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2.
  • Zoccali, Carmine, et al. (author)
  • Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease : translational opportunities and challenges
  • 2022
  • In: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 37, s. 14-23
  • Research review (peer-reviewed)abstract
    • Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.
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3.
  • Abtahi, Farhad, 1981-, et al. (author)
  • Pro-inflammatory Blood Markers and Heart Rate Variability in Apnoea as a Reflection of Basal Vagal Tone
  • Other publication (other academic/artistic)abstract
    • Pro-inflammatory cytokines play a crucial role in inflammatory response, which istightly regulated by the nervous system to avoid the damage caused by inflammation. There isevidence for a cholinergic anti-inflammatory pathway that includes afferent and efferent vagalnerves that sense the inflammation and stimulate the anti-inflammatory response. Non-functionalanti-inflammatory response might lead to excessive and chronic inflammation e.g., rheumatoidarthritis (RA), inflammatory bowel disease (IBD), and poor outcome. Heart rate variability(HRV) has been proposed as a potential tool to monitor the level of anti-inflammatory activitythrough the monitoring of vagal activity. In this paper, the association of pro-inflammatorymarkers with HRV indices is evaluated. We used a database called “Heart Biomarker Evaluationin Apnea Treatment (HeartBEAT)” that consists of 6±2 hours of Electrocardiogram (ECG)recordings during nocturnal sleep from 318 patients at baseline and 301of them at 3 monthsfollow-up. HRV indices are calculated from ECG recordings of 5-360 minutes. The results showa statistically significant correlation between heart rate (HR) and pro-inflammatory cytokines,independent of duration of ECG analysis. HRV indices e.g., standard deviation of all RRintervals (SDNN) show an inverse relation to the pro-inflammatory cytokines. Longer ECGrecordings show a higher potential to reflect the level of anti-inflammatory response. In light oftheories for the cholinergic anti-inflammatory pathway, a combination of HR and HRV as areflection of basal vagal activity might be a potential prognostic tool for interventional guidance.
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4.
  • Abtahi, Farhad, 1981- (author)
  • Towards Heart Rate Variability Tools in P-Health : Pervasive, Preventive, Predictive and Personalized
  • 2016
  • Doctoral thesis (other academic/artistic)abstract
    • Heart rate variability (HRV) has received much attention lately. It has been shown that HRV can be used to monitor the autonomic nervous system and to detect autonomic dysfunction, especially vagal dysfunction. Reduced HRV is associated with several diseases and has also been suggested as a predictor of poor outcomes and sudden cardiac death. HRV is, however, not yet widely accepted as a clinical tool and is mostly used for research. Advances in neuroimmunity with an improved understanding of the link between the nervous and immune systems have opened a new potential arena for HRV applications. An example is when systemic inflammation and autoimmune disease are primarily caused by low vagal activity; it can be detected and prognosticated by reduced HRV. This thesis is the result of several technical development steps and exploratory research where HRV is applied as a prognostic diagnostic tool with preventive potential. The main objectives were 1) to develop an affordable tool for the effective analysis of HRV, 2) to study the correlation between HRV and pro-inflammatory markers and the potential degree of activity in the cholinergic anti-inflammatory pathway, and 3) to develop a biofeedback application intended for support of personal capability to increase the vagal activity as reflected in increased HRV. Written as a compilation thesis, the methodology and the results of each study are presented in each appended paper. In the thesis frame/summary chapter, a summary of each of the included papers is presented, grouped by topic and with their connections. The summary of the results shows that the developed tools may accurately register and properly analyse and potentially influence HRV through the designed biofeedback game. HRV can be used as a prognostic tool, not just in traditional healthcare with a focus on illness but also in wellness. By using these tools for the early detection of decreased HRV, prompt intervention may be possible, enabling the prevention of disease. Gamification and serious gaming is a potential platform to motivate people to follow a routine of exercise that might, through biofeedback, improve HRV and thereby health.
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  • Anders, Hans Joachim, et al. (author)
  • Recommendations for the management of patients with immune-mediated kidney disease during the severe acute respiratory syndrome coronavirus 2 pandemic
  • 2020
  • In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 35:6, s. 920-925
  • Journal article (peer-reviewed)abstract
    • The coronavirus disease 2019 (COVID-19) pandemic has created major challenges for all countries around the globe. Retrospective studies have identified hypertension, cardiovascular disease, diabetes and older age as risk factors for high morbidity and mortality from COVID-19. There is a general concern that patients with immune-mediated kidney diseases, namely those on immunosuppressive therapies and/or those with more advanced kidney failure, could particularly be at risk for adverse outcomes due to a compromised antiviral immunity. Uncertainties exist on how management routines should be reorganized to minimize the risk of severe acute respiratory syndrome coronavirus 2 infection and what measures are necessary for infected patients. The aim of the present review of the Immunonephrology Working Group of the European Renal Association-European Dialysis and Transplant Association is to provide recommendations for the management of patients with immune-mediated kidney diseases based on the available evidence, similar circumstances with other infectious organisms and expert opinions from across Europe. Such recommendations may help to minimize the risk of encountering COVID-19 or developing complications during COVID-19 in patients with immune-mediated kidney disease.
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7.
  • Anders, Hans Joachim, et al. (author)
  • The management of lupus nephritis as proposed by EULAR/ERA 2019 versus KDIGO 2021
  • 2023
  • In: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 38:3, s. 551-561
  • Journal article (peer-reviewed)abstract
    • In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies.
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8.
  • Antovic, Aleksandra, et al. (author)
  • Microparticles Expressing Myeloperoxidase and Complement C3a and C5a as Markers of Renal Involvement in Antineutrophil Cytoplasmic Antibody-associated Vasculitis
  • 2020
  • In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 47:5, s. 714-721
  • Journal article (peer-reviewed)abstract
    • Objective. To investigate expression of terminal complement components C3a and C5a on circulating myeloperoxidase (MPO)-positive microparticles (MPO+MP) in relation to disease activity and renal involvement in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods. Forty-six clinically well-characterized patients with AAV and 23 age-and sex-matched healthy controls were included. The concentration of MPO+MP expressing C3a and C5a was analyzed from citrate plasma by flow cytometry. Serum levels of C3a and C5a were determined using commercial ELISA. The assessment of vasculitis disease activity was performed using the Birmingham Vasculitis Activity Score (BVAS). Among patients, 23 had active disease with BVAS >= 2 and 14 patients had active renal flares. Results. AAV patients had significantly increased expression of C3a and C5a on MPO+MP compared to controls (both p < 0.0001). When the group of patients with active AAV was divided according to the presence of renal activity, the concentration of MPO+MP expressing C3a and C5a was significantly higher in patients with renal involvement compared to patients with nonrenal disease and controls (p < 0.05 and p < 0.01, respectively). The serum levels of C3a were significantly decreased (p < 0.01) in the renal subgroup, while there were no changes in serum levels of C5a comparing the renal and nonrenal groups. There was significant correlation between the disease activity measured by BVAS and the levels of C3a and C5a expressed on MPO+MP. Conclusion. Determination of C3a and C5a on MPO+MP might be considered as a novel biomarker of renal involvement in patients with AAV and may be of importance in the pathogenetic process.
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9.
  • Antovic, A., et al. (author)
  • Risks and treatment related aspects of COVID-19 infection in patients with ANCA-associated vasculitis
  • 2023
  • In: Scandinavian Journal of Rheumatology. - : Taylor & Francis. - 0300-9742 .- 1502-7732. ; 52:4, s. 418-423
  • Journal article (peer-reviewed)abstract
    • Objective Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) require immunosuppressive therapy for disease control and relapse prevention and may be at risk for severe coronavirus disease 2019 (COVID-19). The study objective was to analyse risk factors and outcomes of COVID-19 in well-characterized AAV patients. Method Data were retrieved from March 2020 to May 2021 from medical records of AAV cohorts in Stockholm and Uppsala, Sweden. COVID-19 was confirmed by positive PCR test or by ELISA. Severe COVID-19 was defined as need for non-invasive ventilation, intensive care unit care, and/or death. Age, gender, ANCA antibody type, ongoing immunosuppressive medication, and estimated glomerular filtration rate were recorded. Results The cohort comprised 310 AAV patients, of whom 29 (9%) were diagnosed with COVID-19. Four deaths were attributed to COVID-19. Fifteen patients (52%) were on prednisolone in the COVID-19 group and 130 (46%) in the non-COVID group, with significantly higher doses in COVID-19 patients (p < 0.01). Ongoing induction therapy was more prevalent in the COVID-19 group (p < 0.01). Severe COVID-19 was diagnosed in 9/29 (31%). Significant risk factors for severe COVID-19 were impaired kidney function (p = 0.01) and more intense immunosuppressive therapy (p = 0.02), with a trend for age (p = 0.07). Maintenance therapy with rituximab was not associated with severe COVID-19. Conclusions Our findings highlight risks and suggest that more attention should be given to optimal AAV treatment in a pandemic situation. They also emphasize the need for continued shielding, mitigation strategies, and effective vaccination of AAV patients.
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10.
  • Awan, Ahmed Arslan Yousuf, et al. (author)
  • Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2022 Clinical Practice Guideline
  • 2023
  • In: Annals of Internal Medicine. - : AMER COLL PHYSICIANS. - 0003-4819 .- 1539-3704. ; 176, s. 1648-1655
  • Journal article (peer-reviewed)abstract
    • Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 clinical practice guideline on prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease (CKD) is an update of the 2018 guideline from KDIGO.Methods: The KDIGO Work Group (WG) updated the guideline, which included reviewing and grading new evidence that was identified and summarized. As in the previous guideline, the WG used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of recommendations and used expert judgment to develop recommendations. New evidence led to updating of recommendations in the chapters on treatment of hepatitis C virus (HCV) infection in patients with CKD (Chapter 2), management of HCV infection before and after kidney transplant (Chapter 4), and diagnosis and management of kidney disease associated with HCV infection (Chapter 5). Recommendations in chapters on detection and evaluation of hepatitis C in CKD (Chapter 1) and prevention of HCV transmission in hemodialysis units (Chapter 3) were not updated because of an absence of significant new evidence.Recommendations: The 2022 updated guideline includes 43 graded recommendations and 20 ungraded recommendations, 7 of which are new or modified on the basis of the most recent evidence and consensus among the WG members. The updated guidelines recommend expanding treatment of hepatitis C with sofosbuvir-based regimens to patients with CKD glomerular filtration rate categories G4 and G5, including those receiving dialysis; expanding the donor pool for kidney transplant recipients by accepting HCV-positive kidneys regardless of the recipient's HCV status; and initiating direct-acting antiviral treatment of HCV-infected patients with clinical evidence of glomerulonephritis without requiring kidney biopsy. The update also addresses the use of immunosuppressive regimens in such patients.
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  • Blankestijn, Peter J., et al. (author)
  • Nephrology: achieving sustainability
  • 2020
  • In: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 35:12, s. 2030-2033
  • Journal article (other academic/artistic)abstract
    • n/a
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12.
  • Bredewold, Obbo W, et al. (author)
  • Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients : A Randomized Clinical Trial
  • 2023
  • In: Kidney Medicine. - : Elsevier. - 2590-0595. ; 5:1
  • Journal article (peer-reviewed)abstract
    • RATIONALE & OBJECTIVE: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.STUDY DESIGN: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial.SETTING & PARTICIPANTS: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion.INTERVENTION: Continuation with a CNI-based regimen or switch to belatacept for 12 months.OUTCOMES: Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness.RESULTS: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss.LIMITATIONS: The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year.CONCLUSIONS: We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate.FUNDING: The trial has received a financial grant from Bristol-Myers Squibb.TRIAL REGISTRATION: EudraCT no. 2013-001178-20.
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  • Brolin, Sara, et al. (author)
  • Exploring the educational needs of patients with systemic vasculitis using the educational needs assessment tool
  • 2022
  • In: Rheumatology. - : Oxford University Press. - 2514-1775. ; 6:2
  • Journal article (peer-reviewed)abstract
    • Objectives: Knowledge and health literacy enable patients to monitor symptoms and disease impact. Educational needs have previously been explored in rheumatology, but scarcely for patients with ANCA-associated vasculitis (AAV). The aim of the study was to assess the educational needs among patients with AAV using the educational needs assessment tool (ENAT).Methods: This was a cross-sectional observational study including adults with AAV. Educational needs were captured by ENAT. Total ENAT (0-117 points, with higher numbers indicating higher educational need) and the seven domains (managing pain, movement, feelings, disease process, treatment, self-management and support systems) were explored regarding sex, age, education, diagnosis, disease duration and disease activity. To compare domains, a percentage response (0-100%) was calculated.Results: One hundred and seventy-eight individuals (50% men; 34% with disease duration ≤2 years) were included. The total ENAT mean was 66.5 (s.d. 26.6; 57%), with domains as follows: disease process, 78%; self-management, 69%; treatments, 64%; feelings, 56%; managing pain, 48%; support systems, 47%; and movement, 41%. Higher educational needs were found among women in the domains movement, feelings and disease process and in total ENAT (all P < 0.04) compared with men. Higher educational needs were also seen in patients with disease duration ≤2 years regarding disease process, self-management and support systems and in total ENAT compared with patients with longer disease duration (all P < 0.03).Conclusion: This study revealed great educational needs among AAV patients. Some groups expressed higher needs (women and those with shorter disease duration). Increased education for patients with AAV might lead to improved self-care and treatment adherence.
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  • Bruchfeld, Annette, et al. (author)
  • C5a receptor inhibitor avacopan in immunoglobulin A nephropathy - an open-label pilot study
  • 2022
  • In: Clinical Kidney Journal. - : Oxford University Press. - 2048-8505 .- 2048-8513. ; 15:5, s. 922-928
  • Journal article (peer-reviewed)abstract
    • Background Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody-associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin-angiotensin-aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m(2) or >45 mL/min/1.73 m(2) if eGFR has not declined >10 mL/min/1.73 m(2) over the previous 24 weeks. If the UPCR remained at >1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period. Results A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of similar to 50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions This short-term pilot study showed an improvement in the slope of the UPCR, with similar to 50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit.
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16.
  • Bruchfeld, Annette (author)
  • Hepatitis C in chronic kidney disease and kidney transplantation : with special reference to epidemiology and treatment
  • 2003
  • Doctoral thesis (other academic/artistic)abstract
    • Hepatitis C (HCV) is a clinical problem in infected kidney transplant patients but is also a cause of renal disease and vasculitis. Standard therapy for HCV is a combination of interferon and ribavirin. Renal patients have mostly been treated with interferon monotherapy since ribavirin has been contraindicated in renal insufficiency with a GFR (glomerular filtration rate) < 50 ml/min. A cohort of 520 HCV-negative and 51 HCV-positive patients transplanted between 1989 and 1997 at Huddinge University Hospital was studied with last follow-up 2002. The methods used were univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazards model. We confirmed that HCV is an independent risk factor for both patient (p<0.0012) and graft- survival (p<0.0003) after kidney transplantation in line with previous studies. After adjusting for age, gender, diabetes, previous transplants, type of transplant and time in renal replacement therapy (RRT) HCV remained significantly more important than time in RRT for long-term outcome after kidney transplantation. This has not been well characterized before. The results lend support to the suggestion that successful anti-viral HCV therapy prior to transplantation may be preferable to an early transplant for long-term patient and graft survival after kidney transplantation. However, this remains to be confirmed in prospective studies. In order to optimise ribavirin therapy in patients with renal disease a high-performance liquid chromatography (HPLC) method for ribavirin plasma concentration measurement was developed. A trough level interval of 7-17µmol/L was found in 10 patients with normal renal function treated with interferon-alpha and ribavirin. The ribavirin monitoring method was used in 6 HCV infected dialysis patients in study and in 7 patients with renal insufficiency with HCV-related renal disease in study. The method enabled clinical use of ribavirin in combination with interferon-alpha in these patients with fair tolerability. However this required reduced ribavirin doses, close monitoring of ribavirin plasma concentrations and surveillance of side effects. Ribavirin-associated anaemia, the main side effect, was handled by means of medium-high doses of erythropoietin as well as low- dose iron therapy, thereby avoiding blood transfusions. Viral response during treatment in all 13 HCV replicating patients was 85%. Although the studies were small and uncontrolled ribavirin in addition to interferon-alpha is likely to have had an additive effect in renal insufficient patients. Overall 383 ribavirin samples from 63 patients were collected, 44 with normal serum creatinine and 19 with renal impairment with an estimated GFR of 5-57 ml/min. A population pharmacokinetic analysis was performed using non-linear mixed effect modelling (NONMEM) evaluating population factors as age, gender, body weight, serum creatinine and estimated GFR. Estimated GFR was found to be a significantly better predictor of ribavirin clearance than body weight alone. A small non-renal clearance dependant on body weight and age and a significant inter- individual 40 % variability in ribavirin total clearance remained, not explained by GFR and body weight. The results indicate that ribavirin should mainly be dosed on renal function and not on body weight alone. A dosing schedule is proposed based on these findings. Ribavirin monitoring is strongly recommended in renal patients. Further studies including patients with normal GFR should be of interest considering the inter-individual variability in ribavirin total clearance and in order to identify a possible therapeutic ribavirin target concentration for HCV infection.
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17.
  • Bruchfeld, Annette (author)
  • The COVID-19 pandemic: consequences for nephrology
  • 2021
  • In: Nature Reviews Nephrology. - : NATURE RESEARCH. - 1759-5061 .- 1759-507X. ; 17, s. 81-82
  • Journal article (other academic/artistic)abstract
    • The consequences of the COVID-19 pandemic have been devastating; however, evidence suggests that patients with, or at risk of, kidney disease are disproportionally affected. Patients on dialysis and kidney transplant recipients are at higher risk of adverse outcomes from COVID-19, whereas, conversely, patients with severe COVID-19 are at increased risk of acute kidney injury, with short-term and possibly long-term consequences for nephrological care.
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18.
  • Caravaca-Fontán, Fernando, et al. (author)
  • The management of membranous nephropathy—an update
  • 2022
  • In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 37:6, s. 1033-1042
  • Journal article (peer-reviewed)abstract
    • In recent decades, several important advances have taken place in the understanding of the pathogenesis underlying membranous nephropathy (MN) that have sparked renewed interest in its management. Four landmark trials in MN and a fifth clinical trial—which was a pilot study—have been published in recent years. The results from some of these trials have had a significant impact on the recommendations included in the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases, representing a significant step forward compared with the previous guideline in several aspects, including diagnosis, disease monitoring and treatment strategies. However, considering the rapidly evolving advances in the knowledge of MN and the recent publication of the STARMEN and RI-CYCLO trials, several recommendations contained in the guideline warrant updates. This article provides a perspective of the Immunonephrology Working Group of the European Renal Association regarding the management of MN in native kidneys of adult patients.
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  • Cortazar, Frank B., et al. (author)
  • Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan
  • 2023
  • In: KIDNEY INTERNATIONAL REPORTS. - : ELSEVIER SCIENCE INC. - 2468-0249. ; 8:4, s. 860-870
  • Journal article (peer-reviewed)abstract
    • Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cyto-plasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m2 in the avacopan group and 4.1 ml/min per 1.73 m2 in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR <= 20 ml/min per 1.73 m2. Methods: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. Results: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR <= 20 ml/min per 1.73 m2. At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m2 in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was $2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m2, respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. Conclusion: Among patients with baseline eGFR <= 20 ml/min per 1.73 m2 in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.
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20.
  • Dahlqvist, Johanna, 1979-, et al. (author)
  • Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
  • 2022
  • In: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8, s. 3461-3470
  • Journal article (peer-reviewed)abstract
    • Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
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21.
  • Ekman, Diana, et al. (author)
  • Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis
  • 2023
  • In: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 62:9, s. 3213-3218
  • Journal article (peer-reviewed)abstract
    • Objective: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. Methods: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. Results: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. Conclusions: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.
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22.
  • Erlandsson, H., et al. (author)
  • Observational study of risk factors associated with clinical outcome among elderly kidney transplant recipients in Sweden - a decade of follow-up
  • 2021
  • In: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 34:11, s. 2363-2370
  • Journal article (peer-reviewed)abstract
    • Kidney transplantation (Ktx) in elderly has become increasingly accepted worldwide despite their higher burden of comorbidities. We investigated important risk factors affecting long-term patient and graft survival. We included all (n = 747) Ktx patients >60 years from 2000 to 2012 in Sweden. Patients were age-stratified, 60-64, 65-69 and >70 years. Follow-up time was up to 10 years (median 7.9 years, 75% percentile >10 years). Primary outcome was 10-year patient survival in age-stratified groups. Secondary outcomes were 5-year patient and graft survival in age-stratified groups and the impact of risk factors including Charlson comorbidity index (CCI) on patient and graft survival. Mortality was higher in patients >70 years, after 10 years (HR 1.94; 95% CI 1.24-3.04; P = 0.004). Males had a higher 10-year risk of death (HR 1.39; CI 95% 1.04-1.86; P = 0.024). Five-year patient survival did not differ between age groups. In multivariate Cox analysis (n = 500), hazard ratio for 10-year mortality was 4.6 in patients with CCI >= 7 vs. <4 (95% CI 2.42-8.62; P = 0.0001). Higher CCI identified ESKD patients with 4.6 times higher risk of death after Ktx. We suggest that this index should be used as a part of the preoperative evaluation in elderly.
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23.
  • Erlandsson, Helen, et al. (author)
  • Scoring of medial arterial calcification predicts cardiovascular events and mortality after kidney transplantation
  • 2022
  • In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 291:6, s. 813-823
  • Journal article (peer-reviewed)abstract
    • Background Progression of vascular calcification causes cardiovascular disease, which is the most common cause of death in chronic kidney failure and after kidney transplantation (KT). The prognostic impact of the extent of medial vascular calcification at KT is unknown. Methods In this prospective cohort study, we investigated the impact of medial calcification compared to a mix of intimal and medial calcification represented by coronary artery calcification (CAC score) and aortic valve calcification in 342 patients starting on kidney failure replacement therapy. The primary outcomes were cardiovascular events (CVE) and death. The median follow-up time was 6.4 years (interquartile range 3.7-9.6 years). Exposure was CAC score and arteria epigastrica medial calcification scored as none, mild, moderate, or severe by a pathologist at time of KT (n = 200). We divided the patients according to kidney failure replacement therapy during follow-up, that is, living donor KT, deceased donor KT, or dialysis. Results Moderate to severe medial calcification in the arteria epigastrica was associated with higher mortality (p = 0.001), and the hazard ratio for CVE was 3.1 (95% confidence interval [CI] 1.12-9.02, p < 0.05) compared to no or mild medial calcification. The hazard ratio for 10-year mortality in the dialysis group was 33.6 (95% CI, 10.0-113.0, p < 0.001) compared to living donor recipients, independent of Framingham risk score and prevalent CAC. Conclusion Scoring of medial calcification in the arteria epigastrica identified living donor recipients as having 3.1 times higher risk of CVE, independent of traditional risk factors. The medial calcification score could be a reliable method to identify patients with high and low risk of CVE and mortality following KT.
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24.
  • Faustini, Francesca, et al. (author)
  • First exposure to rituximab is associated to high rate of anti-drug antibodies in systemic lupus erythematosus but not in ANCA-associated vasculitis
  • 2021
  • In: Arthritis Research & Therapy. - : BMC. - 1478-6362. ; 23:1
  • Journal article (peer-reviewed)abstract
    • Background Anti-drug antibodies (ADAs) can impact on the efficacy and safety of biologicals, today used to treat several chronic inflammatory conditions. Specific patient groups may be more prone to develop ADAs. Rituximab is routinely used for ANCA-associated vasculitis (AAV) and as off-label therapy for systemic lupus erythematosus (SLE), but data on occurrence and predisposing factors to ADAs in these diseases is limited. Objectives To elucidate the rate of occurrence, and risk factors for ADAs against rituximab in SLE and AAV. Methods ADAs were detected using a bridging electrochemiluminescent (ECL) immunoassay in sera from rituximab-naive (AAV; n = 41 and SLE; n = 62) and rituximab-treated (AAV; n = 22 and SLE; n = 66) patients. Clinical data was retrieved from medical records. Disease activity was estimated by the SLE Disease Activity Index-2000 (SLEDAI-2 K) and the Birmingham Vasculitis Activity Score (BVAS). Results After first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients. Samples were obtained at a median (IQR) time of 5.5 (3.7-7.0) months (AAV), and 6.0 (5.0-7.0) months (SLE). ADA-positive SLE individuals were younger (34.0 (25.9-40.8) vs 44.3 (32.7-56.3) years, p = 0.002) and with more active disease (SLEDAI-2 K 14.0 (10.0-18.5) vs. 8.0 (6.0-14), p = 0.0017) and shorter disease duration (4.14 (1.18-10.08) vs 9.19 (5.71-16.93), p = 0.0097) compared to ADA-negative SLE. ADAs primarily occurred in nephritis patients, were associated with anti-dsDNA positivity but were not influenced by concomitant use of corticosteroids, cyclophosphamide or previous treatments. Despite overall reduction of SLEDAI-2 K (12.0 (7.0-16) to 4.0 (2.0-6.7), p < 0.0001), ADA-positive individuals still had higher SLEDAI-2 K (6.0 (4.0-9.0) vs 4.0 (2.0-6.0), p = 0.004) and their B cell count at 6 months follow-up was higher (CD19 + % 4.0 (0.5-10.0) vs 0.5 (0.4-1.0), p = 0.002). At retreatment, two ADA-positive SLE patients developed serum sickness (16.7%), and three had infusion reactions (25%) in contrast with one (5.2%) serum sickness in the ADA-negative group. Conclusions In contrast to AAV, ADAs were highly prevalent among rituximab-treated SLE patients already after the first course of treatment and were found to effect on both clinical and immunological responses. The high frequency in SLE may warrant implementations of ADA screening before retreatment and survey of immediate and late-onset infusion reactions.
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25.
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26.
  • Gauckler, Philipp, et al. (author)
  • COVID-19 outcomes in patients with a history of immune-mediated glomerular diseases
  • 2023
  • In: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 14
  • Journal article (peer-reviewed)abstract
    • Introduction: Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce.Methods: We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes.Results: Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 +/- 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 +/- 17.91 versus 39.77 +/- 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 +/- 0.80 g/dL versus 3.99 +/- 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively).Conclusion: Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases.
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27.
  • Gauckler, Philipp, et al. (author)
  • Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown?
  • 2020
  • In: Autoimmunity Reviews. - : Elsevier BV. - 1568-9972 .- 1873-0183. ; 19:11
  • Research review (peer-reviewed)abstract
    • Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.
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28.
  • Gauckler, Philipp, et al. (author)
  • Rituximab in Membranous Nephropathy
  • 2021
  • In: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 6:4, s. 881-893
  • Research review (peer-reviewed)abstract
    • Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of “the new standard.”
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29.
  • Gertow, Joanna, et al. (author)
  • Altered Protein Composition of Subcutaneous Adipose Tissue in Chronic Kidney Disease
  • 2017
  • In: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 2:6, s. 1208-1218
  • Journal article (peer-reviewed)abstract
    • Introduction: Loss of renal function is associated with high mortality from cardiovascular disease (CVD). Patients with chronic kidney disease (CKD) have altered circulating adipokine and nonesterified fatty acid concentrations and insulin resistance, which are features of disturbed adipose tissue metabolism. Because dysfunctional adipose tissue contributes to the development of CVD, we hypothesize that adipose tissue dysfunctionality in patients with CKD could explain, at least in part, their high rates of CVD. Therefore we characterized adipose tissue from patients with CKD, in comparison to healthy controls, to search for signs of dysfunctionality. Methods: Biopsy samples of subcutaneous adipose tissue from 16 CKD patients and 11 healthy controls were analyzed for inflammation, fibrosis, and adipocyte size. Protein composition was assessed using 2dimensional gel proteomics combined with multivariate analysis. Results: Adipose tissue of CKD patients contained significantly more CD68-positive cells, but collagen content did not differ. Adipocyte size was significantly smaller in CKD patients. Proteomic analysis of adipose tissue revealed significant differences in the expression of certain proteins between the groups. Proteins whose expression differed the most were a-1-microglobulin/ bikunin precursor (AMBP, higher in CKD) and vimentin (lower in CKD). Vimentin is a lipid droplet-associated protein, and changes in its expression may impair fatty acid storage/mobilization in adipose tissue, whereas high levels of AMBP may reflect oxidative stress. Discussion: These findings demonstrate that adipose tissue of CKD patients shows signs of inflammation and disturbed functionality, thus potentially contributing to the unfavorable metabolic profile and increased risk of CVD in these patients.
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30.
  • Grigore, Teodora V. V., et al. (author)
  • Fibroblast growth factor 23 is independently associated with renal magnesium handling in patients with chronic kidney disease
  • 2023
  • In: Frontiers in Endocrinology. - : FRONTIERS MEDIA SA. - 1664-2392. ; 13
  • Journal article (peer-reviewed)abstract
    • BackgroundDisturbances in magnesium homeostasis are common in patients with chronic kidney disease (CKD) and are associated with increased mortality. The kidney is a key organ in maintaining normal serum magnesium concentrations. To this end, fractional excretion of magnesium (FEMg) increases as renal function declines. Despite recent progress, the hormonal regulation of renal magnesium handling is incompletely understood. Fibroblast Growth Factor 23 (FGF23) is a phosphaturic hormone that has been linked to renal magnesium handling. However, it has not yet been reported whether FGF23 is associated with renal magnesium handling in CKD patients. MethodsThe associations between plasma FGF23 levels, plasma and urine magnesium concentrations and FEMg was investigated in a cross-sectional cohort of 198 non-dialysis CKD patients undergoing renal biopsy. ResultsFGF23 was significantly correlated with FEMg (Pearsons correlation coefficient = 0.37, p<0.001) and urinary magnesium (-0.14, p=0.04), but not with plasma magnesium. The association between FGF23 and FEMg remained significant after adjusting for potential confounders, including estimated glomerular filtration rate (eGFR), parathyroid hormone and 25-hydroxyvitamin D. ConclusionsWe report that plasma FGF23 is independently associated with measures of renal magnesium handling in a cohort of non-dialysis CKD patients. A potential causal relationship should be investigated in future studies.
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31.
  • Hafez, Gaye, et al. (author)
  • Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients
  • 2023
  • In: Clinical Kidney Journal. - : OXFORD UNIV PRESS. - 2048-8505 .- 2048-8513. ; 16:12, s. 2378-2392
  • Research review (peer-reviewed)abstract
    • There is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood-brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects. Graphical Abstract
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32.
  • Harper, Lorraine, et al. (author)
  • Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up
  • 2012
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 71:6, s. 955-960
  • Journal article (peer-reviewed)abstract
    • Introduction The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study. Methods Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised. Results Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs. Discussion Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.
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33.
  • Hilderman, Marie, et al. (author)
  • Cholinergic anti-inflammatory pathway activity in dialysis patients : a role for neuroimmunomodulation?
  • 2015
  • In: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 8:5
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through the vagus nerve and the α-7-nicotinic acetylcholine receptor (α7nAChR) on macrophages and immune cells. Sympathetic/parasympathetic imbalance and chronic inflammation are both linked to poor outcome in dialysis patients. The aim of this study was to investigate CAP activity in these patients.METHODS: Twenty dialysis patients, 12 hemodialysis (HD) and 8 peritoneal dialysis (PD) patients (12 male, 8 female; age range 47-83 years) and 8 controls (5 male, 3 female; age range 31-52 years) were analyzed for C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1b (IL-1b), IL-6 and IL-10 at baseline. The cytokines were then assessed after whole blood stimulation ex vivo with lipopolysaccharide (LPS) (10 and 100 ng/mL) and again in the presence of 45 and 90 μmol/L GTS-21, a cholinergic α7nAChR agonist.RESULTS: CRP, TNF, IL-1 and IL-6 were significantly higher, whereas IL-10 was significantly lower at baseline in patients compared with controls. After LPS stimulation, TNF increased significantly more in patients than in controls but decreased to similar levels in both groups after addition of GTS-21. IL-6 attenuation was comparable with TNF and the IL-1b pattern was similar but remained significantly higher in patients. Interestingly, IL-10 increased after GTS-21 in a dose-dependent manner, but only in patients. Results in HD and PD patients did not differ.CONCLUSIONS: The response of immune cells after LPS exposure and cholinergic stimulation suggests a functional CAP in dialysis patients. It may thus be possible to target the α7nAChR control of cytokine release as an anti-inflammatory strategy and thereby improve outcome in these patients.
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34.
  • Hilderman, Marie, et al. (author)
  • The cholinergic anti-inflammatory pathway in chronic kidney disease-review and vagus nerve stimulation clinical pilot study
  • 2020
  • In: Nephrology, Dialysis and Transplantation. - : OXFORD UNIV PRESS. - 0931-0509 .- 1460-2385. ; 35:11, s. 1840-1852
  • Research review (peer-reviewed)abstract
    • Inflammation and autonomic dysfunction are common findings in chronic and end-stage kidney disease and contribute to a markedly increased risk of mortality in this patient population. The cholinergic anti-inflammatory pathway (CAP) is a vagal neuro-immune circuit that upholds the homoeostatic balance of inflammatory activity in response to cell injury and pathogens. CAP models have been examined in preclinical studies to investigate its significance in a range of clinical inflammatory conditions and diseases. More recently, cervical vagus nerve stimulation (VNS) implants have been shown to be of potential benefit for patients with chronic autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. We have previously shown that dialysis patients have a functional CAP ex vivo. Here we review the field and the potential role of the CAP in acute kidney injury and chronic kidney disease (CKD) as well as in hypertension. We also present a VNS pilot study in haemodialysis patients. Controlling inflammation by neuroimmune modulation may lead to new therapeutic modalities for improved treatment, outcome, prognosis and quality of life for patients with CKD.
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35.
  • Hilderman, Marie, et al. (author)
  • The cholinergic anti-inflammatory pathway in resistant hypertension treated with renal denervation
  • 2019
  • In: Molecular Medicine. - : Springer Science and Business Media LLC. - 1076-1551 .- 1528-3658. ; 25:1
  • Journal article (peer-reviewed)abstract
    • Renal denervation (RDN) reduces sympathetic tone and may alter the sympathetic-parasympathetic balance. The autonomic nervous system is partly a regulator of innate immunity via the cholinergic anti-inflammatory pathway (CAP) which inhibits inflammation via the vagus nerve. Placental Growth Factor (PlGF) influences a neuro-immunological pathway in the spleen which may contribute to hypertension. The aim of this study was to investigate if modulation of renal sympathetic nerve activity affects CAP in terms of cytokine release as well as levels of PlGF.
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36.
  • Hilhorst, Marc, et al. (author)
  • Prophylactic and early outpatient treatment of COVID-19 in patients with kidney disease: considerations from the Immunonephrology Working Group of the European Renal Association (ERA-IWG)
  • 2023
  • In: Nephrology, Dialysis and Transplantation. - : OXFORD UNIV PRESS. - 0931-0509 .- 1460-2385. ; 38:8, s. 1807-1816
  • Journal article (peer-reviewed)abstract
    • The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to rapid vaccine development and large global vaccination schemes. However, patients with immune-mediated kidney disease, chronic kidney diseases and kidney transplant recipients show high non-response rates to vaccination despite more than three vaccinations and, consequently, reduced viral clearance capacity when infected while receiving certain immunosuppressants, carrying an elevated risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. SARS-CoV-2 evolution has been characterized by the emergence of novel variants and spike mutations contributing to waning efficacy of neutralizing antibodies. To this end, the therapeutic field expands from vaccination towards a combined approach of immunization, pre-exposure prophylaxis and early post-exposure treatment using direct-acting antivirals and neutralizing monoclonal antibodies to treat early in the disease course and avoid hospitalization. This expert opinion paper from the Immunonephrology Working Group of the European Renal Association (ERA-IWG) summarizes available prophylactic and/or early treatment options (i.e. neutralizing monoclonal antibodies and direct-acting antivirals) of SARS-CoV-2-infected patients with immune-mediated kidney disease, chronic kidney disease and kidney transplant recipients.
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37.
  • Ivkovic, Vanja, et al. (author)
  • Endothelin receptor antagonists in diabetic and non-diabetic chronic kidney disease
  • 2024
  • In: Clinical Kidney Journal. - : OXFORD UNIV PRESS. - 2048-8505 .- 2048-8513. ; 17:4
  • Research review (peer-reviewed)abstract
    • Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality, affecting >800 million persons globally. While we still lack efficient, targeted therapies addressing the major underlying pathophysiologic processes in CKD, findings of several recent trials have brought about a shifting landscape of promising therapies. The endothelin system has been implicated in the pathophysiology of CKD and endothelin receptor antagonists are one class of drugs for which we have increasing evidence of efficacy in these patients. In this review we summarize the most recent findings on the safety and efficacy of endothelin receptor antagonists in diabetic and non-diabetic CKD, future directions of research and upcoming treatments.
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38.
  • Jayne, David R W, et al. (author)
  • Glomerulonephritides.
  • 2014
  • In: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3, s. 27-29
  • Conference paper (peer-reviewed)
  •  
39.
  • Jayne, David R. W., et al. (author)
  • Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis
  • 2017
  • In: Journal of the American Society of Nephrology. - : AMER SOC NEPHROLOGY. - 1046-6673 .- 1533-3450. ; 28:9, s. 2756-2767
  • Journal article (peer-reviewed)abstract
    • Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a amp;gt;= 50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.
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40.
  • Jonasdottir, Asta Dogg, et al. (author)
  • Augmented thrombin formation is related to circulating levels of extracellular vesicles exposing tissue factor and citrullinated histone-3 in anti-neutrophil cytoplasmic antibody-associated vasculitides
  • 2023
  • In: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 10
  • Journal article (peer-reviewed)abstract
    • ObjectivesTo study circulating myeloperoxidase (MPO)-positive extracellular vesicles (MPO+EVs) exposing citrullinated histone-3 (H3Cit), tissue factor (TF), and plasminogen (Plg) in association to thrombin generation in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV).MethodsWe have involved well-characterized patients with AAV together with population-based controls. Flow cytometry was used to assess the levels of MPO+EVs in citrated plasma. MPO+EVs were phenotyped by anti-MPO-antibodies together with anti-CD142 (anti-TF), anti-H3Cit, and anti-Plg antibodies. A modified Calibrated Automated Thrombogram (CAT) assay was utilized to measure thrombin generation in plasma initiated by EVs-enriched pellets. The activity of AAV was evaluated with the Birmingham Vasculitis Activity Score (BVAS).ResultsThis study comprised 46 AAV patients, 23 in the active stage of the disease and 23 in remission, as well as 23 age- and sex matched population-based controls. Augmented levels of all investigated MPO+ EVs were found in active AAV patients in comparison to the subgroup of patients in remission and controls. Thrombin generation, measured by endogenous thrombin potential (ETP) and peak of thrombin formation, was higher in plasma when triggered by EVs-enriched pellet from AAV patients. ETP and peak were associated with the levels of MPO+TF+ and MPO+H3Cit+ EVs. Additionally, MPO+TF+ EVs correlated with the disease activity evaluated with BVAS.ConclusionAugmented thrombin generation is found in AAV patients regardless of disease activity and is associated with higher exposure of TF and H3Cit on MPO+EVs. This may contribute to the increased risk of thrombosis seen in AAV patients.
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41.
  • Jonasdottir, A. D., et al. (author)
  • Pentraxin-3-a potential biomarker in ANCA-associated vasculitis
  • 2023
  • In: Scandinavian Journal of Rheumatology. - : Taylor & Francis Ltd. - 0300-9742 .- 1502-7732. ; 52:3, s. 293-301
  • Journal article (peer-reviewed)abstract
    • Objective The aim of this study was to investigate pentraxin-3 (PTX3) as a potential biomarker of inflammatory activity in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at baseline and 6 month follow-up in a longitudinal cohort. Method Plasma PTX3 levels were measured in 79 newly diagnosed or relapsing AAV patients at baseline and 6 month follow-up, and in 23 healthy controls. Urinary PTX3 levels were measured in 34 of the patients. C-reactive protein (CRP), creatinine, and albuminuria were measured and the cumulative glucocorticoid dose at inclusion was calculated. The Birmingham Vasculitis Activity Score (BVAS) was assessed at baseline and follow-up. Results Plasma PTX3 levels were significantly higher at baseline than at 6 months (2.85 vs 1.23 ng/mL, p < 0.001). Plasma and urinary PTX3 levels correlated with BVAS at baseline (rho = 0.45, p < 0.001, and rho = 0.49, p = 0.008, respectively). A significant correlation between both plasma and urinary PTX3 levels and estimated glomerular filtration rate and albuminuria was found. However, there was no correlation between plasma and urinary PTX3 levels. At baseline, plasma and urinary PTX3 levels were significantly higher in patients with kidney involvement. PTX3 levels did not correlate with CRP, nor was there a correlation between CRP levels and BVAS at baseline. Conclusion Plasma and urinary PTX3 seem to reflect disease activity in AAV better than the commonly used CRP. PTX3 may have a potential role as a biomarker in monitoring disease activity in AAV patients, particularly in patients with kidney involvement.
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42.
  • Kalantar-Zadeh, Kamyar, et al. (author)
  • Nomenclature in nephrology : preserving renal and nephro in the glossary of kidney health and disease
  • 2021
  • In: JN. Journal of Nephrology. - : SPRINGER HEIDELBERG. - 1121-8428 .- 1724-6059. ; 34:3, s. 639-648
  • Journal article (peer-reviewed)abstract
    • A recently published nomenclature by a "Kidney Disease Improving Global Outcomes" (KDIGO) Consensus Conference suggested that the word "kidney" should be used in medical writings instead of "renal" or "nephro" when referring to kidney disease and kidney health. Whereas the decade-old move to use "kidney" more frequently should be supported when communicating with the public-at-large, such as the World Kidney Day, or in English speaking countries in communications with patients, care-partners, and non-medical persons, our point of view is that "renal" or "nephro" should not be removed from scientific and technical writings. Instead, the terms can coexist and be used in their relevant contexts. Cardiologists use "heart" and "cardio" as appropriate such as "heart failure" and "cardiac care units" and have not replaced "cardiovascular" with "heartvessel", for instance. Likewise, in nephrology, we consider that "chronic kidney disease" and "continuous renal replacement therapy" should coexist. We suggest that in scientific writings and technical communications, the words "renal" and "nephro" and their derivatives are more appropriate and should be freely used without any pressure by medical journals to compel patients, care-partners, healthcare providers, researchers and other stakeholders to change their selected words and terminologies. We call to embrace the terms "kidney", "renal" and "nephro" as they are used in different contexts and ask that scientific and medical journals not impose terminology restrictions for kidney disease and kidney health. The choice should be at the discretion of the authors, in the different contexts including in scientific journals.
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43.
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44.
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45.
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46.
  • Kronbichler, Andreas, et al. (author)
  • Diagnosis and management of ANCA-associated vasculitis
  • 2024
  • In: The Lancet. - : ELSEVIER SCIENCE INC. - 0140-6736 .- 1474-547X. ; 403:10427
  • Research review (peer-reviewed)abstract
    • Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.
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47.
  • Kronbichler, Andreas, et al. (author)
  • Recommendations for the use of COVID-19 vaccines in patients with immune-mediated kidney diseases
  • 2021
  • In: Nephrology, Dialysis and Transplantation. - : OXFORD UNIV PRESS. - 0931-0509 .- 1460-2385. ; 36:7, s. 1160-1168
  • Research review (peer-reviewed)abstract
    • Coronavirus disease 2019 (COVID-19) vaccine platforms are becoming available and are the most promising strategy to curb the spread of severe acute respiratory syndrome coronavirus 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 of the European Renal Association-European Dialysis and Transplant Association discuss 13 frequently asked questions regarding the 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 disease activity following the administration of COVID-19 vaccines. Some of the candidates induce signalling pathways, which also promote autoimmune kidney diseases, e.g. type I interferons in systemic lupus erythematosus. Efficacy estimates would thus far favour 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 of reducing the 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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48.
  • Kronbichler, Andreas, et al. (author)
  • The COVID-19 pandemic and ANCA-associated vasculitis - reports from the EUVAS meeting and EUVAS education forum
  • 2021
  • In: Autoimmunity Reviews. - : Elsevier. - 1568-9972 .- 1873-0183. ; 20:12
  • Research review (peer-reviewed)abstract
    • The Coronavirus Disease 2019 (COVID-19) pandemic influenced the management of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A paucity of data exists on outcome of patients with vasculitis following COVID-19, but mortality is higher than in the general population and comparable to patients undergoing haemodialysis or kidney transplant recipients (reported mortality rates of 20-25%). Delays in diagnosis have been reported, which are associated with sequelae such as dialysis-dependency. Management of ANCA-associated vasculitis has not changed with the aim to suppress disease activity and reduce burden of disease. The use of rituximab, an important and widely used agent, is associated with a more severe hospital course of COVID-19 and absence of antibodies following severe acute respiratory syndrome (SARS)-CoV-2 infections, which prone patients to re-infection. Reports on vaccine antibody response are scarce at the moment, but preliminary findings point towards an impaired immune response, especially when patients receive rituximab as part of their treatment. Seropositivity was reported in less than 20% of patients when rituximab was administered within the prior six months, and the antibody response correlated with CD19+ B-cell repopulation. A delay in maintenance doses, if disease activity allows, has been suggested using a CD19+ B-cell guided strategy. Other immunosuppressive measures, which are used in ANCA-associated vasculitis, also impair humoral and cellular vaccine responses. Regular measurements of vaccine response or a healthcare-policy time-based strategy are indicated to provide additional doses ("booster") of COVID-19 vaccines. This review summarizes a recent educational forum and a recent virtual meeting of the European Vasculitis Society (EUVAS) focusing on COVID-19.
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49.
  • Levin, A., et al. (author)
  • The role of dendrin in IgA nephropathy
  • 2023
  • In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 38:2, s. 311-321
  • Journal article (peer-reviewed)abstract
    • Background Immunoglobulin A nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus, where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV. Methods Glomerular gene expression was measured using microarray on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IF) staining (IgAN patients, n = 4; nephrectomized kidneys, n = 3) and semi-quantified by immunogold electron microscopy (IgAN/IgAV patients, n = 21; MN, n = 5; living kidney donors, n = 6). Histopathological grading was performed according to the Oxford and Banff classifications. Clinical data were collected at the time of biopsy and follow-up. Results Dendrin mRNA levels were higher (P = .01) in IgAN patients compared with MN patients and controls and most prominently in patients with preserved kidney function and fewer chronic histopathological changes. Whereas IF staining did not differ between groups, immunoelectron microscopy revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with a slower annual progression rate and milder histopathological changes. Conclusion Dendrin messenger RNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.
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50.
  • Lundtoft, Christian, et al. (author)
  • The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population
  • 2024
  • In: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 10:2, s. 1-10
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.
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