Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4?

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.

Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies.

RATIONALE & OBJECTIVE: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. STUDY DESIGN: Cross-sectional cohort study. SETTING & PARTICIPANTS: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other." RESULTS: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases. LIMITATIONS: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). CONCLUSIONS: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.

"Point of no return" in unilateral renal ischemia reperfusion injury in mice.

BACKGROUND: In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as "point of no return" leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney. METHODS: Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy. RESULTS: Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-ß1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia. CONCLUSIONS: This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as "point of no return" leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury.

Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease.

Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria.

PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling.

Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside-in signaling pathway triggering NET formation is unknown. Here, we show that the receptor-interacting protein kinase (RIPK)-1-stabilizers necrostatin-1 or necrostatin-1s and the mixed lineage kinase domain-like (MLKL)-inhibitor necrosulfonamide prevent monosodium urate (MSU) crystal- or PMA-induced NET formation in human and mouse neutrophils. These compounds do not affect PMA- or urate crystal-induced production of ROS. Moreover, neutrophils of chronic granulomatous disease patients are shown to lack PMA-induced MLKL phosphorylation. Genetic deficiency of RIPK3 in mice prevents MSU crystal-induced NET formation in vitro and in vivo. Thus, neutrophil death and NET formation may involve the signaling pathway defining necroptosis downstream of ROS production. These data imply that RIPK1, RIPK3, and MLKL could represent molecular targets in gout or other crystallopathies.

The innate immune system in human systemic lupus erythematosus.

Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system.

Tumor necrosis factor superfamily ligand mRNA expression profiles differ between humans and mice during homeostasis and between various murine kidney injuries.

BACKGROUND: Several tumour necrosis factor (TNF) based therapeutics have already been approved for human use and several others are emerging. Therefore, we determined the mRNA expression levels of the TNF superfamily ligands (TNFSF) - e.g. TNF-α, lymphotoxin (LT)-α, LT-ß, Fas-L (CD95-L), TNF-related apoptosis-inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), 4-1BBL, OX40-L (CD252) and amyloid precursor protein (APP) in healthy human and mouse solid organs. METHODS: We used quantitative real time-PCR to analyse mRNA expression levels of TNFSF ligands. Murine models of acute ischemic renal injury, chronic oxalate nephropathy, and immune complex glomerulonephritis were used. Renal injury was assessed by PAS staining, and infiltrating immune cells were analysed by immunohistochemistry. Data was analysed using non-parametric ANOVA (non-parametric; Kruskal-Wallis test). RESULTS: We observed significant differences in the mRNA expression levels of TNFSF ligands in human and mouse solid organs. Furthermore, we determined their mRNA expressions during acute and chronic kidney injuries in mice. Our data demonstrate that the mRNA expression levels of TNFSF vary depending on the type of tissue injury - for example, acute ischemic renal injury, chronic crystalline nephropathy, and immune complex glomerulonephritis. In addition, we observed that mRNA expressions of TNFSF ligands are differentially regulated during the course of a transient ischemic renal injury (IRI) and chronic kidney modelling. We observed that TNF-α, LT-ß, and 4-1BBL were significantly upregulated during the progression of IRI and crystal-induced chronic kidney disease (CKD), whereas only 4-1BBL and TNF-α were significantly upregulated and LT-ß was significantly downregulated during the progression of immune complex glomerulonephritis. The mRNA expression of Fas-L was higher during IRI whereas it decreased in a time dependent manner during the progression of crystal-induced CKD. CONCLUSION: We conclude that the injury- and species-specific differences of TNFSF ligands must be considered in order to avoid the misinterpretation and wrong conclusions during data extrapolation between species.

Next generation sequencing and functional analysis of patient urine renal progenitor-derived podocytes to unravel the diagnosis underlying refractory lupus nephritis.

Often the cause of refractory lupus nephritis (RLN) remains unclear. We performed next-generation sequencing for podocyte genes in an RLN patient and identified compound heterozygosity for APOL1 risk alleles G1 and G2 and a novel homozygous c.[1049C>T]+[1049C>T] NPHS1 gene variant of unknown significance. To test for causality renal progenitor cells isolated from urine of this patient were differentiated into podocytes in vitro. Podocytes revealed aberrant nephrin trafficking, cytoskeletal structure and lysosomal leakage, and increased detachment as compared with podocytes isolated from controls. Thus, lupus podocytopathy can be confirmed as a cause of RLN by functional genetics on patient-derived podocytes.

Interleukin-22 in kidney injury and regeneration.

Interleukins have become well-known regulators of innate and adaptive immunity-related tissue inflammation. Recently, IL-22 has gained a lot of interest for its unique functions in maintaining and regaining epithelial integrity. IL-22 is exclusively secreted by different immune cell subsets, while IL-22 receptors are mainly expressed by epithelial cells. As the kidney is largely an epithelial organ, the functional role of IL-22 in the kidney deserves to be explored in detail. Here, we briefly summarize the key features of IL-22 biology and review the available data on its expression and functional roles in kidney injury and kidney regeneration. Furthermore, we provide suggestions on how to explore this evolving field in the future.

Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis.

BACKGROUND: The treatment of lupus nephritis (LN) remains problematic because the current treatment regimen based on unspecific immunosuppressants such as steroids, cyclophosphamide and mycophenolate has significant side effects and is often inefficient. B-cell ablation with the chimeric anti-CD20 antibody rituximab (RTX) has been considered as an alternative treatment option but the randomized controlled LUNAR trial failed to show any additive effect of RTX beyond a steroid-mycophenolate mofetil (MMF) combination for LN type III/IV/V in incident patients. At present, no such trial is available for the use of RTX in refractory LN. METHODS: We analysed existing evidence on this topic by performing a systematic analysis of reports that document outcomes of RTX treatment for refractory LN. RESULTS: Out of 233 reports, we selected 26 for analysis, which described 300 patients with a mean follow-up of 60 weeks. The complete or partial response criteria were met by 87% of patients with LN class III, 76% with class IV and 67% with class V, respectively. Mixed classes responded in 76% of patients. RTX induced complete responses in 60% (type III), 45% (type IV), 40% (type V) and 24% (mixed types), respectively. CONCLUSIONS: Our systematic review of existing evidence suggests that RTX effectively induces remission of LN in patients who have not achieved remission with standard therapies. Another randomized controlled trial should be conducted to test the efficacy of RTX in refractory LN.

Tissues use resident dendritic cells and macrophages to maintain homeostasis and to regain homeostasis upon tissue injury: the immunoregulatory role of changing tissue environments.

Most tissues harbor resident mononuclear phagocytes, that is, dendritic cells and macrophages. A classification that sufficiently covers their phenotypic heterogeneity and plasticity during homeostasis and disease does not yet exist because cell culture-based phenotypes often do not match those found in vivo. The plasticity of mononuclear phagocytes becomes obvious during dynamic or complex disease processes. Different data interpretation also originates from different conceptual perspectives. An immune-centric view assumes that a particular priming of phagocytes then causes a particular type of pathology in target tissues, conceptually similar to antigen-specific T-cell priming. A tissue-centric view assumes that changing tissue microenvironments shape the phenotypes of their resident and infiltrating mononuclear phagocytes to fulfill the tissue's need to maintain or regain homeostasis. Here we discuss the latter concept, for example, why different organs host different types of mononuclear phagocytes during homeostasis. We further discuss how injuries alter tissue environments and how this primes mononuclear phagocytes to enforce this particular environment, for example, to support host defense and pathogen clearance, to support the resolution of inflammation, to support epithelial and mesenchymal healing, and to support the resolution of fibrosis to the smallest possible scar. Thus, organ- and disease phase-specific microenvironments determine macrophage and dendritic cell heterogeneity in a temporal and spatial manner, which assures their support to maintain and regain homeostasis in whatever condition. Mononuclear phagocytes contributions to tissue pathologies relate to their central roles in orchestrating all stages of host defense and wound healing, which often become maladaptive processes, especially in sterile and/or diffuse tissue injuries.

IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production.

The IFN-regulatory factors IRF1, IRF3, IRF5, and IRF7 modulate processes involved in the pathogenesis of systemic lupus and lupus nephritis, but the contribution of IRF4, which has multiple roles in innate and adaptive immunity, is unknown. To determine a putative pathogenic role of IRF4 in lupus, we crossed Irf4-deficient mice with autoimmune C57BL/6-(Fas)lpr mice. IRF4 deficiency associated with increased activation of antigen-presenting cells in C57BL/6-(Fas)lpr mice, resulting in a massive increase in plasma levels of TNF and IL-12p40, suggesting that IRF4 suppresses cytokine release in these mice. Nevertheless, IRF4 deficiency completely protected these mice from glomerulonephritis and lung disease. The mice were hypogammaglobulinemic and lacked antinuclear and anti-dsDNA autoantibodies, revealing the requirement of IRF4 for the maturation of plasma cells. As a consequence, Irf4-deficient C57BL/6-(Fas)lpr mice neither developed immune complex disease nor glomerular activation of complement. In addition, lack of IRF4 impaired the maturation of Th17 effector T cells and reduced plasma levels of IL-17 and IL-21, which are cytokines known to contribute to autoimmune tissue injury. In summary, IRF4 deficiency enhances systemic inflammation and the activation of antigen-presenting cells but also prevents the maturation of plasma cells and effector T cells. Because these adaptive immune effectors are essential for the evolution of lupus nephritis, we conclude that IRF4 promotes the development of lupus nephritis despite suppressing antigen-presenting cells.

[Impact of the experience of urological senior physicians in Germany on professional and personal aspects]. / Welchen Einfluss hat die Dauer der Oberarzttätigkeit auf die Berufsausübung und Zufriedenheit urologischer OberärztInnen in Deutschland?

BACKGROUND: Urological senior physicians in Germany are a heterogeneous group with various clinical priorities and career objectives. To date, there are no reliable data concerning the impact of the time span for which senior physicians have been holding their position on professional, personal and position-linked aspects. MATERIAL AND METHODS: The objective of this study was a comparative analysis of perspectives, private and professional settings, specific job-related activities and individual professional goals of urological senior physicians in Germany based on their experience in this position assessed as number of years (dichotomised at 8 years as senior physician). As part of a cross-sectional study, a 55-item web-based questionnaire was designed, which was sent via a link to members of a mailing list of the German Society of Urology. The survey was available for urological senior physicians between February and April 2019. Group differences were evaluated using multivariate regression models. RESULTS: 107 of 192 evaluable questionnaires were completed by senior physicians holding this position for less than 8 years (< 8y senior physicians), 85 were completed by senior physicians holding this position for at least 8 years (≥ 8y senior physicians). < 8y senior physicians worked significantly more often at university hospitals (42.1 % vs. 18.8 %, p = 0.002). Overall, 82.4 % of ≥ 8y senior physicians assessed themselves autonomously safe in performing open surgery, compared to 39.3 % among < 8y senior physicians (p < 0.001). No significant differences concerning the self-assessment were found for endourological procedures (94.1 % vs. 87.9 %) and for the overall lower-rated self-assessment concerning laparoscopy (29.4 % vs. 20.6 %) and robotic surgery (14.1 % vs. 10.3 %). Despite the high management responsibility associated with their position, only about one third of participants (34.8 %) had received specific postgraduate education preparing them for managing and executive tasks. CONCLUSION: This study shows significant differences among senior physicians regarding surgical skills depending on the time span they hold their position. Moreover, there is considerable dissatisfaction regarding the development of leadership skills and the preparation for managing tasks. In order to ensure availability of senior staff members for the field of urology in the future, it is important to consider their professional needs and to overcome existing shortcomings by education programs within well-orchestrated human resources development strategies.

Learning in peer teaching of patient relations and communication skills at the "Anamnesegruppen" Munich - proof-of-concept and lessons learned.

Background: Due to the ban on classroom teaching during the pandemic, the Munich "Anamnesegruppen" had to be switched to e-learning at short notice. There were no established concepts for this, which is why digitalization was piloted and evaluated for feasibility. Student "Anamnesegruppen": "Anamnesegruppen" have existed for over 50 years and are organized as independent student peer teaching. In small groups of medical and psychology students, interviews with patients are conducted once a week during the semester. This is followed by a feedback and discussion round, in which ethical and professional questions are discussed in addition to the patient's medical history. The goal is to train the participants' ability to communicate and reflect. Adaptation to digital methods: The anamnesis seminars have been moved to a virtual group room using video conference. Patients were mainly recruited from the participants' circle of acquaintances. The group size was set at eight people each in four groups and supervised by a pair of student tutors. Confidentiality and data protection declarations were obtained in writing. Results: By switching to digital anamnesis groups, all four groups were successfully completed. Both the final supervision of the tutors and the electronic evaluation of the participants yielded positive feedback. Compared to the two previous evaluations of the semesters in classroom sessions, there were no significant differences in the evaluation. Discussion: The continuously good evaluation results, which did not differ between the digital format and the classroom course of the previous semesters, show that an ad hoc conversion to digital teaching is possible. We want to stress the fact that elements reflecting the doctor-patient relationship were successfully preserved. For the similarly structured Balint groups, virtual sessions may also be considered. Further research, especially prospective, is desirable in order to better understand the possibilities of digital teaching in this area.

Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS.

In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was <18 years. In 7/24 index patients with adult disease onset, a disease-causing variant could be identified by ES leading to a diagnostic yield of 29%. Eight different variants were identified in six known genes associated with monogenic kidney diseases. Six of these variants had been described before as disease-causing. In patients with a disease-causing variant, the median age at disease onset and end-stage renal disease was 26 and 38 years, respectively. The overall median time to a definite genetic diagnosis was 9 years. In 29% of patients with adult disease onset and suspected hereditary FSGS, a monogenic cause could be identified. The long delay up to the definite genetic diagnosis highlights the importance of obtaining an early genetic diagnosis to allow for personalized treatment options including weaning of immunosuppressive treatment, avoidance of repeated renal biopsy, and provision of accurate genetic counseling.

High IL-22RA1 gene expression is associated with poor outcome in muscle invasive bladder cancer.

BACKGROUND: The cell surface interleukin 22 (IL-22) receptor complex is mainly expressed in epithelial and tissue cells like pancreatitis cells. Recent studies described that IL-22R was overexpressed in malignant diseases and was associated with a poor overall survival (OS). The role of IL-22RA1 gene expression in muscle invasive bladder cancer (MIBC) has not been investigated, yet. OBJECTIVES: The aim of this study was to analyze the role of IL-22RA1 gene expression in patients with MIBC. METHODS: In a cohort of 114 patients with MIBC who underwent radical cystectomy, IL-22RA1 gene expression was analyzed with qRT-PCR and correlated with clinical parameters. Furthermore, Kaplan-Meier and Cox regression analysis were performed. For validation, an in silico dataset (TCGA 2017, n=407) was reanalyzed. RESULTS: IL-22RA1 gene expression was independent of clinicopathological parameters like age (P=0.2681), T stage (P=0.2130), nodal status (P=0.3238) and lymph vascular invasion (LVI, P=0.5860) in patients with MIBC. A high expression of IL-22RA1 was associated with a shorter OS (P=0.0040) and disease-specific survival (P=0.0385). Furthermore, a shorter disease-free survival (DFS) was also associated with a high expression of IL-22RA1 (P=0.0102). In the multivariable analysis, IL-22RA1 expression was an independent prognostic predictors regarding OS (P=0.0096, HR=0.48). In the TCGA cohort, IL-22RA1 expression was independent regarding to OS and DFS. CONCLUSION: A high IL-22RA1 gene expression was associated with worse outcome. Furthermore, IL-22RA1 represented an independent predictor regarding OS in our cohort and therefore might be used for risk stratification in patients with MIBC.

Clinical Case Discussions - a novel, supervised peer-teaching format to promote clinical reasoning in medical students.

Background: Clinical reasoning (CR) is a clinical core competence for medical students to acquire. While the necessity for CR teaching has been recognized since the early 20th century, to this day no consensus on how to best educate students in CR exists. Hence, few universities have incorporated dedicated CR teaching formats into their medical curriculum. We propose a novel case-based, peer-taught and physician-supervised collaborative learning format, dubbed "Clinical Case Discussions" (CCDs) to foster CR in medical students. Project description: We present the curricular concept of CCDs and its development according to a six-step approach (problem identification and general needs assessment; targeted needs assessment; goals and objectives; educational strategies; implementation; evaluation and feedback). Our goal is to strengthen the physician roles (CanMEDS/NKLM) and CR competence of medical students. CCDs are offered at our institution as an elective course and students work on real-life, complex medical cases through a structured approach. Over the course of five years we evaluated various aspects of the course and trained student teachers to optimize our course concept according to the feedback of our participants. We also obtained intro and exit self-assessments of CR competence using an established CR questionnaire. Results: We found an unmet need for CR teaching, as medical students in their clinical years view CR as highly important for later practice, but only 50% have ever heard of CR within the curriculum. Acceptance of CCDs was consistently high with over 85% of participants strongly agreeing that they would re-participate in the course and recommend it to a friend. Additionally, we observed significant improvements in CR self-assessments of participants. Conclusion: CCDs are a feasible teaching format to improve students' CR competence, have a high acceptance and involve students in medical education through peer-teaching.

Isn't here just there without a "t" - to what extent can digital Clinical Case Discussions compensate for the absence of face-to-face teaching?

Objective: COVID-19 challenges curriculum managers worldwide to create digital substitutes for classroom teaching. Case-based teaching formats under expert supervision can be used as a substitute for practical bedside teaching, where the focus is on teaching clinical reasoning skills. Methods: For medical students of LMU and TU Munich, the interactive, case-based, and supervised teaching format of Clinical Case Discussion (CCD) was digitised and implemented as dCCD in their respective curricula. Case discussions were realised as videoconferences, led by a student moderator, and took place under the supervision of a board-certified clinician. To prevent passive participation, additional cognitive activations were implemented. Acceptance, usability, and subjective learning outcomes were assessed in dCCDs by means of a special evaluation concept. Results: With regard to acceptance, students were of the opinion that they had learned effectively by participating in dCCDs (M=4.31; SD=1.37). The majority of students also stated that they would recommend the course to others (M=4.23; SD=1.62). The technical implementation of the teaching format was judged positively overall, but findings for usability were heterogeneous. Students rated their clinical reasoning skills at the end of the dCCDs (M=4.43; SD=0.66) as being significantly higher than at the beginning (M=4.33; SD=0.69), with low effect size, t(181)=-2.352, p=.020, d=0.15. Conclusion: Our evaluation data shows that the dCCD format is well-accepted by students as a substitute for face-to-face teaching. In the next step, we plan to examine the extent to which participation in dCCDs leads to an increase in objectively measured clinical reasoning skills, analogous to a face-to-face CCD with on-site attendance.

[Prevention of "contrast-induced" acute kidney injury - practical considerations]. / Prävention der "Kontrastmittel-induzierten" Nephropathie ­ was ist zu beachten?

Acute kidney injury (AKI) episodes after iodine radiocontrast application are decreasing since non-ionic agents are routinely used. Retrospective studies (in total comprising more than 100 000 patients) DO NOT show increased AKI rates after CT scans with the application of radiocontrast (vs. uncontrasted CT scans). AKI rates are generally higher after intra-arterial (i. a.) compared with intra-venous (i. v.) radiocontrast application - cholesterol embolism due to catheter manipulation does play a role in this setting. Because of the multifactorial pathogenesis the term "contrast-associated AKI" (CA-AKI) should be used preferentially. The AMACING trial, which prospectively evaluated the use of i. v. volume administration before contrast application to prevent CA-AKI, DID NOT show a benefit for volume therapy. Instead, the trial found a significant increase in symptomatic heart failure episodes in patients after volume administrastion. "Hydration" before (emergency) contrasted CT scans therefore can put patients at risk through both volume overload and diagnostic delay. The PRESERVE trial prospectively evaluated the use of volume administration and N-acetyl cysteine (NAC) before i. a. contrast application to prevent CA-AKI. While NAC, which was placebo controlled, did not show any benefit (and therefore should not be used anymore), all patients in the PRESERVE trial received i. v. volume (either sodium chloride or sodium bicarbonate). Interestingly, the incidence of CA-AKI in both groups was below 5 % and hence almost half of what was expected based on previous trials. If the baseline volume status is checked in order to avoid overload, volume administration in patients with i. a. contrast application can be safely performed until definitive data are available. The type of solution can be pragmatically guided by the patient's acid base status. While preventive measures to avoid CA-AKI are limited, the clinical relevance of (any) AKI remains - new data showing increased morbidity and mortality with creatinine increments of onl 0.3 mg/dl. In order to distinguish CA-AKI from other, potentially treatably forms of AKI (e. g. pre- or post-renal AKI), early consultation of a nephrologist seems favorable.

Can clinical case discussions foster clinical reasoning skills in undergraduate medical education? A randomised controlled trial.

OBJECTIVE: Fostering clinical reasoning is a mainstay of medical education. Based on the clinicopathological conferences, we propose a case-based peer teaching approach called clinical case discussions (CCDs) to promote the respective skills in medical students. This study compares the effectiveness of different CCD formats with varying degrees of social interaction in fostering clinical reasoning. DESIGN, SETTING, PARTICIPANTS: A single-centre randomised controlled trial with a parallel design was conducted at a German university. Study participants (N=106) were stratified and tested regarding their clinical reasoning skills right after CCD participation and 2 weeks later. INTERVENTION: Participants worked within a live discussion group (Live-CCD), a group watching recordings of the live discussions (Video-CCD) or a group working with printed cases (Paper-Cases). The presentation of case information followed an admission-discussion-summary sequence. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinical reasoning skills were measured with a knowledge application test addressing the students' conceptual, strategic and conditional knowledge. Additionally, subjective learning outcomes were assessed. RESULTS: With respect to learning outcomes, the Live-CCD group displayed the best results, followed by Video-CCD and Paper-Cases, F(2,87)=27.07, p<0.001, partial η2=0.384. No difference was found between Live-CCD and Video-CCD groups in the delayed post-test; however, both outperformed the Paper-Cases group, F(2,87)=30.91, p<0.001, partial η2=0.415. Regarding subjective learning outcomes, the Live-CCD received significantly better ratings than the other formats, F(2,85)=13.16, p<0.001, partial η2=0.236. CONCLUSIONS: This study demonstrates that the CCD approach is an effective and sustainable clinical reasoning teaching resource for medical students. Subjective learning outcomes underline the importance of learner (inter)activity in the acquisition of clinical reasoning skills in the context of case-based learning. Higher efficacy of more interactive formats can be attributed to positive effects of collaborative learning. Future research should investigate how the Live-CCD format can further be improved and how video-based CCDs can be enhanced through instructional support.