Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle. Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80. Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite. In addition, the ability of DCs to initiate T-cell proliferation and to produce the proinflammatory cytokines IL-12 and tumour necrosis factor-α was markedly impaired by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-κB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M. These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of leflunomide in inflammatory diseases, including RA.

Used hemodialysis membranes (HD-M) are a valuable reservoir of biological information. Proteins bind to HD-M, but whether this process depends on the type of membrane or patient factors or selectively affects specific protein classes has not been adequately elucidated. State-of-the-art proteomics techniques are capable of identifying and quantifying this therapy-specific subproteome to enable the analysis of disease- or membrane-induced pathophysiologies. We demonstrate the feasibility of the deep proteomic characterization of the extracorporeal proteome adsorbed to HD-M. A shotgun proteomics approach using nano-flow liquid chromatography coupled to mass-spectrometry identified 1648 unique proteins eluted by a chaotropic buffer from the HD-M of eight patients. In total, 995 proteins were present in all eluates; a more stringent approach showed that a core proteome of 310 proteins could be identified independently in all samples. Stability of the dialyzer proteome was demonstrated by a >90% re-identification rate on longitudinal samples of a single patient. The core proteome showed an overrepresentation of pathways of hemostasis and the immune system, and showed differences in membrane materials (polysulfone vs. helixone). This study demonstrates that optimized conditions combined with high-performance proteomics enable the in-depth exploration of the subproteome bound to HD-M, yielding a stable core proteome that can be exploited to study patient-specific factors and improve hemodialysis therapy.

SARS-CoV-2 led to considerable morbidity/mortality worldwide and tremendously impacted on daily life. Strict lockdown measures were implemented early to contain the viral outbreak in Austria. Massive changes in organizational structures of healthcare facilities followed with unclear implications on the care of non-COVID-19-affected patients. We studied the nationwide impact of COVID-19 on kidney transplantation in Austria during the first six months of 2020. Concurrent with general lockdown measures, all kidney transplant activity was suspended from 13 March to 9 April. Nevertheless, between January and June, total transplant (p = 0.48) and procured donor organ numbers (p = 0.6) did not differ significantly from earlier years. Ten (0.18%) of 5512 prevalent Austrian kidney transplant recipients were diagnosed with SARS-CoV-2. The case fatality rate (one death; 10%) in renal transplant patients was less than in other countries but higher than in Austria’s general population (2.4%). We conclude that early and strict general lockdown measures imposed by the government allowed an early, however cautious, re-opening of Austrian transplant programs and played a crucial role for the favorable outcomes of SARS-CoV-2 in Austrian kidney transplant patients. Even though it may be uncertain whether similar results may be obtainable in other countries, the findings may support early intervention strategies during similar episodes in the future.

Purpose of review: With the aging population of kidney transplant candidates, a history of malignancy is an increasingly prevalent finding. Tumors can constitute a contraindication for transplantation or can lead to a delay of acceptance to the waiting-list. Current waiting time guidelines mainly refer to early data collected nearly 30 years ago, when the knowledge on tumors was, by current standards, still limited. Recent findings: Today, cancers can usually be divided into many different biological subtypes, according to histological and molecular subclassification and the availability of genetic testing. A more precise stratification and targeted antitumor therapies have led to better therapy outcomes or even cures from certain malignancies and to a better appreciation of tumor risks for the patient. Summary: Even though transplant patients do have an increased risk for malignancies, it is often overlooked that patients, while on dialysis, are equally prone to develop a tumor. Competing risks (e.g. cardiovascular, mortality risks) through prolonged time on dialysis have to be equally considered, when the decision for acceptance of a patient to the waiting-list is made. Current waiting time suggestions should be critically reconsidered for every patient after a thorough discussion with an oncologist, including new diagnostic and therapeutic strategies, as well as novel risk stratifications.

Zusammenfassung: Es ist bis heute unklar, welche kardialen Untersuchungen bei Patienten mit Niereninsuffizienz in Vorbereitung auf eine Nierentransplantation durchgeführt werden sollen. Das hohe kardiovaskuläre Risiko von Nierenpatienten bedingt allerdings eine Abklärung vor dem geplanten Eingriff. Während manche Zentren bei den vorgesehenen Untersuchungen sehr zurückhaltend sind, schlagen andere eine invasive Untersuchung mittels Koronarangiographie vor. Eine konsequente Einschätzung der Vortestwahrscheinlichkeit einer kardialen Pathologie sollte vor der Testauswahl erfolgen, um unnötige nichtinvasive Test bei Hochrisikopatienten zu vermeiden. Wird schließlich eine koronare Herzerkrankung nachgewiesen, sind weitere Frage nach der adäquaten Versorgung der kritischen Koronarläsionen zu klären, obwohl eine breite evidenzbasierte Datenlage dazu noch nicht existiert. Ob einer konservativen Behandlung oder einer Sanierung mittels Angioplastie/Stenting bzw. einer Bypassoperation der Vorzug gegeben wird, hängt von der Ausprägung der Koronarerkrankung ab und muss in Absprache mit Kardiologen und Herzchirurgen festgelegt werden.