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Was ist neu? Klinische, serologische, histopathologische Diagnostik der ANCA-assoziierten Vaskulitis Zentraler Bestandteil der Diagnostik der AAV mit renaler Manifestation sind die Bestimmung von PR3- und MPO-ANCA sowie die Nierenbiopsie. Die Behandlung sollte in einem in AAV erfahrenen Zentrum erfolgen und rasch begonnen werden. Remissionsinduktion Die Remissionsinduktion bei ANCA-assoziierter GN erfolgt mit Cyclophosphamid oder Rituximab in Kombination mit Kortikosteroiden. Die Leitlinie gibt Hilfestellung zur Therapieauswahl. Studienbasiert wird eine schnellere Steroidreduktion empfohlen. Remissionserhaltung Zur Remissionserhaltung stehen Rituximab und Azathioprin zur Verfügung. Die Leitlinie gibt Hilfestellung zu Auswahl und Dauer der Therapie, die sich insbesondere nach dem Rezidivrisiko richtet. Anti-GBM-Erkrankung Die Plasmapherese gehört zur Standardtherapie der Anti-GBM-Erkrankung, ist jedoch bei der ANCA-assoziierten GN einer Einzelfallentscheidung bei fulminantem Verlauf vorbehalten. Transplantation Eine Nierentransplantation kann bei ANCA-assoziierter GN nach mindestens 6-monatiger Remission unabhängig vom ANCA-Status erfolgen, bei Patienten mit Anti-GBM-Erkrankung nur nach negativem Antikörpernachweis.

Kidney disease represents an increasing global health problem. Its mitigation requires effective communication between all stakeholders involved in assessment, diagnosis and therapy and individuals affected by kidney disease. However, as of today the nomenclature for kidney function and kidney disease is far from uniform. In 2019, the international non-profit organization Kidney Disease: Improving Global Outcomes (KDIGO) has implemented a consensus process to develop a glossary in English language to standardize the nomenclature for kidney function, kidney structure and kidney disease. Guiding principles for this process were (1) precision, (2) patient-centeredness and (3) consistency with KDIGO guidelines. The current position paper includes a translation of this nomenclature into German that was developed on behalf of the national societies for nephrology in Germany, Austria and Switzerland.Nierenkrankheiten stellen ein zunehmendes Gesundheitsproblem dar, dessen Eindämmung eine effektive Kommunikation zwischen den an Erfassung, Diagnostik und Therapie Beteiligten sowie den betroffenen Patientinnen und Patienten erfordert. Die Nomenklatur für Nierenfunktion und Nierenkrankheiten ist jedoch bislang nicht einheitlich. Die internationale, gemeinnützige Organisation Kidney Disease: Improving Global Outcomes (KDIGO) hat deshalb 2019 in einem Konsensus-Prozess ein englischsprachiges Glossar entwickelt, um die Begriffe zur Beschreibung von Nierenfunktion, Nierenstruktur und Nierenkrankheiten zu vereinheitlichen. Leitprinzipien bei der Entwicklung dieser Nomenklatur waren (1) Präzision, (2) Patientenzentrierung und (3) Konsistenz mit bisherigen KDIGO-Leitlinien. Das vorliegende Positionspapier beinhaltet eine deutsche Übersetzung dieses Glossars, die im Auftrag der nephrologischen Fachgesellschaften in Deutschland, Österreich und der Schweiz entwickelt wurde.

The following report presents a 30-year-old male with an exceptional course of systemic sarcoidosis. He showed multiple organ threatening manifestations such as aortitis, which led to an aortic replacement-procedure twice, as well as asymptomatic neurosarcoidosis, severe chorioretinitis and vertebral granuloma. Complete diagnostic evaluation has been failed initially. After 4 years of exclusive prednisolone therapy, we reassessed the patient and initiated additional azathioprine-therapy. Chronic sarcoidosis reappeared with severe ophthalmic progression which required TNF-α blockade. Infliximab followed by adalimumab administration led to decline of manifestations of sarcoidosis as seen in follow-up cranial MRI-studies, by regressive chorioretinitis in both eyes and permanent low levels of serological markers of inflammation. Chronic sarcoidosis can be a severe systemic inflammatory disease that can involve any organ. Complete diagnostic evaluation including biopsy is necessary for a suitable treatment. Although there are no randomized controlled trials, we can confirm that TNF-α-agents can be a suitable treatment for severe chronic sarcoidosis.

ZusammenfassungDie Granulomatose mit Polyangiitis (GPA) und die mikroskopische Polyangiitis (MPA) stellen als primäre nekrotisierende Kleingefäßvaskulitiden die häufigsten ANCA-assoziierten Vaskulitiden dar. Bei diesen, früher oft tödlich verlaufenden Erkrankungen kann heute durch eine Stadien-adaptierte Immunsuppression in den meisten Fällen eine Remission erzielt werden. Diese mündet jedoch nicht in eine Heilung oder medikamentenfreie Langzeitremission. Es bedarf deshalb einer remissionserhaltenden Therapie. Aktuelle randomisierte kontrollierte Studien zeigen, dass unter einer remissionserhaltenden Behandlung mit halbjährlich verabreichtem anti-B-Zell-Antikörper Rituximab weniger Rezidive auftreten als unter der bisherigen Standardmedikation mit Azathioprin bei vergleichbarem Nebenwirkungsprofil. Diese Daten führten 2018 zur Zulassung von Rituximab als remissionserhaltende Therapie der GPA und MPA. Unter einer solchen Rituximab-Therapie muss mit einer Immunglobulindepletion sowie späten Zytopenien mit begleitenden Infekten gerechnet werden. Leitlinien und Expertenempfehlungen zu Infektprophylaxen, Impfungen und Immunglobulinsubstitution werden in diesem Beitrag vorgestellt.

In 2021 new KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the management of glomerular diseases were published.For ANCA-associated glomerulonephritis the new recommendations comprise a more rapid steroid taper during induction treatment with cyclophosphamide or rituximab, the advice against routine use of plasma exchange, the choice of drug for and duration of maintenance treatment in accordance with predictors of relapse. A kidney transplant should be performed after at least 6 months of remission irrespective of the ANCA titer in ANCA-associated disease, and 6 months after absence of anti-GBM-antibodies in anti-GBM-disease.KLINISCHE, SEROLOGISCHE, HISTOPATHOLOGISCHE DIAGNOSTIK DER ANCA-ASSOZIIERTEN VASKULITIS: Zentraler Bestandteil der Diagnostik der AAV mit renaler Manifestation sind die Bestimmung von PR3- und MPO-ANCA sowie die Nierenbiopsie. Die Behandlung sollte in einem in AAV erfahrenen Zentrum erfolgen und rasch begonnen werden.Die Remissionsinduktion bei ANCA-assoziierter GN erfolgt mit Cyclophosphamid oder Rituximab in Kombination mit Kortikosteroiden. Die Leitlinie gibt Hilfestellung zur Therapieauswahl. Studienbasiert wird eine schnellere Steroidreduktion empfohlen.Zur Remissionserhaltung stehen Rituximab und Azathioprin zur Verfügung. Die Leitlinie gibt Hilfestellung zu Auswahl und Dauer der Therapie, die sich insbesondere nach dem Rezidivrisiko richtet.Die Plasmapherese gehört zur Standardtherapie der Anti-GBM-Erkrankung, ist jedoch bei der ANCA-assoziierten GN einer Einzelfallentscheidung bei fulminantem Verlauf vorbehalten.Eine Nierentransplantation kann bei ANCA-assoziierter GN nach mindestens 6-monatiger Remission unabhängig vom ANCA-Status erfolgen, bei Patienten mit Anti-GBM-Erkrankung nur nach negativem Antikörpernachweis.

Due to advances in treatment, antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is no longer a universally fatal condition; however, difficulties remain in managing its chronic relapsing-remitting course. Current standard of care1 aims to control the multi-system damaging vasculitis but exposes patients to the risk of severe treatment toxicities in the short and long-term, particularly from high-dose or prolonged steroid use. Moreover, a lack of knowledge around disease recognition in real-world clinical practice often impedes patient access to the required specialist care. In this article, three experts in the field of AAV, Prof Annette Bruchfeld, Prof Kirsten de Groot, and Prof David Jayne, offer their views on the current status of disease assessment and management. In a series of interviews conducted by the European Medical Journal in June and July 2019, the experts identified present challenges and future goals, and discussed the impact of remission and relapse on patients with AAV. In particular, they voiced their concerns over the clinical risks of therapy versus sustained disease control and suggested how improvements in healthcare services and communication could transform patient care.

ZUSAMMENFASSUNGAphereseverfahren finden neben ihrem etablierten Einsatz in derTransplantations- und Transfusionsmedizin vor allem in der Therapie autoimmunologischer entzündlich-rheumatischer und neurologischer Erkrankungen zunehmende klinische Anwendung. Ihre grundsätzliche Funktionsweise liegt im Entzug pathophysiologisch wirksamer Blutbestandteile (v. a. IgG-Antikörper) und weiteren immunmodulatorischen Effekten. Mögliche Apheresemodalitäten sind die unselektive Plasmapherese mit nachfolgendem Ersatz des entzogenen Plasmas durch verschiedenartige Substituate sowie die selektivere Immunadsorption. Die Therapie ist logistisch aufwendig, jedoch für den Patienten nebenwirkungsarm.

Background Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective – studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period. Methods GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future. Discussion In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period. Trial registration German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866. Registered 10 May 2019.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most frequent primary necrotizing small vessel vasculitides. In these formerly fatal diseases remission can be induced by stage- and activity-adapted immunosuppressive regimens in the majority of patients. This does not lead to drug-free long-term remission or even cure. Consequently, maintenance of remission medication is needed. Recent randomized controlled trials demonstrated that maintenance treatment with the anti-B-cell antibody Rituximab, administered 6-monthly as opposed to azathioprine leads to a significantly lower relapse rate but a similar profile of adverse events. These data enabled the extension of the approval of Rituximab for maintenance of remission treatment of GPA and MPA in Germany in 2018. Guidelines and expert recommendations concerning measures of infection prevention and vaccination of immunosuppressed patients as well as the management of hypogammaglobulinemia and cytopenia on Rituximab are presented in this review.Die Granulomatose mit Polyangiitis (GPA) und die mikroskopische Polyangiitis (MPA) stellen als primäre nekrotisierende Kleingefäßvaskulitiden die häufigsten ANCA-assoziierten Vaskulitiden dar. Bei diesen, früher oft tödlich verlaufenden Erkrankungen kann heute durch eine Stadien-adaptierte Immunsuppression in den meisten Fällen eine Remission erzielt werden. Diese mündet jedoch nicht in eine Heilung oder medikamentenfreie Langzeitremission. Es bedarf deshalb einer remissionserhaltenden Therapie. Aktuelle randomisierte kontrollierte Studien zeigen, dass unter einer remissionserhaltenden Behandlung mit halbjährlich verabreichtem anti-B-Zell-Antikörper Rituximab weniger Rezidive auftreten als unter der bisherigen Standardmedikation mit Azathioprin bei vergleichbarem Nebenwirkungsprofil. Diese Daten führten 2018 zur Zulassung von Rituximab als remissionserhaltende Therapie der GPA und MPA. Unter einer solchen Rituximab-Therapie muss mit einer Immunglobulindepletion sowie späten Zytopenien mit begleitenden Infekten gerechnet werden. Leitlinien und Expertenempfehlungen zu Infektprophylaxen, Impfungen und Immunglobulinsubstitution werden in diesem Beitrag vorgestellt.

ZusammenfassungDas SAPHO-Syndrom ist eine seltene entzündliche Autoimmunerkrankung mit Befall von Haut, Gelenken und Knochen. Klassische Charakteristika der Erkrankung sind Gelenkentzündungen und Enthesitiden am axialen Skelett, an der ventralen Thoraxwand mit Enthesitis der Ligamenta costoclaviculares und Arthritiden der Sternocostalgelenke, Entzündungen von Wirbelkörpern und -gelenken, auch Bandscheiben und Iliosakralgelenken zusammen mit neutrophilen Dermatosen in Form von Acne conglobata, palmoplantarer Pustulose, Pyoderma gangraenosum u. a. Dazu können auch eine Osteitis und Osteomyelitis der Röhrenknochen (meist Femur oder Tibia) und Mono- oder Oligoarthritiden der unteren Extremitäten auftreten. Differenzialdiagnostisch sind Spondarthritiden und die chronisch rekurrierende multifokale Osteomyelitis nicht immer abzugrenzen.Radiologisch sind nach längerem Krankheitsverlauf Hyperostosen an betroffenen Gelenken, Wirbelkörpern und Röhrenknochen nachweisbar. Wie auch bei HLA-B27-assoziierten Spondylarthritiden kann es zu ankylosierenden Veränderungen der Iliosakralgelenke oder Wirbelsäule kommen. Für die Krankheitsentstehung spielen offenbar infektiöse Triggerfaktoren wie z. B. das Propionibacterium acnes eine Rolle, die zu einer überschießenden Immunantwort mit erhöhten Konzentrationen von IL-8, IL-18 und TNF-alpha i. S. führen. Die Entzündungen manifestieren sich dann in Form von sterilen Pseudoabszessen mit Infiltraten neutrophiler Granulozyten hauptsächlich im Bereich der Haut, am axialen Bewegungsapparat und z. T. an den unteren Extremitäten. Zur Diagnostik können im Frühstadium (Krankheitsbeginn Therapeutisch werden in erster Linie NSAR, bei längerfristig aktiven Arthritiden auch Colchicin oder klassische synthetische DMARDS wie Methotrexat, Sulfasalazin und Leflunomid eingesetzt. In der Behandlung der Osteitis sind gute Erfolge mit Bisphosphonaten erzielt worden. Des Weiteren haben sich TNF-alpha-Inhibitoren als längerfristig gut wirksam auf Haut- und Gelenkmanifestationen erwiesen.

Die Granulomatose mit Polyangiitis (GPA) gehort zu den ANCA(Anti-Neutrophile cytoplasmatische Antikorper)-assoziierten Kleingefasvaskulitiden (AAV) und befallt typischerweise den Respirationstrakt und die Nieren. Diese Kasuistik beschreibt einen 46-jahrigen GPA-Patienten mit einem selteneren Organbefallsmuster: Neben einer foudroyant verlaufenden Tetraparese zeigte sich eine schwere ulzerierende Kolitis. Die fruhzeitige Diagnose und die Abgrenzung zu einem septischen Geschehen sind essenziell.

Was ist neu? Stratifizierung ANCA-assoziierter Vaskulitiden (AAV) Da genetische Polymorphismen bei AAV stärker mit dem ANCA-Typ (Proteinase 3 [PR3], Myeloperoxidase [MPO]) als mit dem Krankheitsphänotyp (Granulomatose mit Polyangiitis [GPA] vs. Mikroskopische Polyangiitis [MPA)) assoziiert sind, tritt die phänotypische Unterscheidung zwischen GPA und MPA in den Hintergrund. PR3- und MPO-ANCA sind außerdem prädiktiv für therapeutisches Ansprechen und Rezidivwahrscheinlichkeit. ANCA-Immunfluoreszenztest (ANCA-IFT) Der ANCA-IFT ist zur Diagnostik von AAV zugunsten eines Festphasenimmunoassays auf die ANCA Zielantigene Proteinase 3 und Myeloperoxidase entbehrlich. Pathogenese Bestimmte Untergruppen neutrophiler Granulozyten verstärken und unterhalten die Immunreaktion bei AAV, indem sie extrazelluläre Chromatinnetze bilden (NETs), auf denen sie PR3 und MPO präsentieren. Management von AAV Es gibt eine aktuelle Leitlinie der europäischen rheumatologischen und nephrologischen Fachgesellschaften zum Management von Patienten mit AAV. Ein oraler Komplement-5a-Rezeptor-Inhibitor hat sich in einer Proof of Concept-Studie bei AAV als wirksam erwiesen. IL-5-Antikörper sind für die hypereosinophilen Syndrome zugelassen und damit ein neues Therapieprinzip für die refraktäre eosinophile Granulomatose mit Polyangiitis (EGPA). Biomarker Es sind Biomarker zur Ergänzung der bislang klinischen Einschätzung von Remission, Rezidiv und therapeutischem Ansprechen in der Entwicklung, wovon der lösliche CD163-Marker im Urin eine große Trennschärfe aufweist und Marktreife erlangen dürfte.

Granulomatosis with polyangiitis (GPA) is an ANCA(anti-neutrophil cytoplasmatic antibody)-associated small vessel vasculitis usually affecting the respiratory tract and the kidneys. This article reports on a 46-year-old male patient with a rare organ manifestation pattern of GPA: besides a fulminantly progressive tetraparesis the patient suffered from severe ulcerative colitis. The early diagnosis of GPA with unusual findings and its delineation from a septic event is essential.

Einleitung: Eine deutschsprachige Leitlinie zur Diagnostik und Therapie der ANCA-assoziierten Vaskulitiden sollte erstellt werden. Methoden: Eine Expertenkommission aus 13 Mitgliedern wurde von der DGRh mit der Erstellung der Leitlinie beauftragt. Für eine systematische Literaturrecherche wurden[zum vollständigen Text gelangen Sie über die oben angegebene URL], 45. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 31. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 27. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Objective Endothelial dysfunction, increased cardiovascular events (CVE), and accelerated atherosclerosis have been described in patients with small vessel vasculitis and collagen vascular disease. Identifying predictors of cardiovascular risk will help to optimize short- and long-term care of patients with vasculitis. The present study investigates the predictive role of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its stereoisomer symmetric dimethylarginine (SDMA) for cardiovascular risk, all-cause mortality, and renal function in patients with anti-neutrophil-cytoplasmic antibodies-associated small vessel vasculitis (AASV) subjected to standardized treatment regimens in four European Vasculitis Study Group trials representing all stages of renal disease. Methods Sera from 89 patients with AASV were available for measuring SDMA, ADMA, and arginine using liquid chromatography/mass spectrometry at the time of active disease and remission. Clinical data on disease activity, remission, relapse rate, and 5-year follow-up data for CVE and renal outcome were collected. Results Symmetric dimethylarginine and ADMA levels were not predictive of CVE at 5 years of follow-up. The overall CVE rate was low in the present cohort of AASV (8%). However, SDMA, and not ADMA, levels were significantly associated with poorer survival (death/ESRD) independent of entry glomerular filtration rate. Conclusion This novel outcome in a well-defined group of patients with AASV might indicate a different mechanism of endothelial response in AASV as compared with atherosclerosis. This should be further explored in a larger cohort of AASV patients with a higher CVE rate and/or a longer follow-up. Moreover, these findings should be correlated to other markers of vascular damage.

A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis.One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 μmol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival.Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.ISRCTN13739474.

BACKGROUND: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity. OBJECTIVE: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission. DESIGN: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment. SETTING: 42 centers in 12 European countries. PATIENTS: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease. INTERVENTION: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone. MEASUREMENT: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes). RESULTS: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]). LIMITATIONS: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited. CONCLUSION: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia. PRIMARY FUNDING SOURCE: The European Union.

Objective The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibodyassociated vasculitis. Duration of relapse-free survival was longer among CYC-treated patients than among MTX-treated patients during short-term followup. The aim of the present study was to describe the long-term outcome in patients enrolled in the randomized clinical trial. Methods Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC-treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse-free survival, mortality, and occurrence of other clinical events. Results The median duration of followup was 6 years (range 0.110.8 years). One patient developed end-stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse-free survival tended to be lower in the MTX group (P = 0.056). Conclusion In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long-term followup. However, first-line treatment with MTX was associated with less effective disease control than CYC-based induction therapy. (Less)

Background Atherosclerosis is an inflammatory process mediated by circulating immune cells, including monocytes. There is accumulating evidence for the involvement of Toll-like receptor 4 (TLR-4) as a mediator of atherogenesis. Methods We evaluated the association between CD14+/TLR-4+ monocytes in peripheral blood (flow cytometry) and future cardiovascular events (CVE), e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aortocoronary bypass, stroke and angiographically verified stenosis of peripheral arteries and cardiovascular (CV) death, in 191 patients with chronic kidney disease Stage V receiving hemodialysis therapy. Results At baseline, CD14+/TLR-4+ monocytes correlated significantly with age (r = 0.2; P = 0.007), high-sensitivity C-reactive protein (r = 0.2; P = 0.008) and mean arterial pressure (r = -0.2; P = 0.02), but not with gender (P = 0.5), smoking (P = 0.6) and the presence of diabetes (P = 0.5). During a median follow-up period of 36 [1-54] months, 79 (41%) patients experienced a CVE. A total of 55 patients died during the follow-up period, 25 of those due to a confirmed CV cause. Log-rank test did not reveal statistical significance for TLR-4+ monocytes concerning incident CVE (P = 0.3), CV death (P = 0.85) and overall death (P = 0.8). In a multiple Cox-regression analysis, we identified age (P = 0.003) and smoking (P = 0.001) as the only independent variables associated with incident CVE. Conclusions Unexpectedly, we could not detect an association between CD14+/TLR-4+ monocytes and incident CVE as well as CV death in stable hemodialysis patients. Further studies have to clarify the potential role of this cell population for CV outcome in this population.

Background: Toll-like receptors (TLR) modulate the immune response. We analyzed the relationships between TLR expression in renal tissue with infection, rejection and graft function after kidney transplantation. Methods: TLR-2 and TLR-4 expression was detected by immunohistochemistry in 257 protocol biopsies obtained 6 weeks, 3 and 6 months after transplantation, and in 108 indication biopsies. We correlated TLR expression in different renal tissue compartments with kidney transplant function 6, 12 and 24 months after transplantation, acute cellular rejection in renal grafts (according to the Banff classification), and urinary tract and cytomegalovirus infections. Results: We found a highly consistent correlation of TLR-2 expression in proximal and distal tubules, and in renal vessels (p < 0.001 for all compartments), but not for TLR-4 expression. This holds true for all protocol biopsy time points as well as for indication biopsies. Positive TLR-2 expression in renal tubules was associated with significantly (p < 0.05) better initial graft function as well as graft function 6, 12 and 24 months after transplantation. We also found a significant (p < 0.05) association between TLR-2 expression and lower incidence of acute cellular rejection in early protocol biopsies (6 weeks). In contrast, positive TLR-4 expression was not related to kidney function or acute cellular rejection. Further, the two different TLR subtypes were not related to episodes of urinary tract or cytomegalovirus infections. Conclusion: TLR-2 expression in renal tissue is associated with superior graft function up to 2 years after kidney transplantation. The role of TLR-2 in the immune response against human kidney transplants warrants further investigation.

Podocyte apoptosis initiates progressive glomerulosclerosis in TGF-beta1 transgenic and CD2AP-knockout (CD2AP-/-) mice. It was previously shown that in both mouse models, activation of the TGF-beta pathway is the key event during development of podocyte apoptosis. Furthermore, CD2AP is an important modifier of TGF-beta-induced survival signaling via activation of the phosphoinositol 3-kinase/AKT signaling pathway. This article presents IGF-binding protein-3 (IGFBP-3) as a new modulator of apoptosis and survival signaling in glomerular podocytes. High expression of IGFBP-3 protein in the urine of diseased CD2AP-/- mice was discovered, and IGFBP-3 expression in glomerular podocytes and parietal cells was detected. IGFBP-3 can induce changes in podocyte actin cytoskeleton, leads to apoptosis in cultured murine podocytes, and can enhance TGF-beta1-induced apoptosis in vitro. For studying this process on a molecular level, proapoptotic p38 mitogen-activated protein kinase pathways and antiapoptotic phosphoinositol 3-kinase/AKT pathways were examined in cultured murine podocytes. It was found that IGFBP-3 increments the level of TGF-beta1-induced phosphorylated p38 mitogen-activated protein kinase and decreases the phosphorylation of antiapoptotic AKT. This effect is specific for the co-stimulation of IGFBP-3 with TGF-beta1 because a combination of IGFBP-3 with bone morphogenic protein-7 (BMP-7), another member of the TGF-beta superfamily, results in apoptosis opposing signaling effects with a strong increase of phosphorylated AKT and subsequent functional effects. These results demonstrate that the IGF/IGFBP axis plays an important role in the development of podocyte apoptosis by modulation of TGF-beta and BMP-7-induced pro- and antiapoptotic signals.

The number of circulating endothelial progenitor cells (EPCs) correlates with endothelial dysfunction and cardiovascular risk in humans. We explored whether angiotensin II receptor antagonist therapy affects the number of regenerative EPCs in patients with type 2 diabetes. In a prospective double-blind parallel group study, we randomly treated 18 type 2 diabetics with olmesartan (40 mg) or placebo for 12 weeks. We analyzed circulating CD34 + hematopoietic progenitor cells (flow cytometry) and EPCs (in vitro assay) before and after therapy. We verified the results in a second open trial treating 20 type 2 diabetics with 300 mg of irbesartan for 12 weeks. The number of EPCs was significantly lower in diabetic patients as compared with 38 age-matched healthy subjects (210±10 versus 258±18 per high-power field; P P P P

Background— The hematopoietic cytokine erythropoietin has cytoprotective effects in endothelial cells in vitro that are mediated through direct activation of the pro-survival Akt tyrosine kinase signaling pathway. We tested the hypothesis that low-dose therapy with the long-acting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in vivo in a classic remnant kidney rat model characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis. Methods and Results— Using a parallel group study design, we randomly assigned animals after 5/6 nephrectomy to treatment with either saline (n=36) or 0.1 μg/kg body wt darbepoetin (n=24) subcutaneously once weekly. We monitored hematocrit, blood pressure, and serum creatinine regularly and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Darbepoetin-treated animals had significantly improved survival compared with saline-treated controls (63% versus 33%; P P Conclusions— Low-dose darbepoetin treatment confers vascular and tissue protection that is associated with persistent stimulation of the pro-survival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure.

Uremia causes endothelial progenitor cell deficiency.BackgroundCirculating bone marrow–derived endothelial progenitor cells (EPCs) promote vascular repair. Their number in peripheral blood correlates with endothelial function and cardiovascular risk in humans. We explored whether uremia influences the number of EPCs.MethodsWe assessed circulating CD34+ hematopoietic progenitor cells in whole blood using flow cytometry and EPCs (in vitro assay) in 46 patients with advanced renal failure and in 46 age- and gender-matched healthy subjects. Further, the effect of uremia on EPC differentiation was studied in vitro and in vivo.ResultsBoth in renal patients (r = 0.34, P < 0.02) and in healthy subjects (r = 0.32, P = 0.04) the number of EPCs was significantly correlated to the absolute number of CD34+ hematopoietic progenitor cells. Renal patients had significantly fewer EPCs than healthy subjects, however (167 ± 15 cells/high power field vs. 235 ± 17 cells/high power field; P < 0.05). Uremic serum significantly (P < 0.05) inhibited EPC differentiation and functional activity in vitro. Amelioration of uremia after institution of renal replacement therapy in patients with terminal renal failure also significantly (P < 0.05) increased the number of EPCs.ConclusionUremia inhibits differentiation of EPCs. This may impair cardiovascular repair mechanisms in patients with renal failure.

Background The study aimed at studying efficacy and adverse effects of pulse cyclophosphamide (pCyc) treatment and to compare it to continuous cyclophosphamide (cCyc) for induction of remission in ANCA-associated vasculitides from data in the published literature. Methods A Medline search identified 14 studies, containing more than five patients. From the 11 non-randomized studies, data on outcome following pCyc treatment were extracted. Results were given as fraction of the number of evaluable patients. A meta-analysis was performed on the three prospective, randomized controlled trials to compare outcomes concerning remission, relapses, infection, leucopenia, death and renal failure in patients treated with pCyc as opposed to cCyc. Results The 11 non-randomized studies comprised 202 patients receiving pCyc. Cyc pulses of 375-1000 mg/sqm/pulse were applied at weekly to monthly intervals with different concomitant prednisolone regimens and variable adjunctive therapy. Complete remission was achieved in 112/191, partial remission in 23/191 evaluable patients. Relapses occurred in 68/135 patients, 40/115 patients were non-responders. Leucopenia, infections, haemorrhagic cystitis, and deaths were rare. The meta-analysis, comprising 143 patients, showed that pCyc compared with cCyc treatment was significantly less likely to fail to induce remission (OR 0.29; 95% CI 0.12-0.73) and had a significantly lower risk of infection (OR 0.45; 95% CI 0.23-0.89) and leucopenia (OR 0.36; 95% CI 0.17-0.78). Relapses occurred slightly, although not statistically significantly, more often under pCyc treatment (OR 1.79; 95% CI 0.85-3.75). There were no differences in end-stage renal failure or deaths between the two regimens. Conclusions The currently available, rather sparse data show that pCyc is less toxic than cCyc therapy and is an at least equally potent inductor of remission, but possibly at the expense of a higher relapse rate. The existing data do not give sufficient information on outcomes as time to remission and relapse, irreversible damage or quality of life without which a treatment regimen cannot satisfactorily be evaluated today. A large prospective randomized controlled trial is needed to address these issues and their relative importance.

Available evidence suggests that rituximab may be safe and effective for the treatment of refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Two studies now show that rituximab is not less effective than cyclophosphamide for treating ANCA-associated vasculitides. Should rituximab be the new standard of care for patients with ANCA-associated vasculitis?

Antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases are small-vessel vasculitides, encompassing granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Once considered life-threatening diseases, the introduction of stage-adapted immunosuppressive therapy and medications with decreased toxicity has improved patients' survival. Treatment is biphasic, consisting of induction of remission (3-6 months) for rapid control of disease activity and maintenance of remission (at least 18 months) to prevent disease relapse using therapeutic alternatives that have reduced toxicity. This Review summarizes current treatment strategies for these diseases, with a special focus on long-term follow-up data from key randomized controlled trials and new developments in remission induction and maintenance therapy. Current treatment strategies have substantial short-term and long-term adverse effects, and relapses are frequent; thus, less-toxic and more-effective approaches are needed. Moreover, the optimal intensity and duration of maintenance therapy remains under debate. Clinical trials have traditionally considered ANCA-associated vasculitides as a single disease entity. However, future studies must stratify participants according to their specific disease, clinical features (different types of organ manifestation, PR3-ANCA or MPO-ANCA positivity) and disease severity.

Circulating endothelial cells (CECs) were first detected in the 1970s although convenient techniques to isolate them have only recently become available [1]. These cells have now been shown to be present in a variety of vascular disorders but only a few reports have appeared since the mid-1990s. Very recently we were able to demonstrate grossly elevated numbers of CECs as a novel marker of disease activity in patients with ANCA-associated vasculitis [2]. It appears that this approach to vascular injury has not been appreciated so far and that its use should be evaluated in other vascular disorders as well.

Background Endothelial progenitor cells (EPCs) mediate vascular repair and regeneration. Their number in peripheral blood is related to cardiovascular events in individuals with normal renal function. Methods We evaluated the association between functionally active EPCs (cell culture) and traditional cardiovascular risk factors in 265 patients with chronic kidney disease stage V receiving hemodialysis therapy. Thereafter, we prospectively assessed cardiovascular events, e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aorto-coronary bypass, stroke and angiographically verified stenosis of peripheral arteries, and cardiovascular death in this cohort. Results In our patients EPCs were related only to age (r = 0.154; p = 0.01). During a median follow-up period of 36 months 109 (41%) patients experienced a cardiovascular event. In a multiple Cox regression analysis, we identified EPCs (p = 0.03) and patient age (p = 0.01) as the only independent variables associated with incident cardiovascular events. Moreover, a total of 70 patients died during follow-up, 45 of those due to cardiovascular causes. Log rank test confirmed statistical significance for EPCs concerning incident cardiovascular events (p = 0.02). Conclusions We found a significant association between the number of functionally active EPCs and cardiovascular events in patients with chronic kidney disease. Thus, defective vascular repair and regeneration may be responsible, at least in part, for the enormous cardiovascular morbidity in this population.

Extended daily dialysis (EDD) is increasingly popular in the treatment of acute renal failure (ARF). EDD could remove drugs to a much different degree compared with intermittent standard hemodialysis or continuous renal replacement therapies; however, there are only scarce data on how EDD influences the pharmacokinetics of frequently used drugs. The aim of this study was to determine the pharmacokinetics of two quinolone antibiotics in patients who had anuric ARF and were being treated with EDD. Adult patients who were in the intensive care unit at a tertiary care university hospital and receiving moxifloxacin (n = 10) or levofloxacin (n = 5) therapy were included. The antibiotics were administered intravenously 8 h (400 mg of moxifloxacin) or 12 h (500 mg of levofloxacin) before EDD to study pharmacokinetics off and on EDD. Treatment lasted 8 h; blood and dialysate flow rates were 160 ml/min. In addition to standard pharmacokinetic parameters, the total dialysate concentration of both drugs was measured using a technically simple single-pass batch dialysis system for EDD. Moxifloxacin pharmacokinetics in critically ill patients who had ARF and were undergoing EDD were similar to those in healthy subjects without renal impairment. Levofloxacin, although removed by EDD, had a lower total clearance compared with healthy subjects. According to these findings, anuric critically ill patients who are undergoing EDD should be treated with the standard dosage of moxifloxacin (400 mg/d intravenously). The levofloxacin dosage, however, should be reduced according to the intensity of renal replacement therapy.

In formulating a clear and succinct answer to the question posed by this Viewpoint, the authors highlight several important considerations. They discuss how the choice of induction agent, the presence of risk factors for relapse and the definition of remission can influence the timing of the switch to maintenance therapy and/or the duration of maintenance treatment in patients with ANCA-associated vasculitis.