).

Methods: Substudy 1 was a single-arm open-label study of 12 weekly infusions and tapered corticosteroids, with 6 weeks of follow-up. In substudy 2, patients were randomized 1:1 to receive a course of treatment consisting of once-weekly narsoplimab or vehicle infusions for 12 weeks. After 6 weeks of follow-up, both substudy 2 groups could continue in an open-label extension, receiving 1 or more narsoplimab courses at the investigator's discretion.

Results: The most commonly reported adverse events (AEs) included headache, upper respiratory infection, and fatigue. Most AEs were mild or moderate and transient. No treatment-related serious AEs were reported. All 4 patients who were enrolled in substudy 1 had reductions in 24-hour urine protein excretion (UPE) at week 18, ranging from 54% to 95% compared with baseline. In substudy 2, the vehicle and narsoplimab groups had similar proteinuria reductions at week 18. Eight patients (3 vehicle, 5 narsoplimab) continued in the dosing extension; all received narsoplimab. Median reduction in 24-hour UPE in these 8 patients was 61.4% at 31 to 54 weeks postbaseline. Estimated glomerular filtration rates (eGFR) remained stable in both substudies.

Conclusion: This interim analysis suggests that narsoplimab treatment is safe, is well tolerated, and may result in clinically meaningful reductions in proteinuria and stability of eGFR in high-risk patients with advanced IgAN.
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http://dx.doi.org/10.1016/j.ekir.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609886PMC
November 2020

Deep Learning-Based Segmentation and Quantification in Experimental Kidney Histopathology.

J Am Soc Nephrol 2021 01 5;32(1):52-68. Epub 2020 Nov 5.

Institute of Imaging and Computer Vision, RWTH Aachen University, Aachen, Germany.

Background: Nephropathologic analyses provide important outcomes-related data in experiments with the animal models that are essential for understanding kidney disease pathophysiology. Precision medicine increases the demand for quantitative, unbiased, reproducible, and efficient histopathologic analyses, which will require novel high-throughput tools. A deep learning technique, the convolutional neural network, is increasingly applied in pathology because of its high performance in tasks like histology segmentation.

Methods: We investigated use of a convolutional neural network architecture for accurate segmentation of periodic acid-Schiff-stained kidney tissue from healthy mice and five murine disease models and from other species used in preclinical research. We trained the convolutional neural network to segment six major renal structures: glomerular tuft, glomerulus including Bowman's capsule, tubules, arteries, arterial lumina, and veins. To achieve high accuracy, we performed a large number of expert-based annotations, 72,722 in total.

Results: Multiclass segmentation performance was very high in all disease models. The convolutional neural network allowed high-throughput and large-scale, quantitative and comparative analyses of various models. In disease models, computational feature extraction revealed interstitial expansion, tubular dilation and atrophy, and glomerular size variability. Validation showed a high correlation of findings with current standard morphometric analysis. The convolutional neural network also showed high performance in other species used in research-including rats, pigs, bears, and marmosets-as well as in humans, providing a translational bridge between preclinical and clinical studies.

Conclusions: We developed a deep learning algorithm for accurate multiclass segmentation of digital whole-slide images of periodic acid-Schiff-stained kidneys from various species and renal disease models. This enables reproducible quantitative histopathologic analyses in preclinical models that also might be applicable to clinical studies.
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http://dx.doi.org/10.1681/ASN.2020050597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894663PMC
January 2021

Why Target the Gut to Treat IgA Nephropathy?

Kidney Int Rep 2020 Oct 20;5(10):1620-1624. Epub 2020 Aug 20.

Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.

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http://dx.doi.org/10.1016/j.ekir.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569689PMC
October 2020

Mineral and bone disorder in chronic kidney disease: pioneering studies.

Kidney Int 2020 10;98(4):807-811

Inserm U-1018, Centre de recherche en Épidémiologie et Santé des Populations (CESP), Paris-Ile-de-France-Ouest University, Paris-Sud University, and Paris Saclay University, Villejuif, France.

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http://dx.doi.org/10.1016/j.kint.2020.07.002DOI Listing
October 2020

WNT-β-catenin signalling - a versatile player in kidney injury and repair.

Nat Rev Nephrol 2021 03 28;17(3):172-184. Epub 2020 Sep 28.

Department of Nephrology and Clinical Immunology, University Hospital, Rheinisch Westfälische Technische Hochschule (RWTH), Aachen, Germany.

The WNT-β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT-β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT-β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT-β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT-β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by 'stressed' tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT-β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications.
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http://dx.doi.org/10.1038/s41581-020-00343-wDOI Listing
March 2021

MicroRNAs in Chronic Kidney Disease: Four Candidates for Clinical Application.

Int J Mol Sci 2020 Sep 7;21(18). Epub 2020 Sep 7.

Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University Hospital, 52074 Aachen, Germany.

There are still major challenges regarding the early diagnosis and treatment of chronic kidney disease (CKD), which is in part due to the fact that its pathophysiology is very complex and not clarified in detail. The diagnosis of CKD commonly is made after kidney damage has occurred. This highlights the need for better mechanistic insight into CKD as well as improved clinical tools for both diagnosis and treatment. In the last decade, many studies have focused on microRNAs (miRs) as novel diagnostic tools or clinical targets. MiRs are small non-coding RNA molecules that are involved in post-transcriptional gene regulation and many have been studied in CKD. A wide array of pre-clinical and clinical studies have highlighted the potential role for miRs in the pathogenesis of hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, kidney tubulointerstitial fibrosis, and some of the associated cardiovascular complications. In this review, we will provide an overview of the miRs studied in CKD, especially highlighting miR-103a-3p, miR-192-5p, the miR-29 family and miR-21-5p as these have the greatest potential to result in novel therapeutic and diagnostic strategies.
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http://dx.doi.org/10.3390/ijms21186547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555601PMC
September 2020

Evidence of an intestinal phosphate transporter alternative to type IIb sodium-dependent phosphate transporter in rats with chronic kidney disease.

Nephrol Dial Transplant 2021 01;36(1):68-75

Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany.

Background: Phosphate is absorbed in the small intestine via passive flow and active transport.NaPi-IIb, a type II sodium-dependent phosphate transporter, is considered to mediate active phosphate transport in rodents. To study the regulation of intestinal phosphate transport in chronic kidney disease (CKD), we analyzed the expression levels of NaPi-IIb, pituitary-specific transcription factor 1 (PiT-1) and PiT-2 and the kinetics of intestinal phosphate transport using two CKD models.

Methods: CKD was induced in rats via adenine orThy1 antibody injection. Phosphate uptake by intestinal brush border membrane vesicles (BBMV) and the messenger RNA (mRNA) expression of NaPi-IIb, PiT-1 and PiT-2 were analyzed. The protein expression level of NaPi-IIb was measured by mass spectrometry (e.g. liquid chromatography tandem mass spectrometry).

Results: In normal rats, phosphate uptake into BBMV consisted of a single saturable component and its Michaelis constant (Km) was comparable to that of NaPi-IIb. The maximum velocity (Vmax) correlated with mRNA and protein levels of NaPi-IIb. In the CKD models, intestinal phosphate uptake consisted of two saturable components. The Vmax of the higher-affinity transport, which is thought to be responsible for NaPi-IIb, significantly decreased and the decrease correlated with reduced NaPi-IIb expression. The Km of the lower-affinity transport was comparable to that of PiT-1 and -2. PiT-1 mRNA expression was much higher than that of PiT-2, suggesting that PiT-1 was mostly responsible for phosphate transport.

Conclusions: This study suggests that the contribution of NaPi-IIb to intestinal phosphate absorption dramatically decreases in rats with CKD and that a low-affinity alternative to NaPi-IIb, in particular PiT-1, is upregulated in a compensatory manner in CKD.
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http://dx.doi.org/10.1093/ndt/gfaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771979PMC
January 2021

Single versus dual blockade of the renin-angiotensin system in patients with IgA nephropathy.

J Nephrol 2020 Dec 27;33(6):1231-1239. Epub 2020 Aug 27.

Division of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstr. 30, 52057, Aachen, Germany.

Background: Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial.

Methods: STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m and ESRD onset, were analyzed by logistic regression and linear mixed effects models.

Results: Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies.

Conclusion: In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.
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http://dx.doi.org/10.1007/s40620-020-00836-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701065PMC
December 2020

Cardiovascular complications of chronic kidney disease: pioneering studies.

Kidney Int 2020 09;98(3):522-526

Department of Nephrology and Clinical Immunology, University Hospital, Rheinisch Westfälische Technische Hochschule Aachen, Aachen, Germany.

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http://dx.doi.org/10.1016/j.kint.2020.07.001DOI Listing
September 2020