Christoph Aufricht

Background: Peritoneal dialysis (PD) effluent of kidney failure patients represents an accessible liquid biopsy of the peritoneal cavity, yet the mechanisms determining its molecular composition remain poorly understood. We applied an integrative multi-omics approach to characterize the composition, transport dynamics, and molecular origin of the PD effluentome. Methods: Cell-free effluent, effluent cells, and plasma were collected from stable PD patients during standardized peritoneal equilibration tests in a randomized clinical trial. Targeted metabolomics, proteomics, and transcriptomic profiling were integrated with a reference human plasma proteome to investigate temporal molecular changes, peritoneal transport characteristics, and protein origin. Results: A total of 207 metabolites and 2970 proteins were identified in PD effluent. Metabolites exhibited distinct class-specific transport kinetics, with rapid equilibration of amino acids and biogenic amines, whereas lipids remained markedly underrepresented despite prolonged dwell times, indicating that transport is governed by physicochemical properties beyond molecular size alone. The effluent proteome underwent concordant alteration, with dwell time-dependent enrichment of pathways related to extracellular matrix organization, angiogenesis, coagulation, and tissue repair. Integrative analysis of the effluent proteome, effluent-cell transcriptome, and human plasma proteome resolved distinct plasma-associated, effluent cell-associated, resident peritoneal tissue-associated, and mixed-origin protein populations. Conclusions: This study establishes the first systems-level approach describing the composition, transport dynamics, and molecular origin of the PD effluentome. By transforming PD effluent into a biologically interpretable molecular readout of peritoneal membrane biology, this work provides a reference for the mechanistic interpretation of effluent-derived biomarkers and supports future therapeutic monitoring and precision medicine in PD.

Background: Orodispersible budesonide tablets (OBTs, Jorveza) are approved by the EMA as a therapy option in eosinophilic esophagitis (EoE) in adults. However, data on their use in pediatric patients remain limited and no approved pediatric OBT formulation is currently available in Europe. Therefore, real-world data on off-label use of OBTs in children is needed. Methods: We retrospectively analyzed data on the off-label use of OBTs in eight children (five girls) at a median age of 10.5 years (ranging from 5 to 14). Clinical, histological and safety outcomes were assessed descriptively. Results: Treatment with OBTs was associated with clinical improvement and a reduction in eosinophil counts. Specifically, the median eosinophil count decreased from 38.5 (ranging from 20 to 100) to 0 (ranging from 0 to 20) eosinophils per high-power field. Histological remission, defined as <15 eosinophils per high-power field, was achieved in six of eight patients (75%). Clinical remission was reached in seven of eight patients (87.5%). No severe side effects could be detected. Conclusions: OBTs showed promising clinical and histological responses in this small retrospective pediatric case series. However, larger prospective studies are required before efficacy and safety can be established. Further clinical studies are needed to assess whether OBTs could become an approved pediatric therapy.

Objective The objective of this study was to analyse the narrative life stories of children with end-stage kidney disease (ESKD) and their families to determine how health professionals can effectively support these children to achieve better life outcomes. Design Qualitative narrative biographic study. Setting We invited every long-term survivor of paediatric kidney transplants and their families at the Medical University of Vienna between 2008 and 2013 to participate in this study. Participants Nineteen patients (women: n=8, 42%) and 34 family members (women: n=22, 65%) were interviewed. The patients had a mean age of 7.6 (SD±5.6) years at the time of transplantation and 22.2 (SD±5.4) at the time of interview. Main outcome(s) measure(s) A qualitative narrative biographical analysis was combined with computational structured topic models using the Latent Dirichlet Allocation. Results The overarching finding was the desire for normality in daily life in long-term survivors and their families but with different perceptions of what normality looks like and predominance of this aspect evolving. Different strategies were used by patients (focused on their advancement) and caregivers (normality for all family members). Siblings played a major role in supporting survivors’ social inclusion. Conclusions The strong desire for normality confirms recent findings of the Standardised Outcomes in Nephrology Group initiative, which proposes survival and life participation as core outcomes in children with chronic kidney disease. Our study should be a starting point for an international effort to identify typologies and stratified interventions for children with ESKD and their families, particularly siblings.

Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. By leveraging big data, we have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified repurposing the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (p<0.01) and weight loss (p<0.01), and ameliorated histopathological damage (p<0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repurposing candidate for clinical trial in FSGS. This proof-of-concept study demonstrates the feasibility of translating compounds from our computational technology platform via pre-clinical verification to clinical phase II readiness.

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.

Background: On January 30, 2020, the World Health Organization Emergency Committee declared the rapid worldwide spread of COVID-19 a global health emergency. By December 2020, the safety and efficacy of the first COVID-19 vaccines had been demonstrated. However, international vaccination coverage rates have remained below expectations (in Europe at the time of manuscript submission). Controversial mandatory vaccination is currently being discussed and has already been introduced in some countries (Austria, Greece, and Italy). We used the Twitter survey system as a viable method to quickly and comprehensively gather international public health insights on mandatory vaccination against COVID-19. Objective: The purpose of this study was to better understand the public’s perception of mandatory COVID-19 vaccination in real time using Twitter polls. Methods: Two Twitter polls were developed (in the English language) to seek the public’s opinion on the possibility of mandatory vaccination. The polls were pinned to the Digital Health and Patient Safety Platform’s (based in Vienna, Austria) Twitter timeline for 1 week in mid-November 2021, 3 days after the official public announcement of mandatory COVID-19 vaccination in Austria. Twitter users were asked to participate and retweet the polls to reach the largest possible audience. Results: Our Twitter polls revealed two extremes on the topic of mandatory vaccination against COVID-19. Almost half of the 2545 respondents (n=1246, 49%) favor mandatory vaccination, at least in certain areas. This attitude contrasts with the 45.7% (n=1162) who categorically reject mandatory vaccination. Over one-quarter (n=621, 26.3%) of participating Twitter users said they would never get vaccinated, as reflected by the current Western European and North American vaccination coverage rate. Concatenating interpretation of these two polls should be done cautiously as participating populations might substantially differ. Conclusions: Mandatory vaccination against COVID-19 (in at least certain areas) is favored by less than 50%, whereas it is opposed by almost half of the surveyed Twitter users. Since (social) media strongly influences public perceptions and views, and social media discussions and surveys are specifically susceptible to the “echo chamber effect,” the results should be interpreted as a momentary snapshot. Therefore, the results of this study need to be complemented by long-term surveys to maintain their validity.

New recommendations on evaluation of peritoneal membrane function suggest ruling out catheter dysfunction when evaluating patients with low ultrafiltration capacity. We introduce the use of a combination of parameters obtained from the cycler software PD Link with HomeChoicePro (Baxter International Inc., Illinois, United States) cyclers for predicting catheter dysfunction in automated peritoneal dialysis patients (APD). Out of 117 patients treated at the Medical University of Vienna between 2015 and 2021, we retrospectively identified all patients with verified catheter dysfunction (n = 14) and compared them to controls without clinical evidence of mechanical catheter problems and a recent X-ray confirming PD catheter tip in the rectovesical/rectouterine space (n = 19). All patients had a coiled single-cuff PD catheter, performed tidal PD, and received neutral pH bicarbonate/lactate-buffered PD fluids with low-glucose degradation products on APD. Icodextrin-containing PD fluids were used for daytime dwells. We retrieved cycler data for seven days each and tested parameters' predictive capability of catheter dysfunction. Total number of alarms/week > 7 as single predictive parameter of catheter dislocation identified 85.7% (sensitivity) of patients with dislocated catheter, whereas 31.6% (1-specificity) of control patients were false positive. A combination of parameters (number of alarms/week > 7, total drain time > 22 min, ultrafiltration of last fill < 150 mL) where at least two of three parameters appeared identified the same proportion of patients with catheter dislocation, but was more accurate in identifying controls (21.1% false positive). In contrast to yearly PET measurements, an easily applicable combination of daily cycler readout parameters, also available in new APD systems connected to remote monitoring platforms shows potential for diagnosis of catheter dysfunction during routine follow-up.