IgA-Nephropathie: Die häufigste Glomerulonephritis-Form

Zusammenfassung: Die IgA-Nephropathie (IgAN) ist die weltweit häufigste primäre Glomerulopathie. Meist manifestiert sie sich in der Adoleszenz oder im frühen Erwachsenenalter als wiederkehrende Makrohämaturie (oft getriggert durch einen Infekt der oberen Atemwege bzw. starke körperliche Anstrengung) oder als persistierende Mikrohämaturie, milde Proteinurie, arterielle Hypertonie und/oder Niereninsuffizienz. Sie wird häufig zufällig diagnostiziert. Viele Fälle bleiben wahrscheinlich unentdeckt. In Autopsieserien wird häufig IgA in den Glomeruli nachgeweisen [3, 4], wobei es meist Ablagerungen sind ohne dass eine manifeste IgAN bestanden hat. Nahezu 30% der Patienten leiden an einer chronischen, langsam progredienten Niereninsuffizienz. Die hauptsächlichen prognostischen Faktoren für die Progression der Nephropathie sind der Schweregrad der Niereninsuffizienz zum Zeitpunkt der Diagnose, der Grad der Proteinurie und das Vorliegen einer arteriellen Hypertonie. Eine frühe Identifikation des Vorliegens von Risikofaktoren ist entscheidend, da durch gezielte therapeutische Maßnahmen das Fortschreiten der Niereninsuffizienz vermindert werden kann. Die Nierentransplantation ist trotz der Rezidivrate der IgAN (bis zu 40% innerhalb von 5 Jahren) eine gute Therapieoptio

Time trends in the epidemiology of renal transplant patients with type 1 diabetes mellitus over the last four decades

Background. Diabetes mellitus (DM) type 1 is an important contributor to end-stage renal disease (ESRD) among younger transplant recipients. However, little is known about the changes in epidemiological characteristics of this population. Especially, time to reach ESRD may have changed in type 1 diabetic patients referred for transplantation, resulting in higher age at time of grafting. Such time trends may allow anticipating future developments regarding the demand for organ replacement in this patient group. Methods. We retrospectively analysed 173 patients with type 1 DM undergoing renal transplantation at our institution, stratified into four groups according to year of reaching ESRD (A = 1973-1983, B = 1984-1990, C = 1991-1995 and D = 1996-2002). For each group we determined age at diagnosis of DM, age at time of reaching ESRD and age at time of transplantation. From these data, the interval from diagnosis of DM to ESRD and from ESRD to transplantation was calculated. The results were analysed in relation to gender, year of and age at onset of diabetes. Results. Patients reaching ESRD in more recent years (group D) tended to be both younger at diagnosis of DM and older when reaching ESRD, resulting in higher mean age at transplantation (35.0, 37.5, 39.6 and 41.0 years in groups A, B, C and D, respectively). Accordingly, median duration to ESRD has significantly been prolonged over the last five decades in patients with type 1 DM undergoing renal transplantation (group A: 21.0, B: 20.7, C: 22.3 and D: 28.5 years; P<0.0001), this finding being more pronounced in female patients. Conclusions. The results of our analysis are compatible with a change in epidemiology in patients undergoing kidney transplantation. Older age at time of reaching ESRD may impact significantly on the demand for renal grafts, as patients are already clearly older nowadays when being transplanted. From our data it cannot be concluded whether this development is due to a change in the progression of diabetic nephropathy or may simply reflect a change in the selection of type 1 diabetic patients referred for transplantatio

Hepatitis-B- und -C-assoziierte Glomerulonephritiden

Zusammenfassung: Virale Hepatitiden sind häufig mit extrahepatischen Manifestationen assoziiert. Bei der HepatitisB ist die membranöse Glomerulonephritis (GN) die häufigste histologische Diagnose. Im Rahmen der HepatitisC wird vorwiegend eine membranoproliferative GN mit oder ohne gemischte Kryoglobulinämie beobachtet. Eine zentrale pathogenetische Rolle spielen Immunkomplexe (virale Antigene, antivirale Antikörper, bei Kryoglobulinämie auch Rheumafaktoren). Diese Komplexe werden in der Niere abgelagert und aktivieren Komplement, was schließlich zum Nierenschaden führt. Therapeutisch zentral ist die antivirale Therapie mit dem Ziel der Antigenelimination. Im Falle der HepatitisB kann eine Therapie mit IFNα durchgeführt werden, alternativ mit Lamivudin. Eine immunsuppressive Therapie steht eher im Hintergrund. Bei der HepatitisC ist die Standardtherapie IFNα in Kombination mit Ribavirin. Bei einer zusätzlichen Kryoglobulinämie besteht die Alternative einer Therapie mit Rituximab, bei schwerem Verlauf mit Plasmapherese, Steroiden und Cyclophosphamid. Bei vollständiger Elimination der Virusreplikation ist die Prognose dieser sekundären GN günsti

Incidence of glomerulonephritis in the western part of Switzerland over the last decade.

Glomerulonephritis is a rare yet serious group of diseases with a high risk of progression to end-stage renal disease. For optimal healthcare planning, detailed epidemiological and demographic data are essential. Despite their clinical relevance, these data are largely lacking in Switzerland. The objective of this study was to assess the incidence of the different forms of glomerulonephritis in the western part of Switzerland and its changes over the last 10 years, compared with international data. We listed all renal biopsy reports analysed between 2007 and 2016 at the University hospital of Lausanne, the renal pathology reference centre of all hospitals in the cantons of Vaud, Fribourg, Valais and Neuch&amp;acirc;tel. Biopsies with a first diagnosis of primary glomerulonephritis were included in the analysis. The incidence was calculated as the number of patients newly diagnosed with glomerulonephritis divided by the number of inhabitants of all the above-mentioned cantons during the year under review, as retrieved from the federal statistical office of Switzerland. We collected biopsy reports from 864 patients between 2007 and 2016; 168 biopsies met the inclusion criteria. The most common primary glomerulonephritis was IgA nephropathy at 32.7% of cases, followed by lupus nephritis (29.8%) and pauci-immune glomerulonephritis (11.9%). Overall, the mean incidence of glomerulonephritis was 1.3/100,000/year. Between 2007 and 2016, the incidence of all glomerulonephritis taken together remained stable. The same was true for the incidence of IgA nephropathy, lupus nephritis and pauci-immune glomerulonephritis. In contrast, we observed a trend towards higher creatinine levels, proteinuria and degree of interstitial fibrosis at diagnosis. The incidence of glomerulonephritis in the western part of Switzerland was low and remained stable over time, in line with European data

A general lower bound for collaborative tree exploration

We consider collaborative graph exploration with a set of $k$ agents. All agents start at a common vertex of an initially unknown graph and need to collectively visit all other vertices. We assume agents are deterministic, vertices are distinguishable, moves are simultaneous, and we allow agents to communicate globally. For this setting, we give the first non-trivial lower bounds that bridge the gap between small ($k \leq \sqrt n$) and large ($k \geq n$) teams of agents. Remarkably, our bounds tightly connect to existing results in both domains. First, we significantly extend a lower bound of $\Omega(\log k / \log\log k)$ by Dynia et al. on the competitive ratio of a collaborative tree exploration strategy to the range $k \leq n \log^c n$ for any $c \in \mathbb{N}$. Second, we provide a tight lower bound on the number of agents needed for any competitive exploration algorithm. In particular, we show that any collaborative tree exploration algorithm with $k = Dn^{1+o(1)}$ agents has a competitive ratio of $\omega(1)$, while Dereniowski et al. gave an algorithm with $k = Dn^{1+\varepsilon}$ agents and competitive ratio $O(1)$, for any $\varepsilon > 0$ and with $D$ denoting the diameter of the graph. Lastly, we show that, for any exploration algorithm using $k = n$ agents, there exist trees of arbitrarily large height $D$ that require $\Omega(D^2)$ rounds, and we provide a simple algorithm that matches this bound for all trees

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression. Keywords: EWS-FLI1; Ewing sarcoma; Fimepinostat; HDACi; Protein stabilit

Psychological response and quality of life after transplantation: a comparison between heart, lung, liver and kidney recipients

PRINCIPLES: Various non-specific questionnaires were used to measure quality of life and psychological wellbeing of patients after organ transplantation. At present cross-organ studies dealing specifically with the psychological response to a transplanted organ are non-existent in German-speaking countries. METHODS: The Transplant Effects Questionnaire TxEQ-D and the SF-36 Quality of Life Questionnaire were used to examine the psychological response and quality of life of 370 patients after heart, lung, liver or kidney transplantation. The organ groups were compared with regard to psychosocial parameters. RESULTS: 72% of patients develop a feeling of responsibility for the received organ and its function. This feeling is even stronger towards the patient's key relationships i.e. family, friends, the treatment team and the donor. 11.6% worry about the transplanted organ. Heart and lung patients report significantly fewer concerns than liver and kidney patients. Overall, only a minority of patients report feelings of guilt towards the donor (2.7%), problems in disclosing their transplant to others (2.4%), or difficulties in complying with medical orders (3.5%). Lung transplant patients show significantly better adherence. CONCLUSIONS: A feeling of responsibility towards those one is close to and towards the donor is a common psychological phenomenon after transplantation of an organ. Conscious feelings of guilt and shame are harboured by only a minority of patients. The fact that heart and lung patients worry less about their transplant might have primarily to do with the greater medical and psychosocial support in this group

Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-replete haemodialysis patients

Background. Haemodialysis patients need sustained treatment with intravenous iron because iron deficiency limits the efficacy of recombinant human epoetin therapy in these patients. However, the optimal intravenous iron maintenance dose has not been established yet. Methods. We performed a prospective multicentre clinical trial in iron-replete haemodialysis patients to evaluate the efficacy of weekly low-dose (50 mg) intravenous iron sucrose administration for 6 months to maintain the iron status, and to examine the effect on epoetin dosage needed to maintain stable haemoglobin values in these patients. Fifty patients were enrolled in this prospective, open-label, single arm, phase IV study. Results. Forty-two patients (84%) completed the study. After 6 months of intravenous iron sucrose treatment, the mean ferritin value showed a tendency to increase slightly from 405 ± 159 at baseline to 490 ± 275 µg/l at the end of the study, but iron, transferrin levels and transferrin saturation did not change. The haemoglobin level remained stable (12 ± 1.1 at baseline and 12.1 ± 1.5 g/dl at the end of the study). The mean dose of darbepoetin alfa could be reduced from 0.75 to 0.46 µg/kg/week; epoetin alfa was decreased from 101 to 74 IU/kg/week; and the mean dose of epoetin beta could be reduced from 148 to 131 IU/kg/week at the end of treatment. Conclusions. A regular 50 mg weekly dosing schedule of iron sucrose maintains stable iron stores and haemoglobin levels in haemodialysed patients and allows considerable dose reductions for epoetins. Low-dose intravenous iron therapy may represent an optimal approach to treat the continuous loss of iron in dialysis patient

Corrigendum to "Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization" [Neoplasia volume 27 (2022) pp. 100784/Number C]

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered “undruggable”. An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression