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Patients with non-dialysis-dependant chronic kidney disease (NDD-CKD) and dialysis-dependant chronic kidney disease (DD-CKD) frequently also suffer from thyroid disorders, especially hypothyroidism which is found two to five times more often among them compared to the general population. Emerging research has illustrated the potential prognostic implications of this association as NDD-CKD and DD-CKD patients with hypothyroidism have been shown to have higher mortality rates, and treatment of subclinical hypothyroidism in NDD-CKD patients has been reported to attenuate the decline of glomerular filtration rate over time. This review illustrates the bidirectional, multi-layered interplay between the kidneys and the thyroid gland explaining how pathologies in one organ will affect the other and vice versa. Additionally, it outlines the impact of thyroid disorders on routine parameters of kidney function (especially serum creatinine and serum cystatin C) that nephrologists should be aware of in their clinical practice. Lastly, it summarizes the emerging evidence from clinical studies on how treatment of subclinical hypothyroidism in NDD-CKD and DD-CKD patients may potentially have beneficial effects on kidney function as well as mortality. While most of the research in this area has been performed on adult patients, we specifically discuss what is currently known about thyroid dysfunctions in paediatric CKD patients as well and provide management suggestions. The evidence accumulated so far clearly indicates that further, prospective studies with meticulous methodology are warranted to refine our understanding of thyroid disorders in paediatric and adult CKD patients and establish optimal treatment pathways.

Patients aged ≥60 y represent the fastest growing population among kidney transplant recipients and waitlist patients. They show an elevated infection risk and are frequently transplanted with multiple human leukocyte antigen mismatches. Whether the choice of calcineurin inhibitor influences graft survival, mortality, or key secondary outcomes such as infections in this vulnerable recipient population is unknown.A total of 31 177 kidney transplants from deceased donors performed between 2000 and 2019 at European centers and reported to the Collaborative Transplant Study were analyzed using multivariable Cox and logistic regression analyses. All recipients were ≥60 y old and received tacrolimus (Tac) or cyclosporine A on an intention-to-treat basis, combined with mycophenolic acid or azathioprine plus/minus steroids.The risk of 3-y death-censored graft loss and patient mortality did not differ significantly between Tac- and cyclosporine A-treated patients (hazard ratio 0.98 and 0.95, P = 0.74 and 0.20, respectively). No difference was found in the overall risk of hospitalization for infection (hazard ratio = 0.95, P = 0.19); however, a lower incidence of rejection treatment (hazard ratio = 0.81, P0.001) was observed in Tac-treated patients. Assessment of pathogen-specific hospitalizations revealed no difference in the risk of hospitalization due to bacterial infection (odds ratio = 1.00, P = 0.96), but a significantly higher risk of hospitalization due to human polyomavirus infection was found among Tac-treated patients (odds ratio = 2.45, P = 0.002). The incidence of de novo diabetes was higher for Tac-based immunosuppression (odds ratio = 1.79, P0.001).Calcineurin inhibitor selection has no significant influence on death-censored graft survival, mortality, and overall infection risk in ≥60-y-old kidney transplant recipients.

PURPOSE Careful donor selection is important for kidney transplantations (KT) from suboptimal donors aged ≥65 years. Several tools such as histopathological assessment of preimplant biopsies have been shown to predict allograft survival and can be applied for selection. Whether the explanting surgeon's appraisal is associated with outcomes of KTs from suboptimal donors is unknown. METHODS We compared outcomes of KTs from ≥65-year-old deceased donors performed at our centre between 1999 and 2018 for which grading of macroscopic 'donor arteriosclerosis' (n=104) and 'organ quality' (n=208) as judged by the explanting surgeon and documented on the Eurotransplant kidney organ report was available. RESULTS No association was observed between degree of macroscopic donor arteriosclerosis and death-censored graft survival in univariable or multivariable regression analyses. Compared to KTs from donors with no/mild arteriosclerosis, KTs from donors with moderate/severe arteriosclerosis were associated with a significantly impaired allograft function 3 months, 1 year and 3 years after transplantation (e.g. at 3 years: 176.8 µmol/l vs 137.0 µmol/l, P=0.003). Following multivariable regression analysis, these differences remained significant at 3 months and 3 years after KT. No association was observed between degree of macroscopic arteriosclerosis and mortality or primary non-function as well as no consistent association with delayed graft function and histological arteriosclerosis. Assessment of 'organ quality' was not associated with outcomes. CONCLUSION Our data suggest that the explanting surgeon's assessment of donor arteriosclerosis is associated with allograft function. Larger studies and better standardization of kidney inspection after explantation are required to further explore the impact of surgeon's appraisal in KT.

Die Pravalenz der chronischen Herzinsuffizienz („chronic heart failure“, CHF) bzw. der Leberzirrhose nimmt weltweit zu. Bei etwa 50 % respektive etwa 30 % der Patienten besteht zusatzlich noch eine chronische Nierenerkrankung, die, insbesondere im fortgeschrittenen Stadium, die Therapiemoglichkeiten einschrankt und bei beiden Erkrankungen hydropische Dekompensationen begunstigt. Wahrend sich die Peritonealdialyse (PD) schon seit einiger Zeit als kreislaufschonendes Therapieverfahren fur CHF-Patienten mit dialysepflichtiger, chronischer Nierenerkrankung bewahrt hat, zeigen jungere Studien nun auch positive Effekte fur die peritoneale Ultrafiltration (pUF) bei CHF-Patienten mit noch nicht dialysepflichtiger Nierenerkrankung und rezidivierenden, diuretikarefraktaren Dekompensationen. So konnten mittels pUF die Anzahl und Dauer von Hospitalisierungen aufgrund von dekompensierter CHF sowie die klinische Dyspnoesymptomatik signifikant reduziert werden. Weitere Vorteile sind die Option zur konsequenteren, medikamentosen Blockade des Renin-Angiotensin-Aldosteron-Systems sowie die effektive Mobilisation von kardial bedingtem Aszites. Bei multimorbiden Patienten ohne entsprechende Unterstutzung im hauslichen Umfeld kann die pUF (und die PD) jedoch nicht angeboten werden, da es bisher kaum ambulante Pflege- und Vergutungsstrukturen fur assistierte pUF/PD gibt. Auch bei Leberzirrhosepatienten mit dialysepflichtiger Nierenerkrankung kann die PD als Therapieverfahren erwogen werden, da sie als kontinuierliches Verfahren einen schonenden Volumenentzug ermoglicht, keiner Antikoagulation bedarf und aufgrund der dauerhaften Aszitesdrainage keine therapeutischen Parazentesen mehr notig sind. Studien zeigen zudem kein erhohtes Peritonitisrisiko und keinen exzessiven Proteinverlust uber die PD.

ObjectiveTo evaluate leg-heel chest compression without previous training as an alternative for medical professionals and its effects on distance to potential aerosol spread during chest compression.Methods20 medical professionals performed standard manual chest compression followed by leg-heel chest compression after a brief instruction on a manikin. We compared percentage of correct chest compression position, percentage of full chest recoil, percentage of correct compression depth, average compression depth, percentage of correct compression rate and average compression rate between both methods. In a second approach, potential aerosol spread during chest compression was visualized.ResultsThere was no significant difference between manual and leg-heel compression. The distance to potential aerosol spread could have been increased by leg-heel method.ConclusionUnder special circumstances like COVID-19-pandemic, leg-heel chest compression may be an effective alternative without previous training compared to manual chest compression while markedly increasing the distance to the patient.

Kidney transplantation (KT) from donors with acute kidney injury (AKI) has been associated with delayed graft function (DGF) but similar graft survival compared with KT from donors without AKI. Kidneys from ≥65-year-old donors with comorbidities are more susceptible to cold ischemia time (CIT) and DGF and it is unknown whether such elderly kidneys with AKI can also be transplanted with satisfactory outcomes. All KTs from ≥65-year-old donors performed at our center from 1999 to 2019 (n = 233) were retrospectively analyzed and short- as well as long-term outcomes were compared for KTs from donors with (n = 64) and without AKI (n = 169). There were no significant differences regarding the frequency of DGF as well as the estimated glomerular filtration rate (eGFR) 1 and 3 years post-transplant between the no-AKI and the AKI group (DGF: no-AKI 30.2% vs. AKI 40.6%, P = .17; eGFR at 1-year: 31.9 ml/min/1.73 m

INTRODUCTION Patients with a history of cardiopulmonary resuscitation (CPR) and subsequent brain death are frequently evaluated for organ donation. Whether kidneys from ≥65-year-old braindead donors with a history of CPR can be transplanted with satisfactory outcomes is unknown. MATERIAL & METHODS All kidney transplants (KTs) from ≥65-year-old donors performed at our center from 1999 to 2018 (n = 185) were retrospectively analyzed and outcome was compared for KTs from donors with and without a history of CPR (n = 27 and n = 158, respectively). RESULTS No significant differences in the incidence of delayed graft function (DGF) as well as 1- and 3-year graft function were observed between the CPR and the no-CPR group (DGF: 26.0% vs. 31.0%, p = .76; 1-year serum creatinine: 150.4 μmol/L vs. 177.0 μmol/L, p = .11; 3-year serum creatinine: 150.4 μmol/L vs. 168.2 μmol/L, p = .52, respectively). Death-censored graft survival was comparable after 1 and 5 years (CPR group: 81.5% and 76.7% vs. no-CPR group: 86.6% and 75.7%, p = .70). Likewise, patient survival was not significantly different. Multivariable Cox regression analysis also did not identify CPR as a significant risk factor for graft loss or death. CONCLUSION Our study suggests that, following stringent donor selection, the outcome of KTs from ≥65-year-old braindead donors with and without a history of CPR is comparable.

Background and aims Due to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. Methods CD3-positive, FOXP3-positive and CD8-positive T cells were quantified in 219, 233 and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and LS cancer-free carriers and 26, 22 and 19 LS CRCs, respectively. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled on the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples using the NanoString nCounter platform. Results LS normal mucosa specimens showed significantly elevated CD3-, FOXP3- and CD8-positive T cell densities compared to non-LS controls. Gene expression profiling and cluster analysis revealed distinct immune profiles in LS carrier mucosa with and without cancer manifestation. Long term follow-up of LS carriers within the CAPP2 trial found a correlation between mucosal T cell infiltrate and time to subsequent tumor occurrence. Conclusion LS carriers show elevated mucosal T cell infiltration even in the absence of cancer. The normal mucosa immune profile may be a temporary or permanent tumor risk modifier in LS carriers.

Hantavirus infections are endemic worldwide, and its incidence in Europe has been steadily increasing. In Western Europe, hantavirus infections are typically caused by Puumala hantavirus and cause nephropathia epidemica (NE), a mild form of haemorrhagic fever with renal syndrome. Up to now, there is only little data about the course of acute NE in children, but it has been suggested that hantavirus infections take a lighter course in children when compared to adults. We performed a retrospective analysis of adults and children diagnosed with acute NE in two counties in South-Western Germany to investigate if there are differences in the course of the disease. We reviewed the medical records of 295 adults and 22 children with acute NE regarding clinical presentation, laboratory findings, complications and outcome. Acute kidney injury (AKI) and thrombocytopenia occurred at similar frequencies and severity in both groups. Sudden onset of fever and back/loin pain were two of the three most common symptoms in both adults and children. However, adults presented more frequently with arthralgia and visual disturbances, whereas abdominal pain and nausea/vomiting could be detected more often in children. No significant differences were found in the incidence of complications (haemodialysis, long-term outcome of kidney function, length of hospital stay). The clinical course of acute NE was similar in adults and children with high frequency of AKI as well as thrombocytopenia, but with full recovery of all patients.

The use of kidney allografts from ≥70-y-old donors has increased persistently over the last 20 y. Prolonged cold ischemia time (CIT) is well known to increase graft failure risk. However, despite their growing importance, no data are available on the impact of CIT, specifically on survival of allografts from ≥70-y-old donors.In total, 47 585 kidney transplantations from expanded criteria donors (ECDs) performed during 2000-2017 and reported to the Collaborative Transplant Study were analyzed. The impact of CIT on 5-y death-censored graft and patient survival was studied for transplantations from70-y (n = 33 305) and ≥70-y-old ECDs (n = 14 280).Compared with the reference of ≤12 h CIT, a CIT of 13-18 h did not increase the risk of graft failure significantly, either for recipients of kidneys from70-y or from ≥70-y-old ECDs. In contrast, graft failure risk increased significantly when CIT exceeded 18 h, both in recipients of kidneys from70-y and, more pronounced, from ≥70-y-old ECDs (CIT 19-24 h: hazard ratio [HR] = 1.19 and 1.24; P 0.001; CIT ≥24 h: HR = 1.28 and 1.32, P 0.001 and P =0.003, respectively). Within the 18-h CIT interval, additional HLA matching further improved survival of ECD transplants significantly, whereas the negative impact of a prolonged CIT18 h was stronger in ≥65-y-old recipients and for transplants with multiple HLA mismatches. The influence of CIT on patient survival was less pronounced.CIT, as long it is kept ≤18 h, has no significant impact on survival of kidney transplants, even from ≥70-y-old ECDs.

Background Establishing rapport and empathy between patients and their health care provider is important but challenging in the context of a busy and crowded emergency department (ED). Objective We explore the hypotheses that rapport building, documentation, and time efficiency might be improved in the ED by providing patients a digital tool that uses Bayesian reasoning–based techniques to gather relevant symptoms and history for handover to clinicians. Methods A 2-phase pilot evaluation was carried out in the ED of a German tertiary referral and major trauma hospital that treats an average of 120 patients daily. Phase 1 observations guided iterative improvement of the digital tool, which was then further evaluated in phase 2. All patients who were willing and able to provide consent were invited to participate, excluding those with severe injury or illness requiring immediate treatment, with traumatic injury, incapable of completing a health assessment, and aged Results Respondents strongly endorsed the tool for facilitating conversation (61/81, 75% of patients, 57/78, 73% of physician ratings, and 10/10, 100% of nurse ratings). Most nurses judged the tool as potentially time saving, whereas most physicians only agreed for a subset of medical specialties (eg, surgery). Patients reported high usability and understood the tool’s questions. The tool was recommended by most patients (63/81, 78%), in 53% (41/77) of physician ratings, and in 76% (61/80) of nurse ratings. Questionnaire completion rates were 100% (81/81) by patients and 96% (78/81 enrolled patients) by physicians. Conclusions This pilot confirmed that a larger study in the setting would be feasible. The tool has clear potential to improve patient–health care provider interaction and could also contribute to ED efficiency savings. Future research and development will extend the range of patients for whom the history-taking tool has clinical utility. Trial Registration German Clinical Trials Register DRKS00024115; https://drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024115

BACKGROUND Establishing rapport and empathy between patients and their health care provider is important but challenging in the context of a busy and crowded emergency department (ED). OBJECTIVE We explore the hypotheses that rapport building, documentation, and time efficiency might be improved in the ED by providing patients a digital tool that uses Bayesian reasoning–based techniques to gather relevant symptoms and history for handover to clinicians. METHODS A 2-phase pilot evaluation was carried out in the ED of a German tertiary referral and major trauma hospital that treats an average of 120 patients daily. Phase 1 observations guided iterative improvement of the digital tool, which was then further evaluated in phase 2. All patients who were willing and able to provide consent were invited to participate, excluding those with severe injury or illness requiring immediate treatment, with traumatic injury, incapable of completing a health assessment, and aged RESULTS Respondents strongly endorsed the tool for facilitating conversation (61/81, 75% of patients, 57/78, 73% of physician ratings, and 10/10, 100% of nurse ratings). Most nurses judged the tool as potentially time saving, whereas most physicians only agreed for a subset of medical specialties (eg, surgery). Patients reported high usability and understood the tool’s questions. The tool was recommended by most patients (63/81, 78%), in 53% (41/77) of physician ratings, and in 76% (61/80) of nurse ratings. Questionnaire completion rates were 100% (81/81) by patients and 96% (78/81 enrolled patients) by physicians. CONCLUSIONS This pilot confirmed that a larger study in the setting would be feasible. The tool has clear potential to improve patient–health care provider interaction and could also contribute to ED efficiency savings. Future research and development will extend the range of patients for whom the history-taking tool has clinical utility. CLINICALTRIAL German Clinical Trials Register DRKS00024115; https://drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024115

Background The objective of this study was to identify clinical risk factors for COVID-19 in a German outpatient fever clinic that allow distinction of SARS-CoV-2 infected patients from other patients with flu-like symptoms. Methods This is a retrospective, single-centre cohort study. Patients were included visiting the fever clinic from 4th of April 2020 to 15th of May 2020. Symptoms, comorbidities, and socio-demographic factors were recorded in a standardized fashion. Multivariate logistic regression was used to identify risk factors of COVID-19, on the bases of those a model discrimination was assessed using area under the receiver operation curves (AUROC). Results The final analysis included 930 patients, of which 74 (8%) had COVID-19. Anosmia (OR 10.71; CI 6.07–18.9) and ageusia (OR 9.3; CI 5.36–16.12) were strongly associated with COVID-19. High-risk exposure (OR 12.20; CI 6.80–21.90), especially in the same household (OR 4.14; CI 1.28–13.33), was also correlated; the more household members, especially with flu-like symptoms, the higher the risk of COVID-19. Working in an essential workplace was also associated with COVID-19 (OR 2.35; CI 1.40–3.96), whereas smoking was inversely correlated (OR 0.19; CI 0.08–0.44). A model that considered risk factors like anosmia, ageusia, concomitant of symptomatic household members and smoking well discriminated COVID-19 patients from other patients with flu-like symptoms (AUROC 0.84). Conclusions We report a set of four readily available clinical parameters that allow the identification of high-risk individuals of COVID-19. Our study will not replace molecular testing but will help guide containment efforts while waiting for test results.

IMPORTANCECommunication between patients and healthcare professionals is frequently challenging in the crowded emergency department (ED), with few opportunities to develop rapport or empathy. Digital tools for patients and physicians have been proposed as helpful but their utility is not established.OBJECTIVETo evaluate a patient-facing digital symptom and history taking, as well as handover tool in the waiting room.DESIGNA two-phase, questionnaire-based quality improvement study. Phase I observations guided iterative improvement, which was then further evaluated in Phase II.SETTINGED of a German tertiary referral and major trauma hospital providing interdisciplinary treatment for an average of 120 patients daily.PARTICIPANTSAll patients who were willing/able to provide consent, excluding patients: (i) with severe injury/illness requiring immediate treatment; (ii) with traumatic injury; (iii) incapable of completing a health assessment; or, (iv) under 18 years old. Of 1699 patients presenting to the ED, 815 were eligible based on triage level. With available recruitment staff, 135 were approached, of whom 81 were included in the study.INTERVENTION/OBSERVATIONPatients entered information into the tool, which generated a handover report to be accessed via a clinician dashboard. All users completed evaluation questionnaires. Clinicians were trained to observationally assess the tool as a prototype, without relying upon it for clinical care.MAIN OUTCOMES AND MEASURESPatient and clinician Likert scale ratings of tool performance.RESULTSRespondents were strongly positive in endorsing the tool’s usefulness in facilitating conversation (75% of patients, 73% physicians, 100% nurses). Nurses judged the tool as potentially time saving, whilst physicians assessed it as time saving only in some ED medical specialisms (e.g. Surgery). Patients understood the tool questions and reported high usability. The proportion of patients, physicians and nurses who would recommend the tool was 78%, 53% and 76%.CONCLUSIONS AND RELEVANCEThe system has clear potential to improve patient-HCP interaction and make efficiency savings in the ED. Future research and development will extend the range of patients for which the history collection has clinical utility.Key PointsQuestionCan a patient-facing digital symptom and clinical history taking tool provide conversational support, aid in symptom taking, facilitate record keeping, and lead to improved rapport between patients, physicians and nurses in the emergency department (ED)?FindingsAcceptability was high, with improved rapport experienced 90% of the time for patients, 73% for physicians and 100% for nurses. Nurses assessed the tool as having workflow benefit through potential time saving. Physicians assessed the current tool design as providing time saving in certain ED medical specialisms including Surgery.MeaningThe patient-facing tool for symptom and history taking provided meaningful conversation support and showed potential for efficiency savings, however, further research and testing is required before time savings can be consistently delivered to ED clinicians across the range of relevant ED medical specialisms.

Due to a widespread organ shortage, the use of expanded criteria donors (ECDs) in kidney transplantation has increased persistently, reaching approximately 40% in recent years. Whether human leucocyte antigen (HLA) matching between donor and recipient should be part of allocation algorithms in transplantation of ECD kidneys, and especially of ECD kidneys from ≥70-year-old donors, is still in question. To this end, 135,529 kidney transplantations performed between 2000 and 2017 and reported to the Collaborative Transplant Study were analysed and the impact of HLA-A+B+DR mismatches on death-censored graft and patient survival as well as on rejection episodes was investigated. Results were stratified according to donor status (standard criteria donor (SCD) versus ECD) and age of ECD. HLA incompatibility increased the five-year death-censored graft failure risk similarly strong in recipients of ECD and SCD transplants (hazard ratio (HR) per HLA mismatch 1.078 and 1.075, respectively; p < .001 for both). Its impact on rejection treatments during the first post-transplant year was also significant but slightly weaker for recipients of ECD transplants (risk ratio (RR) per HLA mismatch 1.10 for ECD transplants and 1.13 for SCD transplants; p < .001 for both). Mortality increased gradually from zero to six HLA mismatches in recipients of SCD transplants, whereas for ECD transplants a significant increase was notable only from zero to more than zero mismatches. A significant but slightly less pronounced impact of HLA incompatibility on graft failure was observed in transplants from ≥70- compared with

Purpose of review Due to a substantial lack of kidney donor organs and an increasing number of sensitized recipients, a growing number of kidney transplantations has to be performed across human leukocyte antigen (HLA) and ABO barriers. These transplantations carry an inherent risk of antibody-mediated rejection (AMR) with subsequently impaired graft and patient survival. This review focuses on new developments in desensitization strategies and dedicated programs for sensitized allograft recipients. Recent findings Whereas ABO-incompatible kidney transplantation using rituximab-based desensitization achieves long-term survival rates comparable with ABO-compatible kidney transplantation, HLA-incompatible living kidney transplantation shows no definite survival advantage as compared with staying on the waiting list for an HLA-compatible organ. To overcome HLA-incompatibilities dedicated programs for highly sensitized recipients (such as the Eurotransplant Acceptable Mismatch program) have been established. For optimal graft outcome, these programs should be based on proven acceptable mismatches and not just on avoiding unacceptable antigens. Novel desensitizing agents (e.g. complement inhibitors) that specifically inhibit the molecular pathways of AMR have shown promising results in HLA-incompatible kidney transplantation in smaller studies. Summary Despite ever more challenging conditions, kidney transplantation in highly sensitized patients can be achieved with the use of dedicated programs, well established desensitizing agents and new drugs that specifically inhibit the molecular processes of AMR.

Background and Aims: The development of an esophagorespiratory fistula (ERF) in patients with esophageal cancer (EC) is associated with poor prognosis. We observed a high rate of vocal fold paralysis (VFP) in patients with ERF. Data on prevalence and complications of VFP in ERF are lacking. The present study investigated the incidence of VFP in patients with malignant ERF and examined possible risk factors and the impact on survival. Methods: We performed a retrospective case-control study of 46 institutional cases of EC patients with ERF in a time period of eleven years. Patients were matched to 92 randomly selected controls (EC patients without ERF) in a 1:2 fashion for tumor localization and histology. Demographics, clinical characteristics, recurrence, treatment modalities as well as survival were analyzed. Results: Esophageal cancer patients with ERF developed more often VFP than EC patients without ERF (59% vs. 21%; p=0.02; odds ratio (OR) 4.9). Esophageal cancer patients with ERF had a more pronounced weight loss (7.1 vs. 11.5 kg; P = 0.008), as well as higher rates of esophageal (p=

There is a growing shortage of kidney donors leading to extended transplant waiting times associated with increased mortality. To expand the donor pool, clinicians nowadays regularly accept organs from elderly donors, including those aged ≥70 years. There is only limited and conflicting data whether kidneys from these elderly donors allow for satisfactory allograft outcome rates. To asses this question, the 5-year death censored graft survival of 116,870 adult first deceased donor kidney allograft recipients that were transplanted at European centers between 1997 and 2016 and reported to the "Collaborative Transplant Study" were analyzed using Kaplan-Meier analysis and country stratified Cox regression. The combinations of the two transplant periods 1997-2006 and 2007-2016 with the donor age categories 18-49, 50-59, 60-69, and ≥70 years were considered. From 1997-2006 to 2007-2016, the median donor age increased from 50 to 55 years and the proportion of kidneys from ≥60-year-old donors rose from 24.1 to 38.8%. At the same time, the proportion of kidneys from ≥70-year-old donors more than doubled (6.7 vs. 15.4%). Between 1997-2006 and 2007-2016, the 5-year graft survival improved in all donor age categories. During 2007-2016, the 5-year death censored graft survival of kidneys from ≥70-year-old donors was comparable to that of kidneys from 60 to 69-year-old donors during 1997-2006. This was true both for younger recipients (18-64 years) and older recipients (≥65 years). Among the younger recipients, 45-64-year-old recipients showed the best death censored graft survival rates for kidneys from old donors. In the country-stratified Cox regression analysis, compared to the reference of grafts from 18 to 49-year-old donors, the hazard ratio for grafts from ≥70-year-old donors during 2007-2016 was 1.92, exactly the same as the hazard ratio for grafts from 60 to 69-year-old donors during 1997-2006. Our analysis indicates that within only one further decade (1997-2006 vs. 2007-2016) the 5-year death censored graft survival of kidneys from ≥70-year old donors improved to the level of kidneys from 60 to 69-year-old donors in the previous decade.

OBJECTIVES: Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). Few studies have looked at long-term outcomes of endoscopically visible adenomatous lesions removed by endoscopic resection in these patients. We aimed to assess the risk of developing CRC in UC patients with adenomatous lesions that develop within the segment of colitis compared to the remainder of an ulcerative colitis cohort. METHODS: We identified patients with a confirmed histological diagnosis of UC from 1991 to 2004 and noted outcomes till June 2011. The Kaplan-Meier method was used to estimate cumulative probability of subsequent CRC. Factors associated with risk of CRC were assessed in a Cox proportional hazards model. RESULTS: Twenty-nine of 301 patients with UC had adenomatous lesions noted within the segment of colitis. The crude incidence rate of developing colon cancer in patients with UC was 2.45 (95 % CI 1.06-4.83) per 1000 PYD and in those with UC and polypoid adenomas within the extent of inflammation was 11.07 (95 % CI 3.59-25.83) per 1000 PYD. Adjusted hazards ratio of developing CRC on follow-up in UC patients with polypoid dysplastic adenomatous lesions within the extent of inflammation was 4.0 (95 % CI 1.3-12.4). CONCLUSIONS: The risk of developing CRC is significantly higher in UC patients with polypoid adenomatous lesions, within the extent of inflammation, despite endoscopic resection. Patients and physicians should take the increased risk into consideration during follow-up of these patients.

Bondage and discipline, dominance and submission, sadism and masochism (BDSM) refers to a variety of primarily erotic practices. Although safety is crucial for most BDSM practitioners, there are violent forms that may cause serious injury. We present the case of 61-year-old man with no history of chronic kidney disease who developed severe acute anuric kidney injury following violent BDSM play. He had been strapped tightly onto a wooden spanking bench and then received approximately 1000 vigorous hits onto his bare buttocks and thighs. Subsequently, he developed haematuria and became anuric. Laboratory testing revealed strongly elevated serum creatinine levels. Kidney biopsy was unremarkable except mild tubulointerstitial damage. Urinary production increased spontaneously again after 4 days, and serum creatinine normalised over the course of 4 weeks. We believe that a combination of intermittent abdominal compartment syndrome and blunt kidney trauma may have been responsible for this severe acute kidney injury.

DNA mismatch repair (MMR)-deficient cancers accumulate high numbers of coding microsatellite mutations, which lead to the generation of highly immunogenic frameshift peptide (FSP) neoantigens. MMR-deficient cells can grow out to clinically manifest cancers either if they evade immune cell attack or if local T-cells get exhausted. Therefore, a subset of MSI cancer patients responds particularly well to treatment with immune checkpoint inhibitors. We analyzed whether immune evasion in MMR-deficient cancer mediated by loss of HLA class I or II antigens is related to local immune cell activation status. Microsatellites located in Beta2-microglobulin (B2M) and the HLA class II-regulatory genes RFX5 and CIITA were analyzed for mutations in MMR-deficient colorectal cancers (n = 53). The results were related to CD3-positive and PDCD1 (PD-1)-positive T-cell infiltration. PDCD1 (PD-1)-positive T-cell counts were significantly higher in B2M-mutant compared to B2M-wild type tumors (median: 22.2 cells per 0.25 mm2 vs. 2.0 cells per 0.25 mm2, Wilcoxon test p = 0.002). Increasing PDCD1 (PD-1)-positive T-cell infiltration was significantly related to an increased likelihood of B2M mutations (OR = 1.81). HLA class II antigen expression status was significantly associated with enhanced overall T-cell infiltration, but not related to PDCD1 (PD-1)-positive T-cells. These results suggest that immune evasion mediated by B2M mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PDCD1 (PD-1)-positive T cell infiltration. If B2M mutations interfere with anti-PDCD1 (PD-1)/CD274 (PD-L1) therapy success, we predict that resistance towards anti-PDCD1 (PD-1) therapy may – counterintuitively – be particularly common in patients with MMR-deficient cancers that show high PDCD1 (PD-1)-positive T cell infiltration.

Functional studies on colorectal cancer cells indicated a protective role of the interferon-inducible dsDNA sensor Absent in Melanoma 2 (AIM2) in cancer progression. Given that a high mutation rate and lack of AIM2 expression was previously detected in a subset of colorectal cancers, we here investigated the association of AIM2 expression in tumor cells and patient prognosis (5-year follow-up). A tissue microarray analysis of 476 matched tissue pairs (colorectal tumor and adjacent normal colon epithelium) was performed by two independent observers. Samples from 62 patients were excluded because of missing follow-up information or due to neo-adjuvant therapy before tissue sampling. Out of the remaining 414 tissue pairs, 279 (67.4%) displayed reduced AIM2 expression in cancer cells when compared to epithelial cells of their normal counterpart. Thirty-eight patients (9.18%) had completely lost AIM2 expression in tumor cells. After adjustment for sex, age, cancer stage, tumor site, tumor grade and chemotherapy, complete lack of AIM2 expression was associated with an up to 3-fold increase in overall mortality (HR=2.40; 95% CI=1.44-3.99) and disease specific mortality (HR=3.14; 95% CI=1.75-5.65) in comparison to AIM2-positive tumor samples. Our results demonstrate that lack of AIM2 expression is closely associated with poor outcome in colorectal cancer. The data thus strongly substantiate a protective role of AIM2 against progression of colorectal tumors. Further studies are required to assess whether lack of AIM2 expression may be used as a biomarker for the identification of colorectal cancer patients with poor prognosis.

Functional studies on colorectal cancer cells indicated a protective role of the interferon-inducible dsDNA sensor Absent in Melanoma 2 (AIM2) in cancer progression. Given that a high mutation rate and lack of AIM2 expression was previously detected in a subset of colorectal cancers, we here investigated the association of AIM2 expression in tumor cells and patient prognosis (5-year follow-up). A tissue microarray analysis of 476 matched tissue pairs (colorectal tumor and adjacent normal colon epithelium) was performed by two independent observers. Samples from 62 patients were excluded because of missing follow-up information or due to neo-adjuvant therapy before tissue sampling. Out of the remaining 414 tissue pairs, 279 (67.4%) displayed reduced AIM2 expression in cancer cells when compared to epithelial cells of their normal counterpart. Thirty-eight patients (9.18%) had completely lost AIM2 expression in tumor cells. After adjustment for sex, age, cancer stage, tumor site, tumor grade and chemotherapy, complete lack of AIM2 expression was associated with an up to 3-fold increase in overall mortality (HR=2.40; 95% CI=1.44-3.99) and disease specific mortality (HR=3.14; 95% CI=1.75-5.65) in comparison to AIM2-positive tumor samples. Our results demonstrate that lack of AIM2 expression is closely associated with poor outcome in colorectal cancer. The data thus strongly substantiate a protective role of AIM2 against progression of colorectal tumors. Further studies are required to assess whether lack of AIM2 expression may be used as a biomarker for the identification of colorectal cancer patients with poor prognosis.

Background and Aims: DNA mismatch repair-deficient cancers show microsatellite instability (MSI) and accumulate high numbers of somatic insertion/deletion mutations at repetitive sequence stretches. The high mutational load of MSI cancers leads to the generation of multiple frameshift peptide (FSP) neoantigens, which are highly immunogenic and recognized by the immune system as foreign antigens. MSI cancers respond particularly well to treatment with immune checkpoint inhibitors such as anti-PD-1 antibodies. We systematically analyzed immune evasion phenomena in MSI cancers and aimed to identify factors that are related to and potentially determine PD-1 expression on tumor-infiltrating lymphocytes, focusing on alterations of HLA class I and II antigen presentation pathways in cancer cells. Methods: Microsatellites located in Beta2-microglobulin (B2M) and the HLA class II-regulatory genes RFX5 and CIITA were analyzed for mutations in MSI colorectal cancer specimens (n = 53). HLA class I and II antigen expression was examined by immunohistochemistry. In addition, tumor-infiltrating lymphocytes (CD3-positive T cells, PD-1-positive T cells) were quantified using a semi-automated system. Results: We related B2M mutation and HLA class II antigen expression status of MSI colorectal cancer specimens (n = 56) to CD3- and PD-1 positive T cell infiltration in the tumor. PD-1-positive T cell infiltration was significantly higher in B2M-mutant (mt) compared to B2M-wild type (wt) tumors (median: 22.2 cells per 0.25 mm2 in B2M-mt vs. 2.0 cells per 0.25 mm2 in B2M-wt, Wilcoxon's rank sum test p = 0.002). Increasing PD-1-positive T cell infiltration was significantly related to an increased likelihood of B2M mutation and loss of HLA class I antigen expression (OR = 1.81). In contrast, HLA class II antigen expression status was not related to the proportion of PD-1-positive lymphocytes, but significantly associated with enhanced overall T cell infiltration. Conclusions: These results suggest that immune evasion mediated by B2M mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PD-1-positive T cell infiltration, supporting the validity of the immunoediting concept in MSI colorectal cancers. Moreover, B2M mutation status may predict therapy resistance against anti-PD-1 therapy. Note: This abstract was not presented at the conference. Citation Format: Matthias Kloor, Jonas Janikovits, Julia Krzykalla, Axel Benner, Niels Grabe, Fabian Echterdiek, Meike Mueller, Sandrina Koerner, Aysel Ahadova, Magnus von Knebel Doeberitz. Immune evasion and PD-1-positive T cell infiltration in DNA mismatch repair-deficient colorectal cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A085.

Microsatellite instability (MSI-H) is caused by DNA mismatch repair deficiency and occurs in 15% of colorectal cancers. MSI-H cancers generate highly immunogenic frameshift peptide (FSP) antigens, which elicit pronounced local immune responses. A subset of MSI-H colorectal cancers develops in frame of Lynch syndrome, which represents an ideal human model for studying the concept of immunoediting. Immunoediting describes how continuous anti-tumoral immune surveillance of the host eventually leads to the selection of tumor cells that escape immune cell recognition and destruction. Between 30 and 40% of Lynch syndrome-associated colorectal cancers display loss of HLA class I antigen expression as a result of Beta2-microglobulin (B2M) mutations. Whether B2M mutations result from immunoediting has been unknown. To address this question, we related B2M mutation status of Lynch syndrome-associated colorectal cancer specimens (n = 30) to CD3-positive, CD8-positive and FOXP3-positive T cell infiltration in both tumor and normal mucosa. No significant correlation between B2M mutations and immune cell infiltration was observed in tumor tissue. However, FOXP3-positive T cell infiltration was significantly lower in normal mucosa adjacent to B2M-mutant (mt) compared to B2M-wild type (wt) tumors (mean: 0.98% FOXP3-positive area/region of interest (ROI) in B2M-wt vs. 0.52% FOXP3-positive area/ROI in B2M-mt, p = 0.023). Our results suggest that in the absence of immune-suppressive regulatory T cells (Treg), the outgrowth of less immunogenic B2M-mt tumor cells is favored. This finding supports the immunoediting concept in human solid cancer development and indicates a critical role of the immune milieu in normal colonic mucosa for the course of disease.

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR- DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients’ age, but not with patients’ gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients’ age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.