Potential and Uncertainties of RejectClass in Acute Kidney Graft Dysfunction: An Independent Validation Study.

BACKGROUND: Kidney graft rejections are classified based on the Banff classification. The RejectClass algorithm, initially derived from a cohort comprising mostly protocol biopsies, identifies data-driven phenotypes of acute rejection and chronic pathology using Banff lesion scores. It also provides composite scores for inflammation activity and chronicity. This study independently evaluates the performance of RejectClass in a cohort consisting entirely of indication biopsies. METHODS: We retrospectively applied RejectClass to 441 patients from the German TRABIO (TRAnsplant BIOpsies) cohort who had received indication biopsies. The primary endpoint was death-censored graft failure during 2 y of follow-up. RESULTS: The application of RejectClass to our cohort demonstrated moderately comparable phenotypic features with the derivation cohort, and most clusters indicated an elevated risk of graft loss. However, the reproduction of all phenotypes and the associated risks of graft failure, as depicted in the original studies, was not fully accomplished. In contrast, adjusted Cox proportional hazards analyses substantiated that both the inflammation score and the chronicity score are independently associated with graft loss, exhibiting hazard ratios of 1.7 (95% confidence interval, 1.2-2.3; P = 0.002) and 2.2 (95% confidence interval, 1.8-2.6; P < 0.001), respectively, per 0.25-point increment (scale: 0.0-1.0). CONCLUSIONS: The composite inflammation and chronicity scores may already have direct utility in quantitatively assessing the disease stage. Further refinement and validation of RejectClass clusters are necessary to achieve more reliable and accurate phenotyping of rejection.

Five-year follow-up of a phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

Background: The administration of modified immune cells (MIC) before kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes. We wondered how this approach affected the continued clinical course of these patients. Methods: Ten patients from a phase I clinical trial who had received MIC infusions prior to kidney transplantation were retrospectively compared to 15 matched standard-risk recipients. Follow-up was until year five after surgery. Results: The 10 MIC patients had an excellent clinical course with stable kidney graft function, no donor-specific human leukocyte antigen antibodies (DSA) or acute rejections, and no opportunistic infections. In comparison, a retrospectively matched control group receiving standard immunosuppressive therapy had a higher frequency of DSA (log rank P = 0.046) and more opportunistic infections (log rank P = 0.033). Importantly, MIC patients, and in particular the four patients who had received the highest cell number 7 days before surgery and received low immunosuppression during follow-up, continued to show a lack of anti-donor T lymphocyte reactivity in vitro and high CD19+CD24hiCD38hi transitional and CD19+CD24hiCD27+ memory B lymphocytes until year five after surgery. Conclusions: MIC infusions together with reduced conventional immunosuppression were associated with good graft function during five years of follow-up, no de novo DSA development and no opportunistic infections. In the future, MIC infusions might contribute to graft protection while reducing the side effects of immunosuppressive therapy. However, this approach needs further validation in direct comparison with prospective controls. Trial registration: https://clinicaltrials.gov/, identifier NCT02560220 (for the TOL-1 Study). EudraCT Number: 2014-002086-30.

Study protocol: the TRAnsplant BIOpsies (TRABIO) study - a prospective, observational, multicentre cohort study to assess the treatment of kidney graft rejections.

INTRODUCTION: Despite continued efforts, long-term outcomes of kidney transplantation remain unsatisfactory. Kidney graft rejections are independent risk factors for graft failure. At the participating centres of the TRAnsplant BIOpsies study group, a common therapeutic standard has previously been defined for the treatment of graft rejections. The outcomes of this strategy will be assessed in a prospective, observational cohort study. METHODS AND ANALYSIS: A total of 800 kidney transplantation patients will be enrolled who undergo a graft biopsy because of deteriorating kidney function. Patients will be stratified according to the Banff classification, and the influence of the treatment strategy on end points will be assessed using regression analysis. Primary end points will be all-cause mortality and graft survival. Secondary end points will be worsening of kidney function (≥30% decline of estimated Glomerular Filtration Rate [eGFR] or new-onset large proteinuria), recurrence of graft rejection and treatment response. Baseline data and detailed histopathology data will be entered into an electronic database on enrolment. During a first follow-up period (within 14 days) and subsequent yearly follow-ups (for 5 years), treatment strategies and clinical course will be recorded. Recruitment at the four participating centres started in September 2016. As of August 2020, 495 patients have been included. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the ethics committee of Kiel (AZ B 278/16) and was confirmed by the committees of Munich, Mainz and Stuttgart. The results will be reported in a peer-reviewed journal, according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria. TRIAL REGISTRATION NUMBER: ISRCTN78772632; Pre-results.

[Evaluation of a structured, longitudinal training program for the preparation for the second state exam (M2) - a quantitative analysis]. / Evaluation eines strukturierten Prüfungsvorbereitungsprogramms für das 2. Staatsexamen (M2) nach Neuer Ärztlicher Approbationsordnung: Eine quantitative Analyse.

INTRODUCTION: The implementation of the amendment to the German medical licensing regulations ("Approbationsordnung") in 2002 led to a reduction in the number of state examinations from four to two exams, with the date of the second state exam being shifted to the end of the final clinical year. Students now face a double burden: on the one hand, they need to get ready for their future job, and on the other hand, they need to prepare for the state exam. This is why the Medical Faculty of Heidelberg introduced a preparation programme for the second state exam. The focus of this study was to evaluate the acceptance of the different modules of this programme and to compare the results against each other. METHODS: 39 students (15 male / 24 female; mean age 26.6 ± 1.9 years) took part in the exam preparation programme at the Medical University Hospital Heidelberg. Five different modules were implemented: an informational meeting, a key-feature written exam, case-based multiple-choice exams, a simulated practical examination and a simulated oral examination. Acceptance was measured using a six-point Likert scale (1=very good, 6=unsatisfactory and 1=I completely agree, 6=I completely disagree, respectively) RESULTS: The exam preparation programme as a whole was rated good: overall rating key-feature written exam 3.33 ± 1.17; case-based multiple-choice exams 2.61 ± 1.61; simulated practical exam 1.61 ± 0.54; simulated oral exam 1.55 ± 0.50. A comparison of the different modules demonstrated significantly better ratings for the practical and oral examinations than the case-based multiple-choice exams (p<0.001). DISCUSSION: The presented exam preparation programme is well accepted and facilitates the preparation for the second state exam, particularly with regard to the oral-practical examination.

Increased basolateral sorting of carcinoembryonic antigen in a polarized colon carcinoma cell line after cholesterol depletion-Implications for treatment of inflammatory bowel disease.

AIM: To investigate a possible increase of basolateral expression of carcinoembryonic antigen (CEA) by interfering with the apical transport machinery, we studied the effect of cholesterol depletion on CEA sorting and secretion. METHODS: Cholesterol depletion was performed in polarized Caco-2 cells using lovastatin and methyl-beta-cyclodextrin. RESULTS: We show that CEA is predominantly expressed and secreted at the apical surface. Reduction of the cholesterol level of the cell by 40%-50% with lovastatin and methyl-beta-cyclodextrin led to a significant change of the apical-to-basolateral transport ratio towards the basolateral membrane. CONCLUSION: As basolateral expression of CEA has been suggested to have anti-inflamatory properties, Cholesterol depletion of enterocytes might be a potential approach to influence the course of inflammatory bowel disease.